BioDEX/raw_dataset · Datasets at Hugging Face

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{ "abstract": "A 74-year-old woman with cT4aN2M0, cStage ⅢB gastric cancer underwent neoadjuvant chemotherapy comprising 2 courses of S-1 plus cisplatin, and the clinical response was determined as non-CR/non-PD according to RECIST ver 1.1. Although distal gastrectomy with D2 lymphadenectomy was planned, the tumor was considered as unresectable with peritoneal metastases during laparotomy. After the subsequent chemotherapy with 1 course of capecitabine plus cisplatin, tumor bleeding, and obstruction due to rapid tumor progression occurred. We performed palliative distal gastrectomy; however, the patient died 17 days after gastrectomy. A comprehensive genomic analysis using cancer-gene panel identified the tumor as a microsatellite instability-high(MSI-H). Recently post hoc analysis of the large-scale clinical trials showed no clinical benefit of perioperative chemotherapy in MSI-H gastric cancer. MSI status has a potential to optimize the perioperative treatment strategy in gastric cancer.", "affiliations": "Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences.", "authors": "Otani\|Takahiro\|T\|;Ichikawa\|Hiroshi\|H\|;Hanyu\|Takaaki\|T\|;Ishikawa\|Takashi\|T\|;Sakai\|Takeshi\|T\|;Nemoto\|Mariko\|M\|;Muneoka\|Yusuke\|Y\|;Usui\|Kenji\|K\|;Sudo\|Natsuru\|N\|;Kano\|Yosuke\|Y\|;Nagahashi\|Masayuki\|M\|;Sakata\|Jun\|J\|;Kobayashi\|Takashi\|T\|;Kameyama\|Hitoshi\|H\|;Wakai\|Toshifumi\|T\|", "chemical_list": "D002945:Cisplatin", "country": "Japan", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0385-0684", "issue": "45(13)", "journal": "Gan to kagaku ryoho. Cancer & chemotherapy", "keywords": null, "medline_ta": "Gan To Kagaku Ryoho", "mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002945:Cisplatin; D019008:Drug Resistance, Neoplasm; D005260:Female; D005743:Gastrectomy; D006801:Humans; D053842:Microsatellite Instability; D020360:Neoadjuvant Therapy; D013274:Stomach Neoplasms", "nlm_unique_id": "7810034", "other_id": null, "pages": "1895-1897", "pmc": null, "pmid": "30692390", "pubdate": "2018-12", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Chemoresistance in Microsatellite Instability-High Gastric Cancer-A Case Report.", "title_normalized": "chemoresistance in microsatellite instability high gastric cancer a case report" }	[ { "companynumb": "JP-ACCORD-107986", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CAPECITABINE" }, "drugadditional": "2", "drugadministrationroute": null, "drugauthorizationnumb": "202593", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTRIC CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "3000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CAPECITABINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": "2", "drugadministrationroute": null, "drugauthorizationnumb": "206774", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTRIC CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "112", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN." } ], "patientagegroup": null, "patientonsetage": "74", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "54", "reaction": [ { "reactionmeddrapt": "Tumour haemorrhage", "reactionmeddraversionpt": "21.1", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "OTANI T, ICHIKAWA H, HANYU T, ISHIKAWA T, SAKAI T, NEMOTO M, ET. AL. CHEMORESISTANCE IN MICROSATELLITE INSTABILITY-HIGH GASTRIC CANCER-A CASE REPORT. VOLUME 45, NO. 13 DECEMBER 2018", "literaturereference_normalized": "chemoresistance in microsatellite instability high gastric cancer a case report", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190222", "receivedate": "20190222", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15993840, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" } ]
{ "abstract": "BACKGROUND\nExtensive data have been accumulated for adults who have undergone ABO-incompatible (ABOi)-living kidney transplantation (LKT). In contrast, available published data on pediatric recipients who underwent ABOi-LKT from the early to middle 2000s is very limited. Thus, pediatric ABOi-LKT has remained relatively rare, and there is a lack of large, multicenter data.\n\n\nMETHODS\nWe analyzed data from the Japanese Kidney Transplant Registry to clarify the patient and graft outcomes of pediatric recipients who underwent ABOi-LKT from 2002 to 2015. A total of 102 ABOi and 788 ABO-compatible (ABOc) recipients were identified in this study. All recipients had received basiliximab and a triple immunosuppressive protocol comprising calcineurin inhibitors, mycophenolate mofetil, and steroids. The ABOi recipients also received preconditioning therapies including B-cell depletion by a splenectomy or rituximab treatment and therapeutic apheresis.\n\n\nRESULTS\nDeath rates for ABOi and ABOc recipients were 0.17 versus 0.17 deaths per 100 patient-years. Graft loss rates for ABOi and ABOc recipients were 1.58 versus 1.45 events per 100 patient-years. No particular causes of death or graft loss predominantly affected ABOi or ABOc recipients.\n\n\nCONCLUSIONS\nThe results of this registry analysis suggest that pediatric ABOi-LKT can be performed efficiently. Although further studies are clearly required to perform pediatric ABOi-LKT more safely and less invasively, ABOi-LKT is now an acceptable treatment for pediatric patients with end-stage renal disease.", "affiliations": "Department of Pediatric Nephrology, Tokyo Women's Medical University, School of Medicine, Tokyo, Japan.;Department of Medical Informatics Center for Information, Jichi Medical University, Tochigi, Japan.;Department of Nephrology, Faculty of Medicine, Toho University, Tokyo, Japan.;Department of Nephrology, Faculty of Medicine, Toho University, Tokyo, Japan.;Department of Transplantation and Regenerative Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan.;National Center for Geriatrics and Gerontology, Aichi, Japan.;Niigata Organ Transplant Foundation, Niigata, Japan.;Kamata Minami-guchi Kidney Clinic, Tokyo, Japan.", "authors": "Hattori\|Motoshi\|M\|;Mieno\|Makiko\|M\|;Shishido\|Seiichiro\|S\|;Aikawa\|Atsushi\|A\|;Ushigome\|Hidetaka\|H\|;Ohshima\|Shinichi\|S\|;Takahashi\|Kota\|K\|;Hasegawa\|Akira\|A\|;\|\|\|", "chemical_list": "D000017:ABO Blood-Group System; D007166:Immunosuppressive Agents", "country": "United States", "delete": false, "doi": "10.1097/TP.0000000000002259", "fulltext": null, "fulltext_license": null, "issn_linking": "0041-1337", "issue": "102(11)", "journal": "Transplantation", "keywords": null, "medline_ta": "Transplantation", "mesh_terms": "D000017:ABO Blood-Group System; D000293:Adolescent; D000367:Age Factors; D001787:Blood Group Incompatibility; D002648:Child; D004359:Drug Therapy, Combination; D005260:Female; D006084:Graft Rejection; D006085:Graft Survival; D006648:Histocompatibility; D006801:Humans; D007166:Immunosuppressive Agents; D007564:Japan; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D019520:Living Donors; D008297:Male; D012042:Registries; D013156:Splenectomy; D013997:Time Factors; D016896:Treatment Outcome", "nlm_unique_id": "0132144", "other_id": null, "pages": "1934-1942", "pmc": null, "pmid": "29781948", "pubdate": "2018-11", "publication_types": "D016428:Journal Article", "references": null, "title": "Outcomes of Pediatric ABO-incompatible Living Kidney Transplantations From 2002 to 2015: An Analysis of the Japanese Kidney Transplant Registry.", "title_normalized": "outcomes of pediatric abo incompatible living kidney transplantations from 2002 to 2015 an analysis of the japanese kidney transplant registry" }	[ { "companynumb": "JP-ROCHE-2224520", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BASILIXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG WHEN BODY WEIGHT WAS {35 KG; 20 MG WHEN BODY WEIGHT WAS }35 KG", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BASILIXIMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "050722", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "600 TO 1200 MG/M2 PER DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOSPORIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "041", "drugauthorizationnumb": "103705", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INFUSION", "drugdosagetext": "150-375 MG/M2", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SULFAMETHOXAZOLE/TRIMETHOPRIM" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 TO 15 MG/KG", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cytomegalovirus infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Viral infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Polyomavirus-associated nephropathy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumocystis jirovecii pneumonia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Post procedural infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Adenoviral haemorrhagic cystitis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sepsis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bacterial infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrointestinal infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fungal infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Epstein-Barr virus associated lymphoproliferative disorder", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urinary tract infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": ", MIENO M, SHISHIDO S, ET AL OUTCOMES OF PEDIATRIC ABO-INCOMPATIBLE LIVING KIDNEY TRANSPLANTATIONS FROM 2002 TO 2015: AN ANALYSIS OF THE JAPANESE KIDNEY TRANSPLANT REGISTRY. TRANSPLANTATION 2018?102 (11):1934-1942.", "literaturereference_normalized": "outcomes of pediatric abo incompatible living kidney transplantations from 2002 to 2015 an analysis of the japanese kidney transplant registry", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190115", "receivedate": "20190102", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15780764, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" } ]
{ "abstract": "Spinal myoclonus following neuraxial anesthesia is rare. This report describes a case of myoclonus-like involuntary movement that occurred during the recovery from epidural anesthesia for a cesarean delivery. The patient's symptom improved with the administration of benzodiazepine, and the patient recovered with no neurological sequelae. In conclusion, epidural anesthesia can cause spinal myoclonus, which can be treated with a benzodiazepine.", "affiliations": "Department of Anesthesiology and Pain Medicine, Graduate School, Kyung Hee University.;Department of Anesthesiology and Pain Medicine, Graduate School, Kyung Hee University.;Department of Anesthesia and Pain Medicine, Kyung Hee University Hospital.;Department of Anesthesia and Pain Medicine, Kyung Hee University Hospital.;Department of Anesthesiology and Pain Medicine, Kyung Hee University Hospital at Gangdong.;Department of Anesthesiology and Pain Medicine, Graduate School, Kyung Hee University; Department of Anesthesia and Pain Medicine, Kyung Hee University Hospital.;Department of Anesthesiology and Pain Medicine, Graduate School, Kyung Hee University; Department of Anesthesiology and Pain Medicine, Kyung Hee University Hospital at Gangdong. Electronic address: [email protected].", "authors": "Kang\|Hee Yong\|HY\|;Lee\|Sang Wook\|SW\|;Hong\|Eun Pyo\|EP\|;Sim\|Yeo Hae\|YH\|;Lee\|Su-Mi\|SM\|;Park\|Sung Wook\|SW\|;Kang\|Jong-Man\|JM\|", "chemical_list": "D000779:Anesthetics, Local; D000927:Anticonvulsants; D008012:Lidocaine; D000077554:Levobupivacaine; D008874:Midazolam; D002045:Bupivacaine", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0952-8180", "issue": "34()", "journal": "Journal of clinical anesthesia", "keywords": "Cesarean delivery; Epidural anesthesia; Involuntary movement; Spinal myoclonus", "medline_ta": "J Clin Anesth", "mesh_terms": "D061605:Administration, Intravenous; D000328:Adult; D000762:Anesthesia Recovery Period; D000767:Anesthesia, Epidural; D000773:Anesthesia, Obstetrical; D000779:Anesthetics, Local; D000927:Anticonvulsants; D002045:Bupivacaine; D002585:Cesarean Section; D005260:Female; D006801:Humans; D007268:Injections, Epidural; D000077554:Levobupivacaine; D008012:Lidocaine; D008874:Midazolam; D009207:Myoclonus; D011247:Pregnancy", "nlm_unique_id": "8812166", "other_id": null, "pages": "392-4", "pmc": null, "pmid": "27687419", "pubdate": "2016-11", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Myoclonus-like involuntary movements following cesarean delivery epidural anesthesia.", "title_normalized": "myoclonus like involuntary movements following cesarean delivery epidural anesthesia" }	[ { "companynumb": "KR-MYLANLABS-2016M1028187", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "EPHEDRINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EPHEDRINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LIDOCAINE" }, "drugadditional": null, "drugadministrationroute": "008", "drugauthorizationnumb": "091058", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "15 ML OF 2% INJECTION", "drugenddate": null, "drugenddateformat": null, "drugindication": "INDUCTION OF ANAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LIDOCAINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PHENYLEPHRINE\\PHENYLEPHRINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MICROG", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PHENYLEPHRINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LIDOCAINE" }, "drugadditional": null, "drugadministrationroute": "008", "drugauthorizationnumb": "091058", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "5 ML OF 2% INJECTION", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LIDOCAINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "EPHEDRINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EPHEDRINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEVOBUPIVACAINE" }, "drugadditional": null, "drugadministrationroute": "008", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "15 ML OF 0.75% INJECTION", "drugenddate": null, "drugenddateformat": null, "drugindication": "INDUCTION OF ANAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOBUPIVACAINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEVOBUPIVACAINE" }, "drugadditional": null, "drugadministrationroute": "008", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 ML OF 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MYOCLONUS-LIKE INVOLUNTARY MOVEMENTS FOLLOWING CESAREAN DELIVERY EPIDURAL ANESTHESIA. J-CLIN-ANESTH 2016;34:392-394.", "literaturereference_normalized": "myoclonus like involuntary movements following cesarean delivery epidural anesthesia", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20160707", "receivedate": "20160707", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12537712, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" }, { "companynumb": "KR-WATSON-2016-15763", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "EPHEDRINE" }, "drugadditional": null, "drugadministrationroute": "065", 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"drugtreatmentdurationunit": null, "medicinalproduct": "PHENYLEPHRINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "OXYTOCIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXYTOCIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LIDOCAINE" }, "drugadditional": null, "drugadministrationroute": "008", "drugauthorizationnumb": "080377", "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNK", "drugdosagetext": "5 ML, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "012", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LIDOCAINE (UNKNOWN)" } ], "patientagegroup": null, "patientonsetage": "30", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "70", "reaction": [ { "reactionmeddrapt": "Myoclonus", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dysarthria", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KANG HY, LEE SW, HONG EP, SIM YH, LEE SM, PARK SW ET AL.. MYOCLONUS-LIKE INVOLUNTARY MOVEMENTS FOLLOWING CESAREAN DELIVERY EPIDURAL ANESTHESIA. J. CLIN. ANESTH.. 2016;(34):392-4.", "literaturereference_normalized": "myoclonus like involuntary movements following cesarean delivery epidural anesthesia", "qualification": "1", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20160720", "receivedate": "20160720", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12576295, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20161109" } ]
{ "abstract": "The genetically variable CYP450 isozymes are responsible for the metabolism of up to 80% of commonly used drugs, many of which are detected in cases of unexpected or suspicious death in Australia. The aim of this study was to examine the genetic profiles of individuals in a cohort of Australian deceased individuals dying of drug toxicity (219), natural disease (150), external injury (109) or unascertained (8) causes, to determine if there was an over-representation of individuals with a genetic predisposition to altered drug metabolism in cases attributed to drug toxicity compared with other causes. Single nucleotide polymorphisms (SNP) of CYP1A2, 2C9, 2C19, 2D6, 3A4 and 3A5 were analyzed. There were 27 cases (6.1%) that were CYP2D6 poor metabolizers (PM) and an additional 8 cases (1.7 %) that were CYP2C19 PMs. Around 31% of the cases were CYP2D6 intermediate-poor metabolizers, with a number of cases exhibiting drug combinations that were likely to have caused pharmacokinetic or pharmacodynamic interactions. There was no correlation between cause of death type and CYP2D6 metabolizer status. Increased enzyme activity was also indicated by the presence of hyperinducible variants such as CYP1A2*1F, which was observed at a frequency of 48%.", "affiliations": "Victorian Institute of Forensic Medicine, Department of Forensic Medicine, Monash University, 57-83 Kavanagh Street, Southbank 3006, Victoria, Australia. [email protected]", "authors": "Pilgrim\|Jennifer L\|JL\|;Ruiz\|Yarimar\|Y\|;Gesteira\|Alejandro\|A\|;Cruz\|Raquel\|R\|;Gerostamoulos\|Dimitri\|D\|;Carracedo\|Angel\|A\|;Drummer\|Olaf H\|OH\|", "chemical_list": "D003577:Cytochrome P-450 Enzyme System", "country": "Netherlands", "delete": false, "doi": "10.2174/1389200211209050679", "fulltext": null, "fulltext_license": null, "issn_linking": "1389-2002", "issue": "13(5)", "journal": "Current drug metabolism", "keywords": null, "medline_ta": "Curr Drug Metab", "mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002423:Cause of Death; D003577:Cytochrome P-450 Enzyme System; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D011041:Poisoning; D020641:Polymorphism, Single Nucleotide; D014739:Victoria; D055815:Young Adult", "nlm_unique_id": "100960533", "other_id": null, "pages": "679-92", "pmc": null, "pmid": "22299824", "pubdate": "2012-06-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Characterization of single nucleotide polymorphisms of cytochrome p450 in an Australian deceased sample.", "title_normalized": "characterization of single nucleotide polymorphisms of cytochrome p450 in an australian deceased sample" }	[ { "companynumb": "AU-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-271052", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "MIRTAZAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MIRTAZAPINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DIAZEPAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIAZEPAM." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYPROHEPTADINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYPROHEPTADINE." }, { "actiondrug": "6", 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CHARACTERIZATION OF SINGLE NUCLEOTIDE POLYMORPHISMS OF CYTOCHROME P450 IN AN AUSTRALIAN DECEASED SAMPLE. 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CHARACTERIZATION OF SINGLE NUCLEOTIDE POLYMORPHISMS OF CYTOCHROME P450 IN AN AUSTRALIAN DECEASED SAMPLE. 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CHARACTERIZATION OF SINGLE NUCLEOTIDE POLYMORPHISMS OF CYTOCHROME P450 IN AN AUSTRALIAN DECEASED SAMPLE. 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CHARACTERIZATION OF SINGLE NUCLEOTIDE POLYMORPHISMS OF CYTOCHROME P450 IN AN AUSTRALIAN DECEASED SAMPLE. 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CHARACTERIZATION OF SINGLE NUCLEOTIDE POLYMORPHISMS OF CYTOCHROME P450 IN AN AUSTRALIAN DECEASED SAMPLE. 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CHARACTERIZATION OF SINGLE NUCLEOTIDE POLYMORPHISMS OF CYTOCHROME P450 IN AN AUSTRALIAN DECEASED SAMPLE. 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GEROSTAMOULOS D, CARRACEDO A, ET AL. CHARACTERIZATION OF SINGLE NUCLEOTIDE POLYMORPHISMS OF CYTOCHROME P450 IN AN AUSTRALIAN DECEASED SAMPLE. CURR DRUG METAB. 2012?13(5):679-692", "literaturereference_normalized": "characterization of single nucleotide polymorphisms of cytochrome p450 in an australian deceased sample", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20201215", "receivedate": "20201215", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18615036, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210114" }, { "companynumb": "AU-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-271112", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "NORDAZEPAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NORDIAZEPAM" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CODEINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CODEINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "TRAMADOL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "75964", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAMADOL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PHENOBARBITAL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PHENOBARBITONE" } ], "patientagegroup": null, "patientonsetage": "35", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "PILGRIM JL, RUIZ Y, GESTEIRA A, CRUZ R, GEROSTAMOULOS D, CARRACEDO A, ET AL. CHARACTERIZATION OF SINGLE NUCLEOTIDE POLYMORPHISMS OF CYTOCHROME P450 IN AN AUSTRALIAN DECEASED SAMPLE. CURR DRUG METAB. 2012?13(5):679-692", "literaturereference_normalized": "characterization of single nucleotide polymorphisms of cytochrome p450 in an australian deceased sample", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20201215", "receivedate": "20201215", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18615486, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210114" }, { "companynumb": "AU-BAUSCH-BL-2020-033317", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CODEINE" }, "drugadditional": "3", 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INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VENLAFAXINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OXYCODONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXYCODONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DIAZEPAM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "020648", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIAZEPAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PARACETAMOL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MORPHINE" }, "drugadditional": 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"Intentional product use issue", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PILGRIM J, RUIZ Y, GESTEIRA A, CRUZ R, GEROSTAMOULOS D, CARRACEDO A, DRUMMER O. CHARACTERIZATION OF SINGLE NUCLEOTIDE POLYMORPHISMS OF CYTOCHROME P450 IN AN AUSTRALIAN DECEASED SAMPLE. CURRENT DRUG METABOLISM. 2012?13 (5):679-692.", "literaturereference_normalized": "characterization of single nucleotide polymorphisms of cytochrome p450 in an australian deceased sample", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": null, "receiptdate": "20201120", "receivedate": "20201120", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18529389, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210114" }, { "companynumb": "AU-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-271148", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DRONABINOL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "THC" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "TRAMADOL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "75964", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAMADOL." } ], "patientagegroup": null, "patientonsetage": "31", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Intentional self-injury", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PILGRIM JL, RUIZ Y, GESTEIRA A, CRUZ R, GEROSTAMOULOS D, CARRACEDO A, ET AL. CHARACTERIZATION OF SINGLE NUCLEOTIDE POLYMORPHISMS OF CYTOCHROME P450 IN AN AUSTRALIAN DECEASED SAMPLE. CURR DRUG METAB. 2012?13(5):679-692", "literaturereference_normalized": "characterization of single nucleotide polymorphisms of cytochrome p450 in an australian deceased sample", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20201215", "receivedate": "20201215", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18615459, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210114" }, { "companynumb": "AU-JNJFOC-20120907557", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DIAZEPAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIAZEPAM." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ALCOHOL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, 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"OXYCODONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXYCODONE" } ], "patientagegroup": "5", "patientonsetage": "46", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Intentional overdose", "reactionmeddraversionpt": "24.0", 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CHARACTERIZATION OF SINGLE NUCLEOTIDE POLYMORPHISMS OF CYTOCHROME P450 IN AN AUSTRALIAN DECEASED SAMPLE. 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CHARACTERIZATION OF SINGLE NUCLEOTIDE POLYMORPHISMS OF CYTOCHROME P450 IN AN AUSTRALIAN DECEASED SAMPLE. CURR DRUG METAB. 2012?13(5):679-692", "literaturereference_normalized": "characterization of single nucleotide polymorphisms of cytochrome p450 in an australian deceased sample", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20201215", "receivedate": "20201215", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18615462, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210114" }, { "companynumb": "AU-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-271145", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "FLUOXETINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "76990", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUOXETINE" } ], "patientagegroup": null, "patientonsetage": "90", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intentional self-injury", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PILGRIM JL, RUIZ Y, GESTEIRA A, CRUZ R, GEROSTAMOULOS D, CARRACEDO A, ET AL. CHARACTERIZATION OF SINGLE NUCLEOTIDE POLYMORPHISMS OF CYTOCHROME P450 IN AN AUSTRALIAN DECEASED SAMPLE. CURR DRUG METAB. 2012?13(5):679-692", "literaturereference_normalized": "characterization of single nucleotide polymorphisms of cytochrome p450 in an australian deceased sample", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20201215", "receivedate": "20201215", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18615460, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210114" }, { "companynumb": "AU-MYLANLABS-2020M1098886", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DIAZEPAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIAZEPAM." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CITALOPRAM HYDROBROMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "077042", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CITALOPRAM" } ], "patientagegroup": null, "patientonsetage": "53", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "PILGRIM JL, RUIZ Y, GESTEIRA A, CRUZ R, GEROSTAMOULOS D, CARRACEDO A, ET AL. CHARACTERIZATION OF SINGLE NUCLEOTIDE POLYMORPHISMS OF CYTOCHROME P450 IN AN AUSTRALIAN DECEASED SAMPLE. 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CHARACTERIZATION OF SINGLE NUCLEOTIDE POLYMORPHISMS OF CYTOCHROME P450 IN AN AUSTRALIAN DECEASED SAMPLE. 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CHARACTERIZATION OF SINGLE NUCLEOTIDE POLYMORPHISMS OF CYTOCHROME P450 IN AN AUSTRALIAN DECEASED SAMPLE. 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CHARACTERIZATION OF SINGLE NUCLEOTIDE POLYMORPHISMS OF CYTOCHROME P450 IN AN AUSTRALIAN DECEASED SAMPLE. 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CHARACTERIZATION OF SINGLE NUCLEOTIDE POLYMORPHISMS OF CYTOCHROME P450 IN AN AUSTRALIAN DECEASED SAMPLE. 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CHARACTERIZATION OF SINGLE NUCLEOTIDE POLYMORPHISMS OF CYTOCHROME P450 IN AN AUSTRALIAN DECEASED SAMPLE. 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CHARACTERIZATION OF SINGLE NUCLEOTIDE POLYMORPHISMS OF CYTOCHROME P450 IN AN AUSTRALIAN DECEASED SAMPLE. 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{ "abstract": "A 61-year-old man with a diagnosis of rectal cancer underwent assisted laparoscopic rectal amputation. Recurrence occurred, and treatment with FOLFIRI plus bevacizumab was initiated at our department. After 12 treatment courses, he developed abdominal pain at home. Emergency surgery was performed for the stoma perforation. We confirmed the diverticular perforation in the resected specimen. In our case, we found a para-stoma hernia and considered it to be the cause of perforation together with bevacizumab administration. Molecular-targeted drugs contribute to improving treatment outcomes in malignant tumors, but specific adverse events such as perforation have been reported. In addition, as causes of sigmoid colon perforation such as that of the stoma, cases associated with intestinal operation, constipation, and para-stoma hernia are suggested. In our case of hyperpolarization due to a para-stoma hernia, administration of bevacizumab was considered the cause of the perforation. This was a case that could be rescued with surgery.", "affiliations": "Dept. of Surgery, Toda Chuo General Hospital.", "authors": "Watanabe\|Mitsuru\|M\|;Sumi\|Tetsuo\|T\|;Udou\|Ryutaro\|R\|;Enomoto\|Masaya\|M\|;Matsudo\|Takaaki\|T\|;Tachibana\|Shingo\|S\|;Mimuro\|Akihiro\|A\|;Katsumata\|Kenji\|K\|;Tsuchida\|Akihiko\|A\|", "chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000068258:Bevacizumab", "country": "Japan", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0385-0684", "issue": "46(1)", "journal": "Gan to kagaku ryoho. Cancer & chemotherapy", "keywords": null, "medline_ta": "Gan To Kagaku Ryoho", "mesh_terms": "D000074322:Antineoplastic Agents, Immunological; D000068258:Bevacizumab; D012809:Colon, Sigmoid; D003125:Colostomy; D006801:Humans; D007416:Intestinal Perforation; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D012004:Rectal Neoplasms", "nlm_unique_id": "7810034", "other_id": null, "pages": "148-150", "pmc": null, "pmid": "30765670", "pubdate": "2019-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "A Case of Diverticular Perforation of Sigmoid Colostomy during FOLFIRI plus BevacizumabTreatment.", "title_normalized": "a case of diverticular perforation of sigmoid colostomy during folfiri plus bevacizumabtreatment" }	[ { "companynumb": "JP-PFIZER INC-2019077187", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "IRINOTECAN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "020571", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC (AFTER 12 TREATMENT COURSES)", "drugenddate": null, "drugenddateformat": null, "drugindication": "RECTAL CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IRINOTECAN HCL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BEVACIZUMAB" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG/KG, CYCLIC ( 12 TREATMENT COURSES)", "drugenddate": null, "drugenddateformat": null, "drugindication": "RECTAL CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BEVACIZUMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEUCOVORIN CALCIUM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC (AFTER 12 TREATMENT COURSES)", "drugenddate": null, "drugenddateformat": null, "drugindication": "RECTAL CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CALCIUM FOLINATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC (AFTER 12 TREATMENT COURSES)", "drugenddate": null, "drugenddateformat": null, "drugindication": "RECTAL CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUOROURACIL 5 FU" } ], "patientagegroup": null, "patientonsetage": "61", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Diverticular perforation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WATANABE, M.. A CASE OF DIVERTICULAR PERFORATION OF SIGMOID COLOSTOMY DURING FOLFIRI PLUS BEVACIZUMABTREATMENT. JAPANESE JOURNAL OF CANCER + CHEMOTHERAPY. 2019?46 (1):148-150", "literaturereference_normalized": "a case of diverticular perforation of sigmoid colostomy during folfiri plus bevacizumabtreatment", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190305", "receivedate": "20190221", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15992130, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190418" } ]
{ "abstract": "BACKGROUND\nInhibitors of dipeptidyl peptidase (DPP)-IV have been suspected in the onset of bullous pemphigoid for several years now. However, comparative studies assessing the link between DPP-IV inhibitor exposure and bullous pemphigoid have not yet been performed.\n\n\nOBJECTIVE\nTo detect, from the French Pharmacovigilance Database (FPVD), a signal of risk of bullous pemphigoid during DPP-IV inhibitor exposure by comparative study.\n\n\nMETHODS\nAll spontaneous reports of DPP-IV inhibitor-related bullous pemphigoid recorded in the FPVD between April 2008 and August 2014 were described. We conducted disproportionality analyses (case-noncase method) to assess the link between DPP-IV inhibitors and bullous pemphigoid, calculating reporting odds ratios (RORs). We also compared DPP-IV inhibitor-induced bullous pemphigoid reports rated per million defined daily doses dispensed during the study period.\n\n\nRESULTS\nAmong 217 331 spontaneous adverse drug reaction reports registered in the FPVD, 1297 involved DPP-IV inhibitors. Among these observations, 42 were bullous pemphigoid (vildagliptin, n = 31; sitagliptin, n = 10; saxagliptin, n = 1). The ROR for pooled DPP-IV inhibitors was 67·5 [95% confidence interval (CI) 47·1-96·9]. Disproportionality was also observed for each DPP-IV inhibitor: vildagliptin (ROR 225·3, 95% CI 148·9-340·9), sitagliptin (ROR 17·0, 95% CI 8·9-32·5) and saxagliptin (ROR 16·5, 95% CI 2·3-119·1). Analyses adjusted on dispensing data led to similar results.\n\n\nCONCLUSIONS\nThese data confirm a strong signal for an increased risk of bullous pemphigoid during DPP-IV inhibitor exposure. This adverse drug reaction is observed for each DPP-IV inhibitor, suggesting a class effect. The signal was higher with vildagliptin than with the other DPP-IV inhibitors.", "affiliations": "Centre Régional de Pharmacovigilance du Nord Pas-de-Calais, Univ.Lille, CHU Lille, F-59000, Lille, France.;Service de Médecine Interne, CHU de Toulouse, Toulouse, France.;Service de Dermatologie, CHU de Toulouse, Toulouse, France.;Centre Régional de Pharmacovigilance du Nord Pas-de-Calais, Univ.Lille, CHU Lille, F-59000, Lille, France.;Service Pharmacie, Centre Hospitalier de Valenciennes, Valenciennes, France.;Centre Régional de PharmacoVigilance, Hôpital Henri Mondor, Assistance Publique Hôpitaux de Paris, Créteil, France.;Centre Régional de PharmacoVigilance, Département de Pharmacologie Médicale et Toxicologie, Faculté de Médecine et CHRU, Montpellier, France.;Centre Régional de PharmacoVigilance, Service de Pharmacologie Clinique et Pharmacovigilance, Assistance Publique des Hôpitaux de Marseille, Aix Marseille Université, Marseille, France.;Centre Régional de Pharmacovigilance du Nord Pas-de-Calais, Univ.Lille, CHU Lille, F-59000, Lille, France.", "authors": "Béné\|J\|J\|;Moulis\|G\|G\|;Bennani\|I\|I\|;Auffret\|M\|M\|;Coupe\|P\|P\|;Babai\|S\|S\|;Hillaire-Buys\|D\|D\|;Micallef\|J\|J\|;Gautier\|S\|S\|;\|\|\|", "chemical_list": "D054873:Dipeptidyl-Peptidase IV Inhibitors", "country": "England", "delete": false, "doi": "10.1111/bjd.14601", "fulltext": null, "fulltext_license": null, "issn_linking": "0007-0963", "issue": "175(2)", "journal": "The British journal of dermatology", "keywords": null, "medline_ta": "Br J Dermatol", "mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D054873:Dipeptidyl-Peptidase IV Inhibitors; D003875:Drug Eruptions; D005260:Female; D005602:France; D006801:Humans; D008297:Male; D008875:Middle Aged; D010391:Pemphigoid, Bullous; D060735:Pharmacovigilance; D012307:Risk Factors; D056737:Safety-Based Drug Withdrawals", "nlm_unique_id": "0004041", "other_id": null, "pages": "296-301", "pmc": null, "pmid": "27031194", "pubdate": "2016-08", "publication_types": "D003160:Comparative Study; D016428:Journal Article", "references": null, "title": "Bullous pemphigoid and dipeptidyl peptidase IV inhibitors: a case-noncase study in the French Pharmacovigilance Database.", "title_normalized": "bullous pemphigoid and dipeptidyl peptidase iv inhibitors a case noncase study in the french pharmacovigilance database" }	[ { "companynumb": "NVSC2019FR035712", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "VILDAGLIPTIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "101706", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VILDAGLIPTIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "75965", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pemphigoid", "reactionmeddraversionpt": "22.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "BENE J, MOULIS G, BENNANI I, AUFFRET M, COUPE P, BABAI S ET AL.. BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. BRITISH JOURNAL OF DERMATOLOGY. 2016?175:296-301", "literaturereference_normalized": "bullous pemphigoid and dipeptidyl peptidase iv inhibitors a case noncase study in the french pharmacovigilance database", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20191115", "receivedate": "20191115", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17036324, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "FR-MYLANLABS-2016M1058713", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VILDAGLIPTIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VILDAGLIPTIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALLOPURINOL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "018659", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALLOPURINOL." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pemphigoid", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "BENE J, MOULIS G, BENNANI I, AUFFRET M, COUPE P, BABAI S, ET AL. BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. BR-J-DERMATOL 2016;175(2):296-301.", "literaturereference_normalized": "bullous pemphigoid and dipeptidyl peptidase iv inhibitors a case noncase study in the french pharmacovigilance database", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20170105", "receivedate": "20170105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13088834, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "FR-ZYDUS-013270", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ESCITALOPRAM OXALATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "077734", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESCITALOPRAM" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VILDAGLIPTIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VILDAGLIPTIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "077060", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RISPERIDONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "078516", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RISPERIDONE." } ], "patientagegroup": null, "patientonsetage": "82", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pemphigoid", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "BENE J, MOULIS G, BENNANI I, AUFFRET M, COUPE P, BABAI S, ET AL. BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. BR-J-DERMATOL 2016;175(2):296-301.", "literaturereference_normalized": "bullous pemphigoid and dipeptidyl peptidase iv inhibitors a case noncase study in the french pharmacovigilance database", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20170110", "receivedate": "20170110", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13101668, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "FR-MYLANLABS-2016M1058755", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "075973", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VILDAGLIPTIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VILDAGLIPTIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pemphigoid", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "BENE J, MOULIS G, BENNANI I, AUFFRET M, COUPE P, BABAI S, ET AL. BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. BRITISH JOURNAL OF DERMATOLOGY. 2016?175(2):296-301", "literaturereference_normalized": "bullous pemphigoid and dipeptidyl peptidase iv inhibitors a case noncase study in the french pharmacovigilance database", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20191115", "receivedate": "20191115", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17037568, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "FR-MYLANLABS-2016M1058701", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "075973", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "SITAGLIPTIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SITAGLIPTIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pemphigoid", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "BENE J, MOULIS G, BENNANI I, AUFFRET M, COUPE P, BABAI S, ET AL. BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. BR-J-DERMATOL 2016;175(2):296-301.", "literaturereference_normalized": "bullous pemphigoid and dipeptidyl peptidase iv inhibitors a case noncase study in the french pharmacovigilance database", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20170105", "receivedate": "20170105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13088862, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "FR-JNJFOC-20161004731", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RISPERIDONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "020272", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RISPERIDONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pemphigoid", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BENE J, MOULIS G, BENNANI I, AUFFRET M, COUPE P, BABAI S, ET AL. BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. BRITISH JOURNAL OF DERMATOLOGY 2016;175(2):296-301.", "literaturereference_normalized": "bullous pemphigoid and dipeptidyl peptidase iv inhibitors a case noncase study in the french pharmacovigilance database", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20161007", "receivedate": "20161007", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12828332, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "NVSC2019FR035714", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "75965", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VILDAGLIPTIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "101706", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VILDAGLIPTIN" } ], "patientagegroup": null, "patientonsetage": "86", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pemphigoid", "reactionmeddraversionpt": "22.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "BENE J, MOULIS G, BENNANI I, AUFFRET M, COUPE P, BABAI S ET AL.. BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. BRITISH JOURNAL OF DERMATOLOGY. 2016?175:296-301", "literaturereference_normalized": "bullous pemphigoid and dipeptidyl peptidase iv inhibitors a case noncase study in the french pharmacovigilance database", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20191115", "receivedate": "20191115", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17036332, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "FR-TEVA-728007ISR", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "VILDAGLIPTIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VILDAGLIPTIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "75978", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pemphigoid", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "BENE J, MOULIS G, BENNANI I, AUFFRET M, COUPE P, BABAI S, ET AL. BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. BR-J-DERMATOL 2016;175(2):296-301.", "literaturereference_normalized": "bullous pemphigoid and dipeptidyl peptidase iv inhibitors a case noncase study in the french pharmacovigilance database", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20170111", "receivedate": "20170111", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13105982, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "FR-MYLANLABS-2016M1058767", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "VILDAGLIPTIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VILDAGLIPTIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "075973", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pemphigoid", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "BENE J, MOULIS G, BENNANI I, AUFFRET M, COUPE P, BABAI S, ET AL. BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. BR-J-DERMATOL 2016;175(2):296-301.", "literaturereference_normalized": "bullous pemphigoid and dipeptidyl peptidase iv inhibitors a case noncase study in the french pharmacovigilance database", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20170105", "receivedate": "20170105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13089662, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "NVSC2019FR035697", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACAMPROSATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACAMPROSATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREGABALIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREGABALIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VILDAGLIPTIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "101706", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VILDAGLIPTIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "75985", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pemphigoid", "reactionmeddraversionpt": "22.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Eosinophilia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BENE J, MOULIS G, BENNANI I, AUFFRET M, COUPE P, BABAI S ET AL.. BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. BRITISH JOURNAL OF DERMATOLOGY. 2016?175(2):296-301", "literaturereference_normalized": "bullous pemphigoid and dipeptidyl peptidase iv inhibitors a case noncase study in the french pharmacovigilance database", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20191115", "receivedate": "20191115", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17037602, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "FR-TEVA-728034ISR", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "75978", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "SITAGLIPTIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SITAGLIPTIN" } ], "patientagegroup": null, "patientonsetage": "45", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pemphigoid", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "BENE J, MOULIS G, BENNANI I, AUFFRET M, COUPE P, BABAI S, ET AL. BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. BR-J-DERMATOL 2016;175(2):296-301.", "literaturereference_normalized": "bullous pemphigoid and dipeptidyl peptidase iv inhibitors a case noncase study in the french pharmacovigilance database", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20170111", "receivedate": "20170111", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13106212, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "NVSC2019FR035702", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "VILDAGLIPTIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "101706", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VILDAGLIPTIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "75985", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": "75", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Eosinophilia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pemphigoid", "reactionmeddraversionpt": "22.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "BENE J, MOULIS G, BENNANI I, AUFFRET M, COUPE P, BABAI S, ET AL.. BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. BRITISH JOURNAL OF DERMATOLOGY. 2016?175(2):296-301", "literaturereference_normalized": "bullous pemphigoid and dipeptidyl peptidase iv inhibitors a case noncase study in the french pharmacovigilance database", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20191115", "receivedate": "20191115", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17036822, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "NVSC2019FR035709", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "75985", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VILDAGLIPTIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "101706", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VILDAGLIPTIN" } ], "patientagegroup": null, "patientonsetage": "80", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pemphigoid", "reactionmeddraversionpt": "22.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "BENE J, MOULIS G, BENNANI I, AUFFRET M, COUPE P, BABAI S ET AL.. BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. BRITISH JOURNAL OF DERMATOLOGY. 2016?175(2):296-301", "literaturereference_normalized": "bullous pemphigoid and dipeptidyl peptidase iv inhibitors a case noncase study in the french pharmacovigilance database", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20191115", "receivedate": "20191115", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17036340, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "FR-TEVA-728032ISR", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "75978", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "SITAGLIPTIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SITAGLIPTIN" } ], "patientagegroup": null, "patientonsetage": "65", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pemphigoid", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "BENE J, MOULIS G, BENNANI I, AUFFRET M, COUPE P, BABAI S, ET AL. BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. BR-J-DERMATOL 2016;175(2):296-301.", "literaturereference_normalized": "bullous pemphigoid and dipeptidyl peptidase iv inhibitors a case noncase study in the french pharmacovigilance database", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20170110", "receivedate": "20170110", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13101680, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "FR-MYLANLABS-2016M1058784", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "VILDAGLIPTIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VILDAGLIPTIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "075973", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pemphigoid", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "BENE J, MOULIS G, BENNANI I, AUFFRET M, COUPE P, BABAI S, ET AL. BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. BR-J-DERMATOL 2016;175(2):296-301.", "literaturereference_normalized": "bullous pemphigoid and dipeptidyl peptidase iv inhibitors a case noncase study in the french pharmacovigilance database", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20170105", "receivedate": "20170105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13089670, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "FR-TEVA-728021ISR", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "75978", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VILDAGLIPTIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VILDAGLIPTIN" } ], "patientagegroup": null, "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pemphigoid", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "BENE J, MOULIS G, BENNANI I, AUFFRET M, COUPE P, BABAI S, ET AL. BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. BR-J-DERMATOL 2016;175(2):296-301.", "literaturereference_normalized": "bullous pemphigoid and dipeptidyl peptidase iv inhibitors a case noncase study in the french pharmacovigilance database", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20170112", "receivedate": "20170112", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13109660, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "NVSC2019FR035715", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "75965", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VILDAGLIPTIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "101706", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VILDAGLIPTIN" } ], "patientagegroup": null, "patientonsetage": "70", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pemphigoid", "reactionmeddraversionpt": "22.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "BENE J, MOULIS G, BENNANI I, AUFFRET M, COUPE P, BABAI S ET AL.. BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. BRITISH JOURNAL OF DERMATOLOGY. 2016?175:296-301", "literaturereference_normalized": "bullous pemphigoid and dipeptidyl peptidase iv inhibitors a case noncase study in the french pharmacovigilance database", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20191115", "receivedate": "20191115", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17036330, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "FR-MYLANLABS-2016M1058714", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ESCITALOPRAM OXALATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESCITALOPRAM" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VILDAGLIPTIN" }, "drugadditional": "2", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VILDAGLIPTIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "075973", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RISPERIDONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RISPERIDONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pemphigoid", "reactionmeddraversionpt": "19.1", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "BENE J, MOULIS G, BENNANI I, AUFFRET M, COUPE P, BABAI S, ET AL. BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. BR-J-DERMATOL 2016;175(2):296-301.", "literaturereference_normalized": "bullous pemphigoid and dipeptidyl peptidase iv inhibitors a case noncase study in the french pharmacovigilance database", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20170105", "receivedate": "20170105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13089660, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "FR-TEVA-728020ISR", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "VILDAGLIPTIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VILDAGLIPTIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "75978", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": "80", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pemphigoid", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "BENE J, MOULIS G, BENNANI I, AUFFRET M, COUPE P, BABAI S, ET AL. BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. BR-J-DERMATOL 2016;175(2):296-301.", "literaturereference_normalized": "bullous pemphigoid and dipeptidyl peptidase iv inhibitors a case noncase study in the french pharmacovigilance database", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20170112", "receivedate": "20170112", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13109220, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "FR-MYLANLABS-2016M1058698", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "SITAGLIPTIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SITAGLIPTIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "075973", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pemphigoid", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BENE J, MOULIS G, BENNANI I, AUFFRET M, COUPE P, BABAI S, ET AL. BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE.. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. BR-J-DERMATOL 2016;175(2):296-301.", "literaturereference_normalized": "bullous pemphigoid and dipeptidyl peptidase iv inhibitors a case noncase study in the french pharmacovigilance database", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20170112", "receivedate": "20170112", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13109233, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "FR-TEVA-728036ISR", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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{ "abstract": "The emergence of Multisystem Inflammatory Syndrome (MIS-C) following SARS-CoV-2 infection in children and adolescents provided a new diagnostic and management challenge as there is limited knowledge about this condition and its natural history. In existing literature on MIS-C, there are currently no data about long-term outcomes. We report the case of a 14-year-old boy, with no significant past medical history, who presented a condition of multiorgan dysfunction due to MIS-C, after a SARS CoV-2 infection, and subsequent clinical-laboratory signs of hepatic steatosis at short-term follow-up. The case suggests how hepatic steatosis may be a possible sequela following SARS-CoV-2 infection, MIS-C and its medical treatment. Therefore, a close and long-term follow-up is needed to establish the pathophysiology and the evolution of this condition in patients following MIS-C.", "affiliations": "Department of Pediatrics, University of Perugia, 06132 Perugia, Italy.;Department of Pediatrics, University of Perugia, 06132 Perugia, Italy.;Department of Pediatrics, University of Perugia, 06132 Perugia, Italy.;Department of Pediatrics, University of Perugia, 06132 Perugia, Italy.;Department of Pediatrics, University of Perugia, 06132 Perugia, Italy.", "authors": "Sica\|Rossella\|R\|0000-0002-3990-4117;Pennoni\|Serena\|S\|;Penta\|Laura\|L\|;Di Cara\|Giuseppe\|G\|;Verrotti\|Alberto\|A\|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.3390/ijerph18136961", "fulltext": "\n==== Front\nInt J Environ Res Public Health\nInt J Environ Res Public Health\nijerph\nInternational Journal of Environmental Research and Public Health\n1661-7827\n1660-4601\nMDPI\n\n34209719\n10.3390/ijerph18136961\nijerph-18-06961\nCase Report\nNew Onset of Hepatic Steatosis Post-Severe Multisystem Inflammatory Syndrome in Children (MIS-C): A Case Report\nhttps://orcid.org/0000-0002-3990-4117\nSica Rossella \nPennoni Serena\nPenta Laura\nDi Cara Giuseppe\nVerrotti Alberto\nTchounwou Paul B. Academic Editor\nDepartment of Pediatrics, University of Perugia, 06132 Perugia, Italy; [email protected] (S.P.); [email protected] (L.P.); [email protected] (G.D.C.); [email protected] (A.V.)\n Correspondence: [email protected]\n29 6 2021\n7 2021\n18 13 696125 5 2021\n23 6 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nThe emergence of Multisystem Inflammatory Syndrome (MIS-C) following SARS-CoV-2 infection in children and adolescents provided a new diagnostic and management challenge as there is limited knowledge about this condition and its natural history. In existing literature on MIS-C, there are currently no data about long-term outcomes. We report the case of a 14-year-old boy, with no significant past medical history, who presented a condition of multiorgan dysfunction due to MIS-C, after a SARS CoV-2 infection, and subsequent clinical-laboratory signs of hepatic steatosis at short-term follow-up. The case suggests how hepatic steatosis may be a possible sequela following SARS-CoV-2 infection, MIS-C and its medical treatment. Therefore, a close and long-term follow-up is needed to establish the pathophysiology and the evolution of this condition in patients following MIS-C.\n\nMIS-C\nSARS-CoV-2\nhepatic steatosis\nultrasonography\ntransaminases\n==== Body\n1. Introduction\n\nSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was first identified in Wuhan, China, in December 2019 and then spread rapidly worldwide causing coronavirus disease 2019 (COVID-19) which became the first pandemic of the 21st century by number of deaths. Unlike adults, in which cytokine storm is frequently accompanied by severe respiratory involvement with development of acute respiratory distress syndrome, children with COVID-19 may be asymptomatic or only have mild symptoms. The most prevalent symptom of COVID-19 in pediatric population is fever, followed by cough, upper respiratory tract symptoms, diarrhea and nausea/vomiting. Only a small percentage of children with COVID-19 required Pediatric Intensive Care Unit (PICU) level care or mechanical ventilation [1]. Conversely, in the latter half of April 2020, reports from the UK [2] and Italy [3], followed by the U.S, described a novel syndrome whose features resembled those of known entities such as Kawasaki Disease (KD), toxic shock syndrome (TSS), and macrophage activation syndrome (MAS), which could lead to shock and multiple organ failure, requiring PICU. This novel syndrome is referred to interchangeably as Multisystem Inflammatory Syndrome in Children (MIS-C) associated with COVID 19 or Pediatric Inflammatory Multisystem Syndrome Temporally associated with SARS CoV-2 (PIMS TS). In a case series comparing children and adolescents with MIS-C vs. those with severe COVID-19, MIS-C was distinguished by having more severe cardiovascular or mucocutaneous involvement and extreme inflammation with a higher neutrophil/leucocyte ratio, higher c-reactive protein (CRP) level and more thrombocytopenia than patients with COVID-19 [4]. Initially, it was believed that this syndrome was specifically related to children and adolescents, but reports of cases of multisystem inflammatory syndrome in adults have recently been described, referring to this syndrome as Multisystem Inflammatory Syndrome in Adults Associated with SARS-CoV-2 Infection (MIS-A) [5]. These reports demonstrates that SARS-CoV-2 can cause this clinical manifestation in subjects of any age. The pathophysiology of this syndrome is under intense investigation but so far remains unclear. It is believed that this syndrome results from an abnormal immune response to the virus. Carter et al. performed a serum profiling of MIS-C patients that revealed high levels of interleukin-1β (IL-1β), IL-6, IL-8, IL-10, IL-17, interferon-γ and differential T and B cell subset lymphopenia in the acute phase. Moreover, high CD64 expression on neutrophils and monocytes, and high HLA-DR expression on γδ and CD4+CCR7+ T cells in the acute phase, suggested that these immune cell populations were activated. Antigen-presenting cells had low HLA-DR and CD86 expression, potentially indicative of impaired antigen presentation. All of these features normalized over the resolution phase [6]. In addition, the hyperinflammatory state was found to be different from that in adult severe COVID-19 and KD. Consiglio et al. performed a systems-level analysis of immune cells, cytokines and antibodies in the blood of children presenting with MIS-C as compared to children with mild SARS-CoV-2 infection and children with KD. They noticed that several details of the hyperinflammatory state in children with MIS-C were different from the hyperinflammation seen in adults and children with acute SARS-CoV-2 infection and that of children with KD as well. In particular, they found that IL-17 is most important in KD but it is significantly lower in MIS-C patients, indicating a difference in the underlying immunopathology [7]. Clinical features of MIS-C are variable and characterized mostly by persistent fever; mucocutaneous symptoms including conjunctivitis and rash; gastrointestinal symptoms, including vomiting, abdominal pain, and/or diarrhea; cardiac abnormalities such as myocardial dysfunction, myocardial infarction with increased serum concentrations of troponin and pro-B-type natriuretic peptide (proBNP), coronary artery dilation or aneurysm, arrhythmia and a compromised hemodynamic status which can lead to acute renal and hepatic failure; neurologic findings including headache, irritability and encephalopathy; and coagulopathy. On 13 May 2020, the Center for Disease Control (CDC) issued a case definition specifying that the patient should be <21 years old, have fever, with laboratory evidence of inflammation (including, but not limited to, 1 or more of the following: an elevated CRP, erythrocyte sedimentation rate, fibrinogen, procalcitonin, D-dimer, ferritin, lactate dehydrogenase, IL-6, elevated neutrophils, reduced lymphocytes and low albumin level), and evidence of clinically severe illness requiring hospitalization, with multisystem (>2) organ involvement (cardiac, renal, respiratory, haematological, gastrointestinal, dermatological or neurological), in the absence of an alternative plausible diagnosis, as well as evidence of SARS-CoV-2 infection or exposure [8]. In existing pediatric literature on MIS-C, only short-term outcomes were reported [9], as there are currently no published reports detailing long term outcomes in these patients.\n\n2. Case Report\n\nOn 1 March 2021, a 14-year-old boy was admitted to the Pediatric Emergency Department with compromised general status. He was found to be alert and oriented, febrile with 38.2 °C, tachycardic (118/beats/min), hypotensive (60/40 mmHg), saturating 100% on room air breathing 42 breaths per minute. Upon clinical examination, he was found to be dehydrated, with jaundiced skin, capillary refill 3–4 s, cold extremities with feeble peripheral pulses, palmoplantar erythema and edema, diffusely painful abdomen and palpable hepatosplenomegaly. He was in a condition of multiorgan failure: acute kidney injury, hepatosplenomegaly with increased inflammatory markers, in particular of IL-6 (144.6 pg/mL) and compromised hemodynamic status with reduction of left ventricular ejection fraction. We also noticed elevated values of alanine aminotransferase (ALT) (139 UI/L), aspartate aminotransferase (AST) (102 UI/L) and indices of cholestasis. Given the family history of SARS-CoV-2 infection and the positivity of SARS-CoV-2 IgG from serum, he was diagnosed with MIS-C. The patient’s compromised hemodynamic status required vasoactive support at the Cardiac Intensive Care Unit for the first 3–4 days of hospitalization. He was treated with intravenous immunoglobulin (2g/kg over 48 h) and pulse Methylprednisolone (10 mg/kg a bolus twice a day for 3 days and then progressively reduced). In consideration of the elevation of D-dimer (5734 ng/mL), a prophylactic antithrombotic therapy was started with low-molecular-weight heparin and aspirin (3 mg/kg/day). During hospital course, we noticed an improvement of his general conditions, with return to clinical baseline and progressive normalization of laboratory alterations, particularly of ALT and cholestatic indices. Ultrasonography of the abdomen was performed prior to discharge, and we found no abnormalities (Figure 1). He was discharged at day 14 with indication to continue therapy with Aspirin and Prednisone per os, in progressive decalage according to the tapering strategy.\n\nFollowing discharge, the patient was re-evaluated in a follow-up visit program (physical examination, laboratory tests and echocardiography) during which we started to taper off prednisone (until 1 mg/Kg/day). On 23 March, at the first follow-up visit, the patient was found to be in good conditions, without particular findings on the physical examination. The laboratory tests were normal except for the elevation of ALT (122 UI/L). On the second follow-up visit, 30 days following the onset of MIS-C, the patient was completely asymptomatic but clinical assessment revealed palpable hepatomegaly (2 cm below the costal margin) and further elevation of ALT (143 UI/L) on laboratory testing. AST, serum bilirubin and all the other lab parameters were normal. Ultrasonography of the abdomen was performed and revealed that hepatomegaly was secondary to hepatic steatosis (Figure 1), with absence of pre-existing obesity (BMI 19.2) and signs of Nonalcoholic Fatty Liver Disease (NAFLD). Moreover, any other existing or previous inflammatory pathology was excluded. The following follow-up visits, laboratory tests (Figure 2) and ultrasonographies of the abdomen showed data suggesting hepatic steatosis as well. We did not introduce a drug therapy but we started a lifestyle approach including dietary improvements and increasing physical activity. Our patient was referred to a Pediatric Gastroenterologist. Currently, the patient is in good general clinical condition, with an optimal recovery of cardiac and renal function and not on drug therapy, as steroid therapy was withdrawn during the follow-up visit program. Nevertheless, our patient still has hepatic steatosis which was also confirmed by ultrasonography of the abdomen performed during the most recent follow-up visit on 27 May.\n\n3. Discussion\n\nSARS-CoV-2 may cause a systemic disease with possible involvement of other organs besides the respiratory system, including the liver, because of ubiquitous distribution of the main viral entry receptor, namely angiotensin converting enzyme 2 (ACE2). In particular, the virus spike protein binds ACE2 to gain cell entry and transmembrane serine protease 2 (TMPRSS2) and paired basic amino acid cleaving enzyme (FURIN) are also important for infection. Therefore, the expression of these receptors provided early clues for putative hepatic permissive cells [10]. A study of Pirola et al. demonstrates that gene expression levels for ACE2 are highest in cholangiocytes compared with alveolar type 2 cells, followed in turn by sinusoidal endothelial cells and hepatocytes, thus supporting the possibility that SARS-CoV-2 may cause direct liver injury by viral cytopathic effect. The cytopathic effect may be due to a direct mechanism such as lysis or by necrotic and/or apoptotic effects. Furthermore, the expression pattern in cell clusters associated with numerous active immune pathways, for example, inflammatory macrophages, natural killer cells, plasma cells, mature B cells and cells of the liver endothelial microenvironment, opens the possibility of SARS-CoV-2 immune-mediated liver damage [11]. Therefore, the pathophysiology of the liver involvement in COVID-19 and MIS-C is still unclear, but it is believed that the injury might be caused by hepatocellular infection with direct cytopathic effects of SARS-CoV-2 or an immune-mediated response with inflammatory damage. In addition, hypoxic/shock-related circulatory compromise, endothelial dysfunction, microthrombi formation and drug-induced liver injury (e.g., corticosteroids, lopinavir, ritonavir, tocilizumab and remdesivir) may be involved [12]. COVID-19-associated liver injury is defined as any liver damage occurring during disease course and treatment of COVID-19 patients, with or without pre-existing liver disease [13] and typically leads to a temporary moderate elevation of liver tests without significant hepatic synthetic function impairment. Patients with SARS-CoV-2 infection and elevated ALT are at risk of a more severe disease course including longer hospitalization and ICU stays [14]. Patients with greater elevations in serum ALT levels often have high levels of CRP, which is synthesized by the liver, D- dimer, ferritin and IL-6. IL-6 is produced by monocytes, macrophages and T cells in response to activation of the innate and adaptive immune system, and is the most important driver of CRP production, and high IL-6 levels are associated with liver injury in COVID-19 [10]. Hepatitis is also common in children with MIS-C, and it is associated with a more severe presentation of the syndrome [15]. COVID-19-associated hepatocellular injury is characterized by moderate steatosis, lobular and portal inflammation, apoptotic and/or necrotic foci and elevation of plasma ALT and AST [16]. Microvesicular and macrovesicular steatosis have been observed in liver autopsies of COVID-19 patients who presented with SARS-CoV-2 infection and, in some cases, SARS-CoV-2 hepatocellular infection has been proven [16,17]. Induction of host de novo lipogenesis might be crucial for SARS-CoV-2 life cycle as enhanced de novo lipogenesis could supply the virus with sufficient amounts of lipids to generate the vesicular systems required for viral replication and exocytosis [16]. Moreover, steatosis might be caused by SARS-CoV-2 induced mitochondrial dysfunction and Endoplasmic reticulum (ER) stress, which can induce de novo lipogenesis [16,18]. There are observations that suggest that SARS-CoV-2 affects mitochondrial activity, for instance, mitochondrial crista abnormalities were found in liver specimen of COVID-19 patients [17]. In addition, electron microscopy examinations proved SARS-CoV-2 hepatocellular infection and reported a pathological ER dilatation in infected hepatocytes, which is the most probable cause of ER stress [17]. In addition, the coronavirus S protein might play a key role in ER stress induction [19]. SARS-CoV-2 infection might also activate mTOR, inducing de novo lipogenesis and eventually inhibiting autophagy (as a mechanism of viral degradation) and facilitating viral escape from the immune system [16]. Moreover, significantly increased mTOR activity has been revealed upon IL-6 stimulation [20], and IL-6 is one of the most important cytokines involved in MIS-C. Additionally, it is important to differentiate hepatic lipid accumulation as a result of SARS-CoV-2 infection and MIS-C from pre-existing NAFLD, which has been shown to increase the risk for poor outcome [21]. Therefore, we hypothesize that hepatic steatosis in our patient might be caused by SARS-COV-2 infection, COVID-19 and MIS-C. We do not exclude that liver damage and consequent steatosis might be caused by an immune-mediated inflammatory response to the virus or by hypoxic/shock-related circulatory compromised status, endothelial dysfunction and/or microthrombi formation. Furthermore, drug-induced liver damage should not be excluded. In a retrospective chart review of a cohort of children treated with a multidisciplinary approach and consensus-driven algorithm, the short-term outcomes of these patients were found to be generally favorable [9]. However, in existing literature on MIS-C, there are no data concerning the mid-long-term outcomes of these patients. Although much of the discussion around MIS-C and its outcomes has centered on cardiac manifestations and sequelae, such as left ventricular (LV) dysfunction and coronary aneurysms, providers must be aware of the hepatic damage which might be caused either by SARS-CoV-2 infection and immune-mediated response. We suggest that close follow-up for these patients would be needed to assess the evolution of hepatic damage following MIS-C.\n\n4. Conclusions\n\nThe emergence of MIS-C following SARS-CoV-2 infection in children and adolescents provided new diagnostic, therapeutic and follow-up challenges as there is limited knowledge about this condition and its natural history. The hepatic consequences of SARS- CoV-2 infection are due to possible direct cytopathic effect, systemic inflammation and immune dysfunction and are an important component of both COVID-19 and MIS-C. Moreover, pre-existing NAFLD should be distinguished from hepatic lipid accumulation as a result of SARS-CoV-2 infection and MIS-C. Currently, there are no data reporting mid-long-term outcomes in patients following MIS-C. We report a case with an excellent cardiac and renal outcome but with a new onset of hepatic steatosis. New onset of hepatic steatosis might be one of the sequelae following SARS-CoV-2 infection, MIS-C and its treatment, mainly the prolonged use of corticosteroids. Furthermore, we suggest that hepatic steatosis after COVID-19 and MIS-C might be underdiagnosed as few patients do undergo abdominal ultrasonography monitoring. Diagnosis of hepatic steatosis is easily accessible through an abdominal ultrasound, which is a low-cost, non-invasive examination. We suggest that it can be very useful to identify this potential damage early. Therefore, more studies are needed to establish the pathophysiology and the evolution of this condition in patients following MIS-C. We suggest that long-term follow-up is needed and would be essential to define the late outcomes of these patients.\n\nAuthor Contributions\n\nConceptualization and methodology R.S., S.P. and L.P.; validation, A.V. and G.D.C.; writing—original draft preparation, R.S. and S.P.; writing—review and editing, R.S., S.P. and L.P.; supervision, A.V. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research received no external funding.\n\nInstitutional Review Board Statement\n\nNot applicable.\n\nInformed Consent Statement\n\nInformed consent was obtained from the subject involved in the study.\n\nConflicts of Interest\n\nThe authors declare no conflict of interest.\n\nFigure 1 (a) Ultrasonography of the abdomen performed at discharge demonstrating normal dimension of the liver and a homogenous pattern. (b) Ultrasonography of the liver performed during follow-up demonstrating hepatomegaly and a hyperechoic liver, suggestive of hepatic steatosis.\n\nFigure 2 Graphic representation of the ALT and AST levels over time which demonstrates the decrease in ALT and AST during hospitalization (A) and then a new rise of the ALT with stable low AST levels during follow-up visits (B).\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Mantovani A. Rinaldi E. Zusi C. Beatrice G. Saccomani M.D. Dalbeni A. Coronavirus disease 2019 (COVID-19) in children and/or adolescents: A meta-analysis Pediatr. Res. 2021 89 733 737 10.1038/s41390-020-1015-2 32555539\n2. Riphagen S. Gomez X. Gonzalez-Martinez C. Wilkinson N. Theocharis P. Hyperinflammatory shock in children during COVID-19 pandemic Lancet 2020 39 1607 1608 10.1016/S0140-6736(20)31094-1\n3. Verdoni L. Mazza A. Gervasoni A. Martelli L. Ruggeri M. Ciuffreda M. Bonanomi E. D’Antiga L. An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: An observational cohort study Lancet 2020 395 1771 1778 10.1016/S0140-6736(20)31103-X 32410760\n4. Feldstein L.R. Tenforde M.W. Friedman K.G. Rose E.B. Dapul H. Soma V.L. Maddux A.B. Mourani P.M. Bowens C. Maamari M. Characteristics and Outcomes of US Children and Adolescents with Multisystem Inflammatory Syndrome in Children (MIS-C) Compared with Severe Acute COVID-19 JAMA 2021 325 1074 1087 10.1001/jama.2021.2091 33625505\n5. Morris S.B. Schwartz N.G. Patel P. Abbo L. Beauchamps L. Balan S. Lee E.H. Paneth-Pollak R. Geevarughese A. Lash M.K. Case Series of Multisystem Inflammatory Syndrome in Adults Associated with SARS-CoV-2 Infection—United Kingdom and United States, March–August 2020 MMWR 2020 69 1450 1456 10.15585/mmwr.mm6940e1 33031361\n6. Carter M.J. Fish M. Jennings A. Doores K.J. Wellman P. Seow J. Acors S. Graham C. Timms E. 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Med. 2020 1 4 10.1007/s42399-020-00631-3 33173850\n\n", "fulltext_license": "CC BY", "issn_linking": "1660-4601", "issue": "18(13)", "journal": "International journal of environmental research and public health", "keywords": "MIS-C; SARS-CoV-2; hepatic steatosis; transaminases; ultrasonography", "medline_ta": "Int J Environ Res Public Health", "mesh_terms": "D000293:Adolescent; D000086382:COVID-19; D002648:Child; D005234:Fatty Liver; D006801:Humans; D008297:Male; D000086402:SARS-CoV-2; D018746:Systemic Inflammatory Response Syndrome", "nlm_unique_id": "101238455", "other_id": null, "pages": null, "pmc": null, "pmid": "34209719", "pubdate": "2021-06-29", "publication_types": "D002363:Case Reports", "references": "32437830;33826804;32170806;32386565;32966765;17670839;32352224;32410760;33692570;33211859;33173850;33206767;32810894;33031361;19081072;32555539;30213506;33190346;33625505;32812012", "title": "New Onset of Hepatic Steatosis Post-Severe Multisystem Inflammatory Syndrome in 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NEW ONSET OF HEPATIC STEATOSIS POST?SEVERE MULTISYSTEM INFLAMMATORY SYNDROME IN CHILDREN (MIS?C): A CASE REPORT. 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"METHYLPREDNISOLONE" }, "drugadditional": "2", "drugadministrationroute": "065", "drugauthorizationnumb": "202691", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "PULSE METHYLPREDNISOLONE (10 MG/KG A BOLUS TWICE A DAY FOR 3 DAYS)", "drugenddate": "202103", "drugenddateformat": "610", "drugindication": null, "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "12", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "20210301", "drugstartdateformat": "102", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, 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"drugstartdate": "202103", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "2", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "STARTED TO TAPER OFF PREDNISONE (UNTIL 1 MG/KG/DAY)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "202103", "drugstartdateformat": "610", "drugstructuredosagenumb": "1", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "14", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatomegaly", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Hepatic steatosis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20210323" } }, "primarysource": { "literaturereference": "SICA R, PENNONI S, PENTA L, DI CARA G, VERROTTI A. NEW ONSET OF HEPATIC STEATOSIS POST?SEVERE MULTISYSTEM INFLAMMATORY SYNDROME IN CHILDREN (MIS?C): A CASE REPORT. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH. 2021?18(13):ARTICLE NUMBER 6961. DOI: 10.3390/IJERPH18136961.", "literaturereference_normalized": "new onset of hepatic steatosis post severe multisystem inflammatory syndrome in children mis c a case report", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "IT", "receiptdate": "20210730", "receivedate": "20210730", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19638723, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" } ]
{ "abstract": "To investigate the inter-individual variability in duration of anti-vascular endothelial growth factor (VEGF) treatment effect in neovascular age-related macular degeneration (nvAMD).\n\n\n\nProspective observational multi-centered study.\n\n\n\nForty-eight patients with nvAMD treated with anti-VEGF injections were included. Both treatment naive (n=25) as well as patients who had previously received treatment with ranibizumab (n=23) more than one month prior to their enrollment were recruited.\n\n\n\nPatients received injection with ranibizumab (0.5 mg/0.05 ml) and were followed weekly for 4 weeks with spectral-domain OCT (SD-OCT) assessing the time to maximal reduction of central retinal thickness (CRT) and the presence of intraretinal and subretinal fluid. Other data collected included age, gender, visual acuity, axial length, lens status, and previous injections. The Shapiro-Wilk test was used to examine normal distributions for all variables. Correlations were examined by calculating Spearman's correlation coeficient. Distributions of quantitative variables are described as means (±SD). Qualitative variables are summarized by counts and percentage.\n\n\n\nTime to maximal reduction of CRT and intra- and subretinal fluid after ranibizumab injection.\n\n\n\nA total of 48 eyes of 48 patients (age 74.8±8.3 years, 62.5% female, 52% treatment naive, 35.4% pseudophakic) were assessed. Two-thirds (64.6%) reached maximal CRT reduction earlier than the standard 4-week interval: 6.3% at 1 week postinjection, 22.9% at 2 weeks postinjection, and 35.4% at 3 weeks postinjection. Only 35.4% of patients had maximal CRT reduction at 4 weeks. Twenty percent of treatment-naive and 34.8% of non-naive patients had a week-4 CRT that was >35 μm thicker than the earlier occuring lowest CRT value (nadir). The time to maximal CRT reduction was not related to axial length, age, lens status, or history of injections.\n\n\n\nOptimal dosing interval for maximal CRT reduction may be less than 4 weeks for a significant proportion of patients. Most patients will be classified as complete responders if intervals less than 4 weeks are used to assess anti-VEGF treatment response. Disease load rather than eye size appears to be the driver of anti-VEGF treatment duration and therefore, dosing interval needs to be optimized in the cohort of short-term responders.", "affiliations": "Department of Ophthalmology, University of Crete, Heraklion, Greece; Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts; Korgialenio Benakio General Hospital, Athens, Greece.;Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts.;Department of Ophthalmology, University of Crete, Heraklion, Greece.;Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts.;OMMA Eye Institute, Athens, Greece.;Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts.;Korgialenio Benakio General Hospital, Athens, Greece.;Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts.;Department of Ophthalmology, University of Crete, Heraklion, Greece.;Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts. Electronic address: [email protected].", "authors": "Bontzos\|Georgios\|G\|;Bagheri\|Saghar\|S\|;Ioanidi\|Larissa\|L\|;Kim\|Ivana\|I\|;Datseris\|Ioannis\|I\|;Gragoudas\|Evangelos\|E\|;Kabanarou\|Stamatina\|S\|;Miller\|Joan\|J\|;Tsilimbaris\|Miltiadis\|M\|;Vavvas\|Demetrios G\|DG\|", "chemical_list": "D020533:Angiogenesis Inhibitors; D042461:Vascular Endothelial Growth Factor A; D000069579:Ranibizumab", "country": "United States", "delete": false, "doi": "10.1016/j.oret.2019.11.004", "fulltext": null, "fulltext_license": null, "issn_linking": "2468-6530", "issue": "4(12)", "journal": "Ophthalmology. Retina", "keywords": null, "medline_ta": "Ophthalmol Retina", "mesh_terms": "D000368:Aged; D020533:Angiogenesis Inhibitors; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D058449:Intravitreal Injections; D008297:Male; D011446:Prospective Studies; D000069579:Ranibizumab; D013997:Time Factors; D041623:Tomography, Optical Coherence; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A; D014792:Visual Acuity; D057135:Wet Macular Degeneration", "nlm_unique_id": "101695048", "other_id": null, "pages": "1138-1145", "pmc": null, "pmid": "31937473", "pubdate": "2020-12", "publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study", "references": "17021318;23929309;23352196;21791509;21282580;22374154;28660277;25882328;28527040;21526923;16581423;16483659;22818800;23538578;20920825;23901256;21733918;25217857;30269186;26447985;26309891;19516114;29769445;15671306;19815292;19118696;18408176;23966368;28469938;17386270;28893454;18930553;23084240;17021319;28926193;23453513;29142592;26981331;24143065;24084496;15885778", "title": "Nonresponders to Ranibizumab Anti-VEGF Treatment Are Actually Short-term Responders: A Prospective Spectral-Domain OCT Study.", "title_normalized": "nonresponders to ranibizumab anti vegf treatment are actually short term responders a prospective spectral domain oct study" }	[ { "companynumb": "GR-ROCHE-2534228", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RANIBIZUMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "125156", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "0.5MG/0.5ML", "drugenddate": null, "drugenddateformat": null, "drugindication": "NEOVASCULAR AGE-RELATED MACULAR DEGENERATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RANIBIZUMAB." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neovascular age-related macular degeneration", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PRIVACY, BAGHERI S, LOANIDI L, KIM I, DATSERIS I, GRAGOUDAS E ET AL. NONRESPONDERS TO RANIBIZUMAB ANTI-VEGF TREATMENT ARE ACTUALLY SHORT-TERM RESPONDERS: A PROSPECTIVE SPECTRAL-DOMAIN OCT STUDY.. OPTHALMOLOGY RETINA. 2020?:1-8.", "literaturereference_normalized": "nonresponders to ranibizumab anti vegf treatment are actually short term responders a prospective spectral domain oct study", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20200319", "receivedate": "20200130", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17350900, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" } ]
{ "abstract": "Metformin-associated lactic acidosis [MALA] is a potentially fatal condition characterized by an elevation in serum lactate in patients with metformin exposure. An 82-year-old man with no prior renal history was brought to hospital after being found by his family in a confused state. He had a history of type 2 diabetes mellitus, and his medications included regular metformin. On arrival to our hospital he was conscious but confused and noted recent decreased oral intake. Initial investigations revealed severe acidemia (pH <6.75, undetectable bicarbonate), with elevated serum lactate, urea, creatinine, and hyperkalemia. He was treated with intravenous dextrose, crystalloids, and bicarbonate and underwent urgent hemodialysis. The patient responded well to supportive therapies and achieved full renal recovery one week after admission. He was discharged feeling well, with a new antihyperglycemic medication regimen. This case highlights the potential for life-threatening acidemia in cases of MALA. The case is further unique in that the patient was conscious and responded to questions on arrival, despite the serious metabolic disturbance, and recovered completely. From a safety standpoint, health care providers should advise and educate their patients about discontinuing metformin and other potentially harmful medications in the context of acute illness with volume contraction.", "affiliations": "Department of Medicine, The Ottawa Hospital, University of Ottawa, Ottawa, ON, Canada.;Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, ON, Canada.;Department of Medicine, Division of Nephrology, Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada.", "authors": "Gershkovich\|Benjamin\|B\|0000-0001-7914-9067;McCudden\|Christopher\|C\|;Burns\|Kevin D\|KD\|0000-0002-1482-5826", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1155/2018/4696182", "fulltext": "\n==== Front\nCase Rep NephrolCase Rep NephrolCRINCase Reports in Nephrology2090-66412090-665XHindawi 10.1155/2018/4696182Case ReportA Unique Case of Metformin-Associated Lactic Acidosis http://orcid.org/0000-0001-7914-9067Gershkovich Benjamin \n1\nMcCudden Christopher \n2\nhttp://orcid.org/0000-0002-1482-5826Burns Kevin D. [email protected]\n3\n\n1Department of Medicine, The Ottawa Hospital, University of Ottawa, Ottawa, ON, Canada\n2Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, ON, Canada\n3Department of Medicine, Division of Nephrology, Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, CanadaAcademic Editor: Ze'ev Korzets\n\n2018 15 11 2018 2018 46961829 10 2018 30 10 2018 Copyright © 2018 Benjamin Gershkovich et al.2018This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Metformin-associated lactic acidosis [MALA] is a potentially fatal condition characterized by an elevation in serum lactate in patients with metformin exposure. An 82-year-old man with no prior renal history was brought to hospital after being found by his family in a confused state. He had a history of type 2 diabetes mellitus, and his medications included regular metformin. On arrival to our hospital he was conscious but confused and noted recent decreased oral intake. Initial investigations revealed severe acidemia (pH <6.75, undetectable bicarbonate), with elevated serum lactate, urea, creatinine, and hyperkalemia. He was treated with intravenous dextrose, crystalloids, and bicarbonate and underwent urgent hemodialysis. The patient responded well to supportive therapies and achieved full renal recovery one week after admission. He was discharged feeling well, with a new antihyperglycemic medication regimen. This case highlights the potential for life-threatening acidemia in cases of MALA. The case is further unique in that the patient was conscious and responded to questions on arrival, despite the serious metabolic disturbance, and recovered completely. From a safety standpoint, health care providers should advise and educate their patients about discontinuing metformin and other potentially harmful medications in the context of acute illness with volume contraction.\n\nUniversity of Ottawa\n==== Body\n1. Introduction\nMetformin, a medication of the biguanide class, is a commonly used first line oral agent for the treatment of type II diabetes mellitus [DM2] [1]. Metformin improves glycemic control in DM2 via several complex mechanisms, including an increase in peripheral insulin sensitivity, improvement in peripheral glucose uptake, and a decrease in hepatic gluconeogenesis [2–4]. Since metformin is primarily excreted in the urine, dose adjustments are recommended for estimated glomerular filtration rate levels of 45 mL/minute/1.73 m2 or less [5]. The most common adverse effects of chronic metformin use are gastrointestinal complaints, including nausea, bloating, and diarrhea [6].\n\nThe rarest and most dangerous complication of metformin use is metformin-associated lactic acidosis [MALA]. The incidence of MALA in patients without renal disease is low, with a reported estimate of 5 cases per 100,000 patient-years [7]. The pathophysiology of MALA is thought to be multifactorial in nature. In rat models, metformin has been shown to promote lactate production in enterocytes [8]. Additionally, given that lactate is one of the substrates for hepatic gluconeogenesis, an accumulation of lactate may occur when this process is inhibited by metformin [9].\n\nVarious reports have documented high mortality rates for MALA. A case series of 49 patients with MALA reported an overall mortality rate of 45% [10]. The same study found that the degree of serum lactate elevation and serum metformin concentration do not appear to play prognostic roles. A separate retrospective study, involving 42 patients admitted to the intensive care unit, concluded that MALA related to intentional metformin overdose portends a much more favorable prognosis compared with MALA related to incidental metformin accumulation with concurrent medical illness [11]. Higher mortality was associated with increased age, lower arterial pH, elevated prothrombin time, and need for mechanical ventilation and vasoactive medications.\n\nHere we describe a case of MALA in an elderly patient, who presented with confusion and unremarkable vital signs, despite demonstrating a profound depression in arterial pH and serum bicarbonate concentration. The patient fully recovered with fluid resuscitation, bicarbonate administration, and institution of hemodialysis therapy.\n\n2. Case Presentation\nAn 82-year-old man who lived alone was brought to a regional hospital from his home after being found by his family in a confused state. His past medical history was significant for DM2, hypertension, dyslipidemia, benign prostatic hyperplasia, and chronic back pain. His medications consisted of metformin 1000 mg p.o. BID, sitagliptin 50 mg p.o. BID, ramipril 10 mg p.o. daily, tamsulosin 0.4 mg p.o. daily, hydrochlorothiazide 25 mg p.o. daily, and meloxicam 7.5 mg p.o. daily. He had no known prior history of cardiac or renal disease, and baseline serum creatinine [Cr] was 79 μmol/L.\n\nOn initial assessment, the patient was in no acute distress, although he was disoriented and confused [Glasgow Coma Scale 14]. He complained of mild nausea with recent decreased oral intake, but there was no history of diarrhea. He had no history of infectious symptoms, toxic ingestions, recent medication changes, or witnessed seizure activity. On physical examination he had normal cardiorespiratory findings and no focal neurologic signs. His initial vital signs were blood pressure 150/83 mm Hg, heart rate 124/min, respiratory rate 33/min, oxygen saturation 100% on room air, and temperature 34.9° Celsius. His initial bloodwork results revealed a profound metabolic acidosis and acute kidney injury [Table 1].\n\nA chest X-ray was unremarkable, and his electrocardiogram showed a wide QRS complex, prolonged PR interval, and peaked T waves.\n\nHe was initially treated with intravenous [i.v.] dextrose, a crystalloid bolus, and calcium gluconate, and his potassium was shifted intracellularly with inhaled salbutamol and i.v insulin. He also received one ampule of i.v. sodium bicarbonate. Given his profound metabolic disturbances, he was urgently transferred by ambulance to the local tertiary care centre for expedited management and consideration of dialysis. Upon arrival to the Emergency Department of the tertiary care hospital, he was oriented to person and place but not time, and vital signs were: blood pressure 110/80 mm Hg, heart rate 80/min, respiratory rate 20/min, and oxygen saturation 100% on room air. Within 30 minutes of arrival his mean arterial pressure [MAP] dropped to <65 mm Hg, and he required norepinephrine and vasopressin infusions as well as consultation with the intensive care unit [ICU]. At this time he also received a bolus of 1.5 litres of normal saline, and his axillary temperature was measured as 32.1° Celsius. An arterial blood gas [ABG] revealed profound metabolic acidemia (Table 2).\n\nBlood cultures and serum toxicology screen for ethanol, methanol, isopropanol, acetone, ethylene glycol, acetaminophen, salicylates, and tricyclic antidepressants were negative. His remaining metabolic workup, including plasma thyroid stimulating hormone and plasma cortisol, was normal. Computerized tomography of the head, abdomen, and pelvis were negative for acute findings with no evidence of urinary obstruction or hydronephrosis. An assay for serum metformin level was unfortunately not available at our institution.\n\nThe patient's level of consciousness remained stable, and he consistently protected his airway. He required infusion of vasoactive agents for approximately 20 hours to maintain adequate blood pressure. He was heated externally using warming blankets, and his urine output during the first 24 hours of admission was 205 mL. In addition to treatment with i.v. crystalloid and bicarbonate, he underwent urgent hemodialysis treatment [dialysate HCO3− concentration of 36 mEq/L] via central venous access, which was repeated the next day. After two days he was transferred out of the ICU and went on to achieve renal recovery [serum Cr 95 μmol/L on day 8 of hospitalization] with restoration of urine output, acid-base and electrolyte balance. His functional status at the time of discharge was at his baseline. The metformin was discontinued from the day of admission, and he was prescribed a new regimen of oral antihyperglycemic medications for his diabetes.\n\n3. Discussion\nThis patient presented with acute kidney injury associated with severe hyperkalemia, hypoglycemia, and a profound metabolic acidemia with elevated anion gap and serum lactate levels. The patient's high anion gap metabolic acidosis was likely due to lactic acidosis and acute kidney injury, and he demonstrated appropriate respiratory compensation. Despite having severely depressed pH and HCO3− levels however, the patient maintained consciousness throughout and did not require ventilatory support. Although a serum metformin assay was not available at our institution, other causes of elevated serum lactate including sepsis and tissue ischemia were ruled out, and there was no evidence of hepatic disease or toxic ingestions. Although the patient's transient hypotension may have contributed to his lactic acidosis, his serum lactate was significantly elevated on initial presentation, prior to the requirement of vasoactive agents. Overall, his presentation was in keeping with MALA.\n\nIn this case, it is unclear what precipitated the patient's rapid decline and initial presentation to hospital, as history was limited. However, based on his medication profile and laboratory findings, it is possible that he developed acute kidney injury secondary to extracellular volume contraction in the setting of nonsteroidal anti-inflammatory [meloxicam] and ACE inhibitor [ramipril] use, with resultant hypoglycemia and severe lactic acidosis secondary to metformin accumulation. Thus, this case illustrates the potential danger of volume contraction in elderly patients with DM2 who are treated with renin-angiotensin blockade, nonsteroidal anti-inflammatories and metformin, which can set off a cascade of events leading to life-threatening MALA.\n\nThis case was unique for several other reasons. Firstly, the patient's initial clinical appearance and findings on exam were not suggestive of critical illness, and very much out of keeping with his abnormal biochemical profile. Despite having undetectably low serum pH and bicarbonate values, he was able to maintain an acceptable level of mentation, and consistently protected his airway without the need for intubation. In this regard, a correlation exists between low pH and altered mental status, with progression to coma frequently seen in patients with serum pH <6.9 [12].\n\nAdditionally, although mortality rate is high in cases of MALA [10, 11], this patient had an unusually favorable clinical outcome. His advanced age, requirement of vasopressor therapy, elevated prothrombin time, and extent of acute kidney injury placed him at increased risk of death, yet remarkably he experienced renal recovery and had returned to his baseline functional status by the time of hospital discharge.\n\nHypothermia in MALA has been described previously in several case reports [13–15]. While there does not appear to be a direct relationship between metformin and thermoregulation, it has been hypothesized that hypothermia in cases of severe MALA may be a consequence of systemic vasodilation, which is induced by acidemia [13]. Hypoglycemia is also known to cause hypothermia [16] as a result of decreased available substrate for cellular respiration and heat production. In our patient, the combination of acidemia and hypoglycemia can explain his significant hypothermia, given that central, infectious, traumatic, and other endocrine causes of hypothermia were ruled out.\n\nThe patient's coagulopathy on presentation cannot be explained by liver disease, clotting factor deficiencies, or recent use of anticoagulant medications. It is possible that he may have developed vitamin K deficiency given his history of decreased oral intake. However, his INR and PTT corrected within 12 hours of admission, which is sooner than expected for reversal of a vitamin K deficiency. In human and animal models, acidemia has been shown to inhibit clot formation, which may be due to increased fibrinogen consumption [17, 18]. Additionally, hypothermia inhibits thrombin generation in vitro [19, 20], which may result in the clinical finding of elevated PT and PTT values. Therefore, it is most likely that our patient developed a coagulopathy as a result of the combined effects of hypothermia and acidemia, which corrected shortly after warming and treatment with bicarbonate and hemodialysis.\n\nFinally, an interesting aspect of this case was the result of the ABG that was performed after the patient arrived at the tertiary care centre. The arterial pH and bicarbonate were reported as “<6.75” and “No result”, respectively. These values reflect the fact that the patient's true serum pH and bicarbonate were below the detectable limit for our institution's blood gas analyzer. On a typical blood gas analyzer, pH is measured by detecting the potential difference across a hydrogen-selective membrane. The potential difference is converted to hydrogen ion concentration using the Nernst equation. Bicarbonate is then calculated from pH and pCO2 using the Henderson-Hasselbalch equation [21].\n\nIn contrast, on a typical automated chemistry analyzer, bicarbonate measurement is based on a series of coupled enzyme reactions to convert bicarbonate to other compounds, such as malate. In the process there is a decrease in levels of nicotinamide adenine dinucleotide [NADH], which is measured spectrophotometrically by absorbance at 405 nm. The decrease in NADH concentration is then used to calculate the bicarbonate concentration, as there is a direct proportional relationship between the two variables [22]. Based on the Henderson-Hasselbalch equation, a serum bicarbonate concentration of 0 mmol/L is theoretically not possible. In fact, a set of serum electrolytes done at the time of the above blood gas confirmed a serum bicarbonate of 4 mmol/L in our patient, highlighting the need for vigilance in interpreting the ABG in such settings.\n\nThis case demonstrates the importance of early recognition of MALA in patients taking metformin who present with an unexplained high anion gap metabolic acidosis with elevated lactate levels. Such patients may present with clinical findings that do not correlate with their metabolic derangements and are at risk of rapid deterioration. Despite his advanced age and severe metabolic derangements, our patient had a very favorable outcome, perhaps as a result of prompt medical intervention, coupled with his relatively few medical comorbidities. Additionally, this case highlights the need for healthcare providers to educate patients about the importance of temporarily discontinuing metformin and other potentially nephrotoxic medications in the settings of acute illness and extracellular volume contraction.\n\nAcknowledgments\nFunding for this case report was provided by unrestricted research funds at the Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa.\n\nConsent\nPatient written informed consent for the writing and publication of this case report was obtained on May 6, 2018.\n\nConflicts of Interest\nThe authors declare that there are no conflicts of interest regarding the publication of this article.\n\nTable 1 Initial laboratory results [normal values in parentheses].\n\nHb [g/L]\t130 [140-180]\t\nWBC [x109/L]\t\n17.3 [4.0 – 11.0]\t\nPlatelets [x109/L]\t286 [150 – 400]\t\npH [Venous]\t\n6.85 [7.33 – 7.46]\t\npCO2 [Venous] [mmHg]\t\n19.3 [40.0 – 50.0]\t\nHCO3− [Venous] [mmol/L]\t\n3.4 [22.0 – 27.0]\t\nNa+ [mmol/L]\t145 [135 – 145]\t\nK+ [mmol/L]\t\n8.3 [3.5 – 5.1]\t\nCl− [mmol/L]\t101 [100 – 110]\t\nAnion Gap [mmol/L]\t\n40.6 [5 – 12]\t\nAlbumin [g/L]\t28 [34 – 46]\t\nGlucose [mmol/L]\t\n1.4 [4.0 – 11.0]\t\nCreatinine [µmol/L]\t\n967 [58 – 110]\t\nUrea [mmol/L]\t\n31.2 [2.5 – 7.0]\t\nPO4−2 [mmol/L]\t\n3.68 [0.80 – 1.45]\t\nCa2+ [mmol/L]\t2.43 [2.20 – 2.52]\t\nMg2+ [mmol/L]\t0.84 [0.65 – 0.90]\t\nBilirubin [µmol/L]\t6 [3 – 17]\t\nALT [Alanine Aminotransferase] [U/L]\t22 [20 - 70]\t\nAST [Aspartate Aminotransferase] [U/L]\t32 [15 – 45]\t\nALP [Alkaline Phosphatase] [U/L]\t44 [40 – 115]\t\naPTT [Activated Partial Thromboplastin Time] [s]\t\n45 [22-30]\t\nPT [Prothrombin Time] [s]\t\n21.3 [10.1 – 14.6]\t\nINR [International Normalized Ratio]\t\n1.9 [0.9 – 1.2]\t\nLipase [U/L]\t351 [45 – 300]\t\nLactate [mmol/L]\t\n14.9 [0.5 – 2.2]\t\nCK [Creatinine Kinase] [U/L]\t65 [30 – 200]\t\nTroponin I [ng/L]\t32 [<30]\t\nTable 2 Arterial blood gas, serum lactate level, and serum electrolyte panel.\n\npH [Arterial]\t\n<6.75 [7.38 – 7.46]\t\npCO2 [Arterial] [mmHg]\t\n<12 [32 – 45]\t\nHCO3− [Arterial] [mmol/L]\t\n“No result” [22 - 27]\t\nLactate [mmol/L]\t\n16.0 [0.5 – 2.5]\t\nNa+ [mmol/L]\t142 [136 – 145]\t\nK+ [mmol/L]\t\n5.6 [3.5 – 5.1]\t\nCl− [mmol/L]\t107 [98 – 107]\t\nAnion Gap [mmol/L]\t\n31 [5 – 12]\t\nGlucose [mmol/L]\t13.7 [4.0 – 11.0]\t\nCreatinine [µmol/L]\t\n794 [49 – 93]\t\nUrea [mmol/L]\t\n33.0 [2.1 – 8.0]\n==== Refs\n1 Foretz M. Guigas B. Bertrand L. Pollak M. Viollet B. Metformin: from mechanisms of action to therapies Cell Metabolism 2014 20 6 953 966 10.1016/j.cmet.2014.09.018 25456737 \n2 Rena G. Hardie D. G. Pearson E. R. The mechanisms of action of metformin Diabetologia 2017 60 9 1577 1585 2-s2.0-85026840123 10.1007/s00125-017-4342-z 28776086 \n3 Madiraju A. K. Erion D. M. Rahimi Y. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase Nature 2014 510 7506 542 546 10.1038/nature13270 2-s2.0-84901558868 24847880 \n4 An H. He L. Current understanding of metformin effect on the control of hyperglycemia in diabetes Journal of Endocrinology 2016 228 R97 R106 10.1530/joe-15-0447 26743209 \n5 Lipska K. J. Bailey C. J. Inzucchi S. E. Use of metformin in the setting of mild-to-moderate renal insufficiency Diabetes Care 2011 34 6 1431 1437 2-s2.0-80051978747 10.2337/dc10-2361 21617112 \n6 McCreight L. J. Bailey C. J. Pearson E. R. Metformin and the gastrointestinal tract Diabetologia 2016 59 3 426 435 2-s2.0-84957440490 10.1007/s00125-015-3844-9 26780750 \n7 Salpeter S. R. Greyber E. Pasternak G. A. Salpeter E. E. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus Cochrane Database of Systematic Reviews 2006, https://www-cochranelibrary-com.proxy.bib.uottawa.ca/cdsr/doi/10.1002/14651858.CD002967.pub2/abstract \n8 Bailey C. J. Wilcock C. Day C. Effect of metformin on glucose metabolism in the splanchnic bed British Journal of Pharmacology 1992 105 4 1009 1013 2-s2.0-0026606805 10.1111/j.1476-5381.1992.tb09093.x 1504710 \n9 Sirtori C. R. Pasik C. Re-evaluation of a biguanide, metformin: mechanism of action and tolerability Pharmacological Research 1994 30 3 187 228 2-s2.0-0028139101 10.1016/1043-6618(94)80104-5 7862618 \n10 Lalau J.-D. Race J.-M. Lactic acidosis in metformin-treated patients. Prognostic value of arterial lactate levels and plasma metformin concentrations Drug Safety 1999 20 4 377 384 2-s2.0-0032917623 10.2165/00002018-199920040-00006 10230584 \n11 Seidowsky A. Nseir S. Houdret N. Fourrier F. Metformin-associated lactic acidosis: A prognostic and therapeutic study Critical Care Medicine 2009 37 7 2191 2196 2-s2.0-67649801964 10.1097/CCM.0b013e3181a02490 19487945 \n12 Edge J. A. Roy Y. Bergomi A. Conscious level in children with diabetic ketoacidosis is related to severity of acidosis and not to blood glucose concentration Pediatr Diabetes 2006 7 1 11 5 \n13 Ahmad S. Beckett M. Recovery from ph 6.38: Lactic acidosis complicated by hypothermia Emergency Medicine Journal 2002 19 2 169 171 2-s2.0-0036203620 10.1136/emj.19.2.169 11904273 \n14 Mustafa E. Lai L. Lien Y.-H. H. Rapid recovery from acute kidney injury in a patient with metformin-associated lactic acidosis and hypothermia American Journal of Medicine 2012 125 2 e1 e2 2-s2.0-84856086173 10.1016/j.amjmed.2011.06.016 22269627 \n15 Zibar L. Zibar K. Hemodialysis-refractory metformin-associated lactate acidosis with hypoglycemia, hypothermia, and bradycardia in a diabetic patient with belated diagnosis and chronic kidney disease International Journal of Clinical Pharmacology and Therapeutics 2017 55 4 348 351 2-s2.0-85017318639 10.5414/CP202686 28139970 \n16 Strauch B. S. Felig P. Baxter J. D. Schimpff S. C. Hypothermia in Hypoglycemia Journal of the American Medical Association 1969 210 2 345 346 2-s2.0-1842678553 10.1001/jama.1969.03160280085028 \n17 Engström M. Schött U. Romner B. Reinstrup P. Acidosis impairs the coagulation: A thromboelastographic study Journal of Trauma - Injury Infection and Critical Care 2006 61 3 624 628 2-s2.0-33748747205 10.1097/01.ta.0000226739.30655.75 16966998 \n18 Martini W. Z. Holcomb J. B. Acidosis and coagulopathy: The differential effects on fibrinogen synthesis and breakdown in pigs Annals of Surgery 2007 246 5 831 835 2-s2.0-35648942694 10.1097/SLA.0b013e3180cc2e94 17968176 \n19 Martini W. Z. Pusateri A. E. Uscilowicz J. M. Independent contributions of hypothermia and acidosis to coagulopathy in swine Journal of Trauma - Injury Infection and Critical Care 2005 58 5 1002 1010 2-s2.0-20144368558 10.1097/01.TA.0000156246.53383.9F 15920416 \n20 Martini W. Z. Coagulopathy by hypothermia and acidosis: mechanisms of thrombin generation and fibrinogen availability The Journal of Trauma and Acute Care Surgery 2009 67 1 202 209 10.1097/ta.0b013e3181a602a7 2-s2.0-67651184083 \n21 ABL800 FLEX blood gas analyzer - Radiometer 2018, https://www.radiometeramerica.com/en-us/products/blood-gas-testing/abl800-flex-blood-gas-analyzer?ref=rmed&_ga=2.108419777.271826494.1535327976-1954082072.1535327976&ref=rmed&_ga=2.108419777.271826494.1535327976-1954082072.1535327976 \n22 Saleem M. Dimeski G. Bourne L. Coates P. Artifactually elevated serum bicarbonate results caused by elevated serum lactate dehydrogenase concentrations Annals of Clinical Biochemistry 2013 50 4 365 367 2-s2.0-84890167365 10.1177/0004563212474562 23605134\n\n", "fulltext_license": "CC BY", "issn_linking": "2090-665X", "issue": "2018()", "journal": "Case reports in nephrology", "keywords": null, "medline_ta": "Case Rep Nephrol", "mesh_terms": null, "nlm_unique_id": "101598418", "other_id": null, "pages": "4696182", "pmc": null, "pmid": "30581638", "pubdate": "2018", "publication_types": "D002363:Case Reports", "references": "10230584;11904273;1504710;15920416;16489969;16966998;17968176;19487945;19590336;20091535;21617112;22269627;23605134;24847880;25456737;26743209;26780750;28139970;28776086;7862618", "title": "A Unique Case of Metformin-Associated Lactic Acidosis.", "title_normalized": "a unique case of metformin associated lactic acidosis" }	[ { "companynumb": "US-AUROBINDO-AUR-APL-2021-001474", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LIRAGLUTIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.2 MILLIGRAM, ONCE A DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.2", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LIRAGLUTIDE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "77095", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 GRAM, TWO TIMES A DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Enterococcal infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Myxoedema coma", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Aerococcus urinae infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urosepsis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "AHUJA AC.. 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A UNIQUE CASE OF METFORMIN?ASSOCIATED LACTIC ACIDOSIS. 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A UNIQUE CASE OF METFORMIN?ASSOCIATED LACTIC ACIDOSIS. J?AM?SOC?NEPHROL 2019?30:157 ABSTR. 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JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY. 2019?30:157", "literaturereference_normalized": "a unique case of metformin associated lactic acidosis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210118", "receivedate": "20210118", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18752930, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210419" }, { "companynumb": "CA-INDICUS PHARMA-000568", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MELOXICAM" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "7.5 MG P.O. 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DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "BENIGN PROSTATIC HYPERPLASIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCHLOROTHIAZIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RAMIPRIL" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG P.O. DAILY,", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RAMIPRIL." }, { "actiondrug": null, "activesubstance": null, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG P.O. BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "DYSLIPIDAEMIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SITAGLIPTIN/SITAGLIPTIN PHOSPHATE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "079148", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1000 MG P.O. BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" }, { "actiondrug": null, "activesubstance": null, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.4 MG P.O. DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "BENIGN PROSTATIC HYPERPLASIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TAMSULOSIN/TAMSULOSIN HYDROCHLORIDE" } ], "patientagegroup": "6", "patientonsetage": "82", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "GERSHKOVICH B, MCCUDDEN C, BURNS KD. A UNIQUE CASE OF METFORMIN-ASSOCIATED LACTIC ACIDOSIS. CASE REP NEPHROL. 2018 NOV 15?2018:4696182.", "literaturereference_normalized": "a unique case of metformin associated lactic acidosis", "qualification": "3", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20190108", "receivedate": "20190108", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15799531, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "US-MYLANLABS-2021M1001775", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LIRAGLUTIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.2 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "DIABETES MELLITUS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.2", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LIRAGLUTIDE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "075973", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 GRAM, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "DIABETES MELLITUS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypoxia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypothermia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Mental status changes", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Dysarthria", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "AHUJA AC. A UNIQUE CASE OF METFORMIN?ASSOCIATED LACTIC ACIDOSIS. J?AM?SOC?NEPHROL 2019?30:157 ABSTR. TH?PO176.", "literaturereference_normalized": "a unique case of metformin associated lactic acidosis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210119", "receivedate": "20210119", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18755801, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210419" }, { "companynumb": "US-GLENMARK PHARMACEUTICALS-2021GMK051625", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "078170", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 GRAM, BID (EVERY 12 HOURS)", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LIRAGLUTIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.2 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.2", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LIRAGLUTIDE" } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Enterococcal infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urosepsis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Aerococcus urinae infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Myxoedema coma", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "AHUJA AC.. A UNIQUE CASE OF METFORMIN?ASSOCIATED LACTIC ACIDOSIS. JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY. 2019?30:157", "literaturereference_normalized": "a unique case of metformin associated lactic acidosis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210122", "receivedate": "20210122", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18771213, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20210419" } ]
{ "abstract": "Jaw-opening oromandibular dystonia (O-OMD) is a clinical subtype of OMD, commonly resistant to treatment. Here, we report a distinct case of tardive O-OMD with a characteristic sensory trick, successfully treated with high-dose botulinum toxin (BTX) injection. A 34-year-old male patient presented with involuntary jaw opening, tongue protrusion, dysarthria, and mild cervical dystonia. The patient reported improved abilities to talk and close his mouth after putting something, like a cigarette, between his teeth. After an unsuccessful treatment with anticholinergic medications, the patient received electromyography-guided BTX injection to the lateral pterygoids (through an extraoral approach), sternocleidomastoids, trapezius, tongue, and platysma muscles. Following the injection, the patient reported marked improvements in his ability to talk and close his mouth without using his sensory trick. One month later, we detected a 58.2% improvement in the Abnormal Involuntary Movement Scale score. Therefore, high-dose BTX injection may be an effective alternative in refractory O-OMD.", "affiliations": "Department of Neurology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.;Medical Research Center, Faculty of Medicine, Ain Shams University, Cairo, Egypt.;Internal Medicine Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt.;Department of Psychiatry, Faculty of Medicine, Ain Shams University, Cairo, Egypt.;Department of Neurology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.", "authors": "Shalash\|Ali S\|AS\|;Abushouk\|Abdelrahman Ibrahim\|AI\|;Elsherbeny\|Mohammed Yasser\|MY\|;Elrassas\|Hanan\|H\|;Kamel\|Taha\|T\|", "chemical_list": "D009465:Neuromuscular Agents; D001905:Botulinum Toxins", "country": "India", "delete": false, "doi": "10.4103/0028-3886.266235", "fulltext": null, "fulltext_license": null, "issn_linking": "0028-3886", "issue": "67(4)", "journal": "Neurology India", "keywords": "Botulinum toxin; case report; oromandibular dystonia; sensory trick", "medline_ta": "Neurol India", "mesh_terms": "D000328:Adult; D001905:Botulinum Toxins; D020821:Dystonic Disorders; D005152:Facial Muscles; D006801:Humans; D008297:Male; D009059:Mouth Diseases; D009465:Neuromuscular Agents; D014103:Torticollis", "nlm_unique_id": "0042005", "other_id": null, "pages": "1110-1111", "pmc": null, "pmid": "31512647", "pubdate": "2019", "publication_types": "D002363:Case Reports", "references": null, "title": "Refractory Open Jaw Oromandibular Tardive Dystonia with a Sensory Trick, Treated with Botulinum Toxin: A Case Report.", "title_normalized": "refractory open jaw oromandibular tardive dystonia with a sensory trick treated with botulinum toxin a case report" }	[ { "companynumb": "EG-SUN PHARMACEUTICAL INDUSTRIES LTD-2019RR-228855", "fulfillexpeditecriteria": "1", "occurcountry": "EG", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RISPERIDONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "078464", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 MILLIGRAM, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "SUBSTANCE-INDUCED PSYCHOTIC DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RISPERIDONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MIRTAZAPINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MILLIGRAM, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "SUBSTANCE-INDUCED PSYCHOTIC DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MIRTAZAPINE." } ], "patientagegroup": null, "patientonsetage": "34", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Oromandibular dystonia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SHALASH A, ABUSHOUK A, ELSHERBENY M, ELRASSAS H, KAMEL T. REFRACTORY OPEN JAW OROMANDIBULAR TARDIVE DYSTONIA WITH A SENSORY TRICK, TREATED WITH BOTULINUM TOXIN: A CASE REPORT. NEUROL INDIA. 2019?67(4):1110-1111", "literaturereference_normalized": "refractory open jaw oromandibular tardive dystonia with a sensory trick treated with botulinum toxin a case report", "qualification": "3", "reportercountry": "EG" }, "primarysourcecountry": "EG", "receiptdate": "20191126", "receivedate": "20191126", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17073474, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" } ]
{ "abstract": "Kaposi sarcoma (KS) is the most common tumor in patients with human immunodeficiency virus (HIV), and its frequency is increasing after organ transplantation in HIV-negative patients. A 28-year-old woman had preemptive kidney transplantation from her 48-year-old mother. In the postoperative ninth month, an exophytic mass was found in the upper medial conjunctiva of the right eye. The lesion was excised under local anesthesia, and cryotherapy was applied to the surgical area. The biopsy result was reported as KS. Treatment with tacrolimus was switched to everolimus (EVO), but EVO was discontinued because of pneumonitis. The patient was followed without any recurrences after the excision of the conjunctival lesion. No local or systemic recurrence was observed in the 14th month after surgical excision and local cryotherapy. Local treatment and the reduction of immunosuppressive therapy may be effective in the treatment of conjunctival KS.", "affiliations": "Department of Nephrology, University of Health Sciences, Gazi Yasargil Training and Research Hospital, Diyarbakir, Turkey. Electronic address: [email protected].;Department of Ophthalmology, University of Health Sciences, Gazi Yasargil Training and Research Hospital, Diyarbakir, Turkey.", "authors": "Gunay\|Emrah\|E\|;Oncul\|Hasan\|H\|", "chemical_list": "D007166:Immunosuppressive Agents; D000068338:Everolimus; D016559:Tacrolimus", "country": "United States", "delete": false, "doi": "10.1016/j.transproceed.2019.12.005", "fulltext": null, "fulltext_license": null, "issn_linking": "0041-1345", "issue": "52(2)", "journal": "Transplantation proceedings", "keywords": null, "medline_ta": "Transplant Proc", "mesh_terms": "D000328:Adult; D003230:Conjunctival Neoplasms; D000068338:Everolimus; D005260:Female; D015658:HIV Infections; D006801:Humans; D016867:Immunocompromised Host; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D012514:Sarcoma, Kaposi; D016559:Tacrolimus", "nlm_unique_id": "0243532", "other_id": null, "pages": "622-624", "pmc": null, "pmid": "32035672", "pubdate": "2020-03", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Successful Treatment of Conjunctival Kaposi Sarcoma in a Human Immunodeficiency Virus-Negative Kidney Transplant Recipient: A Case Report.", "title_normalized": "successful treatment of conjunctival kaposi sarcoma in a human immunodeficiency virus negative kidney transplant recipient a case report" }	[ { "companynumb": "NVSC2020TR040417", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", 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"drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "EVEROLIMUS" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "022334", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": 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SUCCESSFUL TREATMENT OF CONJUNCTIVAL KAPOSI SARCOMA IN A HUMAN IMMUNODEFICIENCY VIRUS-NEGATIVE KIDNEY TRANSPLANT RECIPIENT: A CASE REPORT. TRANSPLANTATION PROCEEDINGS. 2020?1-3", "literaturereference_normalized": "successful treatment of conjunctival kaposi sarcoma in a human immunodeficiency virus negative kidney transplant recipient a case report", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20200214", "receivedate": "20200214", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17420514, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200409" }, { "companynumb": "TR-BAUSCH-BL-2020-006178", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "40070", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLIC ACID." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "REDUCED DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLIC ACID." } ], "patientagegroup": null, "patientonsetage": "28", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Conjunctival neoplasm", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Kaposi^s sarcoma", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "GUNAY E, ONCUL H. SUCCESSFUL TREATMENT OF CONJUNCTIVAL KAPOSI SARCOMA IN A HUMAN IMMUNODEFICIENCY VIRUS?NEGATIVE KIDNEY TRANSPLANT RECIPIENT: A CASE REPORT.. TRANSPLANTATION PROCEEDINGS. 2020?1?3. DOI:HTTPS://DOI.ORG/10.1016/J.TRANSPROCEED.2019.12.005", "literaturereference_normalized": "successful treatment of conjunctival kaposi sarcoma in a human immunodeficiency virus negative kidney transplant recipient a case report", "qualification": "1", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20200826", "receivedate": "20200310", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17523738, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201102" }, { "companynumb": "TR-TEVA-2020-TR-1224726", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "65457", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLIC ACID." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "080354", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "EVEROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "210050", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EVEROLIMUS." } ], "patientagegroup": null, "patientonsetage": "28", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Respiratory distress", "reactionmeddraversionpt": "23.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Kaposi^s sarcoma", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pneumonitis", "reactionmeddraversionpt": "23.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "GUNAY E, ONCUL H. SUCCESSFUL TREATMENT OF CONJUNCTIVAL KAPOSI SARCOMA IN A HUMAN IMMUNODEFICIENCY VIRUS-NEGATIVE KIDNEY TRANSPLANT RECIPIENT: A CASE REPORT. TRANSPLANT-PROC 2020?52(2):622-624.", "literaturereference_normalized": "successful treatment of conjunctival kaposi sarcoma in a human immunodeficiency virus negative kidney transplant recipient a case report", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20200421", "receivedate": "20200421", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17687476, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200714" }, { "companynumb": "TR-PBT-000029", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "090802", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": "5", "patientonsetage": "28", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Kaposi^s sarcoma", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "GUNAY E, ONCUL H. SUCCESSFUL TREATMENT OF CONJUNCTIVAL KAPOSI SARCOMA IN A HUMAN IMMUNODEFICIENCY VIRUS-NEGATIVE KIDNEY TRANSPLANT RECIPIENT: A CASE REPORT. TRANSPLANT PROC. 2020 FEB 5. PII: S0041-1345(19)31579-9. DOI: 10.1016/J.TRANSPROCEED.2019.12.005", "literaturereference_normalized": "successful treatment of conjunctival kaposi sarcoma in a human immunodeficiency virus negative kidney transplant recipient a case report", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20200225", "receivedate": "20200225", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17455040, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "TR-ACCORD-174028", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "091195", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "202555", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL/MYCOPHENOLATE SODIUM/MYCOPHENOLIC ACID" } ], "patientagegroup": null, "patientonsetage": "28", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Conjunctival neoplasm", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Kaposi^s sarcoma", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "GUNAY E, ONCUL H. SUCCESSFUL TREATMENT OF CONJUNCTIVAL KAPOSI SARCOMA IN A HUMAN IMMUNODEFICIENCY VIRUS-NEGATIVE KIDNEY TRANSPLANT RECIPIENT: A CASE REPORT. TRANSPLANTATION PROCEEDINGS. 2020.", "literaturereference_normalized": "successful treatment of conjunctival kaposi sarcoma in a human immunodeficiency virus negative kidney transplant recipient a case report", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20200228", "receivedate": "20200228", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17472053, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20200409" } ]
{ "abstract": "BACKGROUND\nRectus sheath haematomas associated with anticoagulation are often self limiting. When large, however, they can even extend into the pelvis and cause compression of adjacent organs such as the bladder. A combined endovascular and surgical approach can decrease the operative exposure necessary to treat this occurrence.\n\n\nMETHODS\nA 42 year old morbidly obese African American female on warfarin treatment for pulmonary embolism presented outside the hospital with pneumonia. During her hospitalisation, she developed a spontaneous right rectus abdominis haematoma below the level of the umbilicus with active bleeding in the extraperitoneal space causing mass compression of the bladder. She developed acute renal failure and became anuric. Following endovascular embolisation of the inferior epigastric artery, surgical exploration was successfully performed to remove the haematoma and relieve the urinary obstruction. Diuresis resumed and renal function normalised without any further evidence of bleeding.\n\n\nCONCLUSIONS\nA large rectus sheath haematoma that extends into the bladder causing renal obstruction can be treated by endovascular embolisation and surgical exploration to limit operative risks and exposure in morbidly obese patients.", "affiliations": "Division of General, Minimally Invasive, and Robotic Surgery, University of Illinois at Chicago, Chicago, IL, USA.;Department of General Surgery Residency Program, University of Illinois at Chicago, Chicago, IL, USA.;Division of Interventional Radiology, University of Illinois at Chicago, Chicago, IL, USA.", "authors": "Gangemi\|A\|A\|;Mashbari\|H N\|HN\|;Bui\|J T\|JT\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1016/j.ejvssr.2017.02.001", "fulltext": "\n==== Front\nEJVES Short RepEJVES Short RepEJVES Short Reports2405-6553Elsevier S2405-6553(17)30003-810.1016/j.ejvssr.2017.02.001Case ReportObstructive Uropathy because of a Large Rectus Sheath Haematoma: A Case Report of Combined Interventional Radiology and Surgical Approach Gangemi A. [email protected]∗Mashbari H.N. bBui J.T. ca Division of General, Minimally Invasive, and Robotic Surgery, University of Illinois at Chicago, Chicago, IL, USAb Department of General Surgery Residency Program, University of Illinois at Chicago, Chicago, IL, USAc Division of Interventional Radiology, University of Illinois at Chicago, Chicago, IL, USA∗ Corresponding author. Division of General, Minimally Invasive, and Robotic Surgery, University of Illinois at Chicago, 840 S. Wood Street, Suite 435E, Chicago, IL 60612, USA.Division of General, Minimally Invasive, and Robotic SurgeryUniversity of Illinois at Chicago840 S. Wood StreetSuite 435EChicagoIL60612USA [email protected] 3 2017 2017 17 3 2017 34 24 27 25 9 2016 20 2 2017 22 2 2017 © 2017 The Authors2017This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Introduction\nRectus sheath haematomas associated with anticoagulation are often self limiting. When large, however, they can even extend into the pelvis and cause compression of adjacent organs such as the bladder. A combined endovascular and surgical approach can decrease the operative exposure necessary to treat this occurrence.\n\nReport\nA 42 year old morbidly obese African American female on warfarin treatment for pulmonary embolism presented outside the hospital with pneumonia. During her hospitalisation, she developed a spontaneous right rectus abdominis haematoma below the level of the umbilicus with active bleeding in the extraperitoneal space causing mass compression of the bladder. She developed acute renal failure and became anuric. Following endovascular embolisation of the inferior epigastric artery, surgical exploration was successfully performed to remove the haematoma and relieve the urinary obstruction. Diuresis resumed and renal function normalised without any further evidence of bleeding.\n\nDiscussion\nA large rectus sheath haematoma that extends into the bladder causing renal obstruction can be treated by endovascular embolisation and surgical exploration to limit operative risks and exposure in morbidly obese patients.\n\nHighlights\n• Rectus heath haematoma (RSH) is uncommon and usually arises from disruption of a branch of the inferior epigastric artery (IEA).\n\n• Obstructive uropathy leading to acute post-renal failure can be a rare presentation.\n\n• Embolisation of the IEA and staged surgical evacuation of the large compressive RSH may be feasible and effective.\n\n\n\nKeywords\nRectus sheath haematomaAcute renal failureObstructive uropathyAnticoagulant therapy\n==== Body\nIntroduction\nRectus sheath haematomas (RSHs) are uncommon and can arise from disruption of a branch of the inferior epigastric artery at its insertion into the rectus abdominis muscle combined with an inability to tamponade the bleeding, especially below the arcuate line. RSHs have been found to be associated with severe bouts of coughing, anticoagulation therapy, subcutaneous abdominal injection of insulin, pregnancy, and connective tissue disorders. Pain and anemia are the most common manifestations. Most RSHs are self limiting and the majority does not cause hypovolemic shock requiring emergency medical or surgical intervention.1 Herein is reported a rare rectus sheath haematoma complicated by compressive obstructive uropathy leading to acute post-renal failure that was successfully treated by a combined endovascular and surgical approach.\n\nReport\nA 42 year old African American female with past medical history significant for morbid obesity (body mass index 63.8 kg/m2), hypertension, systemic lupus erythematosus (SLE), pulmonary emboli on warfarin, and recent diagnosis of pneumonia, presented to an outside hospital with recurrent shortness of breath, severe cough, and new onset diarrhea. On presentation, the patient a had fever (39.4○C) and was tachycardic (106 beats per minute). She had mildly elevated serum creatinine (sCrea; 1.32 mg/dl) (baseline 0.8–0.9 mg/dl), normal haemoglobin (Hb; 10.2 mg/dl), and a normal international normalised ratio (INR; 1.0). Sputum culture revealed influenza A virus subtype H1N1, and stool culture was positive for Clostridium difficile attributable to her recent antibiotic use for the pneumonia. Her influenza infection was treated with oseltamivir and her C. difficile with vancomycin/cefepime. On her first hospital day, the patient began complaining of abdominal pain. CT abdomen/pelvis with contrast showed right rectus abdominis haematoma below the level of the umbilicus with active arterial bleeding in the extraperitoneal pelvis causing mass compression (Figure 1, Figure 2, Figure 3). On the following day, the Hb level was on a downward trend, from 10.2 to 7.7 mg/dl. Two units of fresh frozen plasma (FFP) were given, two units of packed red blood cells were ordered, and the patient was transferred to the tertiary care medical centre. She was admitted to the intensive care unit and found to be anuric, tachycardic, and hypotensive but responsive to intravenous fluid resuscitation (heart rate ranging between 90 and 100 per minutes and systolic blood pressure ranging between 90 and 120 mm Hg with the mean arterial pressure (MAP) > 65 mm Hg). Renal ultrasound showed right hydronephrosis (Fig. 3). Repeat laboratory tests upon transfer showed acute renal failure (sCrea 5.56 mg/dl) and the Hb level going down further from 7.7 to 7.2 mg/dl. The serum vancomycin level was 8.1 μg/ml (normal low 4 μg/ml; normal high 40 μg/ml). Anti-double stranded DNA antibody (anti-dsDNA) IgG and anti-nuclear antibodies (ANAs) for SLE in the serum were not detected. A Foley catheter was placed, and critically elevated bladder pressures (∼50 mmHg) were measured that raised a concern of abdominal compartment syndrome. An emergency surgical consultation was requested. Abdominal examination showed significant tenderness, notably in the suprapubic, right lower, and right upper quadrant over a palpable haematoma. The patient had no urine output for almost 20 hours, with worsening and severe suprapubic pressure and pain. The decision was made to take the patient to the interventional radiology (IR) suite for coil embolisation of the inferior epigastric artery first followed by transfer to the operating room (OR) for evacuation of the compressive right pelvic haematoma.Figure 1 Active arterial haemorrhage into the rectus sheath. Axial computed tomography of the pelvis with contrast shows active arterial haemorrhage into right rectus sheath (white arrowhead) and large haematoma with layering of blood in the pelvis (black arrow).\n\nFigure 1Figure 2 Large rectus sheath haematoma extending into pelvis and compressing the bladder. Sagittal computed tomography abdomen and pelvis shows the haematoma extending into the extraperitoneal pelvis causing displacement and obscuration of the bladder due to the size of the haematoma. Notice the active arterial haemorrhage (white arrowhead).\n\nFigure 2Figure 3 Hydronephrosis. Renal ultrasound shows right hydronephrosis.\n\nFigure 3\n\nIn IR, embolisation of the right inferior epigastric artery was performed. Real time ultrasound guidance was used to access the contralateral femoral artery with placement of a 5F vascular sheath; a reverse curve catheter SOS1 was used to select the right common iliac artery under fluoroscopy. Over a guidewire, this catheter was exchanged for a 5F angled glide catheter that was positioned at the right external iliac artery. An angiogram showed diffusely small arteries related to the hypovolemic state. Then via a coaxial renegade high flow microcatheter and guidewire, the right inferior epigastric artery (RIEA) was selected; the angiogram showed no active arterial bleeding but compressive effects of the haematoma. Embolisation of the RIEA was performed with 0.018 inch tornado microcoils (Fig. 4). Additionally, given the extent of haematoma and the plan for immediate surgical exploration, the right circumflex iliac artery was selected and prophylactic embolisation was performed. The patient was transferred to the OR.Figure 4 Embolisation of right inferior epigastric artery. Coaxial microcatheter into the right inferior epigastric artery shows proximal embolisation with several microcoils.\n\nFigure 4\n\nA lower midline skin incision was performed and a flap was dissected on the right side to separate the skin and subcutaneous layers from the fascial layer. The haematoma was confirmed to be a rectus sheath haematoma by palpation and indirect visualisation through the rectus sheath (Fig. 5). A longitudinal incision over the rectus sheath fascia to the right of the margin of the rectus muscle was performed. The large haematoma was found to extend for at least 25 cm from lateral to medial and from cephalad to caudal, approaching the Retzius space and sitting on top of the bladder and to its right side. The haematoma was then scooped out with a fingers and hand manoeuvre. haemostasis of the oozing surfaces of the surgical field was successfully achieved.Figure 5 Intra-operative evacuation of haematoma. Intra-operative picture showing rectus sheath haematoma visible through the rectus sheath.\n\nFigure 5\n\nThe urinary bladder wall could be visualised through the peritoneal reflection and seemed quite ecchymotic but overall viable. The anterior rectus sheath was re-approximated with interrupted PDS0 sutures. The skin layer was re-approximated. Intra-operatively, clots were noted inside the Foley catheter.\n\nOn the same post-operative day (Day 0), she underwent haemodialysis with ultrafiltration of 500 ml. Her urinary output started to improve immediately and reached 2.6 l/24 hours by the second post-operative day. The sCrea level normalised to 0.99 mg/dl, and post-operative renal ultrasound showed resolution of hydronephrosis (Fig. 6). The patient was restarted on warfarin without any further bleeding. The patient was discharged to a long-term acute care facility and had uneventful clinic follow-up 2 weeks later after having fully recovered.Figure 6 Resolution of hydronephrosis. Post-operative right renal ultrasound shows interval resolution of hydronephrosis.\n\nFigure 6\n\nDiscussion\nThis case supports prior evidence that rectus sheath haematomas developing below the arcuate line tend to bleed more and dissect more extensively because of the lack of tamponade exercised by the posterior sheath and the tendinous inscriptions that are indeed present above the arcuate line. Obstructive uropathy secondary to large RSHs is very rare and usually presents in the setting of hypovolemic shock.2, 3, 4\n\nThe management of RSHs including large ones has shifted over the past few years from an aggressive surgical approach5 to non-operative treatment that is based on withdrawal of anticoagulants and immediate reversal of anticoagulation, with prothrombin complex concentrates being preferred over FFP administration.6 However, this patient developed acute post-renal failure with critically elevated bladder pressures, severe suprapubic pain that was not responsive to analgesics, and right hydronephrosis ipsilateral to the side of the injury. With the degree of renal failure, if left untreated the condition would have led inexorably to irreversible renal damage and possible chronic renal failure. A temporising treatment option could have been nephrostomy tube placement, but this would not have addressed the underlying cause of the obstructive uropathy from the pelvic haematoma. The increased intra-abdominal pressure, hypovolemia, co-existing medical condition (SLE), and the use of nephrotoxic drugs (vancomycin) might have contributed to the onset of acute renal failure although the patient's MAP and serum levels of vancomycin were within normal limits and anti-dsDNA and ANA for SLE were not detected. Furthermore, the critically elevated bladder pressure recorded prior to surgical exploration, the concomitant hydronephrosis on the same side as the RSH, and the prompt restarting of the urinary output post-operatively seem to support the idea that the mass compression of the bladder by this very large haematoma was the cause of the acute renal syndrome. This interpretation of the aetiology is also substantiated by the repeat renal US after surgery which showed resolution of hydronephrosis (Fig. 6).\n\nIt is not known if the chronic treatment with warfarin might have played a role in the aetiology of the RSH since the patient's INR was found to be within normal limits (1.0). Rather, it is believed that the aetiology of the RSH was probably traumatic because of the severe coughing the patient experienced for several days as a result of her pneumonia.\n\nEndovascular embolisation of the inferior epigastric artery has been successfully and effectively performed7 and may prevent further bleeding at the time of the surgical exploration to remove, and at least partially tamponade, the large haematoma.\n\nThis combined approach is of further value when considering that the surgical exploration might fail to find the bleeding source, obligating the surgeon to ligate the inferior epigastric artery at its origin from the femoral artery in close proximity to the inguinal ligament area. A long skin incision extending through the entire lower abdomen and reaching into the groin is potentially associated with suboptimal cosmetic outcome, greater intra-operative blood loss, and peri-operative pain and an overall longer recovery time. One potential disadvantage of the combined endovascular and surgical approach is represented by the unavailability of an endovascular specialist at a local level or lack of available staff after office hours and the need for close coordination with the surgical team so that the patient can be transferred from the endovascular suite to the OR for the staged surgical treatment. At this institution, IR is available 24/7 and works closely with the surgical team; therefore, this consideration did not represent a concern in this case.\n\nConclusion\nA combined approach based on embolisation of the inferior epigastric artery and staged surgical evacuation of a large compressive rectus sheath haematoma leading to acute post-renal failure is feasible and should be considered as an alternative to aggressive surgical intervention requiring ligation of the inferior epigastric artery at its origin. Further studies are needed to provide definitive evidence in favour of this innovative and effective approach that was carried out on this isolated case.\n\nConflict of Interest\nNone.\n\nFunding\nNone.\n==== Refs\nReferences\n1 Hatjipetrou A. Anyfantakis D. Kastanakis M. Rectus sheath hematoma: a review of the literature Int J Surg 13 2015 267 25529279 \n2 Toyonaga J. Tsuruya K. Masutani K. Maeda H. Nakamura K. Taniguchi M. Hemorrhagic shock and obstructive uropathy due to a large rectus sheath hematoma in a patient on anticoagulant therapy Intern Med 48 24 2009 2119 2122 20009404 \n3 Dangle P.P. Patel M.B. Terán M. Chehval M.J. Obstructive uropathy secondary to rectus sheath hematoma W V Med J 109 2 2013 32 33 \n4 Masson J.C. Bollack C. Renaud R. Gandar R. Obstructive uropathy due to hematoma of the sheath of the rectus abdominis muscles J Urol Nephrol (Paris) 81 3 1975 246 249 125349 \n5 Jone T.W. Merendino K.A. The deep epigastric artery: rectus muscle syndrome Am J Surg 103 1962 159 169 14452343 \n6 Berna J.D. Zuazu I. Madrigal M. Garcia-Medina V. Fernandez C. Guirado F. Conservative treatment of large rectus sheath hematoma in patients undergoing anticoagulant therapy Abdom Imaging 25 2000 230 234 10823439 \n7 Magill S.T. del Prado G. Chiovaro J. Embolization of hemorrhaging rectus sheath hematoma J Gen Intern Med 29 2 2014 408 409 24002622\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2405-6553", "issue": "34()", "journal": "EJVES short reports", "keywords": "Acute renal failure; Anticoagulant therapy; Obstructive uropathy; Rectus sheath haematoma", "medline_ta": "EJVES Short Rep", "mesh_terms": null, "nlm_unique_id": "101695075", "other_id": null, "pages": "24-27", "pmc": null, "pmid": "28856329", "pubdate": "2017", "publication_types": "D002363:Case Reports", "references": "125349;24002622;20009404;23600103;14452343;10823439;25529279", "title": "Obstructive Uropathy because of a Large Rectus Sheath Haematoma: A Case Report of Combined Interventional Radiology and Surgical Approach.", "title_normalized": "obstructive uropathy because of a large rectus sheath haematoma a case report of combined interventional radiology and surgical approach" }	[ { "companynumb": "US-TEVA-764069USA", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "OSELTAMIVIR" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "INFLUENZA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OSELTAMIVIR" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "40145", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY EMBOLISM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" }, { "actiondrug": "5", "activesubstance": null, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CLOSTRIDIUM DIFFICILE INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VANCOMYCIN, CEFEPIME" } ], "patientagegroup": null, "patientonsetage": "42", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Abdominal wall haematoma", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Obstructive uropathy", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "GANGEMI A, MASHBARI HN, BUI JT. 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OBSTRUCTIVE UROPATHY BECAUSE OF A LARGE RECTUS SHEATH HAEMATOMA: A CASE REPORT OF COMBINED INTERVENTIONAL RADIOLOGY AND SURGICAL APPROACH. 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OBSTRUCTIVE UROPATHY BECAUSE OF A LARGE RECTUS SHEATH HAEMATOMA: A CASE REPORT OF COMBINED INTERVENTIONAL RADIOLOGY AND SURGICAL APPROACH. 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OBSTRUCTIVE UROPATHY BECAUSE OF A LARGE RECTUS SHEATH HAEMATOMA: A CASE REPORT OF COMBINED INTERVENTIONAL RADIOLOGY AND SURGICAL APPROACH. EJVES-SHORT-REP 2017;34:24-27.", "literaturereference_normalized": "obstructive uropathy because of a large rectus sheath haematoma a case report of combined interventional radiology and surgical approach", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170424", "receivedate": "20170424", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13473831, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" } ]
{ "abstract": "To perform meta-analyses of studies evaluating the risk of pre-eclampsia in high-risk insulin-resistant women taking metformin prior to, or during pregnancy.\n\n\n\nA search was conducted of the Medline, EMBASE, Web of Science and Scopus databases. Both randomized controlled trials and prospective observational cohort studies of metformin treatment vs. placebo/control or insulin either prior to or during pregnancy were selected. The main outcome measure was the incidence of pre-eclampsia in each treatment group.\n\n\n\nOverall, in five randomized controlled trials comparing metformin treatment (n = 611) with placebo/control (n = 609), no difference in the risk of pre-eclampsia was found [combined/pooled risk ratio (RR), 0.86 (95% CI 0.33-2.26); P = 0.76; I2 = 66%]. Meta-analysis of four cohort studies again showed no significant effect [RR, 1.21 (95% CI 0.56-2.61); P = 0.62; I2 = 30%]. A meta-analysis of eight randomized controlled trials comparing metformin (n = 838) with insulin (n = 836), however, showed a reduced risk of pre-eclampsia with metformin [RR, 0.68 (95% CI 0.48-0.95); P = 0.02; I2 = 0%]. No heterogeneity was present in the metformin vs. insulin analysis of randomized controlled trials, whereas high levels of heterogeneity were present in studies comparing metformin with placebo/control. Pre-eclampsia was a secondary outcome in most of the studies. The mean weight gain from time of enrolment to delivery was lower in the metformin group (P = 0.05, metformin vs. placebo; P = 0.004, metformin vs. insulin).\n\n\n\nIn studies randomizing pregnant women to glucose-lowering therapy, metformin was associated with lower gestational weight gain and a lower risk of pre-eclampsia compared with insulin.", "affiliations": "Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.;Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.;Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.;Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.;Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.;Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.;Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.", "authors": "Alqudah\|A\|A\|;McKinley\|M C\|MC\|;McNally\|R\|R\|;Graham\|U\|U\|;Watson\|C J\|CJ\|;Lyons\|T J\|TJ\|;McClements\|L\|L\|0000-0002-4911-1014", "chemical_list": "D007004:Hypoglycemic Agents; D007328:Insulin; D008687:Metformin", "country": "England", "delete": false, "doi": "10.1111/dme.13523", "fulltext": null, "fulltext_license": null, "issn_linking": "0742-3071", "issue": "35(2)", "journal": "Diabetic medicine : a journal of the British Diabetic Association", "keywords": null, "medline_ta": "Diabet Med", "mesh_terms": "D000328:Adult; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2; D016640:Diabetes, Gestational; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents; D007328:Insulin; D007333:Insulin Resistance; D008687:Metformin; D008875:Middle Aged; D064887:Observational Studies as Topic; D011225:Pre-Eclampsia; D011247:Pregnancy; D011254:Pregnancy in Diabetics; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors; D016896:Treatment Outcome; D015430:Weight Gain; D055815:Young Adult", "nlm_unique_id": "8500858", "other_id": null, "pages": "160-172", "pmc": null, "pmid": "29044702", "pubdate": "2018-02", "publication_types": "D016428:Journal Article; D017418:Meta-Analysis; D013485:Research Support, Non-U.S. Gov't; D000078182:Systematic Review", "references": null, "title": "Risk of pre-eclampsia in women taking metformin: a systematic review and meta-analysis.", "title_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis" }	[ { "companynumb": "PK-ALKEM LABORATORIES LIMITED-PK-ALKEM-2018-00893", "fulfillexpeditecriteria": "2", "occurcountry": "PK", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "INSULIN NOS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INSULIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, AND INCREASED UP TO 2500 MG IN 3 DIVIDED DOSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "PK", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735484, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "IT-ALKEM LABORATORIES LIMITED-IT-ALKEM-2018-00941", "fulfillexpeditecriteria": "2", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1700-3000 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERINSULINAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. 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RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "PK", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735494, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2018-00931", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2-2.55 G/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "POLYCYSTIC OVARIES", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETICMEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "US", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735544, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "PK-ALKEM LABORATORIES LIMITED-PK-ALKEM-2018-00894", "fulfillexpeditecriteria": "2", "occurcountry": "PK", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, AND INCREASED UP TO 2500 MG IN 3 DIVIDED DOSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "INSULIN NOS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INSULIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "PK", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735487, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "IT-ALKEM LABORATORIES LIMITED-IT-ALKEM-2018-00944", "fulfillexpeditecriteria": "2", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1700-3000 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERINSULINAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "IT", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735337, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "PK-ALKEM LABORATORIES LIMITED-PK-ALKEM-2018-00895", "fulfillexpeditecriteria": "1", "occurcountry": "PK", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, AND INCREASED UP TO 2500 MG IN 3 DIVIDED DOSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypoglycaemia neonatal", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "PK", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735488, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2018-00933", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2-2.55 G/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "POLYCYSTIC OVARIES", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETICMEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "US", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735548, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "GH-ALKEM LABORATORIES LIMITED-GH-ALKEM-2018-00979", "fulfillexpeditecriteria": "2", "occurcountry": "GH", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, INCREASED GRADUALLY OVER TWO (2) WEEKS, TO MEET GLYCEMIC TARGETS", "drugenddate": null, "drugenddateformat": null, "drugindication": "GESTATIONAL DIABETES", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GH", "receiptdate": "20181217", "receivedate": "20181217", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15729698, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "PK-ALKEM LABORATORIES LIMITED-PK-ALKEM-2018-00908", "fulfillexpeditecriteria": "2", "occurcountry": "PK", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, AND INCREASED UP TO 2500 MG IN 3 DIVIDED DOSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "PK", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735498, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "PK-ALKEM LABORATORIES LIMITED-PK-ALKEM-2018-00883", "fulfillexpeditecriteria": "2", "occurcountry": "PK", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, AND INCREASED UP TO 2500 MG IN 3 DIVIDED DOSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Gastrointestinal disorder", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "PK", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735478, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "IT-ALKEM LABORATORIES LIMITED-IT-ALKEM-2018-00943", "fulfillexpeditecriteria": "2", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1700-3000 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERINSULINAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "IT", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735326, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "PK-ALKEM LABORATORIES LIMITED-PK-ALKEM-2018-00906", "fulfillexpeditecriteria": "1", "occurcountry": "PK", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "INSULIN NOS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INSULIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, AND INCREASED UP TO 2500 MG IN 3 DIVIDED DOSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypoglycaemia neonatal", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "PK", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735486, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "PK-ALKEM LABORATORIES LIMITED-PK-ALKEM-2018-00905", "fulfillexpeditecriteria": "1", "occurcountry": "PK", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, AND INCREASED UP TO 2500 MG IN 3 DIVIDED DOSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "INSULIN NOS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INSULIN" } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypoglycaemia neonatal", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "PK", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735496, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "IT-ALKEM LABORATORIES LIMITED-IT-ALKEM-2018-00937", "fulfillexpeditecriteria": "2", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1700-3000 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERINSULINAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "IT", "receiptdate": "20181217", "receivedate": "20181217", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15729729, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "PK-ALKEM LABORATORIES LIMITED-PK-ALKEM-2018-00885", "fulfillexpeditecriteria": "2", "occurcountry": "PK", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, AND INCREASED UP TO 2500 MG IN 3 DIVIDED DOSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrointestinal disorder", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "PK", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735479, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2018-00935", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2-2.55 G/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "POLYCYSTIC OVARIES", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETICMEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "US", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735549, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "GH-ALKEM LABORATORIES LIMITED-GH-ALKEM-2018-00980", "fulfillexpeditecriteria": "2", "occurcountry": "GH", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, INCREASED GRADUALLY OVER TWO (2) WEEKS, TO MEET GLYCEMIC TARGETS", "drugenddate": null, "drugenddateformat": null, "drugindication": "GESTATIONAL DIABETES", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GH", "receiptdate": "20181217", "receivedate": "20181217", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15729699, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "PK-ALKEM LABORATORIES LIMITED-PK-ALKEM-2018-00897", "fulfillexpeditecriteria": "1", "occurcountry": "PK", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, AND INCREASED UP TO 2500 MG IN 3 DIVIDED DOSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypoglycaemia neonatal", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "PK", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735489, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "PK-ALKEM LABORATORIES LIMITED-PK-ALKEM-2018-00889", "fulfillexpeditecriteria": "2", "occurcountry": "PK", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, AND INCREASED UP TO 2500 MG IN 3 DIVIDED DOSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "INSULIN NOS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INSULIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "PK", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735482, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "PK-ALKEM LABORATORIES LIMITED-PK-ALKEM-2018-00904", "fulfillexpeditecriteria": "1", "occurcountry": "PK", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, AND INCREASED UP TO 2500 MG IN 3 DIVIDED DOSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "INSULIN NOS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INSULIN" } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypoglycaemia neonatal", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "PK", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735492, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "IT-ALKEM LABORATORIES LIMITED-IT-ALKEM-2018-00940", "fulfillexpeditecriteria": "2", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1700-3000 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERINSULINAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "IT", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735332, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "GH-ALKEM LABORATORIES LIMITED-GH-ALKEM-2018-00983", "fulfillexpeditecriteria": "2", "occurcountry": "GH", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "INSULIN NOS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GESTATIONAL DIABETES", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INSULIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "INSULIN NOS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INSULIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, INCREASED GRADUALLY OVER TWO (2) WEEKS, TO MEET GLYCEMIC TARGETS", "drugenddate": null, "drugenddateformat": null, "drugindication": "GESTATIONAL DIABETES", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GH", "receiptdate": "20181217", "receivedate": "20181217", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15729702, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "PK-ALKEM LABORATORIES LIMITED-PK-ALKEM-2018-00886", "fulfillexpeditecriteria": "2", "occurcountry": "PK", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, AND INCREASED UP TO 2500 MG IN 3 DIVIDED DOSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Gastrointestinal disorder", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "PK", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735480, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "GH-ALKEM LABORATORIES LIMITED-GH-ALKEM-2018-00981", "fulfillexpeditecriteria": "2", "occurcountry": "GH", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, INCREASED GRADUALLY OVER TWO (2) WEEKS, TO MEET GLYCEMIC TARGETS", "drugenddate": null, "drugenddateformat": null, "drugindication": "GESTATIONAL DIABETES", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GH", "receiptdate": "20181217", "receivedate": "20181217", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15729700, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "PK-ALKEM LABORATORIES LIMITED-PK-ALKEM-2018-00910", "fulfillexpeditecriteria": "2", "occurcountry": "PK", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, AND INCREASED UP TO 2500 MG IN 3 DIVIDED DOSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "PK", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735500, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "PK-ALKEM LABORATORIES LIMITED-PK-ALKEM-2018-00903", "fulfillexpeditecriteria": "1", "occurcountry": "PK", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "INSULIN NOS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INSULIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, AND INCREASED UP TO 2500 MG IN 3 DIVIDED DOSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypoglycaemia neonatal", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "PK", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735495, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "IT-ALKEM LABORATORIES LIMITED-IT-ALKEM-2018-00936", "fulfillexpeditecriteria": "2", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1700-3000 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERINSULINAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "IT", "receiptdate": "20181219", "receivedate": "20181219", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15738165, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "IT-ALKEM LABORATORIES LIMITED-IT-ALKEM-2018-00942", "fulfillexpeditecriteria": "2", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1700-3000 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERINSULINAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "IT", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735335, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2018-00932", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2-2.55 G/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "POLYCYSTIC OVARIES", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETICMEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "US", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735545, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "PK-ALKEM LABORATORIES LIMITED-PK-ALKEM-2018-00887", "fulfillexpeditecriteria": "2", "occurcountry": "PK", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, AND INCREASED UP TO 2500 MG IN 3 DIVIDED DOSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "GESTATIONAL DIABETES", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrointestinal disorder", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "PK", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735481, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "PK-ALKEM LABORATORIES LIMITED-PK-ALKEM-2018-00900", "fulfillexpeditecriteria": "1", "occurcountry": "PK", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, AND INCREASED UP TO 2500 MG IN 3 DIVIDED DOSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypoglycaemia neonatal", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "PK", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735491, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "GH-ALKEM LABORATORIES LIMITED-GH-ALKEM-2018-00982", "fulfillexpeditecriteria": "2", "occurcountry": "GH", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, INCREASED GRADUALLY OVER TWO (2) WEEKS, TO MEET GLYCEMIC TARGETS", "drugenddate": null, "drugenddateformat": null, "drugindication": "GESTATIONAL DIABETES", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GH", "receiptdate": "20181217", "receivedate": "20181217", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15729701, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "PK-ALKEM LABORATORIES LIMITED-PK-ALKEM-2018-00891", "fulfillexpeditecriteria": "2", "occurcountry": "PK", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, AND INCREASED UP TO 2500 MG IN 3 DIVIDED DOSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "INSULIN NOS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INSULIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "PK", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735483, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "PK-ALKEM LABORATORIES LIMITED-PK-ALKEM-2018-00909", "fulfillexpeditecriteria": "2", "occurcountry": "PK", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, AND INCREASED UP TO 2500 MG IN 3 DIVIDED DOSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "PK", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735503, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "IT-ALKEM LABORATORIES LIMITED-IT-ALKEM-2018-00938", "fulfillexpeditecriteria": "2", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1700-3000 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERINSULINAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. 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RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. 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RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GH", "receiptdate": "20181217", "receivedate": "20181217", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15729703, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" } ]
{ "abstract": "BACKGROUND Metformin has a longstanding reputation as the first-line treatment for glycemic control in the setting of diabetes mellitus type 2. A contributing factor to this reputation is metformin having a low risk of inducing hypoglycemia compared to other oral hypoglycemics or insulin. There are no case reports of hypoglycemia while on conventional or therapeutic doses of metformin. This case report is of a patient who developed symptomatic hypoglycemia while being treated with a therapeutic dose of metformin. CASE REPORT A 58-year-old man with history including diabetes mellitus type 2, hypertension, and schizoaffective disorder was dismissed early from work due to symptoms of severe weakness, confusion, diaphoresis, dizziness, shortness of breath, palpitations, and a sensation of feeling hot. Continuous glucose monitoring revealed hypoglycemic episodes up to 4% of the time. The hypoglycemic events appeared to occur primarily between midnight and 7 A.M., with the second likely time frame being between 7A.M. and noon. Within 2 weeks of discontinuing metformin, there were no further \"attacks\", and the chronic daytime fatigue and somnolence significantly improved. CONCLUSIONS This case report suggests that there is a risk of symptomatic hypoglycemia with therapeutic doses of metformin. Although advised to be taken with meals to avoid gastrointestinal upset, patients should also be educated to take metformin with meals to reduce the risk of metformin-associated hypoglycemia.", "affiliations": "Department of Internal Medicine and Psychiatry, Altru Health System, Grand Forks, ND, USA.", "authors": "Joseph\|Chenelle M C\|CMC\|", "chemical_list": "D001786:Blood Glucose; D007004:Hypoglycemic Agents; D008687:Metformin", "country": "United States", "delete": false, "doi": "10.12659/AJCR.931311", "fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923\nInternational Scientific Literature, Inc.\n\n34075013\n10.12659/AJCR.931311\n931311\nArticles\nSymptomatic Hypoglycemia During Treatment with a Therapeutic Dose of Metformin\nJoseph Chenelle M.C. EF\nDepartment of Internal Medicine and Psychiatry, Altru Health System, Grand Forks, ND, U.S.A.\nCorresponding Author: Chenelle M.C. Joseph, e-mail: [email protected]\nAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\n2021\n02 6 2021\n22 e931311-1e931311-4\n26 1 2021\n18 4 2021\n28 4 2021\n© Am J Case Rep, 2021\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)\nPatient: Male, 58-year-old\n\nFinal Diagnosis: Diabetes mellitus type 2\n\nSymptoms: Confusion • diaphoresis • dizziness • dyspnea • palpitation • weakness\n\nMedication: Metformin\n\nClinical Procedure: —\n\nSpecialty: Endocrinology and Metabolic • General and Internal Medicine • Psychiatry\n\nObjective:\n\nUnusual clinical course\n\nBackground:\n\nMetformin has a longstanding reputation as the first-line treatment for glycemic control in the setting of diabetes mellitus type 2. A contributing factor to this reputation is metformin having a low risk of inducing hypoglycemia compared to other oral hypoglycemics or insulin. There are no case reports of hypoglycemia while on conventional or therapeutic doses of metformin. This case report is of a patient who developed symptomatic hypoglycemia while being treated with a therapeutic dose of metformin.\n\nCase Report:\n\nA 58-year-old man with history including diabetes mellitus type 2, hypertension, and schizoaffective disorder was dismissed early from work due to symptoms of severe weakness, confusion, diaphoresis, dizziness, shortness of breath, palpitations, and a sensation of feeling hot. Continuous glucose monitoring revealed hypoglycemic episodes up to 4% of the time. The hypoglycemic events appeared to occur primarily between midnight and 7 A.M., with the second likely time frame being between 7A.M. and noon. Within 2 weeks of discontinuing metformin, there were no further “attacks”, and the chronic daytime fatigue and somnolence significantly improved.\n\nConclusions:\n\nThis case report suggests that there is a risk of symptomatic hypoglycemia with therapeutic doses of metformin. Although advised to be taken with meals to avoid gastrointestinal upset, patients should also be educated to take metformin with meals to reduce the risk of metformin-associated hypoglycemia.\n\nKeywords:\n\nDiabetes Mellitus\nHypoglycemia\nMetformin\n==== Body\nBackground\n\nMetformin has a longstanding reputation as the first-line treatment for glycemic control in the setting of diabetes mellitus type 2. A contributing factor to this reputation is metformin having a low risk of inducing hypoglycemia compared to other oral hypoglycemics or insulin. Metformin is a biguanide, which reduces blood glucose levels by decreasing glucose production by the liver, decreasing intestinal absorption of glucose, and improving insulin sensitivity [1–6]. The more common adverse effects of metformin include nausea, vomiting, flatulence, abdominal pain, and diarrhea, which is why it is advised to take metformin with food [6,7]. Metformin-associated lactic acidosis (MALA) is a rare adverse effect reported in postmarking cases, the majority of which were linked to metformin toxicity and/or predisposing conditions such as hypovolemia, infection or sepsis, acute or chronic kidney disease, or liver cirrhosis [1,4]. There are reports of metformin overdose or toxicity triggering hypoglycemia, but in only 2% of the cases [5]. There are no case reports of hypoglycemia while on conventional or therapeutic doses of metformin. This case report is of a patient who developed symptomatic hypoglycemia while being treated with a therapeutic dose of metformin. Given that the risk of hypoglycemia is rare but not zero, patients should be advised to take metformin with food, not only to minimize potential gastrointestinal adverse effects, but to also minimize the risk of hypoglycemia.\n\nCase Report\n\nA 58-year-old man presented to the clinic 1 day after experiencing what had historically been labelled a “schizophrenic attack”. The symptoms included severe weakness, confusion, diaphoresis, dizziness, shortness of breath, palpitations, and a sensation of feeling hot. This specific “attack” occurred in the morning while he was at work, and lasted approximately 3 hours. During that time, the patient was allowed to rest and was provided snacks. His medical history included diabetes mellitus type 2, hypertension, hyperlipidemia, gastroesophageal reflux disease, and schizoaffective disorder. His medications included aspirin 81 mg daily, lisinopril 10 mg daily, pantoprazole 40 mg daily, immediate-release metformin 500 mg twice daily, simvastatin 20 mg nightly, lurasidone 120 mg daily, sertraline 50 mg daily, and clozapine 250 mg daily.\n\nOn examination during the clinic visit, there were no physical abnormalities. The vital signs were within normal limits, with blood pressure of 118/70 mmHg, heart rate of 87 beats per minute, and oxygen saturation of 96%. He was mildly obese with a body mass index of 30.83. There were no subjective or objective findings indicative of active depression or mania. The patient was not internally stimulated, denied any visual hallucinations, and reported no change in his chronic auditory hallucinations that tell him that he is God. According to the patient’s wife, he had not voiced any recent paranoid or delusional statements, and continued to talk to himself as usual, with no change in behavior.\n\nThe complete blood count revealed normal cell counts, including white blood cell count of 6.30 K/uL with an absolute neutro-phil count of 3490 K/ul and red blood cell count of 5.02 M/uL. The clozapine level was within therapeutic range at 265 ng/mL with a normal combination clozapine + norclozapine level of 432 ng/mL. The comprehensive metabolic panel showed normal electrolytes, and normal liver and kidney function tests, without acidosis. The non-fasting blood glucose was 107 mg/dl. Inflammatory markers (CRP, sedimentation rate), thyroid-stimulating hormone (TSH), brain natriuretic peptide (BNP), and creatine phosphokinase (CPK) were all within normal limits. The serum C-peptide was elevated at 10.3 ng/mL, but the serum insulin and beta-hydroxybutyrate levels were normal at 11.4 mcIU/mL and 0.1 mmol/L, respectively. A CT scan of the abdomen and pelvis with contrast was normal, including no adrenal, pancreatic, or hepatic abnormalities. A transthoracic echocardiogram showed normal left ventricular ejection fraction of 55–60%, mild grade I diastolic dysfunction, and no wall motion or valvular abnormalities.\n\nGiven that the “attack” mimicked symptomatic hypoglycemia, continuous glucose monitor was performed as an out-patient. The monitor was worn for 15 days (from March 25 2020 through April 8 2020), with 100% active continuous glucose monitoring during that time. Most (96%) of the readings were within the target range (70–180 mg/dl), with 4% of the readings being in the hypoglycemic range (54–69 mg/dl). (Figure 1). The average reading was 92 mg/dl. The hypoglycemic events appeared to occur primarily between midnight and 7 A.M., with the second likely time frame being between 7A.M. and noon (Figure 2).\n\nGiven the documented hypoglycemia, metformin was subsequently discontinued. Approximately 1 month after the last “attack”, and approximately 2 weeks after discontinuing metformin, the patient and his wife reported noticing significant improvements. Both parties denied any further “attacks” of any severity. The patient’s wife stated that the patient was no longer “sleeping all the time”, a complaint for which previous sleep studies ruled out obstructive or central sleep apnea. The patient stated that he no longer had to consume “1 to 2 pots of coffee” to combat daytime fatigue. Unfortunately, his insurance would not cover repeat continuous glucose monitoring to reassess for ongoing hypoglycemia. However, repeat fasting blood tests were within normal limits, including glucose of 117 mg/dl, C-peptide 5.0 ng/mL, and creatinine of 0.8 mg/ dl with a GFR of greater than 60 mL/min/1.73 sq m.\n\nDiscussion\n\nMedical and psychiatric evaluations did not support active schizoaffective disorder, orthostatic hypotension, hypoxia, myocarditis, cardiac valvular disorder, an infectious process, or thyroid dysfunction as contributing factors to this patient’s “attack”. Gastrointestinal pathology including insulinoma was also ruled out. Collateral information, including the metformin refill history through the pharmacy, as well as collateral information from his wife (who managed his medications) and from his social worker, verified that metformin use did not exceed the daily dose prescribed. There were no other residents in the home, and his wife was not on any diabetes medications. The initially elevated serum C-peptide level (with normal serum insulin level) were likely due to insulin insensitivity in the setting of type 2 diabetes mellitus and obesity. Due to the time of day of the majority of the hypoglycemic episodes (fasting state overnight), and an inability to perform a blood draw at or adjacent to his workplace, there was no way to capture his insulin level or his glucose level during a hypoglycemic episode.\n\nThe patient’s social worker estimated that he experienced 1 of these “attacks” at least once a month for several years and were attributed to his diagnosis of schizoaffective disorder, bipolar type. However, his wife estimated that he experienced an “attack” at least once or twice a week, at various levels of severity. His wife reported routinely bringing snacks to his work place in an effort to prevent these “attacks”. To her, the “attacks” were attributed to not eating before work, in combination with overexertion at work.\n\nThere are case reports estimating no more than 2% rate of hypoglycemia secondary to metformin overdose or toxicity [4,5], but hypoglycemia at a therapeutic metformin dose is thought to be rare. Several hypotheses have been proposed for metformin-induced hypoglycemia, but are currently controversial. Metformin-induced hypoglycemia hypotheses include a direct link to its mechanism of action – decreased hepatic glucose production and decreased glucose absorption [2]. However, it is thought that additional confounding circumstance(s) are required for hypoglycemia to occur. ACE-inhibitors are hypothesized to cause hypoglycemia by increasing insulin sensitivity, leading to vasodilation in the muscles with increased muscle uptake of glucose. The combination of ACE-inhibitor with 1 or more oral hypoglycemic agents, including metformin, is thought to increase the risk of hypoglycemia [8–10]. However, the risk does not appear to be significant, as ACE-inhibitors in combination with metformin is commonly prescribed in type 2 diabetes mellitus due the ACE-inhibitors’ protective benefits towards diabetic nephropathy. Also, a recent study of the ACE-inhibitors and ARBs with metformin and other oral hypoglycemics revealed no drug-drug interaction causing hypoglycemia (instead, it showed significant increase in total cholesterol and LDL) [11]. A pharmacy review update of medications commonly prescribed in the management of type 2 diabetes mellitus also did not report any hypoglycemic risk with ACE-inhibitors, nor of a significant drug-drug interaction between metformin and ACE-inhibitors [7,12].\n\nOther hypotheses include concurrent presence of a fasting state, alcohol use, and/or strenuous activity [1,2]. Given that this patient has never consumed alcohol, in this case, the hypoglycemia appears to be multifactorial, including treatment with metformin combined with inadequate oral intake and overexertion at work. There were no drug-drug interactions identified between metformin and the following medications: aspirin, pantoprazole, simvastatin [6,13–15]. His psychotropic regimen, both individual medications and as a whole, (clozapine, lurasidone, sertraline), carries a risk of hyperglycemia (but not hypoglycemia) [6,16–18]. They each also carry the potential to minimize the glucose-reducing effects of metformin, while having no direct interaction with metformin. The initial diagnosis of diabetes mellitus type 2 and the initial treatment of immediate-release metformin was in March 2007 based on a fasting glucose 131 mg/dl. Our patient’s A1c had historically been between 5.4% and 6.0% while on metformin, and has ranged from 5.7% to 5.9% after the discontinuation of metformin.\n\nThe patient denied any other diabetic treatments or any previous adjustments in metformin since its initiation. Controlled studies would best determine risk factors for hypoglycemia regarding metformin. However, the rarity of such cases limits the ability to pursue such studies. Genetic studies on individuals who have experienced therapeutically-dosed metformin-induced hypoglycemia could be an alternate area of study.\n\nConclusions\n\nThis case report supports that there is a risk of symptomatic hypoglycemia with therapeutic doses of metformin. Although advised to be taken with meals to avoid gastrointestinal upset, patients should be educated to take metformin with meals to reduce the risk of metformin-associated hypoglycemia, especially in individuals who frequently engage in strenuous activities.\n\nFigure 1. Composition of glucose readings during continuous glucose monitoring.\n\nFigure 2. Frequency and timing of hypoglycemic events throughout a 24-hour period.\n\nDepartment and Institution Where Work Was Done\n\nDepartment of Internal Medicine and Psychiatry, Altru Health System, Grand Forks, ND, U.S.A.\n\nConflict of Interest\n\nNone.\n==== Refs\nReferences:\n\n1. Bodmer M Meier C Krahenbuhl S Metformin, sulfonylureas, or other antidiabetes drugs and the risk of lactic acidosis or hypoglycemia: A nested case-control analysis Diabetes Care 2008 31 2086 91 18782901\n2. Gasim GI Hypoglycemia induced by therapeutic doses of metformin in the absence of other anti-diabetic drugs FS J Pharm 2013 4 1 2\n3. Nasri H Rafieian-Kopaei M Metformin: Current knowledge J Res Med Sci 2014 19 7 658 64 25364368\n4. Jacob T Garrick R Goldberg M Recurrent lactic acidosis and hypoglycemia with inadvertent metformin use: a case of look-alike pills Endocrinol Diabetes Metab Case Rep 2018 2018 17 0148\n5. Aldobeaban S Mzahim B Ali Alshehri A Recurrent hypoglycemia secondary to metformin toxicity in the absence of co-ingestions: A case report J Med Case Rep 2018 12 223 30119705\n6. Metformin: Drug Information UpToDate Lexicomp Wolters Kluwer Health, Inc Riverwoods, IL http://online.lexi.com. [Accessed March 5 2021]\n7. Triplitt C Drug interactions of medications commonly used in diabetes Diabetes Spectrum 2006 19 4 202 11\n8. Elshimy G Techathaveewat P Alysayed M Simple reason for hypoglycemia: ACE inhibitor-induced severe recurrent hypoglycemia in a non-diabetic patient Cureus 2019 11 8 e5449 31489273\n9. May M Schindler C Clinically and pharmacologically relevant interactions of antidiabetic drugs Ther Adv Endocrinol Metab 2016 7 2 69 83 27092232\n10. Vue MH Setter SM Drug-induced glucose alterations part 1: Drug induced hypoglycemia Diabetes Spectrum 2011 24 3 171 77\n11. Daoud N Qadi O Al-talhi D Al-sharabi H Effect of anti-hypertensive agents on Biochemical Parameters in Diabetic Patients in Taif – KSA International Journal of Diabetes and Clinical Research 2019 6 113\n12. Lisinopril: Drug Information UpToDate Wolters Kluwer Health, Inc Riverwoods, IL http://online.lexi.com [Accessed March 5 2021]\n13. Simvastatin: Drug Information UpToDate Wolters Kluwer Health, Inc Riverwoods, IL http://online.lexi.com [Accessed March 5 2021]\n14. Pantoprazole: Drug Information UpToDate Wolters Kluwer Health, Inc Riverwoods, IL http://online.lexi.com [Accessed March 5 2021]\n15. Aspirin: Drug Information UpToDate Wolters Kluwer Health, Inc Riverwoods, IL http://online.lexi.com [Accessed March 5 2021]\n16. Clozapine: Drug Information UpToDate Wolters Kluwer Health, Inc Riverwoods, IL http://online.lexi.com. [Accessed March 5 2021]\n17. Lurasidone: Drug Information UpToDate Wolters Kluwer Health, Inc Riverwoods, IL http://online.lexi.com. [Accessed March 5 2021]\n18. Sertraline: Drug Information UpToDate Wolters Kluwer Health, Inc Riverwoods, IL http://online.lexi.com [Accessed March 5 2021]\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "1941-5923", "issue": "22()", "journal": "The American journal of case reports", "keywords": null, "medline_ta": "Am J Case Rep", "mesh_terms": "D001786:Blood Glucose; D015190:Blood Glucose Self-Monitoring; D003924:Diabetes Mellitus, Type 2; D004359:Drug Therapy, Combination; D006801:Humans; D007003:Hypoglycemia; D007004:Hypoglycemic Agents; D008297:Male; D008687:Metformin; D008875:Middle Aged", "nlm_unique_id": "101489566", "other_id": null, "pages": "e931311", "pmc": null, "pmid": "34075013", "pubdate": "2021-06-02", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "31489273;30119705;25364368;18782901;27092232;29340159", "title": "Symptomatic Hypoglycemia During Treatment with a Therapeutic Dose of Metformin.", "title_normalized": "symptomatic hypoglycemia during treatment with a therapeutic dose of metformin" }	[ { "companynumb": "SD-ALKEM LABORATORIES LIMITED-SD-ALKEM-2021-03887", "fulfillexpeditecriteria": "1", "occurcountry": "SD", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "750 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "DIABETES MELLITUS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "750", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SIMVASTATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "DIABETES MELLITUS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SIMVASTATIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "75 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "DIABETES MELLITUS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": null, "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypoglycaemia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "JOSEPH C.. 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SYMPTOMATIC HYPOGLYCEMIA DURING TREATMENT WITH A THERAPEUTIC DOSE OF METFORMIN. AM?J?CASE?REP 2021?:.", "literaturereference_normalized": "symptomatic hypoglycemia during treatment with a therapeutic dose of metformin", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210902", "receivedate": "20210701", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19483259, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "US-LUPIN PHARMACEUTICALS INC.-2021-10347", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LISINOPRIL" }, "drugadditional": "3", "drugadministrationroute": "065", 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LURASIDONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SIMVASTATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MILLIGRAM, QD (NIGHTLY)", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SIMVASTATIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "090692", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MILLIGRAM, BID, IMMEDIATE?RELEASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": "200703", "drugstartdateformat": "610", "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PANTOPRAZOLE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PANTOPRAZOLE" } ], "patientagegroup": null, "patientonsetage": "58", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypoglycaemia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "JOSEPH CMC. SYMPTOMATIC HYPOGLYCEMIA DURING TREATMENT WITH A THERAPEUTIC DOSE OF METFORMIN. AMERICAN JOURNAL OF CASE REPORTS. 2021?22:E931311:1?4", "literaturereference_normalized": "symptomatic hypoglycemia during treatment with a therapeutic dose of metformin", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210628", "receivedate": "20210628", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19466670, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" } ]
{ "abstract": "BACKGROUND\nA previously repaired right popliteal artery aneurysm via a medial approach with proximal and distal ligation and interval bypass re-presented 7 years after the initial repair with a ruptured 9 × 25.5 cm right popliteal aneurysm.\n\n\nMETHODS\nSurgical repair was complex due to the large size of the aneurysm. Technique and management of popliteal aneurysm repair are discussed, along with a review of the current literature.\n\n\nRESULTS\nA 58-year-old male with a 3.5 cm popliteal artery aneurysm was initially treated with end-to-end prosthetic bypass and proximal/distal aneurysm ligation from a medial-approach without complication. Seven years later, he presented with a 9-cm popliteal aneurysm rupture. Posterior approach endoaneurysmorrhaphy repair was far more complicated than expected with massive blood loss. Despite this, he was discharged without complication POD #5, but on POD #19 presented with cellulitis and underwent incision and drainage of retained hematoma with cultures positive for Strep dysgalactiae. With appropriate treatment, he was healed in 3 months.\n\n\nCONCLUSIONS\nSurgical repair of large popliteal aneurysms can be challenging, but continued aneurysmal degeneration is a potential consequence if the sac continues to be pressurized from patent geniculate arteries. Surgical repair of large popliteal artery aneurysms is complex and requires adjunctive techniques to maximize success. A posterior approach is described and the literature reviewed to support recommendations for primary popliteal artery aneurysm repair and repair of large degenerated popliteal artery aneurysms. We recommend primary popliteal artery aneurysm repair from a posterior approach with endoaneurysmorrhaphy and an interposition bypass. For ruptured large popliteal artery aneurysms, there is a high risk of hemorrhage and wound complications. Therefore, we recommend the use of a tourniquet, surgical drain and to consider the collection of intraoperative cultures to guide potential antibiotic management.", "affiliations": "Spectrum Health Grand Rapids, Michigan State University, College of Human Medicine, Grand Rapids, MI. Electronic address: [email protected].;Spectrum Health Grand Rapids, Michigan State University, College of Human Medicine, Grand Rapids, MI.;Spectrum Health Grand Rapids, Michigan State University, College of Human Medicine, Grand Rapids, MI.", "authors": "Lu\|Joyce J\|JJ\|;Cuff\|Robert F\|RF\|;Chambers\|Christopher M\|CM\|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.avsg.2020.10.018", "fulltext": null, "fulltext_license": null, "issn_linking": "0890-5096", "issue": "72()", "journal": "Annals of vascular surgery", "keywords": null, "medline_ta": "Ann Vasc Surg", "mesh_terms": "D000783:Aneurysm; D017542:Aneurysm, Ruptured; D019917:Blood Vessel Prosthesis Implantation; D018450:Disease Progression; D006801:Humans; D008026:Ligation; D008297:Male; D008875:Middle Aged; D011150:Popliteal Artery; D012086:Reoperation; D013997:Time Factors; D016896:Treatment Outcome", "nlm_unique_id": "8703941", "other_id": null, "pages": "665.e9-665.e13", "pmc": null, "pmid": "33227480", "pubdate": "2021-04", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Open Endoaneurysmorrhaphy of 9-cm Ruptured Popliteal Aneurysm 7 Years after Initial Repair.", "title_normalized": "open endoaneurysmorrhaphy of 9 cm ruptured popliteal aneurysm 7 years after initial repair" }	[ { "companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-047338", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "202155", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CEREBROVASCULAR ACCIDENT PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": null, "patientonsetage": "58", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Procedural haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Haematoma infection", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "LU JJ, CUFF RF, CHAMBERS CM. OPEN ENDOANEURYSMORRHAPHY OF 9?CM RUPTURED POPLITEAL ANEURYSM 7 YEARS AFTER INITIAL REPAIR. ANNALS OF VASCULAR SURGERY. 2021?72:1?5", "literaturereference_normalized": "open endoaneurysmorrhaphy of 9 cm ruptured popliteal aneurysm 7 years after initial repair", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210521", "receivedate": "20210521", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19280579, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" } ]
{ "abstract": "Rivaroxaban is an oral anticoagulant that acts as a direct, competitive factor Xa inhibitor. Large randomized clinical trials have shown that, at a daily dose of 20 mg, Rivaroxaban is at least as effective as dose-adjusted warfarin for the prevention of stroke or other embolic complications in patients with nonvalvular atrial fibrillation (AF). The safety and efficacy of combining Rivaroxaban with an antiplatelet agent for secondary stroke prevention has not been established. We report the case of an elderly patient with permanent AF and coronary heart disease, who had already suffered an ischemic stroke while on warfarin treatment, and was consequently switched to treatment with an association of Rivaroxaban and Aspirin. Her CHA2DS2-VASc score was 9. The patient developed a severe recurrent disabling ischemic stroke. This case goes to show that the novel direct anticoagulants may fail to prevent recurrent stroke in patients at particularly high risk, even when associated with antiplatelet drugs.", "affiliations": "Internal Medicine Clinic, Coagulopathy Section, Department of Cardiovascular and Thoracic Sciences, Padua University, Padua, Italy - [email protected].", "authors": "Bilora\|Franca\|F\|;Adamo\|Angelo\|A\|;Pomerri\|Fabio\|F\|;Prandoni\|Paolo\|P\|", "chemical_list": "D000925:Anticoagulants; D000069552:Rivaroxaban; D001241:Aspirin", "country": "Italy", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0026-4725", "issue": "64(4)", "journal": "Minerva cardioangiologica", "keywords": null, "medline_ta": "Minerva Cardioangiol", "mesh_terms": "D000368:Aged; D000925:Anticoagulants; D001241:Aspirin; D001281:Atrial Fibrillation; D002545:Brain Ischemia; D005260:Female; D006801:Humans; D000069552:Rivaroxaban; D020521:Stroke; D014057:Tomography, X-Ray Computed; D017211:Treatment Failure", "nlm_unique_id": "0400725", "other_id": null, "pages": "494-6", "pmc": null, "pmid": "27228488", "pubdate": "2016-08", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Failure of old and new anticoagulants to prevent ischemic stroke in high-risk atrial fibrillation: a case report.", "title_normalized": "failure of old and new anticoagulants to prevent ischemic stroke in high risk atrial fibrillation a case report" }	[ { "companynumb": "IT-JNJFOC-20160611174", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETYLSALICYLIC ACID" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "RIVAROXABAN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "022406", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIVAROXABAN" } ], "patientagegroup": "6", "patientonsetage": "77", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Ischaemic stroke", "reactionmeddraversionpt": "20.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BILORA F, ADAMO A, POMERRI F, PRANDONI P. FAILURE OF OLD AND NEW ANTICOAGULANTS TO PREVENT ISCHEMIC STROKE IN HIGH-RISK ATRIAL FIBRILLATION: A CASE REPORT. MINERVA CARDIOANGIOL 2016;64(4):494-496.", "literaturereference_normalized": "failure of old and new anticoagulants to prevent ischemic stroke in high risk atrial fibrillation a case report", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20170411", "receivedate": "20160615", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12469366, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": 1, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "IT-BAYER-2016-112089", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021317", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETYLSALICYLIC ACID({=100 MG)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RIVAROXABAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "FILM-COATED TABLET", "drugdosagetext": "20 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIVAROXABAN" } ], "patientagegroup": "6", "patientonsetage": "77", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "19.0", "reactionoutcome": null }, { "reactionmeddrapt": "Ischaemic stroke", "reactionmeddraversionpt": "19.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "BILORA F; ADAMO A; POMERRI F; PRANDONI P. FAILURE OF OLD AND NEW ANTICOAGULANTS TO PREVENT ISCHEMIC STROKE IN HIGH-RISK ATRIAL FIBRILLATION: A CASE REPORT. MINERVA CARDIOANGIOL. 2016;64 (4):494-496", "literaturereference_normalized": "failure of old and new anticoagulants to prevent ischemic stroke in high risk atrial fibrillation a case report", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20160613", "receivedate": "20160613", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12461386, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": 1, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" }, { "companynumb": "IT-CIPLA LTD.-2016IT17026", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "WARFARIN SODIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "90935", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ISCHAEMIC HEART DISEASE PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN SODIUM." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BILORA F, ADAMO A, POMERRI F, PRANDONI P. FAILURE OF OLD AND NEW ANTICOAGULANTS TO PREVENT ISCHEMIC STROKE IN HIGH-RISK ATRIAL FIBRILLATION: A CASE REPORT. MINERVA CARDIOANGIOL. 2016;64 (4):494 TO 496", "literaturereference_normalized": "failure of old and new anticoagulants to prevent ischemic stroke in high risk atrial fibrillation a case report", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20160816", "receivedate": "20160816", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12653809, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" }, { "companynumb": "IT-IPCA LABORATORIES LIMITED-IPC201608-000685", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "200104", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DEEP VEIN THROMBOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2012", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "200104", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ATRIAL FIBRILLATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" } ], "patientagegroup": null, "patientonsetage": "77", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Ischaemic stroke", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "BILORA F,ADAMO A,POMERRI F,PRANDONI P. FAILURE OF OLD AND NEW ANTICOAGULANTS TO PREVENT ISCHEMIC STROKE IN HIGH-RISK ATRIAL FIBRILLATION: A CASE REPORT. MINERVA CARDIOANGIOL 2016 AUG;64(4):494-6.", "literaturereference_normalized": "failure of old and new anticoagulants to prevent ischemic stroke in high risk atrial fibrillation a case report", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20160822", "receivedate": "20160822", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12674291, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" } ]
{ "abstract": "BACKGROUND\nHealth Care Workers (HCWs) are at risk of occupational transmission of HIV, Hepatitis B and Hepatitis C, which can be minimized by following guidelines for standard precautions as well as taking Post Exposure Prophylaxis (PEP) measures. There are limited studies from India documenting details of PEP for HIV and Hepatitis B.\n\n\nOBJECTIVE\nWe aimed to study the efficacy, tolerance, details of PEP regimens used among HCWs exposed to HIV and Hepatitis B as well as vaccination status and (Anti-Hepatitis B Surface Antigen) anti-HBS Antibody Titre Level Among HCWs exposed Hepatitis B.\n\n\nMETHODS\nThis retrospective observational study was done at a rural based tertiary care teaching centre of Western India.\n\n\nMETHODS\nHospital Infection Control Committee of our institute was maintaining a record of all reported incidences of HIV and Hepatitis B positive exposures since 2003. We analysed reported incidences of exposures to HIV and Hepatitis B positive source occurred during the period of January 2003 to December 2015.\n\n\nRESULTS\nOf the total 96 exposures, 48 were to HIV and 48 were to Hepatitis B. Of the 48 exposures to HIV, PEP was warranted in 39. Of 39 exposures, only 14 (35.9%) received PEP within two hours. Basic regimen was used in 22 and expanded in 17 exposures. Only 12 (31.6%) reported side effects to PEP. Zidovudine based regimen was less well tolerated. All side effects were reported by female HCWs only. Of the 48 exposed to Hepatitis B, 33 (68.6%) were completely vaccinated. Out of 33, titre result was not available for eight. Three (12.0%) of remaining 25 were having low titre (<10mIU/ml) of anti-HBS antibody. Five of six with incomplete vaccination status demonstrated anti HBS antibody titre > 100mIU/ml. Of the 48, in 17 (35.4%) incidences no action was required; 23 (47.9%) were managed with booster dose of Hepatitis B vaccine and eight (16.7%) with Hepatitis B immunoglobulin. No cases of sero-conversion was reported either for HIV or Hepatitis B from available data.\n\n\nCONCLUSIONS\nInspite of high incidences of exposures to HIV or Hepatitis B positive source, good efficacy of PEP was observed with no sero-conversion. PEP for HIV was well tolerated; female HCWs were less tolerant. Study emphasized the need for creating awareness about timely reporting of incidence, achieving maximum vaccination against Hepatitis B for all HCWs and need for anti-HBS antibody titre.", "affiliations": "Professor, Department of Medicine, Pramukh Swami Medical College , Karamsad, Gujarat, India .;Professor, Department of Medicine, Pramukh Swami Medical College , Karamsad, Gujarat, India .;Professor and HOD, Department of Medicine, Pramukh Swami Medical College , Karamsad, Gujarat, India .", "authors": "Sheth\|Sanket Pranjivan\|SP\|;Leuva\|Alpa C\|AC\|;Mannari\|Jyoti G\|JG\|", "chemical_list": null, "country": "India", "delete": false, "doi": "10.7860/JCDR/2016/19876.8387", "fulltext": null, "fulltext_license": null, "issn_linking": "0973-709X", "issue": "10(8)", "journal": "Journal of clinical and diagnostic research : JCDR", "keywords": "Anti-HBS antibody titre; Hepatitis B immunoglobulin; Hepatitis B vaccination; Occupational transmission; Tenofovir; Zidovudine", "medline_ta": "J Clin Diagn Res", "mesh_terms": null, "nlm_unique_id": "101488993", "other_id": null, "pages": "OC39-44", "pmc": null, "pmid": "27656485", "pubdate": "2016-08", "publication_types": "D016428:Journal Article", "references": "22308136;26559816;25366873;25577991;23188932;25043080;24278151;25879442;23508479;20606925;26092496;25745570;24432275;21493989;20418554;19172059;23437024;22248951;22058270;16195697;21799569;25368534;22639503;25815093;26545721;27080795;10835856;23616912;20061757;23705668;22684185;24352112;11442229", "title": "Post Exposure Prophylaxis for Occupational Exposures to HIV and Hepatitis B: Our Experience of Thirteen Years at a Rural Based Tertiary Care Teaching Hospital of Western India.", "title_normalized": "post exposure prophylaxis for occupational exposures to hiv and hepatitis b our experience of thirteen years at a rural based tertiary care teaching hospital of western india" }	[ { "companynumb": "IN-VIIV HEALTHCARE LIMITED-IN2016GSK142085", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "INDINAVIR" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INDINAVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ZIDOVUDINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ZIDOVUDINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LAMIVUDINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "020564", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMIVUDINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hyperbilirubinaemia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SHETH SP, LEUVA AC, MANNARI JG.. POST EXPOSURE PROPHYLAXIS FOR OCCUPATIONAL EXPOSURES TO HIV AND HEPATITIS B: OUR EXPERIENCE OF THIRTEEN YEARS AT A RURAL BASED TERTIARY CARE TEACHING HOSPITAL OF WESTERN INDIA.. JOURNAL OF CLINICAL AND DIAGNOSTIC RESEARCH. 2016;10(8):OC39-OC44", "literaturereference_normalized": "post exposure prophylaxis for occupational exposures to hiv and hepatitis b our experience of thirteen years at a rural based tertiary care teaching hospital of western india", "qualification": "3", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20160929", "receivedate": "20160929", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 12791806, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" }, { "companynumb": "IN-GLAXOSMITHKLINE-IN2016GSK142085", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "INDINAVIR" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INDINAVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LAMIVUDINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "020564", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMIVUDINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ZIDOVUDINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ZIDOVUDINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hyperbilirubinaemia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SHETH SP, LEUVA AC, MANNARI JG.. POST EXPOSURE PROPHYLAXIS FOR OCCUPATIONAL EXPOSURES TO HIV AND HEPATITIS B: OUR EXPERIENCE OF THIRTEEN YEARS AT A RURAL BASED TERTIARY CARE TEACHING HOSPITAL OF WESTERN INDIA.. JOURNAL OF CLINICAL AND DIAGNOSTIC RESEARCH. 2016;10(8):OC39-OC44", "literaturereference_normalized": "post exposure prophylaxis for occupational exposures to hiv and hepatitis b our experience of thirteen years at a rural based tertiary care teaching hospital of western india", "qualification": "3", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20160929", "receivedate": "20160929", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 12795026, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" }, { "companynumb": "IN-MYLANLABS-2019M1051138", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "ZIDOVUDINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST HIV INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ZIDOVUDINE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "INDINAVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST HIV INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INDINAVIR" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "LAMIVUDINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "078545", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST HIV INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMIVUDINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hyperbilirubinaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SHETH SP, LEUVA AC, MANNARI JG. POST EXPOSURE PROPHYLAXIS FOR OCCUPATIONAL EXPOSURES TO HIV AND HEPATITIS B: OUR EXPERIENCE OF THIRTEEN YEARS AT A RURAL BASED TERTIARY CARE TEACHING HOSPITAL OF WESTERN INDIA. J-CLIN-DIAGNOSTIC-RES 2016?10(8):OC39-OC44.", "literaturereference_normalized": "post exposure prophylaxis for occupational exposures to hiv and hepatitis b our experience of thirteen years at a rural based tertiary care teaching hospital of western india", "qualification": "1", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20190531", "receivedate": "20190531", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16379151, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" } ]
{ "abstract": "BACKGROUND\nProton pump inhibitors are usually safe, although serious adverse effects can occur. We report the first case of rhabdomyolysis associated with single-dose intravenous esomeprozole administration.\n\n\nMETHODS\nA 45-year-old Korean male visited our emergency room because of persistent lower chest discomfort that started 10 hours before. He had been diagnosed with diabetes and coronary heart disease, but discontinued oral hypoglycemic agents 1 month earlier. He continued to take medications for coronary heart disease. There was no abnormality on an electrocardiogram or in cardiac enzymes. Initial laboratory findings did not show abnormalities for muscle enzymes. Esomeprozole 40 mg was administrated intravenously for the control of his ambiguous chest discomfort. Then, 12 hours later, he complained of abrupt severe right buttock pain. An area of tender muscle swelling 8 cm in diameter was seen on his right buttock area. Creatine kinase and lactate dehydrogenase were elevated to 40,538 and 1326 U/L, respectively. A bone scan using 20 mCi of Tc-hydroxymethylene diphosphonate was compatible with rhabdomyolysis.\n\n\nRESULTS\nHis muscular symptoms, signs, and laboratory findings improved markedly with conservative management, including hydration and urine alkalinization. He is being followed in the outpatient department with no evidence of recurrence.\n\n\nCONCLUSIONS\nWe should keep in mind that single-dose intravenous administration of esomeprazole can induce rhabdomyolysis.", "affiliations": "Department of Internal Medicine, Gyeongsang National University Hospital, Jinju Department of Internal Medicine, Changwon Gyeongsang National University Hospital, Changwon Department of Internal Medicine, Gyeongsang National University School of Medicine, Internal Medicine Institute of Health Science, Gyeongsang National University, Jinju, South Korea.", "authors": "Jeon\|Dae-Hong\|DH\|;Kim\|Yire\|Y\|;Kim\|Min Jeong\|MJ\|;Cho\|Hyun Seop\|HS\|;Bae\|Eun Jin\|EJ\|;Chang\|Se-Ho\|SH\|;Park\|Dong Jun\|DJ\|", "chemical_list": "D054328:Proton Pump Inhibitors; D064098:Esomeprazole", "country": "United States", "delete": false, "doi": "10.1097/MD.0000000000004313", "fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 2744268010.1097/MD.0000000000004313043135200Research ArticleClinical Case ReportRhabdomyolysis associated with single-dose intravenous esomeprazole administration A case reportJeon Dae-Hong MDaKim Yire MDaKim Min Jeong MDaCho Hyun Seop MDaBae Eun Jin MDbChang Se-Ho MD, PhDacdPark Dong Jun MD, PhDbcd∗Mubarak. Muhammed a Department of Internal Medicine, Gyeongsang National University Hospital, Jinjub Department of Internal Medicine, Changwon Gyeongsang National University Hospital, Changwonc Department of Internal Medicine, Gyeongsang National University School of Medicine, Internal Medicined Institute of Health Science, Gyeongsang National University, Jinju, South Korea.∗ Correspondence: Dong Jun Park, Department of Internal Medicine, Changwon Gyeongsang National University Hospital, Internal Medicine, 11, Samjeongja-ro, Seongsan-gu, Changwon-si, Gyeongsangnam-do, South Korea (e-mail: [email protected]).7 2016 22 7 2016 95 29 e431328 4 2016 19 6 2016 29 6 2016 Copyright © 2016 the Author(s). Published by Wolters Kluwer Health, Inc. All rights reserved.2016This is an open access article distributed under the Creative Commons Attribution License 4.0, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nBackground:\nProton pump inhibitors are usually safe, although serious adverse effects can occur. We report the first case of rhabdomyolysis associated with single-dose intravenous esomeprozole administration.\n\nMethods:\nA 45-year-old Korean male visited our emergency room because of persistent lower chest discomfort that started 10 hours before. He had been diagnosed with diabetes and coronary heart disease, but discontinued oral hypoglycemic agents 1 month earlier. He continued to take medications for coronary heart disease. There was no abnormality on an electrocardiogram or in cardiac enzymes. Initial laboratory findings did not show abnormalities for muscle enzymes. Esomeprozole 40 mg was administrated intravenously for the control of his ambiguous chest discomfort. Then, 12 hours later, he complained of abrupt severe right buttock pain. An area of tender muscle swelling 8 cm in diameter was seen on his right buttock area. Creatine kinase and lactate dehydrogenase were elevated to 40,538 and 1326 U/L, respectively. A bone scan using 20 mCi of 99mTc-hydroxymethylene diphosphonate was compatible with rhabdomyolysis.\n\nResults:\nHis muscular symptoms, signs, and laboratory findings improved markedly with conservative management, including hydration and urine alkalinization. He is being followed in the outpatient department with no evidence of recurrence.\n\nConclusion:\nWe should keep in mind that single-dose intravenous administration of esomeprazole can induce rhabdomyolysis.\n\nKeywords\nacute kidney injuryproton pump inhibitorrhabdomyolysisOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nEsomeprazole, the (S)-isomer of omeprazole,[1,2] is available in both oral and intravenous formulations; it is usually indicated for the treatment of gastroesophageal reflux disease (GERD), Helicobacter pylori eradication, and the prevention of nonsteroidal anti-inflammatory drug induced gastric ulcers.[3–5] Numerous clinical trials including many patients have demonstrated that esomeprazole is tolerable and safe for both short- and long-term use.[6–8] Esomeprazole, like other proton pump inhibitors (PPIs), has few adverse effects, with reported rates of adverse effects ranging from 1% to 5%. The most common side effects include headache, diarrhea, abdominal pain, and nausea. These adverse effects, excluding diarrhea, are usually not related with age, dosage, or duration of treatment. Mean changes in laboratory measurements due to esomeprazole are usually small and not clinically meaningful.[5] In addition, esomeprazole did not cause clinically significant electrocardiographic (ECG) changes.[9]\n\nRhabdomyolysis is induced by skeletal muscle breakdown, leading to the leakage of muscle cell contents, such as myoglobin, electrolytes, and other sarcoplasmic proteins, into the circulation.[10,11] Acute kidney injury (AKI) complicated by rhabdomyolysis is quite common, representing about 7% to 10% of all cases of AKI in the United States.[12,13] Eight categories of events are well known to provoke rhabdomyolysis: trauma, exertion, muscle hypoxia, genetic defects, infections, body temperature changes, metabolic and electrolyte disorders, and drugs and toxins.[11,12,14] Rhabdomyolysis associated with PPIs has been reported sporadically.[15–17] However, there has been no report of a PPI associated with rhabdomyolysis after single-dose intravenous administration. Thus, here we report the first case of rhabdomyolysis occurring after single-dose intravenous esomeprazole administration.\n\n2 Case presentation\nA 45-year-old male patient visited the emergency room (ER) because of lower chest discomfort starting 6 hours earlier. He also complained of thirst and limb numbness. His medical history included diabetes mellitus, bronchial asthma, and unstable angina for 4 years, 2 years, and 1 year, respectively. He had been taking aspirin (100 mg/d), clopidogrel (75 mg/d), atorvastatin (10 mg/d), and candesartan (8 mg/d) for 1 year without changes. He took those medicines on the morning of his admission. He regularly used a Symbicort Turbuhaler® (AstraZeneca Korea, Seoul, Republic of Korea) (160/4.5 μg) for asthma management. One month before the present admission, he discontinued the oral hypoglycemic agents prescribed by his primary physician. He denied recent alcohol consumption and had quit smoking 1 year earlier. Except for these symptoms, he initially had no complaints, such as muscular pain, fever, upper respiratory symptoms, or signs, on visiting the ER. He had no history of excessive physical activity or recent trauma.\n\nOn initial physical examination in the ER, his vital signs were as follows: blood pressure, 100/60 mm Hg; heart rate, 71 beats/min; respiratory rate, 20 times/min; and body temperature, 36.6 °C. On chest auscultation, no abnormal sounds, such as rales or wheezing, were audible, and his heartbeat was regular without murmur. His general skin turgor was decreased, and his tongue was dry. His conjunctivae were not anemic and sclerae were not icteric. There were no palpable lymph nodes in the head or neck area. Organomegaly was not seen in the abdomen. No pretibial pitting edema, muscular swelling, or skin color changes were detected on either lower extremity. There was no tenderness in the upper or lower extremities. His muscle power was within normal limits.\n\nCompared with a previous ECG, the rhythm and voltage were unchanged. His initial troponin-I was less than 0.1 ng/mL, creatinine kinase (CK) was 144 U/L (0–190 U/L), lactate dehydrogenase (LDH) was 220 U/L (135–225 U/L), and CK-MB, subunit of CK, was 3.5 ng/mL. Other initial laboratory data were hematocrit 45% (39%–52%), hemoglobin 14.5 g/dL (13–17 g/dL), white blood cell count 11,280/mm3 (4000–10,000/mm3, neutrophils: 68.2%, lymphoid cells: 25.6%, and monocytes: 4.5%), and platelet count 256,000/mm3 (130,000–400,000/mm3). Liver function tests were as follows: alkaline phosphatase 84 IU/L (35–130 IU/L), aspartate aminotransferase (AST) 21 IU/L (0–37 IU/L), alanine aminotransferase (ALT) 42 IU/L (0–41 IU/L), and glucose 696 mg/dL. Hemoglobin A1c (HbA1c) was 9.3% (4.2%–5.9%). Blood urea nitrogen (BUN) and creatinine were 19.9 mg/dL (6.0–20.0 mg/dL) and 1.11 mg/dL (0.6–1.2 mg/dL), respectively. Electrolyte results were sodium 123 mmol/L (135–145 mmol/L), potassium 4.7 mmol/L (3.3–5.1 mmol/L), and chloride 80 mmol/L (98–110 mmol/L). Serum osmolality was 296 mOsm/kg. Urinalysis with micro revealed no protein or blood on a dipstick and red blood cell 1 to 4/high-power field.\n\nContinuous intravenous insulin and hydration with normal saline were started. In addition, 40 mg of esomeprazole was infused intravenously under a suspicion of GERD. Glucose levels, measured by a blood sugar meter, decreased to 240 mg/dL and chest discomfort improved 6 hours after this management. In the mean time, there were no other oral, intramuscular, and intravenous drug therapies except for oral lactulose for his constipation. He felt mild discomfort in the right buttock at that time but did not complain to the medical team. However, he complained of severe right buttock pain 12 hours after the esomeprazole infusion. Tender muscle swelling of 8 cm in diameter was seen in the right buttock area and a reddish skin color change was noted (Fig. 1). Serum CK and LDH levels increased to 40,533 and 1326 U/L, respectively, and AST and ALT levels also increased to 320 and 83 IU/L, respectively. BUN and creatinine levels were 23.9 and 1.49 mg/dL, respectively. We started vigorous hydration through isotonic saline infusion and urine alkalinization by intravenous bicarbonate infusion. Another 40 mg of esomeprazole was administered because we did not regard esomeprazole as the causative agent of the rhabdomyolysis at that time. Serum CK, LDH, AST, and ALT levels were 84,226, 1943, 603, and 171 IU/L, respectively, 24 hours later. On the third day in hospital, he was admitted to the nephrology ward. Esomeprazole was ended, and hydration and alkalinization were continued. Serum CK and LDH levels decreased gradually (Fig. 2A and B), and his muscular symptoms and swelling in the buttock area improved gradually. A bone scan using 20 mCi of 99mTc-hydroxymethylene diphosphonate was performed on the seventh day in hospital and revealed multiple and diffuse uptake in the soft tissues of the right buttock and both lower legs (Fig. 3). His clinical manifestations and laboratory findings improved, so he was discharged on the 12th day. We added oral hypoglycemic agents, linagliptin 5 mg and metformin 500 mg, to his previous drugs (aspirin, clopidogrel, candesartan, and atorvastatin). He is being followed in our outpatient department with no recurrence of rhabdomyolysis at 6 months.\n\nFigure 1 Red and swollen right buttock which is 8 cm in diameter (encircled area).\n\nFigure 2 (A) and (B) The change of serum creatinine kinase, lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase.\n\nFigure 3 Bone scan showing multiple uptakes in both tibia and fibula and right buttock area.\n\n3 Discussion\nWe report here the first case of rhabdomyolysis associated with single-dose esomeprazole intravenous administration. Our patient initially did not show clinical or laboratory evidence of rhabdomyolysis before esomeprazole administration in the ER. He was still in the ER when muscular pain and swelling presented after esomeprazole administration, but we did not suspect a relationship between rhabdomyolysis and esomeprazole, leading to administration of a second esomeprazole dose on the second day. We finally confirmed that esomeprazole was associated with rhabdomyolysis and ended the infusion of esomeprazole after he moved to the ward.\n\nFrom the case reports in VigiBase and in the literature, Clark and Strandell[18] reported 35 cases of rhabdomyolysis associated with PPIs in the literature, a serious reaction to the drugs. They also showed that a statin was taken concomitantly in 12 cases. Other drugs, such as lovastatin, amlodipine, and diazepam, were also taken, although no dates were given. Rhabdomyolysis occurred within the first week in 9 cases, between after 14 days and 3 months of treatment in 4 cases, and between 1.5 and 10 years in 3 additional cases. Time to onset was unknown in 19 cases. However, there are limitations to the report: VigiBase reports are not homogenous with respect to origin or to the probability that a pharmaceutical product caused the adverse reaction. Thus, no pure causal relationship between rhabdomyolysis and PPIs was evident. In our case, the causal relationship seems particularly prominent, in that esomeprazole was intravenously administered without other concomitant medicines except for intravenous insulin in the ER, and muscular symptoms and laboratory changes were confirmed immediately. We think that the administration of insulin is very unlikely to be one of the reasons for the rhabdomyolysis.\n\nFrom PubMed research, 2 cases of rhabdomyolysis associated with esomeprazole have been reported.[19,20] One case occurred in a patient with chronic heart failure and the other was in a patient taking atorvastatin and clarithromycin. The former patient also underwent aortic valve replacement and coronary artery bypass surgery and was administered several other medications including propofol, sufentanil, furosemide, amiodarone, meropenem, linezolid, and cathecholamines. Esomeprazole was administered intravenously (40–80 mg/d) for 1 month. They proposed that the dose of esomeprazole was correlated with rhabdomyolysis.[19] However, his serum CK level was not elevated (although his serum myoglobin level was), but they did not mention the discordance between CK and myoglobin levels. Furthermore, there seemed to be no prominent correlation between esomeprazole withdrawal and restoration of myoglobin levels. The latter patient had a long medication history of atorvastatin (>1 year), a 6-week history of esomeprazole, and received 3 500-mg doses of clarithromycin just before admission.[20] Thus, the rhabdomyolysis seemed not to be associated with esomeprazole, but with clarithromycin.\n\nMost PPIs are metabolized to varying degrees by the hepatic cytochrome P450 enzymatic system, and drug metabolism may be altered by induction or inhibition of the cytochrome P enzymes.[21] According to in vitro studies, esomeprazole was a weak inhibitor of cytochrome P450 (CYP3A4, -2B6, -2D6, -2C9, -2C8, and -1A2), but a potent inhibitor of CYP2C19 in human liver microsomes, compared with other PPIs, and esomeprazole might not reach the plasma concentrations needed to inhibit CYP3A4 in the normal clinical setting.[22] Andersen et al extensively reviewed the pharmacokinetic drug interaction potential of esomeprazole. They showed that esomeprazole did not have clinically relevant interactions with 3A4 substrates, such as quinidine and clarithromycin, or the 2C9 substrate, (S)-warfarin. However, esomeprazole had different interaction with 2C19 substrates including (R)-warfarin, diazepam, and phenytoin.[22]\n\nOne report showed that 3- or 30-minute intravenous esomeprazole (40 mg) provides similar levels of intragastric acid control to the oral formulation,[23,24] although little is known about the pharmacokinetic profile of esomeprazole after intravenous administration (whereas that of the oral formulation is well characterized).[1,2] Niazi et al[25] demonstrated that a higher infusion rate of intravenous esomeprazole showed higher Cmax values, but did not affect other values such as the plasma concentration–time curve, plasma elimination half-life (t1/2), or plasma clearance in healthy volunteers. A previous study also showed that Cmax values were higher after intravenous dosing than after oral dosing.[26] Although the exact mechanism of rhabdomyolysis in our patient with a single-dose injection remains to be determined, an abrupt increase in Cmax after intravenous infusion and drugs, which the patient had taken, might be associated with an elevation of the plasma level of esomeprazole, which might in turn be correlated with toxicity. Other possibility includes an idiosyncratic drug reaction, leading to some myopathy in the way that toxicity may occur after only single-dose use. Lastly, direct toxicity to muscle might be one of the mechanisms that can’t be ignored.[27]\n\nIn conclusion, physicians should keep in mind that a single-dose infusion of esomeprazole might be associated with rhabdomyolysis, directly or indirectly. Early recognition and intervention is important to reduce complications.\n\nAbbreviations: AKI = acute kidney injury, ALT = alanine aminotransferase, AST = aspartate aminotransferase, BUN = blood urea nitrogen, CK = creatinine kinase, ECG = electrocardiograph, ER = emergency room, GERD = gastroesophageal reflux disease, LDH = lactate dehydrogenase, PPI = proton pump inhibitor.\n\nEthics committee approval: Informed consent was obtained from the patient, but this case report did not require an ethics committee approval according to the current laws in our hospital.\n\nThe authors have no funding and conflicts of interest to disclose.\n==== Refs\nReferences\n1 Andersson T Hassa-Alin M Hasselgren G \nPharmacokinetic studies with esomeprazole, the (S)-isomer of omeprazole . Clin Pharmacokinet \n2001 ; 40 :411 –426 .11475467 \n2 Andersson T Rohss K Bredberg E \nPharmacokinetics and pharmacodynamics of esomeprazole, the S-isomer of omeprazole . Aliment Pharmacol Ther \n2001 ; 15 :1563 –1569 .11563995 \n3 Shi S Klotz U \nProton pump inhibitors: an update of their clinical use and pharmacokinetics . Eur J Clin Pharmacol \n2008 ; 64 :935 –951 .18679668 \n4 Blume H Donath F Warnke A \nPharmacokinetic drug interaction profiles of proton pump inhibitors . Drug Safety \n2006 ; 29 :769 –784 .16944963 \n5 Morgner A Miehlke S Labenz J \nEsomeprazole: prevention and treatment of NSAID-induced symptoms and ulcers . Expert Opin Pharmacother \n2007 ; 8 :975 –988 .17472543 \n6 Richter JE Kahrilas PJ Johanson J \nEsomeprazole Study Investigators . Efficacy and safety of esomeprazole compared with omeprazole in GERD patients with erosive esophagitis: a randomized controlled trial . Am J Gastroenterol \n2001 ; 96 :656 –665 .11280530 \n7 Maton PN Vakil NB Levine JG \nEsomeprazole Study Investigators . Safety and efficacy of long term esomeprazole therapy in patients with healed erosive oesophagitis . Drug Saf \n2001 ; 24 :625 –635 .11480494 \n8 Vakil NB Shaker R Johnson DA \nThe new proton pump inhibitor esomeprazole is effective as a maintenance therapy in GERD patients with healed erosive oesophagitis: a 6-month, randomized, double-blind, placebo-controlled study of efficacy and safety . Aliment Pharmacol Ther \n2001 ; 5 :927 –935 .\n9 Hasselgren B Claar-Nillson C Hasselgren C \nStudies in healthy volunteers do not show any electrocardiographic effects with esomeprazole . Clin Drug Invest \n2000 ; 20 :425 –431 .\n10 Warren JD Blumbergs PC Thompson PD \nRhabdomyolysis: a review . Muscle Nerve \n2002 ; 25 :332 –347 .11870710 \n11 Bosch X Poch E Grau JM \nRhabdomyolysis and acute kidney injury . N Engl J Med \n2009 ; 361 :62 –72 .19571284 \n12 Bagley WH Yang H Shah KH \nRhabdomyolysis . Intern Emerg Med \n2007 ; 2 :210 –218 .17909702 \n13 Holt SG Moore KP \nPathogenesis and treatment of renal dysfunction in rhabdomyolysis . Intensive Care Med \n2001 ; 27 :803 –811 .11430535 \n14 Allison RC Bedsole DL \nThe other medical causes of rhabdomyolysis . Am J Med Sci \n2003 ; 326 :79 –88 .12920439 \n15 Nozaki M Suzuki T Hirano M \nRhabdomyolysis associated with omeprazole . J Gastroenterol \n2004 ; 39 :86 .\n16 Bebarta VS King JA McDonough M \nProton pump inhibitor-induced rhabdomyolysis and hyponatremic delirium . Am J Emerg Med \n2008 ; 26 :519.e1 –519.e2 .\n17 Tanaka K Nakada TA Abe R \nOmeprazole-associated rhabdomyolysis . Crit Care \n2014 ; 18 :462 .25184508 \n18 Clark DW Strandell J \nMyopathy including polymyositis: a likely class adverse effect of proton pump inhibitors? \nEur J Clin Pharmacol \n2006 ; 62 :473 –479 .16758264 \n19 Tröger U Reiche I Jepsen MS \nEsomeprazole-induced rhabdomyolysis in a patient with heart failure . Intensive Care Med \n2010 ; 36 :1278 –1279 .20229039 \n20 Sipe BE Jones RJ Bokhart GH \nRhabdomyolysis causing AV blockade due to possible atorvastatin, esomeprazole, and clarithromycin interaction . Ann Pharmacother \n2003 ; 37 :808 –811 .12773066 \n21 Zvyaga T Chang SY Chen C \nEvaluation of six proton pump inhibitors as inhibitors of various human cytochromes P450: focus on cytochrome P450 2C19 . Drug Metab Dispos \n2012 ; 40 :1698 –1711 .22648560 \n22 Andersson T Hassan-Alin M Hasselgren G \nDrug interaction studies with esomeprazole, the (S)-isomer of omeprazole . Clin Pharmacokinet \n2001 ; 40 :523 –537 .11510629 \n23 Wilder-Smith C Röhss K Bondarov P \nEsomeprazole 40 mg administered intravenously (IV) as a 3-min. injection or 30-min. infusion provides the same effective acid control in healthy subjects . Gastroenterology \n2003 ; 124 :A233 .\n24 Röhss K Bondarov P Lundin C \nEsomeprazole 40 mg administered as a 30-minute intravenous infusion provides the same effective acid control as oral administration in healthy subjects . Gastroenterology \n2003 ; 124 \nsuppl 1 :A231 .\n25 Niazi M Ahlbom H Bondarov P \nPharmacokinetics of esomeprazole following varying intravenous administration rates . Basic Clin Pharmacol Toxicol \n2005 ; 97 :351 –354 .16364049 \n26 Hassan-Alin M Andersson T Bredberg E \nPharmacokinetics of esomeprazole after oral and intravenous administration of single and repeated doses to healthy subjects . Eur J Clin Pharmacol \n2000 ; 56 :665 –670 .11214773 \n27 Sivakumar K Dalakas MC \nAutoimmune syndrome induced by omeprazole . Lancet \n1994 ; 344 :619 –620 .\n\n", "fulltext_license": "CC BY", "issn_linking": "0025-7974", "issue": "95(29)", "journal": "Medicine", "keywords": null, "medline_ta": "Medicine (Baltimore)", "mesh_terms": "D000328:Adult; D002637:Chest Pain; D000072700:Conservative Treatment; D064098:Esomeprazole; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D054328:Proton Pump Inhibitors; D012206:Rhabdomyolysis", "nlm_unique_id": "2985248R", "other_id": null, "pages": "e4313", "pmc": null, "pmid": "27442680", "pubdate": "2016-07", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "11421866;11563995;16758264;18410837;16364049;17909702;16944963;20229039;11480494;12920439;11280530;7914991;18679668;11510629;11430535;11214773;17472543;19571284;12773066;11870710;14767743;22648560;25184508;11475467", "title": "Rhabdomyolysis associated with single-dose intravenous esomeprazole administration: A case report.", "title_normalized": "rhabdomyolysis associated 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"drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SODIUM CHLORIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG/ DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN /00002701/" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CANDESARTAN CILEXETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "8 MG/ DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CANDESARTAN CILEXETIL." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Rhabdomyolysis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "JEON D-H, KIM Y, KIM MJ, CHO HS, BAE EJ, CHANG S-H, ET AL. RHABDOMYOLYSIS ASSOCIATED WITH SINGLE-DOSE INTRAVENOUS ESOMEPRAZOLE ADMINISTRATION: A CASE REPORT. MEDICINE 2016;95(29):E4313.", "literaturereference_normalized": "rhabdomyolysis associated with single dose intravenous esomeprazole administration a case report", "qualification": "1", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20160831", "receivedate": "20160831", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12704182, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" } ]
{ "abstract": "The patient was a 55-year-old male who had prominent fasciculation and muscle cramps. Muscle weakness and atrophy of the trunk, respiratory system, and extremities gradually progressed. On the basis of these features, we diagnosed this patient as having amyotrophic lateral sclerosis (ALS), however, the upper motor neuron signs were not significant. Following the detection of the anti-voltage gated potassium channel (VGKC) complex antibody at 907.5 pM (normal < 100 pM) and repetitive discharge in a nerve conduction study, immunotherapy with intravenous immunoglobulin, methylprednisolone (mPSL), double filtration plasmapheresis (DFPP), ciclosporin, and rituximab was introduced. mPSL and DFPP showed only tentative effectiveness for fasciculation and muscle cramps, respectively. Thereafter, muscle weakness progressed. The patient died of type II respiratory failure at the age of 57 years, about 2 years after the onset of the disease. At autopsy, a histopathological diagnosis of ALS with lower-motor-predominant degeneration was made. Characteristic cellular features, including Bunina bodies in the remaining lower motor neurons and phosphorylated TAR DNA-binding protein 43-kDa (pTDP-43)-immunopositive inclusions in both upper and lower motor neuron systems, were evident. At present, an immunological role of the anti-VGKC complex antibody in the development of cramp-fasciculation syndrome has been speculated. In this ALS patient, the antibodies might be associated with pathomechanisms underlying the characteristic symptoms.", "affiliations": "Department of Neurology, Niigata City General Hospital.", "authors": "Sato\|Aki\|A\|;Sakai\|Naoko\|N\|;Shinbo\|Junsuke\|J\|;Hashidate\|Hideki\|H\|;Igarashi\|Shuichi\|S\|;Kakita\|Akiyoshi\|A\|;Yamazaki\|Motoyoshi\|M\|", "chemical_list": "D001323:Autoantibodies; D024642:Potassium Channels, Voltage-Gated", "country": "Japan", "delete": false, "doi": "10.5692/clinicalneurol.54.32", "fulltext": null, "fulltext_license": null, "issn_linking": "0009-918X", "issue": "54(1)", "journal": "Rinsho shinkeigaku = Clinical neurology", "keywords": null, "medline_ta": "Rinsho Shinkeigaku", "mesh_terms": "D000690:Amyotrophic Lateral Sclerosis; D001323:Autoantibodies; D001344:Autopsy; D005207:Fasciculation; D006801:Humans; D008297:Male; D008875:Middle Aged; D024642:Potassium Channels, Voltage-Gated", "nlm_unique_id": "0417466", "other_id": null, "pages": "32-7", "pmc": null, "pmid": "24429646", "pubdate": "2014", "publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article", "references": null, "title": "An autopsy case of amyotrophic lateral sclerosis with prominent muscle cramps, fasciculation, and high titer of anti-voltage gated potassium channel (VGKC) complex antibody.", "title_normalized": "an autopsy case of amyotrophic lateral sclerosis with prominent muscle cramps fasciculation and high titer of anti voltage gated potassium channel vgkc complex antibody" }	[ { "companynumb": "PHHY2014JP016990", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, 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"drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "RILUZOLE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RILUZOLE." } ], "patientagegroup": null, "patientonsetage": "55", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "55.5", "reaction": [ { "reactionmeddrapt": "Respiratory failure", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Disease progression", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Therapeutic response decreased", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Muscular weakness", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SATO A, SAKAI N, SHINBO J, HASHIDATE H, IGARASHI S, KAKITA A ET AL.. AN AUTOPSY CASE OF AMYOTROPHIC LATERAL SCLEROSIS WITH PROMINENT MUSCLE CRAMPS, FASCICULATION, AND HIGH TITER OF ANTI-VOLTAGE GATED POTASSIUM CHANNEL (VGKC) COMPLEX ANTIBODY. CLINICAL NEUROLOGY. 2014;54 (1):32-37", "literaturereference_normalized": "an autopsy case of amyotrophic lateral sclerosis with prominent muscle cramps fasciculation and high titer of anti voltage gated potassium channel vgkc complex antibody", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20141013", "receivedate": "20140213", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 9893544, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150529" } ]
{ "abstract": "BACKGROUND\nIn this study, the data of eight new patients in conjunction with previously reported cases with piperacillin-induced immune hemolytic anemia (PIHA) are described.\n\n\nMETHODS\nFive patients with cystic fibrosis and three patients with other disorders developed massive hemolysis after administration of piperacillin. Serologic tests were carried out using standard techniques. Tests for drug-dependent antibodies (ddab) were performed in the presence and absence of piperacillin and its ex vivo antigens (urine of patients treated with piperacillin).\n\n\nRESULTS\nHemolysis was acute and severe in all eight patients. The direct antiglobulin test was positive in all cases. Sera from four patients reacted with red blood cells (RBCs) in the presence of piperacillin as well as its ex vivo antigens. Sera from three patients showed positive reactivity with untreated RBCs in the presence of piperacillin, and the serum from the remaining patient was reactive only in the presence of piperacillin ex vivo antigens. Other patients with PIHA have been reported in the literature. Three of these patients also had cystic fibrosis.\n\n\nCONCLUSIONS\nTo date approximately 26 patients with PIHA have been described and at least eight of these patients had cystic fibrosis. It is unclear whether patients with cystic fibrosis might be susceptible in developing PIHA.", "affiliations": "Institute for Transfusion Medicine, Charité-University Medicine, Berlin, Germany.", "authors": "Mayer\|Beate\|B\|;Yürek\|Salih\|S\|;Salama\|Abdulgabar\|A\|", "chemical_list": "D000900:Anti-Bacterial Agents; D010878:Piperacillin", "country": "United States", "delete": false, "doi": "10.1111/j.1537-2995.2009.02544.x", "fulltext": null, "fulltext_license": null, "issn_linking": "0041-1132", "issue": "50(5)", "journal": "Transfusion", "keywords": null, "medline_ta": "Transfusion", "mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000744:Anemia, Hemolytic, Autoimmune; D000900:Anti-Bacterial Agents; D005260:Female; D006801:Humans; D008297:Male; D010878:Piperacillin", "nlm_unique_id": "0417360", "other_id": null, "pages": "1135-8", "pmc": null, "pmid": "20051057", "pubdate": "2010-05", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Piperacillin-induced immune hemolysis: new cases and a concise review of the literature.", "title_normalized": "piperacillin induced immune hemolysis new cases and a concise review of the literature" }	[ { "companynumb": "DE-IBIGEN-2021.09908", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PIPERACILLIN SODIUM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PIPERACILLIN." } ], "patientagegroup": "5", "patientonsetage": "19", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemolytic anaemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Autoimmune haemolytic anaemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Intravascular haemolysis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "BEATE MAYER, SALIH YREK, AND ABDULGABAR SALAMA. PIPERACILLIN INDUCED IMMUNE HEMOLYSIS: NEW CASES AND A CONCISE REVIEW OF THE LITERATURE. TRANSFUSION 2010?50:1135 1138. 10.1111/J.1537 2995.2009.02544.X.", "literaturereference_normalized": "piperacillin induced immune hemolysis new cases and a concise review of the literature", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20210223", "receivedate": "20210223", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18928774, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20210420" }, { "companynumb": "DE-IBIGEN-2021.09910", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PIPERACILLIN SODIUM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "()", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PIPERACILLIN." } ], "patientagegroup": "5", "patientonsetage": "29", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemolytic anaemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Intravascular haemolysis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Autoimmune haemolytic anaemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "BEATE MAYER, AND ABDULGABAR SALAMA. PIPERACILLIN?INDUCED IMMUNE HEMOLYSIS: NEW CASES AND A CONCISE?REVIEW OF THE LITERATURE. TRANSFUSION 2010?50:1135,1138. 2009", "literaturereference_normalized": "piperacillin induced immune hemolysis new cases and a concise review of the literature", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20210223", "receivedate": "20210223", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18928546, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20210420" }, { "companynumb": "DE-IBIGEN-2021.09909", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PIPERACILLIN SODIUM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "()", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PIPERACILLIN." } ], "patientagegroup": "5", "patientonsetage": "37", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Autoimmune haemolytic anaemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Intravascular haemolysis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Haemolytic anaemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "BEATE MAYER, SALIH AND ABDULGABAR SALAMA. PIPERACILLIN?INDUCED IMMUNE HEMOLYSIS: NEW CASES AND A CONCISE REVIEW OF THE LITERATURE. TRANSFUSION 2010?50:1135?1138.", "literaturereference_normalized": "piperacillin induced immune hemolysis new cases and a concise review of the literature", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20210223", "receivedate": "20210223", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18928899, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20210420" }, { "companynumb": "DE-IBIGEN-2021.09913", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "PIPERACILLIN SODIUM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "?", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PIPERACILLIN." } ], "patientagegroup": "4", "patientonsetage": "18", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemolytic anaemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Intravascular haemolysis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Autoimmune haemolytic anaemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "BEATE MAYER, SALIH AND ABDULGABAR SALAMA. PIPERACILLIN?INDUCED IMMUNE HEMOLYSIS: NEW CASES AND A CONCISE REVIEW OF THE LITERATURE. TRANSFUSION 2010?50:1135?1138. 2009.", "literaturereference_normalized": "piperacillin induced immune hemolysis new cases and a concise review of the literature", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20210223", "receivedate": "20210223", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18928643, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20210420" } ]
{ "abstract": "Central nervous system (CNS) histoplasmosis occurs in 5-20% of all cases and is most commonly seen in immunosuppressed patients who have acquired immunodeficiency syndrome (AIDS) or have received organ transplant. The prevalence of histoplasmosis in patients greater than 65 years old between the years of 1999-2008 in the state of Texas was about 2-3 cases per 100,000 patients year. Since 1990 with the discovery of Triazoles, itraconazole (ICZ) has become the standard initial and suppressive therapy in patients with mild-moderate histoplasmosis without CNS involvement. However, poor penetration of ICZ into the brain, in vitro fluconazole resistance and lack of controlled-trials pose challenge in the treatment of cerebral histoplasmosis.", "affiliations": "Internal Medicine, The University of Texas Health Science Center/Christus Good Shepherd Medical Center, Longview, USA.;Internal Medicine, The University of Texas Health Science Center/Christus Good Shepherd Medical Center, Longview, USA.;Internal Medicine, The University of Texas Health Science Center/Christus Good Shepherd Medical Center, Longview, USA.;Internal Medicine, The University of Texas Health Science Center/Christus Good Shepherd Medical Center, Longview, USA.;Internal Medicine, Methodist Richardson Medical Center, Richardson, USA.", "authors": "Peddi\|Prashanth\|P\|;Challa\|Tejo\|T\|;Meegada\|Sreenath\|S\|;Annakula\|Madhavi\|M\|;Mar\|Evan\|E\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.7759/cureus.7064", "fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.7064\nInternal Medicine\nHIV/AIDS\nInfectious Disease\nA Case of Histoplasmosis with Central Nervous System Relapse after Itraconazole Therapy Needs Further Research\nMuacevic Alexander Adler John R Peddi Prashanth 1 Challa Tejo 1 Meegada Sreenath 1 Annakula Madhavi 1 Mar Evan 2 \n1 \nInternal Medicine, The University of Texas Health Science Center/Christus Good Shepherd Medical Center, Longview, USA \n\n2 \nInternal Medicine, Methodist Richardson Medical Center, Richardson, USA \n\nSreenath Meegada [email protected]\n21 2 2020 \n2 2020 \n12 2 e706416 2 2020 21 2 2020 Copyright © 2020, Peddi et al.2020Peddi et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/28211-a-case-of-histoplasmosis-with-central-nervous-system-relapse-after-itraconazole-therapy-needs-further-researchCentral nervous system (CNS) histoplasmosis occurs in 5-20% of all cases and is most commonly seen in immunosuppressed patients who have acquired immunodeficiency syndrome (AIDS) or have received organ transplant. The prevalence of histoplasmosis in patients greater than 65 years old between the years of 1999-2008 in the state of Texas was about 2-3 cases per 100,000 patients year. Since 1990 with the discovery of Triazoles, itraconazole (ICZ) has become the standard initial and suppressive therapy in patients with mild-moderate histoplasmosis without CNS involvement. However, poor penetration of ICZ into the brain, in vitro fluconazole resistance and lack of controlled-trials pose challenge in the treatment of cerebral histoplasmosis.\n\nhistoplasmosisitraconazoletreatment failurecns penetrationring enhancing lesionsThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nHistoplasmosis is a fungal infection caused by Histoplasma capsulatum which is one of the common fungal respiratory infections, endemic in Africa, Latin America, Asia, central and southeastern states of the United States [1]. Most of the documented histoplasmosis infections are asymptomatic in immunocompetent individuals, and are self-resolving. Symptomatic cases of infections are seen in patients who are immunocompromised like acquired immunodeficiency syndrome (AIDS), transplant patients on immunosuppressants, patients with ventriculoperitoneal shunts, and patients on steroids [1]. Here we present a patient with history of adrenal histoplasmosis status post bilateral adrenalectomy presenting with central nervous system (CNS) histoplasmosis despite being on itraconazole (ICZ) therapy.\n\nCase presentation\nA 56-year-old white male from Texas with history of adrenal histoplasmosis status post bilateral adrenalectomy who had completed two weeks of Amphotericin-B and one year of ICZ treatment presented to us with encephalopathy for one day and weight loss for two months. The patient’s wife was present and stated that the patient had a shuffled walk, poor memory, and when the wife attempted to walk the patient he would be falling to his left side repeatedly. The patient had immediate and remote memory intact. However, his recent memory was diminished and he was not capable of remembering the past 1.5 days. It was noticed that the patient had trouble with repetition in speech, and his fluency appeared to be slowed. In regards to cerebellar function, a patient is capable of performing rapid alternating movements but experiences some difficulty in performing finger-to-nose test and hesitation towards the end when attempting to touch a finger. The patient had initial computed tomography (CT) imaging performed which showed multiple areas of vasogenic edema involving the frontal lobes bilaterally and the left parietal lobe. Shortly after initial imaging, the patient had a magnetic resonance imaging (MRI) brain, which revealed ring enhancing lesions throughout the brainstem, cerebellum and cerebral hemispheres (Figures 1-3).\n\nFigure 1 MRI brain with IV contrast showing ring enhancing lesions in cerebral cortex, one lesion close to ventricle (Arrows pointing)\nFigure 2 MRI brain showing ring enhancing lesion in cerebellar hemisphere (Arrow pointing)\nFigure 3 MRI brain different slice showing ring enhancing lesions in cerebral hemispheres (Arrows pointing)\nThe patient was started on IV Decadron whilst further workup was started and Infectious Disease was consulted. The patient was found to have an elevated erythrocyte sedimentation rate (ESR) of 48 mm/hr and C-reactive protein (CRP) of 19 mg/dL and urinary histoplasma antigen was positive. The patient was initially started on: Amphotericin B liposomal, Leucovorin, Pyrimethamine and Sulfadiazine. The patient also had negative toxoplasmosis and human immunodeficiency virus (HIV) workup. All treatments other than Amphotericin B liposomal were discontinued. An initial stereotactic brain biopsy and histoplasma polymerase chain reaction (PCR) were obtained, but after being examined both in house and after being sent to Washington University in St. Louis, MO, the sample was not able to decipher the diagnosis after 3-4 weeks. Tissue culture was positive for Histoplasma capsulatum per DNA probe. The patient experienced acute renal failure believed to be from Amphotericin B, so for a period of about two weeks before definitive diagnosis the patient was switched to IV fluconazole with resolution of his acute renal failure. Almost one month after the initial stereotactic biopsy, an open window brain biopsy of a granuloma occurred. Intraoperative pathology of the biopsy showed yeast consistent with histoplasmosis (Figure 4).\n\nFigure 4 Patient’s open window brain biopsy with Gomori methenamine silver stain positive for histoplasma\nSubsequent tissue cultures confirmed the diagnosis. He was treated with Amphotericin-B for six weeks followed by long-term fluconazole. His neurological impairment improved considerably and he is now back to his baseline mental status.\n\nDiscussion\nThe diagnosis of isolated CNS histoplasmosis can be quite challenging particularly in immunocompetent patients. However, a combination of high index of suspicion, clinical features, imaging studies and testing spinal fluid or urine for Histoplasma antigen might be useful. Identifying the histoplasma in the brain either by stereotactic or open biopsy remains gold standard for diagnosis of CNS histoplasma [1]. Patients with CNS histoplasmosis can present with chronic meningitis, encephalitis, hydrocephalus, parenchymal lesions involving the brain and spinal cord resulting in stroke, seizures, confusion, memory impairment [1,2]. Due to rarity of the CNS histoplasmosis and due to lack of randomized or comparative trials definitive treatment for CNS histoplasmosis in immunocompetent persons remains unclear. However, updated clinical practice guidelines issued in 2007 offered us guidance based on clinical experience and descriptive studies and provided two level III B recommendations which include 1) Liposomal amphotericin B (5.0 mg/kg daily for a total of 175 mg/kg given over 4-6 weeks) followed by itraconazole (200 mg two or three times daily) for at least one year and until resolution of CSF abnormalities, including Histoplasma antigen levels and 2) Blood levels of itraconazole (ICZ) should be obtained to ensure adequate drug exposure [3]. Checking the serum levels after initiation of therapy and monitoring clinical response by serial lumbar punctures, checking serum and urinary antigens is of paramount importance while patients undergoing proper treatment. With lack of treatment trials it is unclear what azole is preferred treatment for CNS histoplasmosis. Although ICZ has been found to be more active against H. capsulatum, it has poor penetration into the brain. P-glycoprotein-mediated efflux mechanism markedly limits the accumulation of itraconazole in brain tissue [4]. This results in sanctuary sites in the CNS and relapse while ICZ is used as maintenance treatment after amp-B induction in disseminated histoplasmosis, which might be the cause of CNS relapse in our patient. Fluconazole achieves excellent concentration of drugs into the CSF as well as brain parenchyma [5]. Review of the literature identified few reports where the use of fluconazole was highly successful despite its lower efficacy and high chance of developing resistance than itraconazole [6-8]. Patients who do not tolerate itraconazole, or unable to achieve adequate blood levels with either preparation, or are receiving concomitant medications that lead to serious drug interactions with itraconazole, fluconazole may be alternative option like our patient who relapsed while on ICZ therapy which could be either patient non-compliance or intolerance due to drug. Newer azoles (posaconazole, voriconazole) also demonstrate in vitro activity against H. capsulatum similar to itraconazole; absence of in vivo data makes them less favorable [9]. Until more research is done to establish the safety and efficacy of these new azole medications, these drugs are not encouraged to treat the CNS histoplasmosis. New drug delivery systems using nano-particle technology to achieve high concentrations of ICZ into brain tissue might be an option in the near future [10,11].\n\nConclusions\nPatients with disseminated histoplasmosis should be screened for CNS histoplasmosis as it may help to determine the type of treatment. Fluconazole has higher CSF and brain penetration. There are reported cases of successful treatment of CNS histoplasmosis with fluconazole. While it remains an alternative option for patients who do not tolerate itraconazole or fail to achieve target serum drug levels, more studies are needed to establish dosing, safety and efficacy. Newer azoles like posaconazole, voriconazole with in vitro activity against H. capsulatum and new drug delivery systems to achieve better CSF penetration show promise for treatment options in the future. Our case report highlights the need for further research in terms of standard of care for CNS histoplasmosis treatment.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Histoplasmosis with deep CNS involvement: case presentation with discussion and literature review J Neurol Surg Rep Hariri OR Minasian T Quadri SA Dyurgerova A Farr S Miulli DE Siddiqi J 167 172 76 2015 \n2 Central nervous system histoplasmosis: multicenter retrospective study on clinical features, diagnostic approach and outcome of treatment Medicine (Baltimore) Wheat J Myint T Guo Y 245 97 2018 \n3 Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America Clin Infect Dis Wheat LJ Freifeld AG Kleiman MB Baddley JW McKinsey DS Loyd JE Kauffman CA 807 825 45 2007 17806045 \n4 Clinical relevance of the pharmacokinetic interactions of azole antifungal drugs with other coadministered agents Clin Infect Dis Brüggemann RJ Alffenaar JW Blijlevens NM 1441 1458 48 2009 19361301 \n5 Diagnosis and management of central nervous system histoplasmosis Clin Infect Dis Wheat LJ Musial CE Jenny-Avital E 844 852 40 2005 15736018 \n6 A case of HIV-associated cerebral histoplasmosis successfully treated with fluconazole Eur J Clin Microbiol Infect Dis Knapp S Turnherr M Dekan G Willinger B Stingl G Rieger A 658 661 18 1999 10534189 \n7 Fluconazole therapy for histoplasmosis Clin Infect Dis McKinsey DS Kauffman CA Pappas PG 996 1001 23 1996 8922792 \n8 Disseminated histoplasmosis treated by boluses of fluconazole. (Article in French) Med Sante Trop Mandengue Ebenye C Takuefou Mfangam B Nouédoui C Atangana PJA 110 111 25 2015 24854365 \n9 Activity of newer triazoles against Histoplasma capsulatum from patients with AIDS who failed fluconazole J Antimicrob Chemother Wheat LJ Connolly P Smedema M 1235 1239 57 2006 16627592 \n10 Targeted brain delivery of itraconazole via RVG29 anchored nanoparticles J Drug Targeting Chen W Zhan C Gu B Meng Q Wang H Lu W Hou H 228 234 19 2011 \n11 Formulation and delivery of itraconazole to the brain using a nanolipid carrier system Int J Nanomed Lim WM Rajinikanth PS Mallikarjun C Kang Y 2117 2126 9 2014\n\n", "fulltext_license": "CC BY", "issn_linking": "2168-8184", "issue": "12(2)", "journal": "Cureus", "keywords": "cns penetration; histoplasmosis; itraconazole; ring enhancing lesions; treatment failure", "medline_ta": "Cureus", "mesh_terms": null, "nlm_unique_id": "101596737", "other_id": null, "pages": "e7064", "pmc": null, "pmid": "32226666", "pubdate": "2020-02-21", "publication_types": "D002363:Case Reports", "references": "19361301;8922792;24833900;24854365;29595679;17806045;20540685;10534189;16627592;26251798;15736018", "title": "A Case of Histoplasmosis with Central Nervous System Relapse after Itraconazole Therapy Needs Further Research.", "title_normalized": "a case of histoplasmosis with central nervous system relapse after itraconazole therapy needs further research" }	[ { "companynumb": "US-MAYNE PHARMA-2020MYN000207", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ITRACONAZOLE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "208901", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HISTOPLASMOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOLSURA" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Histoplasmosis disseminated", "reactionmeddraversionpt": "23.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "PEDDI P, CHALLA T, MEEGADA S, ANNAKULA M, MAR E. A CASE OF HISTOPLASMOSIS WITH CENTRAL NERVOUS SYSTEM RELAPSE AFTER ITRACONAZOLE THERAPY NEEDS FURTHER RESEARCH. CUREUS. 2020?12(2):E7064", "literaturereference_normalized": "a case of histoplasmosis with central nervous system relapse after itraconazole therapy needs further research", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200415", "receivedate": "20200415", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17671540, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200713" } ]
{ "abstract": "To analyze patterns of response in soft tissue sarcomas exposed to pazopanib using CT-morphologic and textural features and their suitability for evaluating therapeutic response.\nRetrospective evaluation of CT response and texture patterns in 33 patients (23 female; mean age: 61.2 years, range, 30-85 years) with soft tissue sarcomas treated with pazopanib from October 2008 to July 2017. Response evaluation was based on modified (m)CHOI-criteria and RECISTv.1.1 and classified as partial response (PR), stable disease (SD), progressive disease (PD). The following CT-texture (CTTA)-parameters were calculated: mean, entropy and uniformity of intensity/average/skewness/entropy of co-occurrence matrix and contrast of neighboring-gray-level-dependence-matrix.\nFollowing mCHOI-criteria, 12 patients achieved PR, 7 SD and 14 PD. As per RECISTv.1.1 9 patients obtained PR, 9 SD and 15 PD. Frequent patterns of response were tumor liquefaction and necrosis (n=4/33, 12.1% each). Further patterns included shrinkage and cavitation (n=2/33, 6.1% each). In responders, differences in mean heterogeneity (p=0.01), intensity (p=0.03), average (p=0.03) and entropy of skewness (p=0.01) were found at follow-up whereas in non-responders, CTTA-parameters did not change significantly. Baseline-CTTA-features differed between responders and non-responders in terms of uniformity of skewness (p=0.045). Baseline-CTTA-parameters did not correlate with any morphologic response pattern.\nMost frequent patterns of response to pazopanib were tumor liquefaction and necrosis. Single CT-textural features show strong association with the response to pazopanib-although limited in relation to specific response patterns.\nTumor liquefication and necrosis are important patterns of response to pazopanib. CT-texture analysis has limited associations with specific response patterns.", "affiliations": "Department of Diagnostic and Interventional Radiology, Eberhard-Karls-University, Hoppe-Seyler-Str.3, 72076 Tübingen, Germany.;Department of Diagnostic and Interventional Radiology, Ulm University, Albert-Einstein-Allee 23, 89081 Ulm, Germany.;Department of Diagnostic and Interventional Radiology, Eberhard-Karls-University, Hoppe-Seyler-Str.3, 72076 Tübingen, Germany.;Department of Diagnostic and Interventional Radiology, Eberhard-Karls-University, Hoppe-Seyler-Str.3, 72076 Tübingen, Germany.;Department of Diagnostic and Interventional Radiology, Eberhard-Karls-University, Hoppe-Seyler-Str.3, 72076 Tübingen, Germany.;Department of Diagnostic and Interventional Radiology, Eberhard-Karls-University, Hoppe-Seyler-Str.3, 72076 Tübingen, Germany.;Department of Diagnostic and Interventional Radiology, Eberhard-Karls-University, Hoppe-Seyler-Str.3, 72076 Tübingen, Germany.", "authors": "Esser\|Michael\|M\|;Kloth\|Cristopher\|C\|;Thaiss\|Wolfgang M\|WM\|;Reinert\|Christian P\|CP\|;Kraus\|Mareen S\|MS\|;Gast\|Gabriel Cc\|GC\|;Horger\|Marius\|M\|", "chemical_list": "D000970:Antineoplastic Agents; D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib", "country": "England", "delete": false, "doi": "10.1259/bjr.20190158", "fulltext": null, "fulltext_license": null, "issn_linking": "0007-1285", "issue": "92(1103)", "journal": "The British journal of radiology", "keywords": null, "medline_ta": "Br J Radiol", "mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D005260:Female; D006801:Humans; D007191:Indazoles; D008297:Male; D008875:Middle Aged; D011743:Pyrimidines; D012189:Retrospective Studies; D012509:Sarcoma; D012983:Soft Tissue Neoplasms; D013449:Sulfonamides; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome", "nlm_unique_id": "0373125", "other_id": null, "pages": "20190158", "pmc": null, "pmid": "31509443", "pubdate": "2019-11", "publication_types": "D016428:Journal Article", "references": "19097774;23093486;20456972;29800950;25526682;23714556;19451427;29857858;29846498;25302110;26500539;23079473;23857966;25793653;29230829;25143189;23109517;25798275;29404187;28652049;27663525;25953002;29152166;29127700;30292263;31113389;26119045;29550245;28898189;20610543;28807589;28895916;19261927;24346105", "title": "CT-morphologic and CT-textural patterns of response in inoperable soft tissue sarcomas treated with pazopanib-a preliminary retrospective cohort study.", "title_normalized": "ct morphologic and ct textural patterns of response in inoperable soft tissue sarcomas treated with pazopanib a preliminary retrospective cohort study" }	[ { "companynumb": "NVSC2019DE059859", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "PAZOPANIB HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "022465", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SOFT TISSUE SARCOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VOTRIENT" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Necrosis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ESSER M, KLOTH C, THAISS WM, REINERT CP, KRAUS MS, GAST GC ET AL.. CT-MORPHOLOGIC AND CT-TEXTURAL PATTERNS OF RESPONSE IN INOPERABLE SOFT TISSUE SARCOMAS TREATED WITH PAZOPANIB-A PRELIMINARY RETROSPECTIVE COHORT STUDY. BRITISH JOURNAL OF RADIOLOGY. 2019?92(1103):1-10", "literaturereference_normalized": "ct morphologic and ct textural patterns of response in inoperable soft tissue sarcomas treated with pazopanib a preliminary retrospective cohort study", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20191206", "receivedate": "20191206", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17123254, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200122" }, { "companynumb": "NVSC2019DE059825", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PAZOPANIB HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "022465", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "UNDIFFERENTIATED SARCOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VOTRIENT" } ], "patientagegroup": null, "patientonsetage": "69", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Therapy partial responder", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Necrosis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tumour pseudoprogression", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ESSER M, KLOTH C, THAISS WM, REINERT CP, KRAUS MS, GAST GC ET AL.. CT-MORPHOLOGIC AND CT-TEXTURAL PATTERNS OF RESPONSE IN INOPERABLE SOFT TISSUE SARCOMAS TREATED WITH PAZOPANIB-A PRELIMINARY RETROSPECTIVE COHORT STUDY. BRITISH JOURNAL OF RADIOLOGY. 2019?92(1103):1-10", "literaturereference_normalized": "ct morphologic and ct textural patterns of response in inoperable soft tissue sarcomas treated with pazopanib a preliminary retrospective cohort study", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20191206", "receivedate": "20191206", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17121747, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "NVSC2019DE059811", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "PAZOPANIB HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "022465", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VOTRIENT" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PAZOPANIB HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "022465", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "800 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "LEIOMYOSARCOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "800", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VOTRIENT" } ], "patientagegroup": null, "patientonsetage": "66", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Tumour necrosis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Intestinal perforation", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ESSER M, KLOTH C, THAISS WM, REINERT CP, KRAUS MS, GAST GC ET AL.. CT-MORPHOLOGIC AND CT-TEXTURAL PATTERNS OF RESPONSE IN INOPERABLE SOFT TISSUE SARCOMAS TREATED WITH PAZOPANIB-A PRELIMINARY RETROSPECTIVE COHORT STUDY. BRITISH JOURNAL OF RADIOLOGY. 2019?92(1103):1-10", "literaturereference_normalized": "ct morphologic and ct textural patterns of response in inoperable soft tissue sarcomas treated with pazopanib a preliminary retrospective cohort study", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20191206", "receivedate": "20191206", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17124377, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200122" }, { "companynumb": "NVSC2019DE059819", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PAZOPANIB HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "022465", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "LEIOMYOSARCOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VOTRIENT" } ], "patientagegroup": null, "patientonsetage": "55", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Necrosis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Therapy partial responder", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ESSER M, KLOTH C, THAISS WM, REINERT CP, KRAUS MS, GAST GC ET AL.. CT-MORPHOLOGIC AND CT-TEXTURAL PATTERNS OF RESPONSE IN INOPERABLE SOFT TISSUE SARCOMAS TREATED WITH PAZOPANIB-A PRELIMINARY RETROSPECTIVE COHORT STUDY. BRITISH JOURNAL OF RADIOLOGY. 2019?92(1103):1-10", "literaturereference_normalized": "ct morphologic and ct textural patterns of response in inoperable soft tissue sarcomas treated with pazopanib a preliminary retrospective cohort study", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20191206", "receivedate": "20191206", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17123036, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "NVSC2019DE059833", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PAZOPANIB HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "022465", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SYNOVIAL SARCOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VOTRIENT" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Synovial sarcoma", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Malignant neoplasm progression", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tumour necrosis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ESSER M, KLOTH C, THAISS WM, REINERT CP, KRAUS MS, GAST GC ET AL.. CT-MORPHOLOGIC AND CT-TEXTURAL PATTERNS OF RESPONSE IN INOPERABLE SOFT TISSUE SARCOMAS TREATED WITH PAZOPANIB-A PRELIMINARY RETROSPECTIVE COHORT STUDY. BRITISH JOURNAL OF RADIOLOGY. 2019?92(1103):1-10", "literaturereference_normalized": "ct morphologic and ct textural patterns of response in inoperable soft tissue sarcomas treated with pazopanib a preliminary retrospective cohort study", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20191206", "receivedate": "20191206", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17121752, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "NVSC2019DE059828", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PAZOPANIB HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "022465", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "LEIOMYOSARCOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VOTRIENT" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Leiomyosarcoma", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Necrosis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Malignant neoplasm progression", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ESSER M, KLOTH C, THAISS WM, REINERT CP, KRAUS MS, GAST GC ET AL.. CT-MORPHOLOGIC AND CT-TEXTURAL PATTERNS OF RESPONSE IN INOPERABLE SOFT TISSUE SARCOMAS TREATED WITH PAZOPANIB-A PRELIMINARY RETROSPECTIVE COHORT STUDY. BRITISH JOURNAL OF RADIOLOGY. 2019?92(1103):1-10", "literaturereference_normalized": "ct morphologic and ct textural patterns of response in inoperable soft tissue sarcomas treated with pazopanib a preliminary retrospective cohort study", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20191206", "receivedate": "20191206", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17120135, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "NVSC2019DE059838", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PAZOPANIB HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "022465", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SOFT TISSUE SARCOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VOTRIENT" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Necrosis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Therapy partial responder", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ESSER M, KLOTH C, THAISS WM, REINERT CP, KRAUS MS, GAST GC ET AL.. CT-MORPHOLOGIC AND CT-TEXTURAL PATTERNS OF RESPONSE IN INOPERABLE SOFT TISSUE SARCOMAS TREATED WITH PAZOPANIB-A PRELIMINARY RETROSPECTIVE COHORT STUDY. BRITISH JOURNAL OF RADIOLOGY. 2019?92(1103):1-10", "literaturereference_normalized": "ct morphologic and ct textural patterns of response in inoperable soft tissue sarcomas treated with pazopanib a preliminary retrospective cohort study", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20191208", "receivedate": "20191208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17125645, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" } ]
{ "abstract": "Chronic leg ulceration is a frequent condition in elderly patients. Chronic wounds that are nonresponsive to 3-month therapy affect approximately 6.5 million people in the United States with a prevalence of 1% and costs estimated at 25 billion dollars per year. Although the main causes are venous insufficiency, lower extremity arterial disease and diabetes, in many cases the etiology is multi-factorial. Approximately 20-23% of non-healing wounds that are refractory to vascular intervention have other etiologies including vasculitis, rheumatoid arthritis and Sjögren syndrome. Adverse drug interactions are the least commonly considered, especially those which involve disease-modifying anti-rheumatic drugs. The authors present a report on a female patient with reported Sjögren syndrome, multiple morbidities and non-healing lower limb ulceration that developed during treatment with methotrexate, and no significant improvement after discontinuation of the drug and after vascular surgery. Microvascular deterioration caused by beta-blockers was considered decisive. Calcium-blocker replacement brought complete healing in the follow-up.", "affiliations": "Department of Geriatrics, National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland.;Department of Geriatrics, National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland.;Department of Geriatrics, National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland.;Department of Geriatrics, National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland.", "authors": "Sławiński\|Piotr\|P\|;Radkowski\|Marcin\|M\|;Lewandowicz\|Andrzej\|A\|;Targowski\|Tomasz\|T\|", "chemical_list": null, "country": "Poland", "delete": false, "doi": "10.5114/reum.2019.86429", "fulltext": "\n==== Front\nReumatologiaReumatologiaRUReumatologia0034-62332084-9834Narodowy Instytut Geriatrii, Reumatologii i Rehabilitacji w Warszawie 8642910.5114/reum.2019.86429Case ReportMixed-etiology leg ulcers in a patient on long-term glucocorticoid therapy Sławiński Piotr Radkowski Marcin Lewandowicz Andrzej Targowski Tomasz Department of Geriatrics, National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, PolandAddress for correspondence: Piotr Sławiński, Department of Geriatrics, National Institute of Geriatrics, Rheumatology and Rehabilitation, 1 Spartańska St., 02-637 Warszawa, Poland. e-mail: [email protected] 6 2019 2019 57 3 173 177 26 2 2019 28 5 2019 Copyright: © 2019 Narodowy Instytut Geriatrii, Reumatologii i Rehabilitacji w Warszawie2019This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License, allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.Chronic leg ulceration is a frequent condition in elderly patients. Chronic wounds that are nonresponsive to 3-month therapy affect approximately 6.5 million people in the United States with a prevalence of 1% and costs estimated at 25 billion dollars per year. Although the main causes are venous insufficiency, lower extremity arterial disease and diabetes, in many cases the etiology is multi-factorial. Approximately 20–23% of non-healing wounds that are refractory to vascular intervention have other etiologies including vasculitis, rheumatoid arthritis and Sjögren syndrome. Adverse drug interactions are the least commonly considered, especially those which involve disease-modifying anti-rheumatic drugs.\n\nThe authors present a report on a female patient with reported Sjögren syndrome, multiple morbidities and non-healing lower limb ulceration that developed during treatment with methotrexate, and no significant improvement after discontinuation of the drug and after vascular surgery. Microvascular deterioration caused by beta-blockers was considered decisive. Calcium-blocker replacement brought complete healing in the follow-up.\n\nmicrocirculation disordersleg ulcerschronic ulcersbeta-blockers\n==== Body\nIntroduction\nChronic ulceration of lower limbs is a frequent condition with a prevalence of 3–5% in the population over 65 [1] and about 8% of elderly patients aged 85 and over. Around 50–70% of treated ulcers heal within 4–6 months, and 8% heal over the next 5 years [2]. Chronic wounds that are unresponsive to 3 months of appropriate wound care affect approximately 6.5 million people in the United States of America (US) with a prevalence of 1% and costs estimated at 25 billion dollars per year [3]. Although the main causes are venous insufficiency, lower extremity arterial disease and diabetes, in many cases the etiology is multi-factorial. In a study in the London population of patients with leg ulcers, venous disease was diagnosed simultaneously with arterial disease, diabetes, lymphedema and rheumatoid arthritis; in 35% of cases more than one cause of leg ulcers occurred [4].\n\nLegs ulcers are a frequent problem in patients with rheumatoid arthritis (RA) and in patients with systemic sclerosis. Approximately 10% of patients with RA experienced leg ulceration. Larger studies have found that at least half of the ulcers in these patients are of multifactorial etiology. Approximately 10% of patients with RA are affected by leg ulcers while as many as 10% of leg ulcers can be associated with RA [5]. Approximately 20–23% of non-healing wounds that are refractory to vascular intervention have other etiology including vasculitis, RA, scleroderma, systemic lupus erythematosus, psoriasis, pyoderma gangrenosum [6], and Sjögren syndrome [7]. Thus, for proper treatment of patients with leg ulcers, it is important to be aware of the differential diagnosis of leg ulceration.\n\nThis article presents a patient with diagnosis of Sjögren’s syndrome, multiple other morbidities and non-healing lower limb ulceration of mixed etiology and highlights the importance of drug selection to optimize microcirculation in anti-ulcerative treatment.\n\nCase report\nAn 82-year-old woman with a long history of sicca syndrome diagnosis, metabolic syndrome comprising obesity, arterial hypertension, and hyperlipidemia, as well as Hashimoto thyroiditis with thyroid insufficiency, congestive heart failure, chronic kidney disease, bilateral cataract and lower limb ulcers, was admitted to the Department of Geriatrics in July 2016 due to symptoms of acute circulatory failure with pitting edema of lower limbs.\n\nIn the last 10-year period, the patient had undergone long-term glucocorticosteroid treatment for Sjögren syndrome. There was no available medical documentation for this period. In 2014, the patient had been hospitalized in the rheumatology department because of acute exacerbation of arthralgia and myalgia shortly after a sudden glucocorticosteroids withdrawal. There were symmetrical hand arthralgias without other signs of inflammation but with an elevated erythrocyte sedimentation rate and C-reactive protein concentration, with negative rheumatoid factor (RF), negative anti-cyclic citrullinated peptide antibodies (ACPA) and antinuclear antibodies (ANA) titer 1 : 80 (Table I). Comparative hand (Fig. 1) and feet radiograms and spine radiograms showed mainly osteoarthritic changes with multiple geodes. Radiograms also revealed calcifications in arterial walls. Schirmer’s test showed decrease of tear secretion (3 mm/5 min in both eyes); there were signs and symptoms of conjunctivitis sicca.\n\nTable I Results of laboratory tests\n\nParameter\tMay 2014\tMarch 2016\tJuly 2016\tOctober 2016\tJuly 2018\t\nRF\t20.0 IU/ml\t20.0 IU/ml\tNo data\tNo data\tNo data\t\nACPA\t< 7.00 U/ml\t< 7.00 U/ml\tNo data\tNo data\tNo data\t\nANA\t1 : 80\t1 : 640\tNo data\tNo data\tNo data\t\nCRP\t58 mg/l\n552.39 nmol/l\t33 mg/l\n314.29 nmol/l\t45 mg/l\n428.58 nmol/l\t19 mg/l\n180.96 nmol/l\t11 mg/l\n104.76 nmol/l\t\nESR\t56 mm/h\t83 mm/h\t95 mm/h\t107 mm/h\t56 mm/h\t\nCreatinine\t0.7 mg/dl\n53.38 μmol/l\t2.0 mg/dl\n152.50 μmol/l\t1.0 mg/dl\n76.25 μmol/l\t0.9 mg/dl\n68.63 μmol/l\t1.10 mg/d\nl83.88 μmol/l\t\nNT-proBNP\tNo data\tNo data\t1100 pg/ml\n130.06 pmol/l\t936.8 pg/ml\n110.77 pmol/l\t783.5 pg/ml\n92.64 pmol/l\t\nRF – rheumatoid factor, ACPA – anti-cyclic citrullinated peptide antibodies, ANA – antinuclear antibodies, CRP – C-reactive protein, ESR – erythrocyte sedimentation rate, NT-proBNP – N-terminal pro-brain natriuretic peptide.\n\nFig. 1 Hands radiogram – osteoarthritic changes with geodes.\n\nThere was no objective confirmation of mouth dryness. The described patient did not agree to a biopsy of the minor salivary glands. The patient did not meet ACR/EULAR 2010 [8] criteria for diagnosis of RA. The patient was diagnosed with unclassified arthritis and successfully treated with methotrexate in an initial dose of 10 mg per week which was increased to 15 mg per week and a small dose of methylprednisolone.\n\nIn March 2016, the patient was re-hospitalized in the same department because of lower limb, shoulder girdle and knee pain, and calf edema. The patient reported night leg pain. Physical examination did not reveal symptoms of joint inflammation but extensive ulcers in both legs with purulent exudation were presented. Laboratory inflammatory markers were elevated, which is presented in Table I.\n\nUltrasonography of the joints and radiography findings matched osteoarthritis and did not support arthritis diagnosis at that moment. Therefore, methotrexate was discontinued and the patient was treated with antibiotics according to the wound culture. After the start of treatment outpatient care was recommended.\n\nDuring the next hospitalization to the Department of Geriatrics in July 2016, the patient reported weakness, dyspnea, orthopnea, mouth and eye dryness, night pain of both lower limbs resulting in sleeplessness and excessive consumption of non-steroid anti-inflammatory analgesics. Due to general weakness and pain the patient spent most time in bed. The list of medications taken by the patient included bisoprolol, ramipril, indapamide, L-thyroxine, allopurinol, naproxen, tramadol, acetaminophen, omeprazole, ibandronic acid and cholecalciferol.\n\nThe examination revealed two extensive ulcerations of lower limbs covering around 2/3 of the right and half of the left calf circumference (Fig. 2A). The patient was hypotonic and hypervolemic. There was crepitation on both lung bases indicating heart failure. The peripheral arterial pulse was hardly palpable. Laboratory tests revealed anemia, elevated inflammatory markers, hyponatremia, and elevated N-terminal pro-brain natriuretic peptide (NT-proBNP) (results summarized in Table I).\n\nFig. 2 Legs ulcerations – healing progress. (A) 13.07.2016, (B) 13.10.2016, (C) 27.01.2017, (D) 19.10.2017.\n\nKlebsiella pneumoniae and Serratia marcescens strains were cultured from the ulcers. Chronic heart failure exacerbation (NYHA III/IV), chronic kidney disease exacerbation, anemia of chronic disease and mixed-etiology leg ulcers were diagnosed.\n\nWounds were debrided, topical and systemic (empirical and targeted) antibiotics were used, analgesics, diuretics were administered and dressings were applied. Due to a significant reduction in hemoglobin concentration and to improve healing conditions it was necessary to transfuse the red blood cell concentrate. No evident positive effect was achieved in treatment of legs ulcers, which remained deep, inflamed, with purulent discharge. Resting lower limb pain persisted. The Doppler ultrasound revealed occlusion of the right femoral artery. The patient was referred for surgery in which femoral-popliteal bypass surgery was performed. A significant reduction in leg edema was observed. Pain complaints resolved almost completely.\n\nIn October 2016, about 3 months after the bypass surgery, the patient was admitted to a regional hospital with critical ischemia of the right lower limb suspected, with accompanying inflammation. Leg amputation was considered, but the patient did not agree to such radical treatment. Therefore the patient was transferred to the Department of Geriatrics for conservative treatment. On admission physical examination revealed extensive deep ulceration of 2/3 of the right calf circumference and two ulcerations on the outer surface of the left calf with dimensions comparable to those during the previous discharge (Fig. 2B), palpable right inguinal lymph nodes, which were confirmed in ultrasound, and large subcutaneous edema, especially of the right limb.\n\nBased on a repeated wound smear culture, targeted ceftazidime was administered intravenously for 11 days. A very slow healing process was noted, and microvascular disorders were taken into consideration as a decisive factor for the impaired healing. Actual cardiology treatment was modified – beta-blocker treatment was replaced with a non-dihydropyridine calcium channel blocker because of a suspected mechanism of peripheral microvascular deterioration by beta-receptor inhibition. Also a vasodilatory drug (bencyclane) was added.\n\nIn the next two weeks a significant reduction in the depth and dimensions of ulcers was observed. Control wound smear cultures were negative. The patient learned to walk with crutches and was discharged to outpatient care. The patient was informed about proper, intensified wound hygiene and change of dressings.\n\nIn the next few weeks, the healing of the left leg ulcer was complete and the right leg ulcer reduced to superficial and 1/3 of the previous size in a follow-up after several months (Figs. 2C and 2D). At the follow-up in July 2018, both legs were cicatrized, the patient was self-reliant in basic daily activities, walking on crutches, painless.\n\nDiscussion\nContemporary medicine offers a broad choice of therapies in leg ulcer healing, varying from conservative treatment with vasodilatory drugs, more and more sophisticated wound dressings, through more aggressive therapy for underlying autoimmune using disease-modifying antirheumatic drugs and biological agents such as TNF-α inhibitors and rituximab as treatment for RA-associated leg ulcers [6], to vascular surgery and split skin grafting [5].\n\nThis case report is intended to underline the role of differential diagnosis in the decision-making process of selecting the appropriate therapy in lower limb ulcers. The proper diagnosis of all factors in ulcer pathogenesis leads to the selection of a suitable therapy and successful healing. Studies showed that glucocorticoids may predispose to skin fragility and thus serve as a risk factor for ulceration in patients with RA and potential other autoimmune diseases as Sjögren’s syndrome. Sometimes it can be difficult to differentiate whether the cause of ulceration is the effect of the disease itself or an adverse effect of the treatment applied for this disease.\n\nIn Sjögren syndrome, leg ulcers may occur as a consequence of leukocytoclastic vasculitis [7]. In such cases, skin biopsy should be performed and other systemic vasculitides should be considered in the differential diagnosis. Laboratory testing for component of complement, anti-neutrophil antibodies and cryoglobulins is indicated. Signs of inflammatory vasculitis ulcers are very similar or the same as in more often ischemic or venous ulcers.\n\nIn this case, the diagnosis of Sjögren syndrome remains controversial. Unfortunately, there is no available objective medical documentation prior to 2014, and all data come from the anamnesis. The patient refused a salivary gland biopsy in the past. Moreover, starting from 2014, the patient did not fulfill the criteria of primary Sjögren syndrome at any stage of the therapy. Rheumatoid factor was negative, ANA titer was initially negative, only in 2016 they were 1 : 640 but without specificity. Anti-Ro/SSA, La/SSB and other ENA antibodies were not detected by dot-blot method in particular [8]. Maślińska et al. [9] describe a positive correlation between ANA titer, anti-Ro, anti-La antibodies and erythrocyte sedimentation rate (ESR) in patients with primary Sjögren syndrome, as important factors in the inflammatory process. Elevated C-reactive protein (CRP) and ESR in the present case were not associated with an autoimmune disease, but with a bacterial wound infection. Thus, we did not perform a skin biopsy and other immune tests. It is worth remembering that a geriatric patient can be afebrile even in a serious infection, and the only signs and symptoms could be discrete changes of mental state, weakness, falls, etc.\n\nWe believe that the reported mouth and eye dryness along with the positive Schirmer’s test were consequences of polypragmasy and the aging process. Smidt et al. [10] found in their cohort study that oral and ocular dryness in older people is correlated with the number of medications used and the number of comorbidities. A diagnosis of more than four diseases was related to 19.7% prevalence of oral and 16.4% prevalence of ocular dryness; the use of more than 6 medications was related to 19.6% prevalence of both. High prevalence and odds ratios for mouth dryness was associated with metabolic diseases (31%), intake of thyroid hormones (27%), beta-blockers (11.8%), paracetamol, and opioids (33.3%), proton pump inhibitors (15.9%), bisphosphonates (25%), diuretics (12.8%) and ACE inhibitors (12%). The patient described was treated with a majority of medications mentioned above.\n\nLeg ulcers emerged about six months after the treatment with methotrexate had started. This immunosuppressive agent changes the immune response to microbes, which in our opinion was crucial for this patient. Even a small injury to the skin exposed to glucocorticosteroids for many years could become easily infected. Unfavorable healing conditions, such as atherosclerotic ischemia, impaired venous flow and immobilization caused by pain promote deep and infected ulcerations. Unfortunately, in 2014, the clinical and radiological image was too unclear to definitely exclude autoimmune arthritis, and the patient was lost from observation for the next two years.\n\nAll these factors resulted in a “net disease” with ulcers of complex etiology as a main symptom. Although the patient received multidisciplinary treatment, a simple change of pharmacotherapy could rupture the net.\n\nMany studies evaluate positive effects of different approaches, but there are very few publications addressing adverse effects of joint therapies which may have detrimental effect on healing. One of our considerations is deterioration of microcirculation caused by the use of beta-blockers. While there is no doubt as to the beneficial influence of this pharmacological class on the circulatory system, we want to point out some specific situations, when these drugs could be harmful. Especially the population of elderly patients, with the burden of atherosclerosis involving small blood vessels, could be prone to deterioration of blood flow due to the blockade of peripheral β-1 receptors, even despite the use of a cardioselective drug (nebivolol) with a vasodilatory component, as we observed in the case described herein.\n\nConclusions\nIt seems that despite the lack of clear recommendations concerning this issue [11–13], replacing the beta blocker with a non-dihydropyridine calcium channel blocker could be critical for healing leg ulcers in some groups of elderly patients.\n\nThe authors declare no conflicts of interest.\n\nAcknowledgments\nThe authors would like to thank Professor Iwona Sudoł-Szopińska, Head of the Radiology Department in the National Institute of Geriatrics, Rheumatology and Rehabilitation for providing them with access to the radiology imaging, and would like to address words of particular gratitude to Doctor Agnieszka Skoczylas for her valuable comments concerning their paper.\n==== Refs\nReferences\n1 Mekkes JR Loots MA Van Der Wal AC Bos JD Causes, investigation and treatment of leg ulceration Br J Dermatol 2003 148 388 401 12653729 \n2 Tendera M Aboyans V Barterlink ML and ESC Committee for Practice Guidelines. ESC Guidelines on the diagnosis and treatment of peripheral artery diseases: Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries: the Task Force on the Diagnosis and Treatment of Peripheral Artery Diseases of the European Society of Cardiology (ESC) Eur Heart J 2011 32 2851 2906 21873417 \n3 Shanmugam VK Angra D Rahim H McNish S Vasculitic and autoimmune wounds J Vasc Surg Venous Lymphat Disord 2017 5 280 292 28214498 \n4 Moffatt CJ Franks PJ Doherty DC Prevalence of leg ulceration in a London population QIM 2004 97 431 471 \n5 Hafne J Schneider E Burg G Cassina PC Management of leg ulcers in patients with rheumatoid arthritis or systemic sclerosis: The importance of concomitant arterial and venous disease J Vasc Surg 2000 32 322 329 10917993 \n6 Shanmugam VK Vasculitic Diseases and Prothrombotic States Contributing to Delayed Healing in Chronic Wounds Curr Dermatol Rep 2016 5 270 277 27833788 \n7 Chapnick SL Merkel PA Skin ulcers in a patient with Sjogren’s Syndrome Arthritis Care Res (Hoboken) 2010 62 1040 1046 20235199 \n8 Aletaha D Neogi T Silman AJ 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative Arthritis Rheum 2010 62 2569 2581 20872595 \n9 Maślińska M Kontny E Kwiatkowska B The relationship between the presence of autoantibodies, indicators of local and systemic inflammation, the serum concentration of B-cell activating factor (BAFF) and the intensity of salivary gland infiltration in patients with primary Sjögren’s syndrome – a preliminary study Reumatologia 2015 53 321 327 27407265 \n10 Smidt D Torpet LA Nauntofte B Associations between oral and ocular dryness, labial and whole salivary flow rates, systemic diseases and medications in a sample of older people Community Debt Oral Epidemiol 2011 39 276 288 \n11 Frołow M Leśniak W Masłowski L Przewlekłe niedokrwienie kończyn dolnych Interna Szczeklika, Medycyna Praktyczna, Kraków 2018 496 503 \n12 Paravastu SC Mendonca DA Da Silva A Beta blockers for peripheral arterial disease Cochrane Database Syst Rev 2013 CD005508 24027118 \n13 Csiki Z Garai I Shemirani AH The effect of metoprolol alone and combined metoprolol-felodipin on the digital microcirculation of patients with primary Raynaud’s syndrome Microvasc Res 2011 82 84 87 21515290\n\n", "fulltext_license": "CC BY-NC-SA", "issn_linking": "0034-6233", "issue": "57(3)", "journal": "Reumatologia", "keywords": "beta-blockers; chronic ulcers; leg ulcers; microcirculation disorders", "medline_ta": "Reumatologia", "mesh_terms": null, "nlm_unique_id": "20130190R", "other_id": null, "pages": "173-177", "pmc": null, "pmid": "31462834", "pubdate": "2019", "publication_types": "D002363:Case Reports", "references": "10917993;12653729;15208431;20235199;20872595;21070322;21515290;21873417;24027118;27407265;27833788;28214498", "title": "Mixed-etiology leg ulcers in a 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"drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "L-THYROXINE /00068001/" } ], "patientagegroup": null, "patientonsetage": "82", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Dry eye", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Insomnia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Pain in extremity", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dry mouth", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Impaired healing", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SLAWINSKI P, RADKOWSKI M, LEWANDOWICZ A, TARGOWSKI T. MIXED-ETIOLOGY LEG ULCERS IN A PATIENT ON LONG-TERM GLUCOCORTICOID THERAPY. REUMATOLOGIA 2019?57(3):173-177.", "literaturereference_normalized": "mixed etiology leg ulcers in a patient on long term glucocorticoid therapy", "qualification": "3", "reportercountry": "PL" }, "primarysourcecountry": "PL", "receiptdate": "20190808", "receivedate": "20190808", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16683308, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20191004" }, { "companynumb": "PL-ROCHE-2389340", "fulfillexpeditecriteria": "1", "occurcountry": "PL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PARACETAMOL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CHOLECALCIFEROL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CHOLECALCIFEROL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "NAPROXEN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NAPROXEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBANDRONIC ACID" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021455", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBANDRONIC ACID." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN,UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ARTHRITIS", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "INDAPAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INDAPAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVOTHYROXINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOTHYROXINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TRAMADOL HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAMADOL HYDROCHLORIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BISOPROLOL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BISOPROLOL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN,UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ALLOPURINOL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALLOPURINOL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RAMIPRIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RAMIPRIL." } ], "patientagegroup": null, "patientonsetage": "82", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Asthenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Serratia infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pain in extremity", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Orthopnoea", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dyspnoea", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dry mouth", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Skin ulcer", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Insomnia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dry eye", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Klebsiella infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201603" } }, "primarysource": { "literaturereference": "STAWINSKI P, RADKOWSKI M, LEWANDOWICZ A AND TARGOWSKI T. MIXED?ETIOLOGY LEG ULCERS IN A PATIENT ON LONG?TERM GLUCOCORTICOID THERAPY. REUMATOLOGIA 2019?57 (3):173?7.", "literaturereference_normalized": "mixed etiology leg ulcers in a patient on long term glucocorticoid therapy", "qualification": "1", "reportercountry": "PL" }, "primarysourcecountry": "PL", "receiptdate": "20191022", "receivedate": "20191022", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16944388, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20201105" }, { "companynumb": "PL-JNJFOC-20190804474", "fulfillexpeditecriteria": "1", "occurcountry": "PL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBANDRONIC ACID" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBANDRONIC ACID." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ARTHRITIS", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "201509", "drugstartdateformat": "610", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "DOSE INCREASED", "drugenddate": "201603", "drugenddateformat": "610", "drugindication": null, "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "SMALL DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2016", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ALLOPURINOL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, 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"drugadministrationroute": "065", "drugauthorizationnumb": "019872", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PARACETAMOL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RAMIPRIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RAMIPRIL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "NAPROXEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NAPROXEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVOTHYROXINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOTHYROXINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "INDAPAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INDAPAMIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "BISOPROLOL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BISOPROLOL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TRAMADOL HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAMADOL HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": "82", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Dry eye", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dry mouth", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201607" } }, "primarysource": { "literaturereference": "SLAWINSKI P, RADKOWSKI M, LEWANDOWICZ A, TARGOWSKI T. MIXED?ETIOLOGY LEG ULCERS IN A PATIENT ON LONG?TERM GLUCOCORTICOID THERAPY. REUMATOLOGIA. 2019?57 (3):173?177.", "literaturereference_normalized": "mixed etiology leg ulcers in a patient on long term glucocorticoid therapy", "qualification": "1", "reportercountry": "PL" }, "primarysourcecountry": "PL", "receiptdate": "20200615", "receivedate": "20190813", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16695796, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20201104" }, { "companynumb": "PL-ACCORD-149475", "fulfillexpeditecriteria": "1", "occurcountry": "PL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "SMALL DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2016", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RAMIPRIL" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "202392", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RAMIPRIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CHOLECALCIFEROL" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "COLECALCIFEROL" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "040716", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201509", "drugstartdateformat": "610", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PARACETAMOL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBANDRONIC ACID" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "206058", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBANDRONIC ACID." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVOTHYROXINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOTHYROXINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "INDAPAMIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INDAPAMIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "BISOPROLOL" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BISOPROLOL" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "040716", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DOSE INCREASED", "drugenddate": "201603", "drugenddateformat": "610", "drugindication": "ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TRAMADOL" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAMADOL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALLOPURINOL" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALLOPURINOL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "NAPROXEN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NAPROXEN." } ], "patientagegroup": null, "patientonsetage": "82", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Serratia infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Dry mouth", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Skin ulcer", "reactionmeddraversionpt": "23.1", "reactionoutcome": "4" }, { "reactionmeddrapt": "Dry eye", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Klebsiella infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201603" } }, "primarysource": { "literaturereference": "SLAWINSKI P, RADKOWSKI M, LEWANDOWICZ A, TARGOWSKI T. MIXED?ETIOLOGY LEG ULCERS IN A PATIENT ON LONG?TERM GLUCOCORTICOID THERAPY. REUMATOLOGIA. 2019?57(3):173?177.", "literaturereference_normalized": "mixed etiology leg ulcers in a patient on long term glucocorticoid therapy", "qualification": "1", "reportercountry": "PL" }, "primarysourcecountry": "PL", "receiptdate": "20190806", "receivedate": "20190730", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16646289, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201104" }, { "companynumb": "PL-TEVA-2019-PL-1093605", "fulfillexpeditecriteria": "1", "occurcountry": "PL", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "BISOPROLOL" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "19982", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BISOPROLOL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "NAPROXEN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NAPROXEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBANDRONIC ACID" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBANDRONIC ACID." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "81099", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG/WEEK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", 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"activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "SMALL DOSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RAMIPRIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RAMIPRIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVOTHYROXINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "L?THYROXINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALLOPURINOL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALLOPURINOL." } ], "patientagegroup": null, "patientonsetage": "82", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Dry eye", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Dry mouth", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Klebsiella infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Serratia infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Insomnia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Skin ulcer", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Impaired healing", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SLAWINSKI P, RADKOWSKI M, LEWANDOWICZ A, TARGOWSKI T. MIXED?ETIOLOGY LEG ULCERS IN A PATIENT ON LONG?TERM GLUCOCORTICOID THERAPY. REUMATOLOGIA 2019?57(3):173?177.", "literaturereference_normalized": "mixed etiology leg ulcers in a patient on long term glucocorticoid therapy", "qualification": "3", "reportercountry": "PL" }, "primarysourcecountry": "PL", "receiptdate": "20190912", "receivedate": "20190820", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16718752, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20201105" }, { "companynumb": "PL-ORION CORPORATION ORION PHARMA-19_00006654", "fulfillexpeditecriteria": "1", "occurcountry": "PL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "INDAPAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INDAPAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBANDRONIC ACID" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBANDRONIC ACID." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVOTHYROXINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED 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"drugseparatedosagenumb": null, "drugstartdate": "2016", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RAMIPRIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, 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"ALLOPURINOL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALLOPURINOL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CHOLECALCIFEROL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CHOLECALCIFEROL" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "BISOPROLOL" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BISOPROLOL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ARTHRITIS", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "201509", "drugstartdateformat": "610", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TRAMADOL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAMADOL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "NAPROXEN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NAPROXEN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DOSE INCREASED", "drugenddate": "201603", "drugenddateformat": "610", "drugindication": null, "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." } ], "patientagegroup": null, "patientonsetage": "82", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Skin ulcer", "reactionmeddraversionpt": "23.1", "reactionoutcome": "4" }, { "reactionmeddrapt": "Chronic kidney disease", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Infected skin ulcer", "reactionmeddraversionpt": "23.1", "reactionoutcome": "4" }, { "reactionmeddrapt": "Cardiac failure chronic", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Impaired healing", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Klebsiella infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Anaemia of chronic disease", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Serratia infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2016" } }, "primarysource": { "literaturereference": "SLAWINSKI P, RADKOWSKI M. MIXED?ETIOLOGY LEG ULCERS IN A PATIENT ON LONG?TERM GLUCOCORTICOID THERAPY. REUMATOLOGIA. 2019?57(3):173?7.", "literaturereference_normalized": "mixed etiology leg ulcers in a patient on long term glucocorticoid therapy", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": null, "receiptdate": "20190801", "receivedate": "20190729", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16641860, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201104" }, { "companynumb": "PL-PFIZER INC-2019320250", "fulfillexpeditecriteria": "1", "occurcountry": "PL", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": "1", 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"activesubstance": { "activesubstancename": "CHOLECALCIFEROL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CHOLECALCIFEROL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RAMIPRIL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RAMIPRIL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, 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"drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NAPROXEN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "INDAPAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INDAPAMIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ALLOPURINOL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALLOPURINOL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "IBANDRONIC ACID" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBANDRONIC ACID." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PARACETAMOL" } ], "patientagegroup": null, "patientonsetage": "82", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Skin ulcer", "reactionmeddraversionpt": "23.0", "reactionoutcome": "4" }, { "reactionmeddrapt": "Klebsiella infection", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Dry eye", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dry mouth", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Insomnia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Serratia infection", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pain in extremity", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201603" } }, "primarysource": { "literaturereference": "SLAWINSKI, P.. MIXED-ETIOLOGY LEG ULCERS IN A PATIENT ON LONG-TERM GLUCOCORTICOID THERAPY. REUMATOLOGIA. 2019?57(3):173-177", "literaturereference_normalized": "mixed etiology leg ulcers in a patient on long term glucocorticoid therapy", "qualification": "1", "reportercountry": "PL" }, "primarysourcecountry": "PL", "receiptdate": "20200619", "receivedate": "20190730", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16647200, "safetyreportversion": 8, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200713" }, { "companynumb": "PL-SA-2019SA199741", "fulfillexpeditecriteria": "1", "occurcountry": "PL", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "BISOPROLOL" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BISOPROLOL SALT NOT SPECIFIED" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVOTHYROXINE SODIUM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK UNK, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RAMIPRIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBANDRONIC ACID" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBANDRONIC ACID." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "INDAPAMIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "018538", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INDAPAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "NAPROXEN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NAPROXEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PARACETAMOL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALLOPURINOL" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALLOPURINOL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PARACETAMOL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RAMIPRIL" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RAMIPRIL." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Insomnia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Renal failure", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intentional product misuse", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Crepitations", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiac failure", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Asthenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypervolaemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dry mouth", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Klebsiella infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Serratia infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pain", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Peripheral swelling", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pain in extremity", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Dyspnoea", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Orthopnoea", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hyponatraemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiac failure chronic", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Skin ulcer", "reactionmeddraversionpt": "23.1", "reactionoutcome": "4" }, { "reactionmeddrapt": "Hypotonia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dry eye", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201603" } }, "primarysource": { "literaturereference": "SLAWINSKI P., RADKOWSKI M., LEWANDOWICZ A., TARGOWSKI T. MIXED?ETIOLOGY LEG ULCERS IN A PATIENT ON LONG?TERM GLUCOCORTICOID THERAPY. REUMATOLOGIA. 2019?57(3):173?177", "literaturereference_normalized": "mixed etiology leg ulcers in a patient on long term glucocorticoid therapy", "qualification": "1", "reportercountry": "PL" }, "primarysourcecountry": "PL", "receiptdate": "20200611", "receivedate": "20190731", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16654003, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201104" }, { "companynumb": "PL-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-216546", "fulfillexpeditecriteria": "1", "occurcountry": "PL", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "201749", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SJOGREN^S SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SJOGREN^S SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Skin ulcer", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SLAWINSKI P, RADKOWSKI M, LEWANDOWICZ A, TARGOWSKI T. MIXED-ETIOLOGY LEG ULCERS IN A PATIENT ON LONG-TERM GLUCOCORTICOID THERAPY. REUMATOLOGIA. 2019?57(3):173-177", "literaturereference_normalized": "mixed etiology leg ulcers in a patient on long term glucocorticoid therapy", "qualification": "3", "reportercountry": "PL" }, "primarysourcecountry": "PL", "receiptdate": "20190812", "receivedate": "20190812", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16691533, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191004" } ]
{ "abstract": "Congenital chylothorax (CC) can result from a congenital malformation or an acquired obstruction or disruption of the thoracic duct. Recently, oral administration of the phosphodiesterase-5 inhibitor, sildenafil, was reported to be effective in resolving non-pulmonary lymphatic malformations in infants and young children. We report a case of CC in a late preterm infant with congenital pulmonary lymphangiectasia where octreotide was not effective, but management with oral sildenafil was successful.", "affiliations": "Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA.;Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA.", "authors": "Malleske\|D T\|DT\|;Yoder\|B A\|BA\|", "chemical_list": "D058986:Phosphodiesterase 5 Inhibitors; D000068677:Sildenafil Citrate", "country": "United States", "delete": false, "doi": "10.1038/jp.2015.10", "fulltext": null, "fulltext_license": null, "issn_linking": "0743-8346", "issue": "35(5)", "journal": "Journal of perinatology : official journal of the California Perinatal Association", "keywords": null, "medline_ta": "J Perinatol", "mesh_terms": "D002916:Chylothorax; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007235:Infant, Premature, Diseases; D008168:Lung; D008171:Lung Diseases; D008200:Lymphangiectasis; D058986:Phosphodiesterase 5 Inhibitors; D000068677:Sildenafil Citrate; D014057:Tomography, X-Ray Computed", "nlm_unique_id": "8501884", "other_id": null, "pages": "384-6", "pmc": null, "pmid": "25917021", "pubdate": "2015-05", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": "22024836;24656411;21364190;22564297;23257321;19019226;17855621;22276841;24997116;15798894;16801173;21538325;15109074;24446440;24372911", "title": "Congenital chylothorax treated with oral sildenafil: a case report and review of the literature.", "title_normalized": "congenital chylothorax treated with oral sildenafil a case report and review of the literature" }	[ { "companynumb": "PHHY2015US174416", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "NITRIC OXIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPOXIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NITRIC OXIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "OCTREOTIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "019667", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 UG/KG, QH", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHYLOTHORAX", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OCTREOTIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "HUMAN IMMUNOGLOBULIN G" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPOGAMMAGLOBULINAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IMMUNOGLOBULIN I.V" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "OCTREOTIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "019667", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY LYMPHANGIECTASIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OCTREOTIDE." } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": "3.28", "reaction": [ { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Chylothorax", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "MALLESKE DT, YODER BA. CONGENITAL CHYLOTHORAX TREATED WITH ORAL SILDENAFIL: A CASE REPORT AND REVIEW OF THE LITERATURE. JOURNAL OF PERINATOLOGY. 2015?35:384-6", "literaturereference_normalized": "congenital chylothorax treated with oral sildenafil a case report and review of the literature", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160216", "receivedate": "20160216", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12080863, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160526" } ]
{ "abstract": "Lamotrigine overdose usually follows a benign pattern, and the majority of cases reported involve a co-ingestant. Prior reports have suggested the possible use of intravenous lipid emulsion in cases of severe sodium channel blockade. We describe the electrocardiographic changes in a massive lamotrigine overdose treated with intravenous lipid emulsion. A 36-year-old male with bipolar disorder ingested 13.5 g of lamotrigine in a suicidal attempt. The lamotrigine level was 78.0 μg/mL. Comprehensive drug screen was negative for all screened compounds. The electrocardiogram demonstrated a prolonged QRS complex and signs suggestive of sodium channel blockade. Refractory to treatment with sodium bicarbonate was treated with intravenous lipid emulsion, with immediate resolution of the electrocardiographic changes. Lamotrigine inhibits the voltage-gated sodium channel opening, attenuating the release of excitatory neurotransmitters. Cardiac intraventricular conduction could be delayed in cases of lamotrigine overdose resulting in QRS and QTc prolongation and R waves >3 mm in leads I and aVR. A potential role for intravenous lipid emulsion therapy has been described in patients with toxic levels of lamotrigine and electrocardiographic changes refractory to the treatment with sodium bicarbonate. Intravenous lipid emulsion has been successfully used in the treatment of lamotrigine cardiac toxicity.", "affiliations": "Division of Cardiology, St. Luke's - Roosevelt Hospital Center, Mount Sinai Health System, Icahn School of Medicine, New York, NY, 10025, USA.;Department of Medicine, St. Luke's - Roosevelt Hospital Center, Mount Sinai Health System, Icahn School of Medicine, 1111 Amsterdam Avenue, New York, NY, 10025, USA. [email protected].;Division of Cardiology, St. Luke's - Roosevelt Hospital Center, Mount Sinai Health System, Icahn School of Medicine, New York, NY, 10025, USA.", "authors": "Chavez\|Patricia\|P\|;Casso Dominguez\|Abel\|A\|;Herzog\|Eyal\|E\|", "chemical_list": "D018692:Antimanic Agents; D014227:Triazines; D061567:Voltage-Gated Sodium Channel Blockers; D000077213:Lamotrigine", "country": "United States", "delete": false, "doi": "10.1007/s12012-014-9300-0", "fulltext": null, "fulltext_license": null, "issn_linking": "1530-7905", "issue": "15(4)", "journal": "Cardiovascular toxicology", "keywords": "Electrocardiogram; Intravenous lipid emulsion; Intraventricular conduction delay; Lamotrigine", "medline_ta": "Cardiovasc Toxicol", "mesh_terms": "D000328:Adult; D018692:Antimanic Agents; D001145:Arrhythmias, Cardiac; D001714:Bipolar Disorder; D062787:Drug Overdose; D004562:Electrocardiography; D006329:Heart Conduction System; D006339:Heart Rate; D006801:Humans; D000077213:Lamotrigine; D008297:Male; D013406:Suicide, Attempted; D013997:Time Factors; D016896:Treatment Outcome; D014227:Triazines; D061567:Voltage-Gated Sodium Channel Blockers", "nlm_unique_id": "101135818", "other_id": null, "pages": "394-8", "pmc": null, "pmid": "25448877", "pubdate": "2015-10", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Evolving Electrocardiographic Changes in Lamotrigine Overdose: A Case Report and Literature Review.", "title_normalized": "evolving electrocardiographic changes in lamotrigine overdose a case report and literature review" }	[ { "companynumb": "US-CIPLA LTD.-2015US04654", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LISINOPRIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LISINOPRIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "077073", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMLODIPINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "EGG PHOSPHOLIPIDS\\SAFFLOWER OIL\\SOYBEAN OIL" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 GM/DL BOLUS", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FAT EMULSION NOS" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute lung injury", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Shock", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CHAVEZ P, DOMINGUEZ A AND HERZOG E. EVOLVING ELECTROCARDIOGRAPHIC CHANGES IN LAMOTRIGINE OVERDOSE: A CASE REPORT AND LITERATURE REVIEW. 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EVOLVING ELECTROCARDIOGRAPHIC CHANGES IN LAMOTRIGINE OVERDOSE: A CASE REPORT AND LITERATURE REVIEW. 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"reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CHAVEZ P, CASSO DOMINGUEZ A, HERZOG E. EVOLVING ELECTROCARDIOGRAPHIC CHANGES IN LAMOTRIGINE OVERDOSE: A CASE REPORT AND LITERATURE REVIEW. 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EVOLVING ELECTROCARDIOGRAPHIC CHANGES IN LAMOTRIGINE OVERDOSE: A CASE REPORT AND LITERATURE REVIEW. 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EVOLVING ELECTROCARDIOGRAPHIC CHANGES IN LAMOTRIGINE OVERDOSE: A CASE REPORT AND LITERATURE REVIEW.. 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EVOLVING ELECTROCARDIOGRAPHIC CHANGES IN LAMOTRIGINE OVERDOSE: A CASE REPORT AND LITERATURE REVIEW. 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EVOLVING ELECTROCARDIOGRAPHIC CHANGES IN LAMOTRIGINE OVERDOSE: A CASE REPORT AND LITERATURE REVIEW. 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"drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NOREPINEPHRINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "EGG PHOSPHOLIPIDS\\SAFFLOWER OIL\\SOYBEAN OIL" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100-ML BOLUS OF 20% LIPID EMULSION", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "012", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FAT EMULSION NOS" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Circulatory collapse", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Acute lung injury", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Tremor", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sinus tachycardia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Generalised tonic-clonic seizure", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pneumonia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Ventricular fibrillation", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pineal gland cyst", "reactionmeddraversionpt": "18.1", "reactionoutcome": null }, { "reactionmeddrapt": "Ventricular tachycardia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pulmonary oedema", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pleural effusion", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Memory impairment", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Coordination abnormal", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intentional overdose", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cerebral disorder", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Brain injury", "reactionmeddraversionpt": "18.1", "reactionoutcome": null }, { "reactionmeddrapt": "Lung consolidation", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Fine motor skill dysfunction", "reactionmeddraversionpt": "18.1", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "DOMINGUEZ A, CHAVEZ P AND HERZOG E. EVOLVING ELECTROCARDIOGRAPHIC CHANGES IN LAMOTRIGINE OVERDOSE: A CASE REPORT AND LITERATURE REVIEW. CARDIOVASC TOXICOL. 2015?15:394-398", "literaturereference_normalized": "evolving electrocardiographic changes in lamotrigine overdose a case report and literature review", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20151019", "receivedate": "20151019", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11639942, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160304" }, { "companynumb": "US-GLENMARK PHARMACEUTICALS EUROPE LIMITED-2015GMK020132", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LAMOTRIGINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "079099", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "13.5 G, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "13.5", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMOTRIGINE." } ], "patientagegroup": null, "patientonsetage": "36", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Intentional overdose", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Electrocardiogram QRS complex prolonged", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Suicide attempt", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CHAVEZ P, CASSO DOMINGUEZ A, HERZOG E. EVOLVING ELECTROCARDIOGRAPHIC CHANGES IN LAMOTRIGINE OVERDOSE: A CASE REPORT AND LITERATURE REVIEW.. CARDIOVASCULAR TOXICOLOGY.. 2015?15(4):394-398", "literaturereference_normalized": "evolving electrocardiographic changes in lamotrigine overdose a case report and literature review", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20151020", "receivedate": "20151020", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11642872, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" }, { "companynumb": "US-JUBILANT CADISTA PHARMACEUTICALS-2015JUB00354", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LAMOTRIGINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "079132", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "13.5 G, ONCE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "13.5", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMOTRIGINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TENOFOVIR" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TENOFOVIR" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RALTEGRAVIR" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG, 2X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RALTEGRAVIR." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LAMOTRIGINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "079132", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "150 MG, 2X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMOTRIGINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "EMTRICITABINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EMTRICITABINE" } ], "patientagegroup": null, "patientonsetage": "36", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cardiotoxicity", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Electrocardiogram QT prolonged", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Intentional overdose", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Quadriplegia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "4" }, { "reactionmeddrapt": "Suicide attempt", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Sinus tachycardia", "reactionmeddraversionpt": "18.1", "reactionoutcome": null }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "18.1", "reactionoutcome": "4" }, { "reactionmeddrapt": "Critical illness myopathy", "reactionmeddraversionpt": "18.1", "reactionoutcome": "4" }, { "reactionmeddrapt": "Bundle branch block right", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "18.1", "reactionoutcome": null }, { "reactionmeddrapt": "Electrocardiogram QRS complex prolonged", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Mental status changes", "reactionmeddraversionpt": "18.1", "reactionoutcome": "4" } ], "summary": null }, "primarysource": { "literaturereference": "CHAVEZ P, CASSO DOMINGUEZ A, HERZOG E. EVOLVING ELECTROCARDIOGRAPHIC CHANGES IN LAMOTRIGINE OVERDOSE: A CASE REPORT AND LITERATURE REVIEW. CARDIOVASC TOXICOL (DOI:10.1007/S12012-014-9300-0). 2015?15(4):394-398", "literaturereference_normalized": "evolving electrocardiographic changes in lamotrigine overdose a case report and literature review", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20151109", "receivedate": "20151109", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11714842, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": 1, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20160304" }, { "companynumb": "US-MYLANLABS-2015M1036200", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "RALTEGRAVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "HIV INFECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RALTEGRAVIR." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TENOFOVIR DISOPROXIL FUMARATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "HIV INFECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TENOFOVIR DISOPROXIL FUMARATE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LAMOTRIGINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "077420", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "150 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "BIPOLAR DISORDER", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMOTRIGINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LAMOTRIGINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "077420", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "90 TABLETS OF 150MG (13.5G INGESTION)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMOTRIGINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Intentional overdose", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Electrocardiogram QRS complex prolonged", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Electrocardiogram QT prolonged", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Suicide attempt", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Critical illness myopathy", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CHAVEZ P, CASSO DOMINGUEZ A, HERZOG E. EVOLVING ELECTROCARDIOGRAPHIC CHANGES IN LAMOTRIGINE OVERDOSE: A CASE REPORT AND LITERATURE REVIEW. CARDIOVASC-TOXICO 2015? 15(4):394-398.", "literaturereference_normalized": "evolving electrocardiographic changes in lamotrigine overdose a case report and literature review", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20151026", "receivedate": "20151026", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11662072, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160304" }, { "companynumb": "US-CIPLA LTD.-2015US07961", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LAMOTRIGINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "077783", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "275 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "TEMPORAL LOBE EPILEPSY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "275", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMOTRIGINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Vertigo", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Craniocerebral injury", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Electrocardiogram abnormal", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Ataxia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Altered state of consciousness", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Nystagmus", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hyporeflexia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Fall", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CHAVEZ P, DOMINGUEZ A AND HERZOG E. EVOLVING ELECTROCARDIOGRAPHIC CHANGES IN LAMOTRIGINE OVERDOSE: A CASE REPORT AND LITERATURE REVIEW. CARDIOVASC TOXICOL. 2015?15:394-398", "literaturereference_normalized": "evolving electrocardiographic changes in lamotrigine overdose a case report and literature review", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20151015", "receivedate": "20151015", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11631930, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160304" }, { "companynumb": "US-ZYDUS-009336", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LAMOTRIGINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "078009", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "ESTIMATED AMOUNT INGESTED AS UP TO 13.5 G (90 TABLETS OF 150 MG)", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": [ { "drugrecuraction": "Conduction disorder" }, { "drugrecuraction": "Myopathy" }, { "drugrecuraction": "Status epilepticus" }, { "drugrecuraction": "Overdose" }, { "drugrecuraction": "Generalised tonic-clonic seizure" }, { "drugrecuraction": "Quadriplegia" } ], "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMOTRIGINE." } ], "patientagegroup": null, "patientonsetage": "36", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Generalised tonic-clonic seizure", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Conduction disorder", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Myopathy", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Quadriplegia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CHAVEZ P, CASSO DOMINGUEZ A, HERZOG E. EVOLVING ELECTROCARDIOGRAPHIC CHANGES IN LAMOTRIGINE OVERDOSE: A CASE REPORT AND LITERATURE REVIEW. CARDIOVASCULAR TOXICOLOGY. 2015 OCT?15(4):394-398.", "literaturereference_normalized": "evolving electrocardiographic changes in lamotrigine overdose a case report and literature review", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20151101", "receivedate": "20151101", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11688540, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" }, { "companynumb": "US-CIPLA LTD.-2015US07956", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "AMITRIPTYLINE" }, "drugadditional": null, 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null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FAT EMULSION NOS" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METOPROLOL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, 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"patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypoglycaemia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Shock", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CHAVEZ P, DOMINGUEZ A AND HERZOG E. EVOLVING ELECTROCARDIOGRAPHIC CHANGES IN LAMOTRIGINE OVERDOSE: A CASE REPORT AND LITERATURE REVIEW. CARDIOVASC TOXICOL. 2015?15:394-398", "literaturereference_normalized": "evolving electrocardiographic changes in lamotrigine overdose a case report and literature review", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20151019", "receivedate": "20151019", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11639930, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" }, { "companynumb": "US-CIPLA LTD.-2015US07955", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LAMOTRIGINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMOTRIGINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DULOXETINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DULOXETINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "EGG PHOSPHOLIPIDS\\SAFFLOWER OIL\\SOYBEAN OIL" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 GM/DL CONCENTRATION OF LIPID EMULSION BOLUS", "drugenddate": null, "drugenddateformat": null, "drugindication": "SHOCK", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FAT EMULSION NOS" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VERAPAMIL HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VERAPAMIL" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Shock", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hyperlipidaemia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CHAVEZ P, DOMINGUEZ A AND HERZOG E. EVOLVING ELECTROCARDIOGRAPHIC CHANGES IN LAMOTRIGINE OVERDOSE: A CASE REPORT AND LITERATURE REVIEW. CARDIOVASC TOXICOL. 2015?15:394-398", "literaturereference_normalized": "evolving electrocardiographic changes in lamotrigine overdose a case report and literature review", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20151019", "receivedate": "20151019", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11639915, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" }, { "companynumb": "US-DRREDDYS-USA/USA/14/0045096", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "RALTEGRAVIR" }, "drugadditional": null, 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"Suicide attempt", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bundle branch block right", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CHAVEZ P, CASSO DOMINGUEZ A, HERZOG E. EVOLVING ELECTROCARDIOGRAPHIC CHANGES IN LAMOTRIGINE OVERDOSE: A CASE REPORT AND LITERATURE REVIEW. CARDIOVASC TOXICOL. 2015?15(4):394-8.", "literaturereference_normalized": "evolving electrocardiographic changes in lamotrigine overdose a case report and literature review", "qualification": "3", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "US", "receiptdate": "20151109", "receivedate": "20141224", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10673731, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" } ]
{ "abstract": "In GM1 gangliosidosis the lack of function of β-galactosidase results in an accumulation of GM1 ganglioside and related glycoconjugates in visceral organs, and particularly in the central nervous system, leading to severe disability and premature death. In the type 2 form of the disease, early intervention would be important to avoid precocious complications. To date, there are no effective therapeutic options in preventing progressive neurological deterioration. Substrate reduction therapy with Miglustat, a N-alkylated sugar that inhibits the enzyme glucosylceramide synthase, has been proposed for the treatment of several lysosomal storage disorders such as Gaucher type 1 and Niemann Pick Type C diseases. However, data on Miglustat therapy in patients with GM1 gangliosidosis are still scarce.\n\n\n\nWe report here the results of Miglustat administration in four Italian children (average age: 55 months, range 20-125) affected by GM1 gangliosidosis type 2 treated in three different Italian pediatric hospitals specialized in metabolic diseases.\n\n\n\nThis treatment was safe and relatively well tolerated by all patients, with stabilization and/or slowing down of the neurological progression in three subjects.", "affiliations": "Clinical Genetics Unit, Department of Pediatric Medicine, Giovanni XXIII Children's Hospital, Bari, Italy.;Department of Biomedical Science and Human Oncology, Pediatric Unit, University of Bari \"Aldo Moro\", Bari, Italy.;Unit of Child Neuropsychiatry, Clinical and Surgical Neurosciences Department, IRCCS Institute Giannina Gaslini, Genoa, Italy.;Unit of Child Neuropsychiatry, Clinical and Surgical Neurosciences Department, IRCCS Institute Giannina Gaslini, Genoa, Italy.;Radiology Unit, Pediatric Hospital Giovanni XXIII, Bari, Italy.;Radiology Unit, Pediatric Hospital Giovanni XXIII, Bari, Italy.;Unit of Rare Diseases, IRCCS Institute Giannina Gaslini, Genoa, Italy.;Department of Clinical Sciences, Division of Pediatrics, Polytechnic University of Marche, OspedaliRiuniti, Presidio Salesi, Ancona, Italy.;Department of Biomedical Science and Human Oncology, Pediatric Unit, University of Bari \"Aldo Moro\", Bari, Italy.;Clinical Genetics Unit, Department of Pediatric Medicine, Giovanni XXIII Children's Hospital, Bari, Italy.;Department of Biomedical Science and Human Oncology, Pediatric Unit, University of Bari \"Aldo Moro\", Bari, Italy.;Department of Medical Translational Sciences Section of Pediatrics, University Federico II Naples, Napoli, Italy.;Department of Medical Translational Sciences Section of Pediatrics, University Federico II Naples, Napoli, Italy.;Neuroradiology Unit, IRCCS Institute Giannina Gaslini, Genoa, Italy.;Paediatric Neurology Unit and Laboratories, Neuroscience Department, Meyer Children's Hospital, Florence, Italy.;Department of Biomedical Science and Human Oncology, Pediatric Unit, University of Bari \"Aldo Moro\", Bari, Italy.", "authors": "Fischetto\|Rita\|R\|;Palladino\|Valentina\|V\|0000-0002-3976-6463;Mancardi\|Maria M\|MM\|;Giacomini\|Thea\|T\|;Palladino\|Stefano\|S\|;Gaeta\|Alberto\|A\|;Di Rocco\|Maja\|M\|0000-0001-9677-880X;Zampini\|Lucia\|L\|;Lassandro\|Giuseppe\|G\|;Favia\|Vito\|V\|;Tripaldi\|Maria E\|ME\|;Strisciuglio\|Pietro\|P\|;Romano\|Alfonso\|A\|;Severino\|Mariasavina\|M\|;Morrone\|Amelia\|A\|0000-0003-2890-8179;Giordano\|Paola\|P\|", "chemical_list": "D065089:Glycoside Hydrolase Inhibitors; D017485:1-Deoxynojirimycin; C059896:miglustat; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase", "country": "United States", "delete": false, "doi": "10.1002/mgg3.1371", "fulltext": "\n==== Front\nMol Genet Genomic Med\nMol Genet Genomic Med\n10.1002/(ISSN)2324-9269\nMGG3\nMolecular Genetics & Genomic Medicine\n2324-9269 John Wiley and Sons Inc. Hoboken \n\n10.1002/mgg3.1371\nMGG31371\nClinical Report\nClinical Reports\nSubstrate reduction therapy with Miglustat in pediatric patients with GM1 type 2 gangliosidosis delays neurological involvement: A multicenter experience\nFISCHETTO et al.Fischetto Rita \n1\[email protected] Palladino Valentina https://orcid.org/0000-0002-3976-6463\n2\n Mancardi Maria M. \n3\n Giacomini Thea \n3\n Palladino Stefano \n4\n Gaeta Alberto \n4\n Di Rocco Maja https://orcid.org/0000-0001-9677-880X\n5\n Zampini Lucia \n6\n Lassandro Giuseppe \n2\n Favia Vito \n1\n Tripaldi Maria E. \n2\n Strisciuglio Pietro \n7\n Romano Alfonso \n7\n Severino Mariasavina \n8\n Morrone Amelia https://orcid.org/0000-0003-2890-8179\n9\n Giordano Paola \n2\n \n1 \nClinical Genetics Unit\nDepartment of Pediatric Medicine\nGiovanni XXIII Children's Hospital\nBari\nItaly\n\n\n2 \nDepartment of Biomedical Science and Human Oncology\nPediatric Unit\nUniversity of Bari “Aldo Moro”\nBari\nItaly\n\n\n3 \nUnit of Child Neuropsychiatry, Clinical and Surgical Neurosciences Department\nIRCCS Institute Giannina Gaslini\nGenoa\nItaly\n\n\n4 \nRadiology Unit\nPediatric Hospital Giovanni XXIII\nBari\nItaly\n\n\n5 \nUnit of Rare Diseases\nIRCCS Institute Giannina Gaslini\nGenoa\nItaly\n\n\n6 \nDepartment of Clinical Sciences\nDivision of Pediatrics\nPolytechnic University of Marche\nOspedaliRiuniti\nPresidio Salesi\nAncona\nItaly\n\n\n7 \nDepartment of Medical Translational Sciences Section of Pediatrics\nUniversity Federico II Naples\nNapoli\nItaly\n\n\n8 \nNeuroradiology Unit\nIRCCS Institute Giannina Gaslini\nGenoa\nItaly\n\n\n9 \nPaediatric Neurology Unit and Laboratories\nNeuroscience Department\nMeyer Children's Hospital\nFlorence\nItaly\n\n* Correspondence\n\nRita Fischetto, Clinical Genetics Unit, Department of Pediatric Medicine, Giovanni XXIII Children's Hospital, Bari, Italy.\n\nEmail: [email protected]\n\n11 8 2020 \n10 2020 \n8 10 10.1002/mgg3.v8.10e137106 3 2020 30 4 2020 01 6 2020 © 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Abstract\nBackground\nIn GM1 gangliosidosis the lack of function of β‐galactosidase results in an accumulation of GM1 ganglioside and related glycoconjugates in visceral organs, and particularly in the central nervous system, leading to severe disability and premature death. In the type 2 form of the disease, early intervention would be important to avoid precocious complications. To date, there are no effective therapeutic options in preventing progressive neurological deterioration. Substrate reduction therapy with Miglustat, a N‐alkylated sugar that inhibits the enzyme glucosylceramide synthase, has been proposed for the treatment of several lysosomal storage disorders such as Gaucher type 1 and Niemann Pick Type C diseases. However, data on Miglustat therapy in patients with GM1 gangliosidosis are still scarce.\n\nMethods\nWe report here the results of Miglustat administration in four Italian children (average age: 55 months, range 20–125) affected by GM1 gangliosidosis type 2 treated in three different Italian pediatric hospitals specialized in metabolic diseases.\n\nConclusion\nThis treatment was safe and relatively well tolerated by all patients, with stabilization and/or slowing down of the neurological progression in three subjects.\n\nIn GM1 gangliosidosis the lack of function of β‐galactosidase results in an accumulation of GM1 gangliosides and related glycoconjugates in visceral organs, especially the central nervous system, leading to severe disability and premature death. In the type 2 form of the disease, early intervention would be important to avoid precocious complications. We report here the results of Miglustat administration in four Italian children (average age: 55 months, range 20–125) affected by GM1 gangliosidosis type 2. This treatment was safe and relatively well tolerated by all patients, with stabilization and/or slowing down of the neurological progression in three subjects.\n\n\nGM1 gangliosidosisMiglustatpediatric source-schema-version-number2.0cover-dateOctober 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.3 mode:remove_FC converted:28.10.2020\n\n\nFischetto \nR \n, \nPalladino \nV \n, \nMancardi \nMM \n, et al. Substrate reduction therapy with Miglustat in pediatric patients with GM1 type 2 gangliosidosis delays neurological involvement: A multicenter experience\n. Mol Genet Genomic Med . 2020 ;8 :e1371\n10.1002/mgg3.1371\n==== Body\n1 INTRODUCTION\nGM1 gangliosidosis is an autosomal recessive disorder caused by the deficiency of β‐galactosidase (GLB1), a lysosomal hydrolase that removes the terminal β‐galactosyl residues from GM1 gangliosides, glycoproteins, and glycosaminoglycans. Lack of β‐galactosidase function results in an accumulation of GM1 ganglioside and related glycoconjugates in visceral organs, and particularly in the central nervous system (CNS) (Sandhoff & Harzer, 2013). The incidence of GM1 gangliosidosis is estimated to be 1 in 100.000–200.000 live births, although prevalence widely differs in the world (Brunetti‐Pierri & Scaglia, 2008).\n\nβ‐galactosidase is encoded by GLB1, a gene located on chromosome 3p21.33 (Yamamoto et al., 1990). To date, more than 200 mutations have been identified (HGMD professional database 2015.3; https://portal.biobase‐international.com/cgibin/portal/login.cgi), differing in the residual enzyme activity that inversely correlates with the clinical severity (Suzuki, Nakamura, & Fukuoka, 1978). Despite the large genetic variability, currently, three main clinical forms have been identified: type 1 (infantile), type 2 (late infantile and juvenile), and type 3 (adult). GM1 gangliosidosis type 1 is characterized by early psychomotor deterioration, visceromegaly, macular cherry‐red spot, skeletal deformities, and death within the first 2 years of life (Suzuki & Oshima, 1993). Type 2 form presents with slowly progressive neurological signs as early locomotor problems, strabismus, muscle weakness, seizures, recurrent bronchopneumonia, and less severe dysmorphisms and skeletal involvement than in type 1. GM1 gangliosidosis type 2 can be divided into a late infantile and a juvenile form. In the late infantile form death occurs within adolescence while patients with the juvenile form can survive longer, with great individual clinical variability (Regier & Tifft, 2013). The adult form (type 3) is characterized by a less severe course and late onset, usually in juvenile age (Cox, 2015; Jarnes Utz et al., 2017; Regier, Proia, D'Azzo, & Tifft, 2016). Data on neuroimaging findings in the different forms of GM1 gangliosidosis are scarce; the reported patterns are nonspecific, including diffuse atrophy and white matter abnormalities (Chen et al., 1998; De Grandis, Di Rocco, Pessagno, Veneselli, & Rossi, 2009; Di Rocco et al., 2005; Gururaj et al., 2005). Type 1 may also present with delayed myelination and hyposignal on T2‐weighted images in the thalami, while type 2 may be associated with T2 hypointensity in the globi pallidi, and type 3 shows T2 hyperintensity within the putamina (Chen et al., 1998; De Grandis et al., 2009; Di Rocco et al., 2005; Erol, Alehan, Pourbagher, Canan, & Vefa, 2006; Gururaj et al., 2005).\n\nTo date, there are no effective drugs for the management of GM1 gangliosidosis that is mainly based on palliative treatments. Especially in the infantile and juvenile forms of GM1 gangliosidosis, early intervention would be important to avoid severe disability and premature death. However, the failure to access glycolipid storage products in CNS cells during critical developmental periods and the absence of clinical markers to evaluate treatment efficacy have hindered progress in developing effective therapies (Jarnes Utz et al., 2017).\n\nRecently, the application of a substrate reduction therapy (SRT) has been evaluated in several lysosomal storage disorders (Hollak & Wijburg, 2014; Parenti, Andria, & Valenzano, 2015). The rationale of SRT is based on the use of synthesis inhibitors of substrates accumulated in lysosomes using specific iminosugars (Jeyakumar, Butters, Dwek, & Platt, 2002). NB‐DNJ (Miglustat, Zavesca®) is a N‐alkylated sugar that is a reversible competitive inhibitor of the glucosylceramide synthase, an enzyme catalyzing the first committed step in the synthesis of lacto‐ and globo‐series glycolipids (Platt, Neises, Dwek, & Butters, 1994). The ability of Miglustat to cross the blood–brain barrier blocking glycolipid storage synthesis has opened new interesting options for the treatment of multiple lysosomal storage disorders, especially those with CNS involvement, such as Gaucher and Niemann Pick type C diseases (Cox et al., 2000; Ficicioglu, 2008; Patterson, Vecchio, Prady, Abel, & Wraith, 2007). Miglustat has also been proposed for treatment of other sphingolipidoses, such as GM1 gangliosidosis. Indeed, GM1 gangliosidosis mouse models demonstrated Miglustat effectiveness in reducing brain GM1 ganglioside content (Kasperzyk et al., 2004; Treiber, Morand, & Clozel, 2007). Data on Miglustat efficacy in patients with GM1 gangliosidosis are scarce but promising, as reported in a few pediatric and adult patients affected by type 1 and 2 forms (Deodato et al., 2017; Garzone et al., 2013; Tifft, Adams, & Morgan, 2007).\n\nHere, we describe the clinical course and adverse effects of Miglustat therapy in four pediatric patients with GM1 gangliosidosis type 2.\n\n2 MATERIALS AND METHODS\nAfter obtaining informed consent and approval from the local ethics committees, we reviewed the clinical and neuroradiological data of four patients with GM1 gangliosidosis treated in three different Italian pediatric hospitals specialized in metabolic diseases. The decision to initiate treatment was based on: (a) good safety profile of Miglustat, (b) good clinical results in other lysosomal storage diseases, and (c) promising preclinical data on GM1 mouse models. Miglustat was dosed according to guidelines for pediatric patients (younger than 12 years) affected by Niemann Pick type C disease. The drug was melted in water to facilitate the assumption and the dosage was progressively increased according to body surface area. Data on drug tolerance and compliance were collected from the mothers with follow‐up calls or during clinical assessment every 3 months. All patients were followed up at regular intervals by a multidisciplinary team and the development of side effects was monitored. Symptoms and signs and neurological evaluation of patients before and after Miglustat therapy are summarized in Table 1.\n\nTable 1 Symptoms and signs and neurological evaluation before and after Miglustat therapy\n\nPatient\tAge at onset of symptoms\tAge at Miglustat initiation\tAge at last follow‐up during Miglustat therapy\tSymptoms and signs\tNeurological evaluation\t\nBefore Miglustat therapy\tAfter Miglustat therapy\tBefore Miglustat therapy\tAfter Miglustat therapy\t\n1\t11 months\t20 months\t5 years\t\nThoracolumbar kyphosis and vertebral beaking (D11 to L4) at X‐ray\n\nAbdominal cystic lymphangioma\n\n\n\t\nSignificant improvement of the thoracic hyperkyphosis and stable appearance of the vertebral anomalies\n\n\n\t\nNormal neurological assessment\n\nNormal WPPSI‐III in verbal and performance IQ scores\n\n\n\tWPPSI‐III: mild worsening in fine motor skills and language\t\n2\t5 years\t10 years and 5 months\t16 years\t\nDevelopmental regression\n\nAttention deficit\n\nDysarthria\n\nExtrapyramidal symptoms\n\nAtypical absences\n\nDiffuse platyspondyly with mild anterior wedging of the lumbar vertebrae at Spinal MRI and X‐ray\n\n\n\tStable\t\nSevere dysarthria\n\nAttention deficit\n\nMild hypotonia\n\nBrisk reflex with mild bilateral clonus\n\nAwkwardness\n\nBradykinesia with freezing\n\nGait ataxia\n\nSevere cognitive impairment (IQ of 34 at WISC‐III Scale) and EDSS score of 7.5\n\n\n\tStable motor and cognitive impairment\t\n3\t5 years\t3 years and 8 months\t10 years and 5 months\tAsymptomatic\t\nDysarthria\n\nAttention deficit\n\nDiffuse platyspondyly with anterior wedging of the lumbar vertebrae at X‐ray\n\nEpileptic alterations at EEG during sleep\n\n\n\tNormal\t\nModerate intellectual disability\n\nClumsiness\n\nDysarthria\n\nSignificative hyperkinesia\n\nAttention deficit\n\nBehavioral problems with heteroaggressivity\n\nPsychomotor agitation outbursts\n\nEDSS score of 5.\n\n\n\t\n4\t18 months\t2 years and 9 months\t6 years and 7 months\t\nHypotonia\n\nDelayed psychomotor development\n\nSteppage gait\n\nSlightly coarse facies (downturned corners of the mouth, convergent strabismus of the left eye, and open bite with sialorrhea)\n\n\n\t\nTotal regression of language\n\nPyramidal and extrapyramidal signs\n\nSeizures\n\nSevere intellectual disability\n\nTotal gross and fine motor regression\n\n\n\t\nHypotonia\n\nDelayed psychomotor development\n\nSteppage gait\n\n\n\t\nTotal regression of language\n\nPyramidal and extrapyramidal signs\n\nSevere intellectual disability\n\nTotal gross and fine motor regression\n\n\n\t\nJohn Wiley & Sons, Ltd2.1 Patient 1\nPatient #1 was born at term after an uneventful pregnancy by spontaneous delivery. He was the first child of a healthy nonconsanguineous couple, with no contributory family history. Normal growth and neurodevelopmental milestones were referred until the age of 11 months. At this time, he was referred to the orthopedist for thoracolumbar kyphosis that was treated with a corset. The first clinical evaluation did not reveal any dysmorphological signs. Spine X‐Ray showed anterior vertebral beaking from D11 to L4, more evident in L1 and L2, associated with marked thoracic kyphosis. Electrocardiogram, echocardiogram, Boel test, fundus oculi and slit lamp examination, neurological assessment, abdomen echography, and hand X‐ray were normal. Routine blood tests, aminoacidemia/uria, acylcarnitines, urinary glycosaminoglycans screening test, and organic acids were normal. At 18 months of age, the patient was operated of an abdominal cystic lymphangioma.\n\nIncreased levels of urinary oligosaccharides were found using thin‐layer chromatographic (TLC) method, while fluorimetric enzyme assay in leucocytes revealed that β‐galactosidase (GLB1) enzyme activity was below normal range (6.9 nM mg−1 h−1; normal values 100–600 nM mg−1 h−1). GLB1 gene analysis was performed, revealing compound heterozygous mutations in c.602G>A p.(Arg201His) (inherited from the mother) and c.841C>T p.(His 281Tyr) (inherited from the father).\n\nBrain MRI and MR spectroscopy performed at 21 months of age were normal (Figure 2A,B). Cognitive assessment was performed with \"Wechsler Preschool And Primary Scale Of Intelligence\" (WPPSI‐III) resulting normal in both verbal and performance IQ scores.\n\nAt 20 months of age, after 2 months of preliminary dietary treatment (lactose‐free aliments), Miglustat therapy was started at a dose of 100 mg/day (subdivided into two doses) and progressively increased to 240 mg/day. At 4 years of age, the total drug amount was fractioned in three doses a day, while at 5 years, in four doses a day. Daily assumption of a probiotic product (Saccharomyces Boulardii) was also started. In the following years, height, weight, and head circumference growth curves were stable, between the 25th and 50th centiles. Orthopedic evaluations revealed a significant improvement of kyphosis with a nonstop use of the corset until the age of 4 years. Spine X‐Rays confirmed a significant improvement of the thoracic hyperkyphosis and a stable appearance of the vertebral anomalies. Follow‐up brain MRI scans at 4 and 5 years of age did not reveal any abnormality. Cognitive assessment using WPPSI‐III performed at 5 years of age showed mild worsening in fine motor skills and language. Routine blood tests were normal, except for mild and transient increase in alanine amino transpherase (ALT) levels.\n\n2.2 Patient 2\nPatient #2 is the first child of healthy nonconsanguineous parents with negative family history. She was born at term after an uneventful pregnancy. She showed a normal psychomotor development until the age of 5 years when she presented with developmental regression associated with attention deficit, dysarthria, and extrapyramidal symptoms. She came to our attention at the age of 9 years when she developed atypical absences with generalized sharp waves (3 Hz) followed by slow waves lasting 20‐12′ at EEG, and she started antiepileptic therapy with lamotrigine. Neurological examination showed severe dysarthria, mild hypotonia, brisk reflex with mild bilateral clonus, awkwardness, bradykinesia with freezing, and gait ataxia; she could not walk without assistance. Neuropsychological evaluation showed severe cognitive impairment (IQ of 34 at WISC‐III Scale) and EDSS score of 7.5. Brain MRI performed at 8 years of age revealed mild cerebral and cerebellar atrophy, white matter signal alterations consistent with lack of myelin, dysmyelination, and reduced thalamic volume (Figure 2D–F). Brain MR spectroscopy was normal. Spinal MRI and X‐ray showed diffuse platyspondyly with mild anterior wedging of the lumbar vertebrae (Figure 1b,c). Routine blood tests were normal, as well as genetic exams including cytogenetic studies, Array – Comparative Genomic Hybridization (Array – CGH), and analysis of subtelomeric regions and MECP2 gene.\n\nFigure 1 Spinal X‐ray and MRI features of the patients. (a) Spinal X‐ray, lateral view, of patient #1 performed at 6 years showing platyspondyly with anterior vertebral beaking from D11 to L4, more evident in L1 and L2 (arrows). (b) Spinal MRI, T2‐weighted sagittal image, and (c) Spinal X‐ray, lateral view, of patient #2 performed at 15 years of age demonstrates diffuse platyspondyly with mild anterior wedging of the lumbar vertebrae. (d) Spinal X‐ray, lateral view, of patient #3 performed at 9 years of age reveals diffuse platyspondyly with mild anterior wedging of the lumbar vertebrae, more evident in L3 (arrow)\n\nMetabolic exams, including blood chromatography of the amino acids, organic acidurias, mucopolysaccharidosis (MPS) urinary screening, plasma chitotriosidase, and fucosidase, mannosidase, were normal while the activity of β‐galactosidase was reduced in lymphocytes (16.2 nM mg−1 h−1; normal values 100–600 nM mg−1 h−1) as well as in cultured skin fibroblasts, leading to the diagnosis of GM1 gangliosidosis. The genetic analysis revealed compound heterozygous mutations in GLB1 in c.602G>A p.(Arg201His) and the novel c.247dup1 p.(Tyr83Leu fsx8).\n\nAt the age of 10 years and 5 months, the clinical picture and neurological examination were stable. Brain MRI showed mild progression of cerebral atrophy with enlargement of the lateral ventricles (Figure 2D′–F′). Therapy with Miglustat was started (age 10 years and 5 months) at the dosage of 100 mg three times a day, gradually increased to 200 mg three times a day. She initially presented occasional diarrhea and mild abdominal pain, spontaneously improving in the following weeks. In the first 4 months of therapy, her body weight decreased from 42.6 to 38.9 kg (BMI from 24.8 to 21.9). Subsequently, in the following 6 years, the BMI was quite stable between 21.1 and 22.3. She has now been on a stable dosage of 600 mg/day for 1 year with good compliance and without relevant adverse events. At last follow‐up, at the age of 16 years, neurological examination showed stable motor and cognitive impairment. Brain MRI revealed further progression of mild cortical atrophy and T2 hypointensity at the level of the globi pallidi, substantia nigra, red nuclei, and cerebellar dentate nuclei, associated with thickening of the skull bones (Figure 2D″–F″).\n\nFigure 2 Brain MRI features of the patients. (A–C) Axial T2‐weighted images of patient #1 performed at 21 months of age reveal normal brain anatomy and signal intensity. (D–F) Axial T2‐weighted images of patient #2 performed at 8 years of age show diffuse white matter hyperintensity, more evident at the level of posterior limbs of internal capsules (arrows), associated with small thalami (asterisks) and mild enlargement of the cerebral and cerebellar subarachnoid spaces. (D′–F′) Corresponding axial T2‐weighted images of the same patient performed at 10 years and 5 months reveal progressive enlargement of the cerebral and cerebellar subarachnoid spaces (thick arrows) and enlargement of the lateral ventricles (asterisks). (D″–F″) Follow‐up axial T2‐weighted images at 16 years reveal further progression of the cerebral atrophy, with thickening of the skull bones (empty arrows) and hypointensity of the globipallidi (arrowheads). (G–I) Axial T2‐weighted images of patient #3 performed at 6 years and 2 months of age reveal normal brain anatomy and signal intensity. (J–L) Axial T2‐weighted images of patient #4 performed at 2 years of age demonstrate mild hyperintensity of the white matter of the centri semiovali (empty arrows) and posterior limbs of internal capsules (arrows). There is also mild enlargement of the cerebral and cerebellar subarachnoid spaces. Note the small thalami (asterisks)\n\n2.3 Patient 3\nPatient #3 is the younger brother of Patient #2. He was born at term after an uneventful pregnancy. He was asymptomatic when GM1 gangliosidosis were diagnosed at the age of 3 years, and he harbored the same compound mutations of his sister. Treatment with Miglustat was started at the age of 3 years and 8 months but was stopped after a week for the appearance of severe hyporexia. Four months later, the treatment was reinitiated at the dosage of 70 mg/twice daily and gradually increased up to 300 mg/day (subdivided into 3 doses). Up to date, he has been on a stable dosage for 3 years with good compliance and insignificant side effects such as occasional abdominal pain with diarrhea. At the age of 5 years, he started to develop dysarthria and attention deficit.\n\nBrain MRI with MR spectroscopy performed at 6 years and 2 months was normal (Figure 2G–I). Spinal X‐ray revealed diffuse platyspondyly with anterior wedging of the lumbar vertebrae, especially of L3 (Figure 1d). At 10 years of age, he presented epileptic alterations at EEG during sleep, without evident clinical seizures and was treated with therapy with topiramate. Neurological examination revealed moderate intellectual disability, clumsiness, dysarthria, significative hyperkinesia, attention deficit, behavioral problems with heteroaggressivity, and psychomotor agitation outbursts. His EDSS score was 5. At last follow‐up, performed at 10 years and 5 months of age, neurological examination revealed a stable clinical course.\n\n2.4 Patient 4\nPatient #4 was born at term after an uneventful pregnancy by spontaneous delivery. At the age of 18 months, he presented with hypotonia, delayed psychomotor development, and a steppage gait characterized by widened base of support and retropulsion of the pelvis. He had slightly coarse facies with downturned corners of the mouth, convergent strabismus of the left eye, and open bite with sialorrhea. Abdominal ultrasound and metabolic screening tests were normal. Brain MRI performed at 2 years of age revealed white matter signal alterations consistent with lack of myelin and dysmyelination in the posterior limbs of internal capsules and pons, mild subarachnoid spaces enlargement, and reduced thalamic volume (Figure 2J–L). At the age of 2 years and 4 months, GM1 gangliosidosis was diagnosed by the β‐galactosidase enzymatic assay and GLB1 gene molecular analysis, which highlighted the presence in heterozygosis of the c.572G>A (p. Ser191Asn) and c.1445G>A (p. Arg482Hys) mutations. The boy started therapy with Miglustat at the age of 2 years and 9 months, at the dosage of 200 mg (subdivided into two doses).\n\nAt the age of 3 years and 2 months, the patient was again hospitalized for night cry, asthenia, and pain. The abdomen ultrasound was normal, while a barium X‐ray examination showed gastroesophageal reflux and therapy was initiated with esomeprazole. The neurological exam showed total regression of language, associated with pyramidal and extrapyramidal signs.\n\nAt the age of 3 years and 7 months, frequent daily seizures appeared, lasting few seconds and characterized by pathological eyes rolling and staring. An EEG showed high‐voltage slow waves and spike waves complexes on the right derivations. He began therapy with levetiracetam at the dosage of 400 mg/die with clinical improvement.\n\nWhen he was 6 years old, he was hospitalized because of significant weight loss, dehydration, sickness, and vomiting. Oral feeding was strongly compromised. A percutaneous gastrostomy was placed. Seven months later, therapy with Miglustat was also suspended. Last clinical follow‐up at 7 years of age revealed severe intellectual disability and total gross and fine motor regression. He depended on his parents for daily survival.\n\n3 DISCUSSION\nWe present our experience of Miglustat administration in four children affected by GM1 gangliosidosis type 2. In GM1 gangliosidosis type 2, the accumulation of GM1 ganglioside in the CNS begins in the early stages of development. Therefore, it has been hypothesized that the progression of the disease could only be avoided with early diagnosis and intervention (Del Vecchio et al., 2008; Jarnes Utz et al., 2017). Some therapeutic strategies have been implemented in animal models, such as bone marrow transplantation (Sano, Tessitore, Ingrassia, & d'Azzo, 2005), intracranial transplant of neuronal stem cells (Sawada et al., 2009), SRT (Elliot‐Smith et al., 2008; Kasperzyk et al., 2004; Suzuki et al., 2007), gene therapies (Baek et al., 2010), and enzyme replacement therapy (Condori et al., 2016). Additionally, a recent study demonstrated that the intracerebroventricular administration of recombinant human β‐galactosidase in a mouse model of GM1 gangliosidosis reduced brain levels of ganglioside and oligosaccharide substrates (Chen et al., 2019).\n\nIn human patients, several interventions have been undertaken to mitigate the relentless progression of disease (Regier et al., 2016). However, the failure to access glycolipid storage products in CNS during critical developmental periods and the absence of clinical markers to evaluate treatment efficacy have hindered progress in developing effective therapies (Jarnes Utz et al., 2017).\n\nSubstrate reduction therapy with oral administration of the iminosugar NB‐DNJ has been demonstrated to be effective in crossing the blood–brain barrier and blocking glycolipid storage synthesis (Kasperzyk et al., 2004; Treiber et al., 2007), thus revealing a potential therapeutic role in lysosomal storage disorders with neurological involvement (Platt et al., 1994). In particular, Miglustat has been approved in Europe and the United States for the treatment of patients with type 1 Gaucher disease with mild‐to‐moderate clinical manifestations for whom intravenous enzyme replacement therapy is not an option (Cox et al., 2000; Ficicioglu, 2008). Subsequently, Miglustat has also been approved for treating progressive neurologic manifestations in children and adults with Niemann Pick disease type C (Patterson et al., 2007).\n\nThe mechanism of Miglustat action has not been completely clarified yet. The efficacy of NB‐DNJ is related to its ability to cross the blood–brain barrier, inhibit the synthesis of storage products, and stabilize the enzyme with an enhancement of the catalytic residual activity (Alfonso et al., 2005; Kuter et al., 2013). Furthermore, several studies have proved the potential role of Miglustat administration in the regulation of the abnormal CNS inflammatory response observed in GM1 gangliosidosis (Jeyakumar et al., 2003), reducing levels of proinflammatory cytokines such as tumor necrosis factor‐α (TNF‐α) and interleukin‐1 beta (IL1‐β) (Jeyakumar et al., 2001; Masciullo et al., 2010; Santoro et al., 2013).\n\nDespite the demonstrated effectiveness of Miglustat in other storage disorders, its use in GM 1 gangliosidosis type 2 has been reported only in a few patients. In 2007, Tifft et al. (2007) reported that Miglustat administration improved neurological functions in two patients with juvenile GM1 gangliosidosis. Recently, Deodato et al. (2017) described similar neurological improvement in the juvenile form of the disease. In our patients, we observed stabilization and/or slowing down of the neurological progression in three of four patients. Of note, the administration of Miglustat was started few months after the genetic confirmation. In particular, patients #1 and #3 received an early diagnosis of GM1 gangliosidosis type 2 and the treatment was started within the fourth year of age, before the onset of neurological symptoms. In patient #1, early treatment limited the disease progression until 5 years of age, when minor motor problems were noticed. Moreover, the improvement of the kyphosis without other novel skeletal manifestations and the absence of neuroimaging abnormalities were indicative of substantial stabilization of the clinical course due to the treatment. In patient #3, who was asymptomatic at the beginning of therapy, we noted a very slow progression of symptomatology, appeared at the age of 5 years and evident since the age of 8 years, thus suggesting a possible role of Miglustat in slowing down the neurological deterioration.\n\nPatient #2 started the therapy rather late in the course of the disease, at the age of 10 years, when neurological symptoms and MRI alterations were already present. Surprisingly, in this case, we observed a stable motor and cognitive impairment for the following 5 years, while brain MRI showed only a minimal progression of the cerebral atrophy. On the other hand, Miglustat therapy was insufficient to avoid worsening of the clinical course in patient #4, who presented with a severe neurological phenotype since the first months of life.\n\nConsensus guidelines for clinical management of children with Niemann Pick type C recommend close clinical monitoring after the initiation of Miglustat therapy (NP‐C Guidelines Working Group, 2009). However, several studies have proved that Miglustat is safe and generally well tolerated, with minor and often transient adverse effects, such as tremor and gastrointestinal disturbances (Belmatoug et al., 2011). In particular, gastrointestinal problems, including diarrhea, abdominal pain, nausea, and weight loss, are mainly dose‐related and limited to the initial phase of the treatment. The mechanism is most likely the inhibition of intestinal disaccharidases leading to reduced absorption of dietary disaccharides and increase in undigested intraluminal oligosaccharides creating an osmotic gradient with the influx of water and electrolytes in the gastrointestinal tract. Subsequent colonic bacterial fermentation reduces caloric supply and triggers flatulence, abdominal distension, pain, and nausea. Of note, these symptoms generally disappear or decrease with dose escalation or discontinued administrations in association with a low‐carbohydrate/lactose diet and probiotic administration (Cox, 2015; Patterson et al., 2007). In this series, two patients presented minor gastrointestinal problems. In particular, patient #2 developed transient diarrhea and abdominal pain, while patient #3 presented severe hyporexia that subsided after brief treatment suspension and did not reappear after Miglustat reintroduction at lower and fractionated doses while occasional abdominal pain with diarrhea persisted. Interestingly, in patient #1, Miglustat therapy was started after 2 months of a preliminary diet based on lactose‐free products and daily assumption of probiotic Saccharomyces Boulardii, thus avoiding gastroenteric symptoms (carbohydrates were preserved in order to maintain an adequate nutrition).\n\nIn conclusion, our findings suggest that Miglustat is relatively well tolerated in children with GM1 type 2 gangliosidosis and seems more effective if used to slow down, rather than treat, both visceral and neurological manifestation, as in Niemann Pick type C pediatric patients (Di Rocco, Dardis, Madeo, Barone, & Fiumara, 2012). The rarity of GM1 gangliosidosis type 2 disease, fast clinical progression, and short lifespan make studies on clinical surveillance and therapeutic efficacy tough, as effective interventions are only possible before irreversible damage occurs. Since definitive conclusions cannot be drawn from small case series, further studies on larger number of patients and with longer follow‐up duration are needed to evaluate of the long‐term therapeutic effects of Miglustat in GM1 type II gangliosidosis.\n\nCONFLICT OF INTEREST\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nAUTHOR CONTRIBUTIONS\nAll authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.\n\nACKNOWLEDGMENTS\nAll authors contributed equally to the study design and performance.\n\nDATA AVAILABILITY STATEMENT\nThe data supporting the findings of the article can be requested to the authors at the following.\n==== Refs\nREFERENCES\n\n\nAlfonso , P. \n, \nPampín , S. \n, \nEstrada , J. \n, \nRodríguez‐Rey , J. C. \n, \nGiraldo , P. \n, \nSancho , J. \n, & \nPocoví , M. \n (2005 ). 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DNA and Cell Biology , 9 , 119 –127\n. 10.1089/dna.1990.9.119 \n2111707\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2324-9269", "issue": "8(10)", "journal": "Molecular genetics & genomic medicine", "keywords": "GM1 gangliosidosis; Miglustat; pediatric", "medline_ta": "Mol Genet Genomic Med", "mesh_terms": "D017485:1-Deoxynojirimycin; D000293:Adolescent; D002490:Central Nervous System; D002648:Child; D002675:Child, Preschool; D004361:Drug Tolerance; D005260:Female; D016537:Gangliosidosis, GM1; D005964:Glucosyltransferases; D065089:Glycoside Hydrolase Inhibitors; D006801:Humans; D007223:Infant; D008297:Male", "nlm_unique_id": "101603758", "other_id": null, "pages": "e1371", "pmc": null, "pmid": "32779865", "pubdate": "2020-10", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016448:Multicenter Study", "references": "20976108;23619106;18387328;32779865;25881001;2111707;24820227;16138252;12615653;20821051;10801168;19647672;8500799;28577204;19279282;26766614;31481471;23683771;19118961;99363;16039881;23785136;25987179;8132559;21779792;22704015;17689147;18524657;15791924;17624027;9802482;15941905;17994547;17052929;15086521;18176072;12366816;28476546;27491214;18728838;11133779", "title": "Substrate reduction therapy with Miglustat in pediatric patients with GM1 type 2 gangliosidosis delays neurological involvement: A multicenter experience.", "title_normalized": "substrate reduction therapy with miglustat in pediatric patients with gm1 type 2 gangliosidosis delays neurological involvement a multicenter experience" }	[ { "companynumb": "IT-ACTELION-A-CH2020-208550", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "MIGLUSTAT" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": 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"reactionmeddraversionpt": "23.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "FISCHETTO R, PALLADINO V, MANCARDI M, GIACOMINI T, PALLADINO S, ET AL. SUBSTRATE REDUCTION THERAPY WITH MIGLUSTAT IN PEDIATRIC PATIENTS WITH GM1 TYPE 2 GANGLIOSIDOSIS DELAYS NEUROLOGICAL INVOLVEMENT: A MULTICENTER EXPERIENCE. MOLECULAR GENETICS + GENOMIC MEDICINE. 2020?E1371", "literaturereference_normalized": "substrate reduction therapy with miglustat in pediatric patients with gm1 type 2 gangliosidosis delays neurological involvement a multicenter experience", "qualification": "1", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20200821", "receivedate": "20200821", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18180587, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "IT-JNJFOC-A-CH2020-208554", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "MIGLUSTAT" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "021348", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "100 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "GALACTOSIALIDOSIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ZAVESCA" } ], "patientagegroup": "3", "patientonsetage": "3", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Asthenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dehydration", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Psychomotor disadaptation syndrome", "reactionmeddraversionpt": "23.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Feeding disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Gastrostomy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Eye movement disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Loss of personal independence in daily activities", "reactionmeddraversionpt": "23.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Intentional product use issue", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Weight decreased", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Speech disorder developmental", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Illness", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Staring", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Crying", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pain", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Extrapyramidal disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intellectual disability", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Upper motor neurone lesion", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrooesophageal reflux disease", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PALLADINO V, PALLADINO S, GIACOMINI T, MANCARDI M, FISCHETTO R. SUBSTRATE REDUCTION THERAPY WITH MIGLUSTAT IN PEDIATRIC PATIENTS WITH GM1 TYPE 2 GANGLIOSIDOSIS DELAYS NEUROLOGICAL INVOLVEMENT: A MULTICENTER EXPERIENCE. MOLECULAR GENETICS + GENOMIC MEDICINE. 2020?E1371.", "literaturereference_normalized": "substrate reduction therapy with miglustat in pediatric patients with gm1 type 2 gangliosidosis delays neurological involvement a multicenter experience", "qualification": "1", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20210119", "receivedate": "20210119", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18758637, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210419" }, { "companynumb": "IT-ACTELION-A-CH2020-208552", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "MIGLUSTAT" }, "drugadditional": "2", "drugadministrationroute": "048", "drugauthorizationnumb": "021348", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "70 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "GALACTOSIALIDOSIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "70", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ZAVESCA" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MIGLUSTAT" }, "drugadditional": "2", "drugadministrationroute": "048", "drugauthorizationnumb": "021348", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "300 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ZAVESCA" } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Abdominal pain", "reactionmeddraversionpt": "23.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "23.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Attention deficit hyperactivity disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Aggression", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Epilepsy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intellectual disability", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dysarthria", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Decreased appetite", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Platyspondylia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Clumsiness", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hyperkinesia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Psychomotor hyperactivity", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "FISCHETTO R, PALLADINO V, MANCARDI M, GIACOMINI T, PALLADINO S, ET AL. SUBSTRATE REDUCTION THERAPY WITH MIGLUSTAT IN PEDIATRIC PATIENTS WITH GM1 TYPE 2 GANGLIOSIDOSIS DELAYS NEUROLOGICAL INVOLVEMENT: A MULTICENTER EXPERIENCE. MOLECULAR GENETICS + GENOMIC MEDICINE. 2020?E1371", "literaturereference_normalized": "substrate reduction therapy with miglustat in pediatric patients with gm1 type 2 gangliosidosis delays neurological involvement a multicenter experience", "qualification": "1", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20200821", "receivedate": "20200821", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18180592, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "IT-ACTELION-A-CH2020-208554", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "MIGLUSTAT" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "021348", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "100 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "GALACTOSIALIDOSIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ZAVESCA" } ], "patientagegroup": null, "patientonsetage": "3", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Illness", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Eye movement disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Psychomotor disadaptation syndrome", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Upper motor neurone lesion", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrooesophageal reflux disease", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dehydration", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrostomy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pain", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Weight decreased", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Loss of personal independence in daily activities", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Speech disorder developmental", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Crying", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Feeding disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Asthenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Staring", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Extrapyramidal disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intellectual disability", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "FISCHETTO R, PALLADINO V, MANCARDI M, GIACOMINI T, PALLADINO S, ET AL. SUBSTRATE REDUCTION THERAPY WITH MIGLUSTAT IN PEDIATRIC PATIENTS WITH GM1 TYPE 2 GANGLIOSIDOSIS DELAYS NEUROLOGICAL INVOLVEMENT: A MULTICENTER EXPERIENCE. MOLECULAR GENETICS + GENOMIC MEDICINE. 2020?E1371", "literaturereference_normalized": "substrate reduction therapy with miglustat in pediatric patients with gm1 type 2 gangliosidosis delays neurological involvement a multicenter experience", "qualification": "1", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20200824", "receivedate": "20200824", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18187921, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" } ]
{ "abstract": "An 83-year-old Japanese man with Alzheimer's disease was admitted to our hospital for treatment of hyponatremia resulting from water intoxication. During hospitalization, the patient developed focal impaired awareness seizures, focal to bilateral tonic-clonic seizures, and subsequent status epilepticus. Electroencephalogram during focal impaired awareness seizures showed rhythmic 5-9 Hz theta activity in the right frontotemporal region. Electroencephalogram during focal to bilateral tonic-clonic seizures showed bilateral polyspikes. Electroencephalogram during an interseizure period revealed sharp waves in the right frontal region. Continuous intravenous administration of midazolam was the only effective treatment for status epilepticus. The patient died of aspiration pneumonia on day 58. Hyponatremia-associated status epilepticus is rare; in the present case, multifocal epileptogenicity resulting from Alzheimer's disease and hyponatremia-associated elevation of glutamate levels in the synaptic cleft may have contributed to the onset of focal to bilateral tonic-clonic seizures with subsequent status epilepticus.", "affiliations": "Department of General Medicine, National Hospital Organization Shibukawa Medical Center, Shibukawa, Japan.;Department of General Medicine, National Hospital Organization Shibukawa Medical Center, Shibukawa, Japan.;Division of Neurosurgery, National Hospital Organization Shibukawa Medical Center, Shibukawa, Japan.", "authors": "Ichioka\|Ken\|K\|;Akuzawa\|Nobuhiro\|N\|https://orcid.org/0000-0002-1204-1294;Takahashi\|Akio\|A\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1177/2050313X20915416", "fulltext": "\n==== Front\nSAGE Open Med Case Rep\nSAGE Open Med Case Rep\nSCO\nspsco\nSAGE Open Medical Case Reports\n2050-313X SAGE Publications Sage UK: London, England \n\n10.1177/2050313X20915416\n10.1177_2050313X20915416\nCase Report\nStatus epilepticus during correction of hyponatremia in a patient\nwith Alzheimer’s disease: A case report\nIchioka Ken 1 https://orcid.org/0000-0002-1204-1294Akuzawa Nobuhiro 1 Takahashi Akio 2 1 Department of General Medicine, National\nHospital Organization Shibukawa Medical Center, Shibukawa, Japan\n2 Division of Neurosurgery, National\nHospital Organization Shibukawa Medical Center, Shibukawa, Japan\nNobuhiro Akuzawa, Department of General\nMedicine, National Hospital Organization Shibukawa Medical Center, 383 Shiroi,\nShibukawa 377-0280, Japan. Email:\[email protected]\n15 4 2020 \n2020 \n8 2050313X2091541620 8 2019 23 2 2020 © The Author(s) 20202020SAGE PublicationsThis article is distributed under the terms of the Creative Commons\nAttribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which\npermits non-commercial use, reproduction and distribution of the work\nwithout further permission provided the original work is attributed as\nspecified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).An 83-year-old Japanese man with Alzheimer’s disease was admitted to our hospital\nfor treatment of hyponatremia resulting from water intoxication. During\nhospitalization, the patient developed focal impaired awareness seizures, focal\nto bilateral tonic-clonic seizures, and subsequent status epilepticus.\nElectroencephalogram during focal impaired awareness seizures showed rhythmic\n5–9 Hz theta activity in the right frontotemporal region. Electroencephalogram\nduring focal to bilateral tonic-clonic seizures showed bilateral polyspikes.\nElectroencephalogram during an interseizure period revealed sharp waves in the\nright frontal region. Continuous intravenous administration of midazolam was the\nonly effective treatment for status epilepticus. The patient died of aspiration\npneumonia on day 58. Hyponatremia-associated status epilepticus is rare; in the\npresent case, multifocal epileptogenicity resulting from Alzheimer’s disease and\nhyponatremia-associated elevation of glutamate levels in the synaptic cleft may\nhave contributed to the onset of focal to bilateral tonic-clonic seizures with\nsubsequent status epilepticus.\n\nAlzheimer’s diseasefocal impaired awareness seizuresfocal to generalized tonic-clonic seizureshyponatremiastatus epilepticuscover-dateJanuary-December 2020typesetterts1\n==== Body\nIntroduction\nThe incidence of new-onset epilepsy in the elderly population is increasing; nearly\n25% of new-onset seizures occur in patients aged over 65 years and the incidence in\nthis population is twice as high as that in children.1 According to a previous study, 1% of elderly individuals have epilepsy.2 Regardless of the presence of precipitating factors, elderly people are more\nprone to develop seizures than younger people and elderly patients with epilepsy\nhave two to three times higher mortality than the general population.2 Moreover, 30% of acute seizures in elderly people may present as status\nepilepticus (SE), with a mortality rate of nearly 40%.2 Most cases of new-onset epilepsy in elderly individuals are secondary to\ncerebrovascular disease, metabolic disturbances, dementia, traumatic brain injury,\ntumor, or pharmacotherapy. Seizures occur in approximately 10% of patients with\nAlzheimer’s disease (AD); two major seizure subtypes observed in this population are\nfocal to bilateral tonic-clonic seizures (FTBTCS) and focal impaired awareness\nseizures (FIAS).2,3\nHowever, FIAS in patients with AD can occur without physical movement, presenting\ninstead as transient increased confusion. Therefore, the incidence of FIAS without\nphysical movement may be underestimated.2–4\n\nWe herein present a case of refractory SE that began with epileptic seizures during\ncorrection of hyponatremia in a patient diagnosed with AD 2 years before\nadmission.\n\nCase presentation\nAn 83-year-old man was admitted to our hospital for evaluation of general malaise. He\nhad a 10-year history of chronic atrial fibrillation and hypertension and had been\ntreated with candesartan (8 mg/day) and warfarin (2 mg/day). Two weeks before\npresentation, the patient had visited a urologist because of transient urinary tract\nhemorrhage. Detailed examination had shown no abnormalities of the urinary tract. He\nhad been advised to drink enough water to prevent urinary obstruction by blood clots\nfor 1–2 weeks. In response, the patient started drinking about 4 L of water per day.\nOne week later, he became aware of fatigability and gait disturbance but continued\ndrinking extra water. His symptoms gradually worsened until he was admitted to the\ngeneral medicine department of our hospital. The patient had no relevant medical or\nfamily history. He was a non-smoker and non-drinker.\n\nOn admission, the patient’s weight was 58 kg and his blood pressure was 102/72 mmHg.\nHe was alert and afebrile. The patient complained of gait disturbance, but physical\nand neurological examination showed no abnormalities. Electrocardiography showed\natrial fibrillation. Plain computed tomography of the neck, chest, and abdomen\nshowed no significant abnormalities. Notably, laboratory tests showed a markedly\ndecreased serum sodium level (105 mEq/L, normal: 138–145 mEq/L). Plasma and urine\nosmolality were 225 and 140 mOsm, respectively. Urine sodium level was undetectable.\nLevels of plasma adrenocorticotropic hormone, cortisol, and antidiuretic hormone\nwere normal, suggesting the possibility of water intoxication. The patient received\n0.5 L of normal saline solution in the emergency department and was transferred to a\ngeneral medicine bed 4 h after emergency department presentation. His serum sodium\nlevel increased by 4 mEq/L over 4 h. Administration of 5% glucose solution was\nstarted at a rate matching urine output to prevent a further increase in serum\nsodium level. On day 2, the patient’s serum sodium level rose to 113 mEq/L. His\nserum sodium level on day 3 was 121 mEq/L. Thereafter his serum sodium level\nincreased by 5 mEq/L per day.\n\nOn day 5, the patient’s serum sodium level was 130 mEq/L. He was alert and was\nimproving. However, he suddenly developed twitching of the left arm lasting for\n30 s, consistent with FIAS, followed by FTBTCS lasting for about 40 min. Assisted\nventilation was started; intravenous diazepam (10 mg) was administered twice but was\nineffective. Therefore, intravenous fosphenytoin sodium (1300 mg) was subsequently\nadministered. FTBTCS stopped after administration of the first dose of fosphenytoin.\nHowever, intermittent twitching of the left arm with impaired awareness resulting\nfrom FIAS continued several times per hour, with each episode lasting more than\n5 min. Moreover, the patient had five episodes of recurrent FTBTCS lasting for about\n30 min each in the first 24 h with prolonged impaired awareness, despite the\naddition of continuous intravenous fosphenytoin (400 mg/day). Ictal\nelectroencephalogram (EEG) during FTBTCS showed bilateral polyspikes but was\nobscured by artifact; ictal EEG during FIAS showed rhythmic 5–9 Hz theta activity in\nthe right frontotemporal region (data not shown). EEG recorded during an\ninterseizure period revealed irregular right frontal sharp waves with theta and\ndelta activities (Figure 1).\nMagnetic resonance imaging (MRI) of the brain showed no obvious signs suggesting\nosmotic demyelination syndrome (ODS); however, marked atrophy of the hippocampus and\ntemporal lobe was seen (Figure\n2). Further questioning of the patient’s family revealed that he had been\ndiagnosed with AD 2 years before admission. Although atrophy of the hippocampus and\ntemporal lobe has been associated with seizures in patients with AD,2–4 no symptomatic epileptic\nseizures had been recognized before hospitalization. On day 6, the frequency of\nFTBTCS decreased, but intermittent FIAS and FTBTCS did not completely disappear.\nCorrection of hyponatremia was suspended to lower serum sodium to 125 mEq/L.\nFosphenytoin administration was discontinued and was replaced with intravenous\nlevetiracetam (1000 mg/day); however, FTBTCS continued intermittently. The addition\nof perampanel (4 mg/day) and clonazepam (3 mg/day) to levetiracetam was ineffective\nat controlling seizures. Administration of lamotrigine (200 mg/day), carbamazepine\n(600 mg/day), and levetiracetam (1000 mg/day) on day 7 was also ineffective.\nContinuous intravenous infusion of midazolam (5 mg/h) was introduced to treat SE on\nday 8. Thereafter, both FIAS and FTBTCS subsided. Repeat MRI of the brain on days 7,\n14, and 28 revealed no obvious lesions suggesting ODS on diffusion-weighted,\nT2-weighted, or fluid attenuation inversion recovery imaging. Reduction of the\nmidazolam dose was not possible because of relapsing seizures. The patient’s general\nstatus gradually deteriorated; he died of aspiration pneumonia on day 58.\n\nFigure 1. Electroencephalogram recorded during interseizure period on day 5. Sharp\nwaves were recorded in the right frontal region (red box). These waveforms\nalso showed disruption of background activity and subsequent emergence of\nslow waves. Low resolution and clipping traces are due to malfunction of the\nrecording device.\n\nFigure 2. Coronal fluid attenuation inversion recovery magnetic resonance imaging of\nthe brain on day 5. Bilateral atrophy of the hippocampus is observed (white\narrows). No other clear abnormal findings, including ischemic\nleukoencephalopathy, were found. Diffusion-weighted imaging of the brain\nshowed no significant abnormalities.\n\nDiscussion\nIn the present case, refractory FIAS and FTBTCS with subsequent SE occurred during\ncorrection of hyponatremia resulting from polydipsia. Hyponatremia may lead to acute\nsymptomatic seizures, which are usually generalized tonic-clonic.5 In addition, acute epileptic seizures and focal neurological deficits are\nidentified concomitantly in 5% of patients with severe hyponatremia (<125 mEq/L).5 When correcting hyponatremia, ODS may also cause seizures,6 but no lesions suggesting ODS were found in the present case. Okazaki et al.7 reported the effects of polydipsia-induced hyponatremia on pre-existing FIAS\nin five patients. In that report, the frequency of symptomatic FIAS increased when\nserum sodium fell below 127 mEq/L; four of the five patients had hippocampal atrophy\nor sclerosis and developed FIAS or FTBTCS. This finding suggests that hyponatremia\nmay aggravate both FIAS and FTBTCS in patients with hippocampal atrophy or\nsclerosis.\n\nIt should be noted that hyponatremic seizures per se are not rare events and are\noften observed in children and women of childbearing age;5 however, SE associated with hyponatremia is rare. To the best of our\nknowledge, only nine patients with SE associated with hyponatremia have been\nreported in the PubMed database in the past 30 years.8–15 Characteristics of the nine\nreported patients and our patient are shown in Table 1. Among these 10 patients, six were\nmale and four were female. Patient age ranged from 10 to 83 years; serum sodium\nlevels ranged from 90 to 126 mEq/L. The causes of hyponatremia were, in the order of\ndescending prevalence, polydipsia (four cases), syndrome of inappropriate secretion\nof antidiuretic hormone (SIADH, three cases), cerebral salt wasting (two cases), and\nadrenal insufficiency (one case). Hence, polydipsia and SIADH may be leading causes\nof hyponatremia-associated SE. Regarding seizure types, generalized tonic-clonic\nseizures were most common (four cases); complex partial seizures (two cases) and\nnon-convulsive SE (two cases) were also observed. Eight patients had no past history\nof epileptic seizures. No patients developed ODS during the treatment of\nhyponatremia. In the nine previously reported cases, antiepileptic drugs effectively\nstopped SE; these patients all recovered without sequelae. Our patient was the only\none with AD and whose outcome was death.\n\nTable 1. Patients with status epilepticus secondary to hyponatremic seizures.\n\nAuthor\tPatient age (years)\tSex\tComorbidities\tHistory of epilepsy\tType of seizures\tCause of hyponatremia\tSerum sodium level (mEq/L)\tAEDs given\tPresence of ODS\tOutcome\t\nPrimavera8\t53\tF\tBorderline personality disorder\t(−)\tNCSE\tPolydipsia\t90\tPB\t(−)\tSurvival\t\nBartolomei9\t68\tM\tDepression, BPH\t(−)\tCPS\tAdrenal insufficiency\t117\tCZP\t(−)\tSurvival\t\nKawaguchi10\t45\tF\tLymphoblastic leukemia, post-BMT\t(−)\tGTC\tSIADH resulting from HHV-6-associated acute limbic\nencephalitis\t109\tUnknown\t(−)\tSurvival\t\nÇelik11\t12\tM\tEpilepsy, cognitive and motor impairment\t(+)\tUnknown\tCerebral salt wasting\t122\tMDZ\t(−)\tSurvival\t\nÇelik11\t10\tM\tRefractory epilepsy, severe intellectual disability\t(+)\tUnknown\tCerebral salt wasting\t120\tUnknown\t(−)\tSurvival\t\nDe Souza Franceschi12\t59\tM\tCLL, post-umbilical cord blood transplantation\t(−)\tNCSE\tSIADH resulting from HHV-6-associated encephalitis\t126\tPHT\nLEV\t(−)\tSurvival\t\nPatel13\t8\tM\tADHD\t(−)\tGTC\tPolydipsia resulting from MPH overdose\t118\tfosPHT\t(−)\tSurvival\t\nHashimoto14\t75\tF\tLeft lung tuberculosis\t(−)\tGTC\tSIADH resulting from lung tuberculosis\t120\tfosPHT\t(−)\tSurvival\t\nKurauchi15\t67\tF\tDepression\t(−)\tNCSE\tPolydipsia\t115\tDZP\nLEV\t(−)\tSurvival\t\nAkuzawa\t83\tM\tPolydipsia, hematuria, Alzheimer’s disease\t(−)\tCPS\nGTC\tPolydipsia\t105\tCZP\nDZP\nfosPHT\nLEV\nLTG\nMDZ\nPER\t(−)\tDeath\t\nADHD: attention-deficit/hyperactivity disorder; AED: antiepileptic drug;\nBMT: bone marrow transplantation; BPH: benign prostate hypertrophy; CLL:\nchronic lymphocytic leukemia; CPS: complex partial seizure; CZP:\nclonazepam; F: female; fosPHT: fosphenytoin; DZP: diazepam; GTC:\ngeneralized tonic-clonic seizure; HHV-6: human herpesvirus-6; LEV:\nlevetiracetam; LTG: lamotrigine; M: male; MDZ: midazolam; MPH:\nmethylphenidate; NCSE: non–convulsive status epilepticus; ODS: osmotic\ndemyelination syndrome; PB: phenobarbital; PER: perampanel; PHT:\nphenytoin; SIADH: syndrome of inappropriate secretion of antidiuretic\nhormone.\n\nInterestingly, our patient showed rhythmic 5–9 Hz theta activity in the right\nfrontotemporal region during FIAS. This finding is similar to the typical ictal EEG\nof temporal lobe epilepsy and is specific for hippocampal seizures.16 In contrast, EEG during a seemingly interseizure period showed irregular\nsharp waves with theta and delta activities in the right frontotemporal region; this\npattern resembles the ictal pattern of temporal lobe epilepsy associated with\nneocortical seizures.16 These observed EEG patterns may also indicate multiple epileptogenic foci.\nAccording to previous studies, hippocampal sclerosis and multifocal spikes on EEG\nmay be associated with FTBTCS in patients with temporal or frontal lobe\nepilepsy.17,18 Moreover, AD is a leading cause of frontal or temporal epilepsy\nin the aged population. AD can cause SE, but SE in our patient was unresponsive to\nfirst-, second-, and third-line therapies and recurred for ⩾24 h.19–22 These characteristics meet the\ncriteria of super-refractory SE, which has a distinctively high mortality (about\n40%).23–25 To our knowledge, no similar\nsuper-refractory SE cases have been reported among AD patients. Factors related to\nthe onset of super-refractory SE in our patient are unclear, but hyponatremia might\nhave accelerated neuronal hyperexcitability resulting from AD-related presynaptic\nglutamate release, leading to SE.4,4,26\n\nThe limitations of our report include the lack of EEG information before\nhospitalization. Regarding EEG data during hospitalization, a mechanical breakdown\nof recording devices prevented capture of complete data and therefore we could not\nshow ictal EEG data during FIAS and FTBTCS. In addition, although this patient was\ndiagnosed with AD 2 years before admission, the precise time of AD onset was\nunclear. Regarding imaging, follow-up MRI of the brain was not performed after day\n28 because of deterioration of the patient’s general status. However, this case\nhighlights interesting mechanisms of FIAS proceeding to FTBTCS or SE and may also\nalert physicians to the potential risk of triggering SE under hyponatremic\nconditions.\n\nIn conclusion, we have presented a case of super-refractory SE during correction of\nchronic hyponatremia. Physicians should be aware of the potential risk of triggering\nSE when correcting hyponatremia in patients with AD.\n\nWe thank Rebecca Tollefson, DVM, from Edanz Group (www.edanzediting.com/ac)\nfor editing a draft of this manuscript.\n\nDeclaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the\nresearch, authorship, and/or publication of this article.\n\nEthical approval: Our institution does not require ethical approval for reporting individual cases\nor case series.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or\npublication of this article.\n\nInformed consent: Written informed consent was obtained from the patient and legally authorized\nrepresentatives including the patient’s wife and son for anonymized patient\ninformation to be published in this article. A copy of this written consent is\navailable for review by the Editor-in-Chief of this journal.\n\nORCID iD: Nobuhiro Akuzawa \nhttps://orcid.org/0000-0002-1204-1294\n==== Refs\nReferences\n1. \nGhosh S Jehi LE. \nNew-onset epilepsy in the elderly: challenges for the\ninternist\n. Cleve Clin J Med \n2014 ; 81 (8 ):\n490 –498\n.25085987 \n2. \nBrodie MJ Kwan P. \nEpilepsy in elderly people\n. BMJ \n2005 ; 331 :\n1317 –1322\n.16322020 \n3. \nPandis D Scarmeas N. \nSeizures in Alzheimer disease: clinical and epidemiological\ndata\n. Epilepsy Curr \n2012 ; 12 (5 ):\n184 –187\n.23118603 \n4. \nVossel KA Tartaglia MC Nygaard HB , et al\nEpileptic activity in\nAlzheimer’s disease: cause and clinical relevance\n.\nLancet Neurol \n2017 ; 16 :\n311 –322\n.28327340 \n5. \nNardone R Brigo F Trinka E. \nAcute symptomatic seizures caused by electrolyte\ndisturbances\n. 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J\nClin Med \n2014 ; 3 :\n1163 –1177\n.26237597\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "2050-313X", "issue": "8()", "journal": "SAGE open medical case reports", "keywords": "Alzheimer’s disease; focal impaired awareness seizures; focal to generalized tonic-clonic seizures; hyponatremia; status epilepticus", "medline_ta": "SAGE Open Med Case Rep", "mesh_terms": null, "nlm_unique_id": "101638686", "other_id": null, "pages": "2050313X20915416", "pmc": null, "pmid": "32313652", "pubdate": "2020", "publication_types": "D002363:Case Reports", "references": "21914716;23173742;17472605;26900382;28850553;16322020;24791089;16102515;21939901;26237597;22577217;24363133;28681418;28424403;26212707;7578663;25085987;27115479;24485931;26754778;25285115;28202866;22429112;9729113;23118603;28327340", "title": "Status epilepticus during correction of hyponatremia in a patient with Alzheimer's disease: A case report.", "title_normalized": "status epilepticus during correction of hyponatremia 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"drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBAMAZEPINE." } ], "patientagegroup": null, "patientonsetage": "83", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "58", "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ICHIOKA K, AKUZAWA N, TAKAHASHI A. STATUS EPILEPTICUS DURING CORRECTION OF HYPONATREMIA IN A PATIENT WITH ALZHEIMER^S DISEASE: A CASE REPORT.. SAGE OPEN MEDICAL CASE REPORTS. 2021?8:1?5.", "literaturereference_normalized": "status epilepticus during correction of hyponatremia in a patient with alzheimer s disease a case report", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20210429", "receivedate": "20210429", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19194964, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" } ]
{ "abstract": "A 26-year-old girl with a longstanding colonization by Pandoraea nosoerga underwent liver-lung transplantation for cystic fibrosis (CF) in 2018. Her brother also suffering from CF was also colonized by P. nosoerga. Despite appropriate perioperative antibiotic therapy, she had post-transplant bacteremic pneumonia caused by extensively drug-resistant P. nosoerga. Drug repurposing was used to optimize treatment options. The cause of post-transplant contamination was studied by comparative whole-genome sequencing including pre- and post-transplant strains and her brother's strains. Post-transplant contamination appeared to be due to her own pre-transplant strain, emphasizing the urgent need to study and implement effective decontamination protocols before transplantation.", "affiliations": "IRD, APHM, MEPHI, IHU-Méditerranée Infection, Aix Marseille Univ, 19-21 boulevard Jean Moulin, 13385, Marseille CEDEX 05, France.;IRD, APHM, MEPHI, IHU-Méditerranée Infection, Aix Marseille Univ, 19-21 boulevard Jean Moulin, 13385, Marseille CEDEX 05, France.;IRD, APHM, MEPHI, IHU-Méditerranée Infection, Aix Marseille Univ, 19-21 boulevard Jean Moulin, 13385, Marseille CEDEX 05, France.;IRD, APHM, MEPHI, IHU-Méditerranée Infection, Aix Marseille Univ, 19-21 boulevard Jean Moulin, 13385, Marseille CEDEX 05, France.;IRD, APHM, MEPHI, IHU-Méditerranée Infection, Aix Marseille Univ, 19-21 boulevard Jean Moulin, 13385, Marseille CEDEX 05, France. [email protected].", "authors": "Peyclit\|Lucie\|L\|;Baron\|Sophie Alexandra\|SA\|;Reynaud-Gaubert\|Martine\|M\|;Cassir\|Nadim\|N\|;Rolain\|Jean-Marc\|JM\|", "chemical_list": null, "country": "Germany", "delete": false, "doi": "10.1007/s10096-021-04235-0", "fulltext": null, "fulltext_license": null, "issn_linking": "0934-9723", "issue": "40(11)", "journal": "European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology", "keywords": "Comparative genomic; Cystic fibrosis; Drug repurposing; Extensively drug-resistant bacteria; Pandoraea", "medline_ta": "Eur J Clin Microbiol Infect Dis", "mesh_terms": null, "nlm_unique_id": "8804297", "other_id": null, "pages": "2403-2406", "pmc": null, "pmid": "33830365", "pubdate": "2021-11", "publication_types": "D016428:Journal Article", "references": "25826590;28711221;28858970;11208624;30069386;32349719;27620956;32389488;30895843;31781066;31245302;31762328;30316849;29056926;27050666", "title": "Fatal Pandoraea nosoerga infection after combined liver-lung transplantation for cystic fibrosis: a recontamination by the pre-transplantation strain.", "title_normalized": "fatal pandoraea nosoerga infection after combined liver lung transplantation for cystic fibrosis a recontamination by the pre transplantation strain" }	[ { "companynumb": "FR-PFM-2022-01303", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOXYCYCLINE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXYCYCLINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOXYCYCLINE" }, "drugadditional": "4", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Bacterial infection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXYCYCLINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "RISPERIDONE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": "078452", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Bacterial infection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RISPERIDONE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CHLORHEXIDINE GLUCONATE" }, "drugadditional": "4", "drugadministrationroute": "003", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, DAILY BATHING", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CHLORHEXIDINE GLUCONATE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Bacterial infection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPIN" } ], "patientagegroup": null, "patientonsetage": "26", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Septic shock", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Disease recurrence", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bacteraemia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Peyclit L, Baron SA, Reynaud-Gaubert M, Cassir N, Rolain JM.. Fatal Pandoraea nosoerga infection after combined liver-lung transplantation for cystic fibrosis: a recontamination by the pre-transplantation strain.. European Journal of Clinical Microbiology + Infectious Diseases.. 2021;40(11):2403-2406", "literaturereference_normalized": "fatal pandoraea nosoerga infection after combined liver lung transplantation for cystic fibrosis a recontamination by the pre transplantation strain", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20220308", "receivedate": "20220308", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20563324, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 1, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220424" }, { "companynumb": "FR-PFM-2022-01303", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOXYCYCLINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "091406", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Bacterial infection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXYCYCLINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RISPERIDONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076288", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Bacterial infection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RISPERIDONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CHLORHEXIDINE GLUCONATE" }, "drugadditional": "3", "drugadministrationroute": "003", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, DAILY BATHING", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CHLORHEXIDINE GLUCONATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Bacterial infection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPIN" } ], "patientagegroup": null, "patientonsetage": "26", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Septic shock", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Disease recurrence", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bacteraemia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Peyclit L, Baron SA, Reynaud-Gaubert M, Cassir N, Rolain JM. Fatal Pandoraea nosoerga infection after combined liver-lung transplantation for cystic fibrosis: a recontamination by the pre-transplantation strain. European Journal of Clinical Microbiology + Infectious Diseases. 2021;40(11):2403-2406", "literaturereference_normalized": "fatal pandoraea nosoerga infection after combined liver lung transplantation for cystic fibrosis a recontamination by the pre transplantation strain", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20220330", "receivedate": "20220330", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20654232, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 1, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220424" } ]
{ "abstract": "The prevalence of fungal otitis externa, or otomycosis, has been increasing in recent decades. Fungi may act as primary pathogens in this condition, or they may occur as secondary infections after prolonged ototopical treatment with antibiotics, which alters the flora of the external auditory canal (EAC) and enables overgrowth of its fungal inhabitants. We report here a case of otomycosis by Candida parapsilosis, Malassezia obtusa, and Malassezia furfur as a secondary infection following prolonged otic ofloxacin treatment. To the best of our knowledge, although isolation of C. parapsilosis and M. furfur from the EAC is not uncommon, the recovery of M. obtusa has not yet been reported. We also conducted a literature review of the searchable data on PubMed concerning the isolation of Malassezia species from the human EAC.", "affiliations": "Laboratory of Medical Mycology and Space Environmental Medicine, School of Medicine, Graduate School of Medicine, Teikyo University, 2-11-1 Kaga, Itabashi, Tokyo, 173-8605, Japan.;Teikyo University Institute of Medical Mycology, Tokyo, Japan.;Department of Sports and Medical Science, Faculty of Medical Technology, Teikyo University, Itabashi, Tokyo, Japan.;Teikyo University Institute of Medical Mycology, Tokyo, Japan.;Department of Otolaryngology, Teikyo University Hospital, Itabashi, Tokyo, Japan.;Teikyo University Institute of Medical Mycology, Tokyo, Japan.;Laboratory of Medical Mycology and Space Environmental Medicine, School of Medicine, Graduate School of Medicine, Teikyo University, 2-11-1 Kaga, Itabashi, Tokyo, 173-8605, Japan. [email protected].", "authors": "Alshahni\|Mohamed Mahdi\|MM\|;Alshahni\|Rima Zakzuk\|RZ\|;Fujisaki\|Ryuichi\|R\|;Tamura\|Takashi\|T\|;Shimizu\|Yuya\|Y\|;Yamanishi\|Chiaki\|C\|;Makimura\|Koichi\|K\|http://orcid.org/0000-0003-1645-3445", "chemical_list": "D015242:Ofloxacin", "country": "Netherlands", "delete": false, "doi": "10.1007/s11046-021-00581-x", "fulltext": null, "fulltext_license": null, "issn_linking": "0301-486X", "issue": "186(6)", "journal": "Mycopathologia", "keywords": "Candida; Malassezia; Ofloxacin; Otitis externa; Otomycosis", "medline_ta": "Mycopathologia", "mesh_terms": "D005658:Fungi; D006801:Humans; D008290:Malassezia; D015242:Ofloxacin; D010032:Otitis Externa; D059249:Otomycosis", "nlm_unique_id": "7505689", "other_id": null, "pages": "871-876", "pmc": null, "pmid": "34410567", "pubdate": "2021-12", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": "11261868;9433684", "title": "A Case of Topical Ofloxacin-Induced Otomycosis and Literature Review.", "title_normalized": "a case of topical ofloxacin induced otomycosis and literature review" }	[ { "companynumb": "JP-TEVA-2021-JP-1968976", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "OFLOXACIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "76182", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Otitis externa", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OFLOXACIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CEFDITOREN PIVOXIL" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Tablet", "drugdosagetext": "3 TIMES A DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Otitis externa", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFDITOREN PIVOXIL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "GARENOXACIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Tablet", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Otitis externa", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GARENOXACIN" } ], "patientagegroup": "5", "patientonsetage": "40", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Ear infection fungal", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Candida infection", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Malassezia infection", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Alshahni MM, Alshahni RZ, Fujisaki R, Tamura T, Shimizu Y, Yamanishi C, et al. A Case of Topical Ofloxacin-Induced Otomycosis and Literature Review. Mycopathol 2021;:.", "literaturereference_normalized": "a case of topical ofloxacin induced otomycosis and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20211102", "receivedate": "20211028", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20008939, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20220303" }, { "companynumb": "JP-MLMSERVICE-20210917-3113714-1", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "OFLOXACIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "76128", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Ear drops", "drugdosagetext": "OTIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "Otitis externa", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "12", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OFLOXACIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CEFDITOREN PIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Tablet", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Otitis externa", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "8", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFDITOREN PIVOXIL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "GARENOXACIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Tablet", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Otitis externa", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GARENOXACIN" } ], "patientagegroup": null, "patientonsetage": "40", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Otitis externa fungal", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Alshahni M, Alshahni R, Fujisaki R, Tamura T, Shimizu Y, Yamanishi C, Makimura K. A case of topical ofloxacin-induced otomycosis and literature review. Mycopathologia. 2021 AUG 19;. doi:10.1007/s11046-021-00581-x", "literaturereference_normalized": "a case of topical ofloxacin induced otomycosis and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20211014", "receivedate": "20211014", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19953759, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220303" }, { "companynumb": "JP-ALVOGEN-2021-ALVOGEN-117421", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "OFLOXACIN" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "76830", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.3% OFLOXACIN?EAR DROPS (TWICE A DAY)", "drugenddate": null, "drugenddateformat": null, "drugindication": "OTITIS EXTERNA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": [ { "drugrecuraction": "Fungal infection" } ], "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OFLOXACIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "KETOCONAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2% SOLUTION ONCE IN A DAY.", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRURITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETOCONAZOLE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CEFDITOREN PIVOXIL" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3 TIMES A DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "OTITIS EXTERNA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": [ { "drugrecuraction": "Fungal infection" } ], "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFDITOREN PIVOXIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "GARENOXACIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "ONCE IN A DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "OTITIS EXTERNA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GARENOXACIN" } ], "patientagegroup": null, "patientonsetage": "48", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Fungal infection", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "ALSHAHNI MM, ALSHAHNI RZ, FUJISAKI R, TAMURA T, SHIMIZU Y, YAMANISHI C, MAKIMURA K. A CASE OF TOPICAL OFLOXACIN?INDUCED OTOMYCOSIS AND LITERATURE REVIEW. MYCOPATHOLOGIA. 2021 AUG 19.", "literaturereference_normalized": "a case of topical ofloxacin induced otomycosis and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20210906", "receivedate": "20210906", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19793753, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20211014" } ]
{ "abstract": "We report a case of rapid eradication of melanoma brain metastases and simultaneous near-fatal encephalomyelitis following double immune checkpoint blockade. Brain damage marker S-100B and C reactive protein increased before symptoms or signs of encephalomyelitis and peaked when the patient fell into a coma. At that point, additional brain damage markers and peripheral T cell phenotype was analyzed. The analyses were repeated four times during the patient's recovery. Axonal damage marker neurofilament light polypeptide (NFL) and astrocytic damage marker glial fibrillar acidic protein (GFAP) were very high in blood and cerebrospinal fluid and gradually normalized after immunosuppression and intensive care. The costimulatory receptor inducible T cell costimulatory receptor (ICOS) was expressed on a high proportion of CD4+ and CD8+T cells as encephalomyelitis symptoms peaked and then gradually decreased in parallel with clinical improvement. Both single and double immune checkpoint inhibitor-treated melanoma patients with other serious immune-related adverse events (irAE) (n=9) also expressed ICOS on a significantly higher proportion of CD4+ and CD8+T cells compared with controls without irAE (n=12). In conclusion, our results suggest a potential role for ICOS on CD4+ and CD8+T cells in mediating encephalomyelitis and other serious irAE. In addition, brain damage markers in blood could facilitate early diagnosis of encephalitis.", "affiliations": "Department of Oncology, Institute of Clinical Sciences, University of Gothenburg Sahlgrenska Academy, Goteborg, Sweden.;Department of Oncology, Institute of Clinical Sciences, University of Gothenburg Sahlgrenska Academy, Goteborg, Sweden.;Department of Oncology, Institute of Clinical Sciences, University of Gothenburg Sahlgrenska Academy, Goteborg, Sweden.;Department of Oncology, Sahlgrenska University Hospital, Goteborg, Sweden.;Department of Oncology, Institute of Clinical Sciences, University of Gothenburg Sahlgrenska Academy, Goteborg, Sweden.;Department of Neuroradiology, Sahlgrenska University Hospital, Goteborg, Sweden.;Department of Anesthesiology and Intensive Care, Sahlgrenska University Hospital, Goteborg, Sweden.;Department of Oncology, Institute of Clinical Sciences, University of Gothenburg Sahlgrenska Academy, Goteborg, Sweden.;Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, University of Gothenburg Sahlgrenska Academy, Goteborg, Sweden.;Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, University of Gothenburg Sahlgrenska Academy, Goteborg, Sweden.;Department of Psychiatry and Neurochemistry, University of Gothenburg Institute of Neuroscience and Physiology, Goteborg, Sweden.;Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg Sahlgrenska Academy, Goteborg, Sweden.;Department of Oncology, Institute of Clinical Sciences, University of Gothenburg Sahlgrenska Academy, Goteborg, Sweden [email protected].", "authors": "Bjursten\|Sara\|S\|;Pandita\|Ankur\|A\|;Zhao\|Zhiyuan\|Z\|;Fröjd\|Charlotta\|C\|;Ny\|Lars\|L\|;Jensen\|Christer\|C\|;Ullerstam\|Tobias\|T\|;Jespersen\|Henrik\|H\|;Borén\|Jan\|J\|;Levin\|Malin\|M\|;Zetterberg\|Henrik\|H\|;Rudin\|Anna\|A\|;Levin\|Max\|M\|0000-0001-9676-5582", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1136/jitc-2021-002732", "fulltext": "\n==== Front\nJ Immunother Cancer\nJ Immunother Cancer\njitc\njitc\nJournal for Immunotherapy of Cancer\n2051-1426\nBMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR\n\n34215689\njitc-2021-002732\n10.1136/jitc-2021-002732\nCase Report\n1506\n2518 1619\nEarly rise in brain damage markers and high ICOS expression in CD4+ and CD8+ T cells during checkpoint inhibitor-induced encephalomyelitis\nBjursten Sara 12\nPandita Ankur 123\nZhao Zhiyuan 12\nFröjd Charlotta 2\nNy Lars 12\nJensen Christer 4\nUllerstam Tobias 5\nJespersen Henrik 126\nBorén Jan 3\nLevin Malin 3\nZetterberg Henrik 78910\nRudin Anna 11\nhttp://orcid.org/0000-0001-9676-5582\nLevin Max 123\n1 Department of Oncology, Institute of Clinical Sciences, University of Gothenburg Sahlgrenska Academy, Goteborg, Sweden\n2 Department of Oncology, Sahlgrenska University Hospital, Goteborg, Sweden\n3 Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, University of Gothenburg Sahlgrenska Academy, Goteborg, Sweden\n4 Department of Neuroradiology, Sahlgrenska University Hospital, Goteborg, Sweden\n5 Department of Anesthesiology and Intensive Care, Sahlgrenska University Hospital, Goteborg, Sweden\n6 Department of Oncology, Akershus University Hospital, Lorenskog, Norway\n7 Department of Psychiatry and Neurochemistry, University of Gothenburg Institute of Neuroscience and Physiology, Goteborg, Sweden\n8 Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Goteborg, Sweden\n9 Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK\n10 UK Dementia Research Institute, UCL, London, UK\n11 Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg Sahlgrenska Academy, Goteborg, Sweden\nCorrespondence to Dr Max Levin; [email protected]\n2021\n2 7 2021\n9 7 e00273210 6 2021\n© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See https://creativecommons.org/licenses/by/4.0/.\n\nWe report a case of rapid eradication of melanoma brain metastases and simultaneous near-fatal encephalomyelitis following double immune checkpoint blockade. Brain damage marker S-100B and C reactive protein increased before symptoms or signs of encephalomyelitis and peaked when the patient fell into a coma. At that point, additional brain damage markers and peripheral T cell phenotype was analyzed. The analyses were repeated four times during the patient’s recovery. Axonal damage marker neurofilament light polypeptide (NFL) and astrocytic damage marker glial fibrillar acidic protein (GFAP) were very high in blood and cerebrospinal fluid and gradually normalized after immunosuppression and intensive care. The costimulatory receptor inducible T cell costimulatory receptor (ICOS) was expressed on a high proportion of CD4+ and CD8+T cells as encephalomyelitis symptoms peaked and then gradually decreased in parallel with clinical improvement. Both single and double immune checkpoint inhibitor-treated melanoma patients with other serious immune-related adverse events (irAE) (n=9) also expressed ICOS on a significantly higher proportion of CD4+ and CD8+T cells compared with controls without irAE (n=12). In conclusion, our results suggest a potential role for ICOS on CD4+ and CD8+T cells in mediating encephalomyelitis and other serious irAE. In addition, brain damage markers in blood could facilitate early diagnosis of encephalitis.\n\nimmunotherapy\nmelanoma\nautoimmunity\nCD4-Positive T-Lymphocytes\nCD8-Positive T-Lymphocytes\nSwedish state under the agreement between the Swedish government and the county councils, the ALF-agreement ALFGBG-717541 ALFGBG-828121 ALFGBG-870351 ALFGBG-933754 http://dx.doi.org/10.13039/501100010223 Stiftelsen Jubileumsklinikens Forskningsfond mot Cancer 2020-313 http://dx.doi.org/10.13039/501100005009 Stiftelsen Assar Gabrielssons Fond special-featureunlocked\n==== Body\nImmune checkpoint blockade increases survival in patients with metastatic malignant melanoma, renal cell carcinoma, and lung cancer.1–4 Double immune checkpoint blockade activates T cells by blocking the inhibitory receptors programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) simultaneously, thereby promoting T cells to kill cancer cells. However, it increases the risk of autoimmune reactions in healthy tissue, immune-related adverse events (irAE).5 Any organ system can be affected by irAE and among the most feared is engagement of the brain, encephalitis.6–8 With the growing use of immune checkpoint blockade in cancer patients, encephalitis cases are expected to increase. A clinical challenge is to quickly and accurately diagnose encephalitis, which is difficult to distinguish from conditions such as progression of brain metastasis or infection that give rise similar symptoms. Also, little is known about the T cell mediated mechanisms promoting encephalitis and other serious irAE.\n\nEncephalomyelitis case and controls\n\nEncephalomyelitis case\n\nA 67-year-old man with metastases of melanoma in the brain, adrenal glands, lung, subcutis, and lymph nodes started double immune checkpoint blockade; PD1-inhibitor nivolumab (1 mg/kg) and the CTLA-4 inhibitor ipilimumab (3 mg/kg) given four times at 3-week intervals (figure 1A). After two treatments, MRI scans (MRI) showed regression of the brain metastases (figure 1B). The day after the fourth treatment, he developed a fever (39.1°C), elevation of C reactive protein (CRP) (45 mg/L), and dizziness. He was admitted to the oncology ward at Sahlgrenska University Hospital and was given IV antibiotics. After 2 days, he developed paraparesis in his lower limbs, decreased consciousness, and respiratory failure. His CRP level increased to 130 mg/L.\n\nFigure 1 Regression of encephalomyelitis induced by double immune checkpoint blockade. (A) shows a clinical overview. (B) shows regression of brain metastases and progression of encephalitis on MRI scans. At baseline, the patient had a 25 mm metastasis in the left portion of the splenium corpus callosum and an 18 mm metastasis in the right cerebellar hemisphere (red arrows). After two treatments (34 days), both metastases had partially regressed. After four treatments (68 days), regression was complete but new diffuse lesions were seen in the posterior horns of the lateral ventricles indicating encephalitis (red arrows). MRI scans were unchanged at day 71 and showed gradual decrease of the lesions in the brain at 78 and 85 days and complete resolution at 112 days. (C) shows serum levels of S-100B and C reactive protein (CRP), starting at baseline. The highest measurements coincided with the most severe symptoms of encephalitis. However, the first peak in S-100B and CRP levels occurred before the patient had any symptoms or radiological findings of encephalitis, suggesting a potential biomarker for early detection. IPI, ipilimumab; IVIG, intravenous immunoglobulin; MMF, mycophenolate mofetil; nivo, nivolumab.\n\nHe was admitted to the intensive care unit (ICU), intubated, and put on mechanical ventilation. On ICU day 1, MRI showed complete regression of his brain metastases but new diffuse lesions in the brain, brainstem, and cerebellum with a bilateral and asymmetric pattern (figure 1B), indicating acute disseminated encephalomyelitis.9 Analyses of cerebrospinal fluid (CSF) suggested autoimmune encephalitis (online supplemental table S1). Immunosuppression with methylprednisolone (1 g daily intravenously) was started. The next day he was alert during sedation stops but required respiratory support, reflecting brain stem damage. MRI on ICU day 3 revealed unchanged brain lesions and lesions in the spinal cord. Cyclophosphamide was administered (1.5 g intravenously as a single dose), but his condition did not improve. On ICU day 6, mycophenolate mofetil (1 g two times per day intravenously) was started to inhibit T and B cell proliferation.10 The next day, he had improved and could be extubated and transferred back to the oncology ward. He had flaccid paraparesis in his lower limbs with minor residual sensation and urine and fecal incontinence. High-dose cortisone and mycophenolate mofetil were continued, and intravenous immunoglobulins were given (35 g daily for 5 days). MRI 10 and 17 days after ICU admission revealed gradual decrease in lesions in the brain and spinal cord (figure 1B).\n\n10.1136/jitc-2021-002732.supp1 Supplementary data\n\nAfter 6 weeks, the patient was discharged from hospital care. Now, he had regained most sensory functions, and he could sit up and operate a wheelchair. After 10 weeks, the inflammatory lesions had resolved on MRI. The immunosuppressant treatment was tapered and permanently discontinued after 14 months. More than 2 years after the first dose of double immune checkpoint blockade, the patient no longer suffers from fecal incontinence and he can walk more than 100 steps with assistive devices. By becoming more independent, the patient’s quality of life has improved significantly and he remains tumor-free.\n\nControl patients with or without irAE\n\nIn addition to the encephalomyelitis patient, we also analyzed T cell characteristics in checkpoint inhibitor-treated patients with (n=9) or without other irAE (n=12) (table 1). The irAE were moderate to severe and occurred during double (n=2, including the encephalomyelitis patient) or single (PD-1) inhibition (n=8). Similarly, samples were obtained from patients without irAE during double (n=2) or single (PD-1) checkpoint inhibition (n=10). In addition, we performed repeated analysis of cytokines and soluble checkpoint proteins in CSF from the encephalomyelitis patient. As controls for this analysis, we used CSF from patients with autoimmune systemic lupus erythematosus without encephalitis (n=4).\n\nTable 1 Patient characteristics\n\nAge\tSex\tBRAF\tTumor stage\tTreatment\tTime to irAE/test†\tAffected organ(s)\tGrade\n(CTCAE 5)‡\tTreatment of irAE\t\n68\tM\tV600K\tIV\tIpi+Nivo\t2 months\tBrain and spinal cord§\t4\tCORT, MMF, IVIG, CP\t\n52\tF\tWt\tIV\tIpi+Nivo\t2 months\tLiver\t4\tCORT, MMF\t\n72\tF\tNot known\tIV\tPembro\t3 months\tBlood (neutropenia)\t4\tCORT, filgrastim\t\n72\tM\tV600\tIV\tPembro\t13 months\tColon\t3\tCORT, infliximab\t\n55\tF\tV600\tIV\tNivo\t14 months\tJoints and muscles\t3\tCORT, MTX\t\n38\tF\tWt\tIV\tNivo¶\t5 months\tJoints and muscles\t3\tCORT\t\n83\tF\tV600E\tIV\tNivo\t1 month\tColon\t3\tCORT, infliximab\t\n53\tM\tV600K\tIV\tNivo\t11 months\tLungs\t2\tCORT\t\n80\tF\tWt\tIV\tNivo\t10 months\tLungs\t2\tCORT\t\n74\tM\tV600K\tIV\tNivo±Relatlimab\t2 months\tJoints and muscles\t2\tCORT\t\n\t \t \t \t \t\t \t\t \t\n71\tM\tWt\tIV\tIpi+Nivo\t9 months\tNo irAE\t0\tnone\t\n80\tM\tWt\tIV\tIpi+Nivo\t2 months\tNo irAE\t0\tnone\t\n80\tM\tV600K\tIV\tPembro\t5 months\tNo irAE\t0\tnone\t\n77\tF\tWt\tIV\tPembro\t4 months\tNo irAE\t0\tnone\t\n82\tF\tWt\tIV\tPembro\t3 months\tNo irAE\t0\tnone\t\n76\tM\tV600E\tIV\tPembro\t3 months\tNo irAE\t0\tnone\t\n67\tM\tV600\tIV\tPembro\t2 months\tNo irAE\t0\tnone\t\n68\tM\tV600E\tIV\tNivo\t4 months\tNo irAE\t0\tnone\t\n62\tF\tV600E\tIV\tNivo\t3 months\tNo irAE\t0\tnone\t\n57\tM\tV600E\tIV\tNivo\t2 months\tNo irAE\t0\tnone\t\n68\tM\tWt\tIII\tNivo\t1 month\tNo irAE\t0\tnone\t\n93\tM\tWt\tIII\tNivo\t1 month\tNo irAE\t0\tnone\t\nStage III: locally advanced disease. Stage IV: metastatic disease.\n\n†Time from treatment start until adverse event (and sample) or time from treatment start until sample in controls without irAE.\n\n‡CTCAE are a set of criteria for the standardized classification of adverse effects of cancer drugs. The scale ranges from grade 0 to grade 5. Grade 0 is no adverse event. Grade one adverse events have no or mild symptoms with or without laboratory abnormalities whereas grade five events are lethal.\n\n§Encephalomyelitis patient.\n\n¶irAE during Nivolumab monotherapy. Ipi/Nivo treatment previously without any side effects.\n\nCORT, corticosteroids; CP, cyclophosphamide; CTCAE, Common Terminology Criteria for Adverse Events; Ipi, ipilimumab; irAE, immune related adverse event; IVIG, intravenous immunoglobuline; MMF, mycophenolate mofetil; MTX, methotrexate; Nivo, nivolumab; Pembro, pembrolizumab; wt, wild type.\n\nMethods\n\nT cell characteristics, brain damage markers, and soluble checkpoint proteins were analyzed as described in online supplemental appendix.\n\nResults\n\nIncidence of encephalitis\n\nThe number of reported cases of encephalitis following both single and double immune checkpoint blockade is increasing and the fatality rate is high (WHO global database VigiBase, online supplemental figure S2).\n\nBrain damage markers and inflammation\n\nRetrospective analysis of blood tests unexpectedly revealed a distinct pattern that was not evident during the patient’s stay. The brain damage marker S-100B and the inflammatory marker CRP covaried strikingly over time (figure 1C), and levels of both were elevated after two treatments with ipilimumab/nivolumab. At that point, the patient had no symptoms, and MRI showed regression of the brain metastases and no signs of encephalitis. After the fourth and final treatment, S-100B and CRP peaked, indicating combined inflammation and brain damage. The patient rapidly deteriorated, and MRI showed acute disseminated encephalomyelitis. These results suggest that brain damage markers in blood may indicate encephalitis before the appearance of typical signs on MRI or clinical neurological symptoms.\n\nExtensive analysis of blood and CSF confirmed brain damage and inflammation (online supplemental figure S3, tables S1 and S4) but showed no signs of infection or autoantibodies (online supplemental tables S1 and S4). The brain damage markers neurofilament light polypeptide (NFL) and glial fibrillar acidic protein (GFAP) were extremely high in both CSF and plasma as symptoms peaked and gradually normalized during immunosuppression (online supplemental figure S3, tables S1 and S3). Tau and S-100B levels were moderately increased (online supplemental table S3). Collectively, these findings suggest severe axonal damage (NFL) and astrocyte injury (GFAP).11 Interferon-γ, tumor necrosis factor-α, and interleukin-6 levels were increased in CSF when symptoms peaked and normalized during recovery (online supplemental figure S3). The checkpoint proteins PD1, PD-L1, and Tim-3 showed a similar pattern (online supplemental figure S4). CTLA-4 and LAG-3 were not elevated.\n\nT cell characteristics\n\nFlow cytometry of peripheral T cells was done on ICU day 2 and repeated four times. The analysis included T cell subtypes, activation markers, costimulatory receptors, inhibitory immune checkpoints, transcription factors, and attack enzymes (online supplemental table S2). In addition to our encephalomyelitis patient, T cell phenotype was also analyzed in patients with other irAE as well as in patients without irAE (table 1). The most striking observation in the encephalomyelitis patient was high expression of inducible T cell costimulatory receptor (ICOS) on all subtypes of CD4 +T helper cells (figure 2A) (online supplemental figure S5) and on CD8+ cytotoxic T cells. ICOS expression on T cells gradually normalized during immunosuppression and in parallel with clinical improvement (figure 2B–D) (online supplemental figure S5B, C). Similarly, high ICOS on CD4+ and CD8+T cells was detected also in patients with other irAE (figure 2A) and decreased when irAEs had resolved (figure 2B). One patient developed grade 4 hepatitis during treatment with double checkpoint inhibition. In this patient, one sample was analyzed before irAE, when liver enzymes were normal. Interestingly ICOS on CD4+ and CD8+T cells increased in parallel with liver enzymes and decreased again after immunosuppression, and subsequent normalization of liver enzymes (figure 3). Collectively, our data indicate that ICOS may promote development of irAE. High ICOS expression could not be explained by longer duration of checkpoint inhibition because the difference was significant also if patients with late irAE (>6 months, 4 patients) were excluded from the analysis (irAE vs non-irAE; ICOS on CD8+ T cells, p<0.010; ICOS on CD4 +T cells, p<0.027). In addition, the difference in ICOS expression was significant also when only patients treated with single PD-1 inhibition was compared (irAE vs non-irAE; ICOS on CD8 +T cells, p<0.0085; ICOS on CD4+T cells, p<0.0062). This indicates that the difference in ICOS was not specific for anti-CTLA-4 treatment. Full data on T cell characteristics is shown in online supplemental figure S6. In addition to ICOS, TIM-3 (an inhibitory checkpoint protein and activation marker) was significantly higher on CD8 +T cells in patients with irAE and normalized when irAE were resolved. Also, PD-1 expression on CD4+ T cells was significantly higher in patients with irAE. The patients with irAE had similar proportion of immunosuppressive regulatory T cells as checkpoint inhibitor-treated controls (online supplemental figure S7). There was no difference in total number of CD8+ cytotoxic T cells, CD4+T helper cells, B cells, or natural killer cells, between our patient and checkpoint inhibitor-treated controls (online supplemental figure S8).\n\nFigure 2 High proportion of ICOS-expressing CD4+ and CD8+T cells during active encephalomyelitis. Panel (A) shows higher proportion of T cells expressing the costimulatory receptor ICOS at the peak of symptoms in checkpoint inhibitor-treated patients with immune-related adverse events (irAE; pink dots and the big red dot which indicates the encephalitis patient) than in patients without irAE (no irAE; green dots) (large dots—double inhibition; small dots—single PD-1-inhibition) (Mann-Whitney U test). The encephalitis patient had the highest proportion of ICOS positive CD4+T cells and the second highest proportion of ICOS-expression on CD8+ cells. (B) shows that immunosuppression decreased the proportion of ICOS expressing CD8+ and CD4+T cells in the encephalitis patient as well as in patients with other irAE (Wilcoxon matched-pairs signed rank test). (C) shows that the proportion of ICOS expressing CD8 (dotted red line) and CD4 (solid red line) T cells decreased in parallel with clinical improvement (box) and with decrease in brain damage marker GFAP in blood. GFAP, glial fibrillar acidic protein; ICOS, inducible T cell costimulatory receptor; PD-1, programmed cell death 1.\n\nFigure 3 High proportion of ICOS-expressing CD4+T cells during severe checkpoint inhibitor-induced hepatitis The figure shows covariation of liver enzymes—aspartate transaminase (AST; solid green line) and alanine aminotransferase (ALT; dotted green line)—and ICOS expression on CD4+T cells (solid red line) before, at the peak of, and after severe checkpoint inhibitor–induced hepatitis (grade 4). ICOS on CD8+T cells (dotted red line) showed a similar, but less pronounced, covariation with liver enzymes. The black triangles indicate time points for double checkpoint inhibition with ipilimumab and nivolumab. ICOS, inducible T cell costimulatory receptor.\n\nDiscussion and conclusion\n\nIn this study, we demonstrate a specific T cell phenotype in a patient with encephalomyelitis as well as in patients with other severe irAE. The most striking feature is high expression of costimulatory receptor ICOS on CD4+ and CD8+T cells. In addition, our study shows that brain damage markers in blood can help in early diagnosis of encephalitis.\n\nirAE are a diverse set of checkpoint inhibitor-induced autoimmune reactions but little is known about the mechanisms promoting irAE.5 Here, we identify high ICOS expression, on both CD4+ and CD8+ cells, during encephalomyelitis and other serious irAE. ICOS decreased when the irAE resolved suggesting that ICOS may promote irAE. In agreement, ICOS has been linked to the development of different autoimmune diseases.12 The association between T cell expression of ICOS and the clinical course of irAE is clear but it is important to clarify if the ICOS molecule promotes irAE. If this is the case, targeting ICOS with antagonists may constitute a therapeutic approach to dampen severe irAE; such as the near-fatal encephalomyelitis described here. However, it is possible that such an intervention, as well as the immunosuppressive treatments used in our patients, may increase the risk of tumor progression or recurrence because ICOS has also been identified as a mediator of response.13 14\n\nDouble immune checkpoint blockade is often more effective than PD-1 inhibition alone, as targeting CTLA-4 also activates CD4 +T cells.15 In mice, the absence of CTLA-4 promotes the expansion of ICOS-positive CD4+ effector T cells, which are important in mediating the response to CTLA-4 inhibition.14–17 Interestingly, high ICOS expression on CD4 +cells also promotes the development of neuromyelitis optica spectrum disorder,18 an autoimmune demyelinating disease of the central nervous system. The high levels of ICOS expression on CD4+ effector cells in our patient could help explain both the efficient eradication of tumor cells and the collateral damage to normal brain cells. Consistent with our data, activated CD4+ memory cells accumulated in inflamed brain tissue from a patient who died from checkpoint inhibitor-induced encephalitis.7 At autopsy, no signs of remaining melanoma brain metastases were found. In combination with previous clinical and experimental data, the findings in our case support a role for ICOS expression on CD4+ cells in mediating an aggressive immune reaction.\n\nThe current case shows that brain damage biomarkers in blood can help to diagnose encephalitis. Our patient had increased levels of the brain damage marker S-100B and CRP after two treatments, when he was asymptomatic and MRI showed no signs of encephalitis. S-100B and CRP peaked after the fourth and final treatment, when his encephalitis rapidly progressed. S-100B was analyzed because it is a melanoma marker. However, it was negative before treatment, and therefore the elevated level reflected treatment-induced brain damage and not progression of melanoma. Additional biomarkers were analyzed in the ICU and repeatedly during recovery. Most notably, the axonal damage marker NFL and the marker of astrocytic injury GFAP were extremely high in both blood and CSF and normalized during improvement. To facilitate diagnosis of encephalitis, we suggest that a set of brain damage markers in blood be included in laboratory panels taken during double-checkpoint inhibition. Our patient developed very severe encephalomyelitis and it needs to be investigated if brain damage markers in blood also indicate less severe cases of encephalitis.\n\nCheckpoint inhibitor-induced encephalitis is a diagnostic challenge. Given our patient’s serious cancer diagnosis, oncologists and intensivists discussed whether he should be admitted to the ICU. The decision to do so was based on the argument that the clinical and radiologic findings were consistent with causes other than cancer progression, such as infection or neurotoxicity. At admission, the patient was unconscious and had central respiratory depression. He would have died without ICU treatment.\n\nIn conclusion, this study suggests a potential role for ICOS on CD4+ and CD8+T cells in mediating encephalitis and other serious irAE. In addition, our case suggests that brain damage markers in blood should be analyzed to facilitate early diagnosis of encephalitis.\n\nWe thank Elisabeth Kapocs for coordinating patient samples, the Department of clinical immunology at Sahlgrenska University Hospital for performing flow cytometry, and Kerstin Andersson for flow cytometry gating. Ellen Nohle is acknowledged for discussing early drafts of the manuscript. We thank Stephen Ordway for editing the manuscript.\n\nEthics statements\n\nPatient consent for publication\n\nNot required.\n\nContributors: Acquisition of data: ML, SB, AP, ZZ, CJ, TU, HJ, HZ, AR. Analysis and interpretation of data: All authors. Writing the manuscript: SB and ML. Review, and/or revision of the manuscript: All authors.\n\nFunding: Supported by funding from the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (ALFGBG-828121 and 870 351 to ML; ALFGBG-717541 to AR; ALFGBG-933754 to SB), Jubileumsklinikens cancerfond (to ML) and Stiftelsen Assar Gabrielssons Fond (to SB).\n\nCompeting interests: None declared.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n\nSupplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.\n==== Refs\nReferences\n\n1 Tawbi HA, Forsyth PA, Algazi A, et al . Combined nivolumab and ipilimumab in melanoma metastatic to the brain. N Engl J Med 2018;379 :722–30. 10.1056/NEJMoa1805453 30134131\n2 Hellmann MD, Paz-Ares L, Bernabe Caro R, et al . Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N Engl J Med 2019;381 :2020–31. 10.1056/NEJMoa1910231 31562796\n3 Larkin J, Chiarion-Sileni V, Gonzalez R, et al . Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med 2019;381 :1535–46. 10.1056/NEJMoa1910836 31562797\n4 Motzer RJ, Rini BI, McDermott DF, et al . 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Blockade of CTLA-4 and PD-1 enhances adoptive T-cell therapy efficacy in an ICOS-Mediated manner. Cancer Immunol Res 2019;7 :1803–12. 10.1158/2326-6066.CIR-18-0873 31466995\n15 Sharma P, Allison JP. Dissecting the mechanisms of immune checkpoint therapy. Nat Rev Immunol 2020;20 :75–6. 10.1038/s41577-020-0275-8 31925406\n16 Wei SC, Levine JH, Cogdill AP, et al . Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade. Cell 2017;170 :1120–33. e1117. 10.1016/j.cell.2017.07.024 28803728\n17 Wei SC, Sharma R, Anang N-AAS, et al . Negative co-stimulation constrains T cell differentiation by imposing boundaries on possible cell states. Immunity 2019;50 :1084–98. 10.1016/j.immuni.2019.03.004 30926234\n18 Xue Q, Li X, Gu Y, et al . Unbalanced expression of ICOS and PD-1 in patients with neuromyelitis optica spectrum disorder. Sci Rep 2019;9 :14130. 10.1038/s41598-019-50479-4 31575949\n\n", "fulltext_license": "CC BY", "issn_linking": "2051-1426", "issue": "9(7)", "journal": "Journal for immunotherapy of cancer", "keywords": "CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; autoimmunity; immunotherapy; melanoma", "medline_ta": "J Immunother Cancer", "mesh_terms": null, "nlm_unique_id": "101620585", "other_id": null, "pages": null, "pmc": null, "pmid": "34215689", "pubdate": "2021-07", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": "27572859;32939077;31332390;32086972;30242316;31575949;31562797;29320654;30926234;30134131;31925406;28803728;21708958;30171200;31562796;31466995;31427204;32055040", "title": "Early rise in brain damage markers and high ICOS expression in CD4+ and CD8+ T cells during checkpoint inhibitor-induced encephalomyelitis.", "title_normalized": "early rise in brain damage markers and high icos expression in cd4 and cd8 t cells during checkpoint inhibitor induced encephalomyelitis" }	[ { "companynumb": "SE-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-071330", "fulfillexpeditecriteria": "1", "occurcountry": "SE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "IPILIMUMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3 MILLIGRAM/KILOGRAM, Q3WK", "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTATIC MALIGNANT MELANOMA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "3", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "3", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IPILIMUMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "NIVOLUMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "125554", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MILLIGRAM/KILOGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTATIC MALIGNANT MELANOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NIVOLUMAB" } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Encephalomyelitis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "BJURSTEN S, PANDITA A, ZHAO Z, FROJD C, NY L, JENSEN C, ET AL. 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EARLY RISE IN BRAIN DAMAGE MARKERS AND HIGH ICOS EXPRESSION IN CD4+ AND CD8+ T CELLS DURING CHECKPOINT INHIBITOR?INDUCED ENCEPHALOMYELITIS. JOURNAL FOR IMMUNOTHERAPY OF CANCER. 2021?9(7):1?7", "literaturereference_normalized": "early rise in brain damage markers and high icos expression in cd4 and cd8 t cells during checkpoint inhibitor induced encephalomyelitis", "qualification": "3", "reportercountry": "SE" }, "primarysourcecountry": "SE", "receiptdate": "20210726", "receivedate": "20210726", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19609291, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" } ]
{ "abstract": "Heparin-induced thrombocytopenia (HIT) can occur following exposure to heparin and is characterized by thrombocytopenia with increased risk for thrombosis. This condition is mediated by formation of immunoglobulin G antibodies against platelet factor 4/heparin complexes that can subsequently lead to platelet activation. Herein, we detail the clinical and laboratory findings, treatments, and outcomes of two patients who developed HIT and thrombosis after undergoing collection of hematopoietic progenitor cells by apheresis (HPC-A) for autologous HPC transplant. Given that heparin may be used during HPC-A collections, these cases emphasize the importance of prompt consideration of HIT in patients that develop thrombocytopenia and thrombosis following HPC-A collection with heparin anticoagulation.", "affiliations": "Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina.;Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina.;Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina.;Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina.;Department of Medicine, University of North Carolina, Chapel Hill, North Carolina.;Department of Medicine, University of North Carolina, Chapel Hill, North Carolina.;Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina.", "authors": "Raval\|Jay S\|JS\|https://orcid.org/0000-0001-9835-957X;Park\|Yara A\|YA\|;Perjar\|Irina\|I\|;Mazepa\|Marshall A\|MA\|https://orcid.org/0000-0003-4294-3069;Vincent\|Benjamin G\|BG\|;Ma\|Alice D\|AD\|;Rollins-Raval\|Marian A\|MA\|", "chemical_list": "D000418:Albumins; D000906:Antibodies; D000925:Anticoagulants; D007074:Immunoglobulin G; C000629325:PF4 protein, human; D010978:Platelet Factor 4; D006493:Heparin", "country": "United States", "delete": false, "doi": "10.1002/jca.21757", "fulltext": null, "fulltext_license": null, "issn_linking": "0733-2459", "issue": "35(1)", "journal": "Journal of clinical apheresis", "keywords": "HIT; apheresis; stem cell collection; thrombocytopenia; thrombosis", "medline_ta": "J Clin Apher", "mesh_terms": "D000368:Aged; D000418:Albumins; D000906:Antibodies; D000925:Anticoagulants; D001781:Blood Component Removal; D057286:Electronic Health Records; D005260:Female; D006412:Hematopoietic Stem Cells; D006493:Heparin; D006801:Humans; D007074:Immunoglobulin G; D008297:Male; D008875:Middle Aged; D015539:Platelet Activation; D010978:Platelet Factor 4; D012189:Retrospective Studies; D012306:Risk; D013921:Thrombocytopenia; D013927:Thrombosis", "nlm_unique_id": "8216305", "other_id": null, "pages": "59-61", "pmc": null, "pmid": "31696530", "pubdate": "2020-01", "publication_types": "D016428:Journal Article", "references": null, "title": "Heparin-induced thrombocytopenia associated with collection of hematopoietic progenitor cells by apheresis.", "title_normalized": "heparin induced thrombocytopenia associated with collection of hematopoietic progenitor cells by apheresis" }	[ { "companynumb": "US-DRREDDYS-USA/USA/19/0116604", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "HEPARIN SODIUM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "017064", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNFRACTIONATED HEPARIN", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "9780", "drugstructuredosageunit": "025", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HEPARIN SODIUM." } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Jugular vein thrombosis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "RAVAL JS, PARK YA, PERJAR I, MAZEPA MA, VINCENT BG, MA AD ET AL. HEPARIN-INDUCED THROMBOCYTOPENIA ASSOCIATED WITH COLLECTION OF HEMATOPOIETIC PROGENITOR CELLS BY APHERESIS. JOURNAL OF CLINICAL APHERESIS. 2019?1-3. DOI: 10.1002/JCA.21757.", "literaturereference_normalized": "heparin induced thrombocytopenia associated with collection of hematopoietic progenitor cells by apheresis", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200127", "receivedate": "20191202", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17097544, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "US-DRREDDYS-USA/USA/19/0116677", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "HEPARIN SODIUM" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "017064", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNFRACTIONATED HEPARIN", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "18378", "drugstructuredosageunit": "025", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HEPARIN SODIUM." } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pulmonary embolism", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Deep vein thrombosis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Heparin-induced thrombocytopenia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "RAVAL JS, PARK YA, PERJAR I, MAZEPA MA, VINCENT BG, MA AD ET AL. HEPARIN-INDUCED THROMBOCYTOPENIA ASSOCIATED WITH COLLECTION OF HEMATOPOIETIC PROGENITOR CELLS BY APHERESIS. JOURNAL OF CLINICAL APHERESIS. 2019?1-3. DOI: 10.1002/JCA.21757.", "literaturereference_normalized": "heparin induced thrombocytopenia associated with collection of hematopoietic progenitor cells by apheresis", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200127", "receivedate": "20191203", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17104927, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" } ]
{ "abstract": "BACKGROUND\nXeroderma pigmentosum is a rare genetic disorder of DNA repair, defined by extreme sensitivity to sunlight, leading to sunburn, skin pigmentation and increased incidence of skin cancers. Cisplatin acts by interfering with DNA repair mechanisms to cause DNA damage and apoptosis. It has indications in many malignancies including bladder, head and neck and lung cancers. Acute kidney injury is a well-known complication of cisplatin.\n\n\nMETHODS\nWe report a 42-year-old male with a long history of Xeroderma pigmentosum treated with adjuvant cisplatin (40 mg/m2) in combination with radiotherapy for cutaneous squamous cell carcinoma of the neck. He presented to clinic prior to his second weekly dose of cisplatin with a severe acute kidney injury and a creatine level of 813 mmol/L and eGFR of 7 mL/min. No myelosuppression was present.\nTreatment consisted of aggressive electrolyte and fluid management. Creatinine levels slowly improved with conservative management without the need for dialysis. Radiation was completed without further cisplatin.\n\n\nCONCLUSIONS\nThree cases of severe adverse effects from cisplatin administration in patients with Xeroderma pigmentosum have been reported, with all fatal. Xeroderma pigmentosum complementation group C plays an important role in the DNA repair process with the recognition and repair of damage to normal cells following cisplatin. Patients with Xeroderma pigmentosum can be carriers of defective Xeroderma pigmentosum complementation group C and if the degree of Xeroderma pigmentosum complementation group C inactivity is significant, fatalities could occur. Physicians should be aware of this rare but potentially lethal toxicity when considering systemic therapy for squamous cell carcinoma in patients diagnosed with Xeroderma pigmentosum.", "affiliations": "Cancer Care Services, Toowoomba Hospital, Australia.;Cancer Care Services, Toowoomba Hospital, Australia.", "authors": "Gilbar\|Peter J\|PJ\|https://orcid.org/0000-0001-7748-1891;Pokharel\|Khageshwor\|K\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1177/10781552211038246", "fulltext": null, "fulltext_license": null, "issn_linking": "1078-1552", "issue": null, "journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners", "keywords": "Xeroderma pigmentosum; acute renal failure; cisplatin; nephrotoxicity", "medline_ta": "J Oncol Pharm Pract", "mesh_terms": null, "nlm_unique_id": "9511372", "other_id": null, "pages": "10781552211038246", "pmc": null, "pmid": "34647821", "pubdate": "2021-10-14", "publication_types": "D016428:Journal Article", "references": null, "title": "Severe cisplatin-induced renal toxicity in a patient with xeroderma pigmentosum.", "title_normalized": "severe cisplatin induced renal toxicity in a patient with xeroderma pigmentosum" }	[ { "companynumb": "AU-MYLANLABS-2021M1082092", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": "091062", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Injection", "drugdosagetext": "40 MILLIGRAM/SQ. METER, QW FOR 7 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "Squamous cell carcinoma of skin", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "20200830", "drugstartdateformat": "102", "drugstructuredosagenumb": "40", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Injection", "drugdosagetext": "12 MILLIGRAM BEFORE THE TREATMENT", "drugenddate": null, "drugenddateformat": null, "drugindication": "Prophylaxis of nausea and vomiting", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "12", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "8 MILLIGRAM, QD FOR 3 DAYS AFTER TREATMENT", "drugenddate": null, "drugenddateformat": null, "drugindication": "Prophylaxis of nausea and vomiting", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "8", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "NETUPITANT\\PALONOSETRON HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Prophylaxis of nausea and vomiting", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NETUPITANT\\PALONOSETRON HYDROCHLORIDE" } ], "patientagegroup": null, "patientonsetage": "42", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Gilbar PJ, Pokharel K. Severe cisplatin-induced renal toxicity in a patient with xeroderma pigmentosum. J-Oncol-Pharm-Pract 2021;null:null.", "literaturereference_normalized": "severe cisplatin induced renal toxicity in a patient with xeroderma pigmentosum", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20211110", "receivedate": "20211110", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20052796, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220303" } ]
{ "abstract": "Prosthetic joint infection (PJI) is a potentially limb-threatening complication of total knee arthroplasty. Phage therapy is a promising strategy to manage such infections including those involving antibiotic-resistant microbes, and to target microbial biofilms. Experience with phage therapy for infections associated with retained hardware is limited. A 62-year-old diabetic man with a history of right total knee arthroplasty 11 years prior who had suffered multiple episodes of prosthetic knee infection despite numerous surgeries and prolonged courses of antibiotics, with progressive clinical worsening and development of severe allergies to antibiotics, had been offered limb amputation for persistent right prosthetic knee infection due to Klebsiella pneumoniae complex. Intravenous phage therapy was initiated as a limb-salvaging intervention.\n\n\n\nThe patient received 40 intravenous doses of a single phage (KpJH46Φ2) targeting his bacterial isolate, alongside continued minocycline (which he had been receiving when he developed increasing pain, swelling, and erythema prior to initiation of phage therapy). Serial cytokine and biomarker measurements were performed before, during, and after treatment. The in vitro anti-biofilm activity of KpJH46Φ2, minocycline and the combination thereof was evaluated against a preformed biofilm of the patient's isolate and determined by safranin staining.\n\n\n\nPhage therapy resulted in resolution of local symptoms and signs of infection and recovery of function. The patient did not experience treatment-related adverse effects and remained asymptomatic 34 weeks after completing treatment while still receiving minocycline. A trend in biofilm biomass reduction was noted 22 hours after exposure to KpJH46Φ2 (P = .063). The addition of phage was associated with a satisfactory outcome in this case of intractable biofilm-associated prosthetic knee infection. Pending further studies to assess its efficacy and safety, phage therapy holds promise for treatment of device-associated infections.", "affiliations": "Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota, USA.;Infectious Diseases Research Laboratory, Mayo Clinic, Rochester, Minnesota, USA.;Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.;Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.;Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota, USA.;Adaptive Phage Therapeutics, Gaithersburg, Maryland, USA.;Adaptive Phage Therapeutics, Gaithersburg, Maryland, USA.;Adaptive Phage Therapeutics, Gaithersburg, Maryland, USA.;Genomics and Bioinformatics Department, Biological Defense Research Directorate, Naval Medical Research Center-Frederick, Fort Detrick, Maryland, USA.;Genomics and Bioinformatics Department, Biological Defense Research Directorate, Naval Medical Research Center-Frederick, Fort Detrick, Maryland, USA.;Genomics and Bioinformatics Department, Biological Defense Research Directorate, Naval Medical Research Center-Frederick, Fort Detrick, Maryland, USA.;Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota, USA.;Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota, USA.", "authors": "Cano\|Edison J\|EJ\|;Caflisch\|Katherine M\|KM\|;Bollyky\|Paul L\|PL\|;Van Belleghem\|Jonas D\|JD\|;Patel\|Robin\|R\|;Fackler\|Joseph\|J\|;Brownstein\|Michael J\|MJ\|;Horne\|Bri'Anna\|B\|;Biswas\|Biswajit\|B\|;Henry\|Matthew\|M\|;Malagon\|Francisco\|F\|;Lewallen\|David G\|DG\|;Suh\|Gina A\|GA\|", "chemical_list": "D000900:Anti-Bacterial Agents", "country": "United States", "delete": false, "doi": "10.1093/cid/ciaa705", "fulltext": null, "fulltext_license": null, "issn_linking": "1058-4838", "issue": "73(1)", "journal": "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America", "keywords": "arthroplasty; bacteriophage therapy; biofilm; phage therapy; prosthetic joint infection", "medline_ta": "Clin Infect Dis", "mesh_terms": "D000900:Anti-Bacterial Agents; D019645:Arthroplasty, Replacement, Knee; D018441:Biofilms; D006801:Humans; D007711:Klebsiella pneumoniae; D008297:Male; D008875:Middle Aged; D000071059:Phage Therapy; D016459:Prosthesis-Related Infections", "nlm_unique_id": "9203213", "other_id": null, "pages": "e144-e151", "pmc": null, "pmid": "32699879", "pubdate": "2021-07-01", "publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't; D013486:Research Support, U.S. Gov't, Non-P.H.S.", "references": "25586931;30157981;31527029;24893003;27822205;27643529;28451862;30597868;17538551;30406049;29588855;30474047;32397354;30180053;30763536;30207891;25662974;29363518;21905786;30395179;24696437;31548497;29294147;27099694;26347362", "title": "Phage Therapy for Limb-threatening Prosthetic Knee Klebsiella pneumoniae Infection: Case Report and In Vitro Characterization of Anti-biofilm Activity.", "title_normalized": "phage therapy for limb threatening prosthetic knee klebsiella pneumoniae infection case report and in vitro characterization of anti biofilm activity" }	[ { "companynumb": "US-drreddys-LIT/USA/22/0150981", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "MINOCYCLINE HYDROCHLORIDE" }, "drugadditional": "4", "drugadministrationroute": "048", "drugauthorizationnumb": "065436", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "REMAINED UNDER PHAGE THERAPY FOR 8 MONTHS WAS MAINTAINED", "drugenddate": null, "drugenddateformat": null, "drugindication": "Klebsiella infection", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": "8", "drugtreatmentdurationunit": "802", "medicinalproduct": "MINOCYCLINE HYDROCHLORIDE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DAPTOMYCIN" }, "drugadditional": "4", "drugadministrationroute": null, "drugauthorizationnumb": "211403", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DAPTOMYCIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PENICILLIN V POTASSIUM" }, "drugadditional": "4", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PENICILLIN V POTASSIUM" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VANCOMYCIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VANCOMYCIN" } ], "patientagegroup": "5", "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pain", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Eosinophilia", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Swelling", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Erythema", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Cano E, Caflisch K, Bollyky P, Belleghem J, Patel R, Fackler J, Brownstein M, Horne B, Biswas B, Henry M, Malagon F, Lewallen D, Suh G. Phage Therapy for Limb-threatening Prosthetic Knee Klebsiella pneumoniae Infection: Case Report and in Vitro Characterization of Anti-biofilm Activity. Clin Infect Dis. 2021;73(1):E144-51.", "literaturereference_normalized": "phage therapy for limb threatening prosthetic knee klebsiella pneumoniae infection case report and in vitro characterization of anti biofilm activity", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220613", "receivedate": "20220613", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20950308, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20220720" }, { "companynumb": "US-NOVARTISPH-NVSC2021US263245", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "64150", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2009", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VANCOMYCIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2009", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VANCOMYCIN" } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Suicidal ideation", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Cano EJ, Caflisch KM, Bollyky PL, Van Belleghem JD, Patel R, Fackler J et al.. Phage therapy for limb-threatening prosthetic knee klebsiella pneumoniae infection: Case report and in vitro characterization of anti-biofilm activity. 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null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Arthritis infective", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2013", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CEFADROXIL" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Arthritis infective", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201505", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFADROXIL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PENICILLIN V POTASSIUM" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Arthritis infective", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201304", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PENICILLIN V POTASSIUM" } ], "patientagegroup": "5", "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Stevens-Johnson syndrome", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Suicidal ideation", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pruritus", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Eosinophilia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rash", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20080101" } }, "primarysource": { "literaturereference": "Cano EJ, Caflisch KM, Bollyky PL, Van Belleghem JD, Patel R, Fackler J, et al. Phage Therapy for Limb-threatening Prosthetic Knee Klebsiella pneumoniae Infection: Case Report and In Vitro Characterization of Anti-biofilm Activity. Clin-Infect-Dis 2021;73(1):e144-e151.", "literaturereference_normalized": "phage therapy for limb threatening prosthetic knee klebsiella pneumoniae infection case report and in vitro characterization of anti biofilm activity", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20211216", "receivedate": "20211202", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20142399, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20220303" }, { "companynumb": "US-MYLANLABS-2021M1086659", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": 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"drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Arthritis infective", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2009", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DOXYCYCLINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "091406", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": "2019", "drugenddateformat": "602", 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"drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Arthritis infective", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MEROPENEM" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Arthritis infective", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2013", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CEFADROXIL" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Arthritis infective", "drugintervaldosagedefinition": null, 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"drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PENICILLIN V POTASSIUM" } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Stevens-Johnson syndrome", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Suicidal ideation", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20080101" } }, "primarysource": { "literaturereference": "Cano EJ, Caflisch KM, Bollyky PL, Van Belleghem JD, Patel R, Fackler J, et al. Phage Therapy for Limb-threatening Prosthetic Knee Klebsiella pneumoniae Infection: Case Report and In Vitro Characterization of Anti-biofilm Activity. 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"RIFAMPICIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Suicidal ideation", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2009" } }, "primarysource": { "literaturereference": "CANO EJ, CAFLISCH KM, BOLLYKY PL, BELLEGHEM JDV, PATEL R, FACKLER J ET AL.. PHAGE THERAPY FOR LIMB?THREATENING PROSTHETIC KNEE KLEBSIELLA PNEUMONIAE INFECTION: CASE REPORT AND IN VITRO CHARACTERIZATION OF ANTI?BIOFILM ACTIVITY. CLIN INFECT DIS.. 2020?UNKNOWN:1?13", "literaturereference_normalized": "phage therapy for limb threatening prosthetic knee klebsiella pneumoniae infection case report and in vitro characterization of anti biofilm activity", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200904", "receivedate": "20200904", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18233100, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "US-LUPIN PHARMACEUTICALS INC.-2021-23274", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { 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"activesubstance": { "activesubstancename": "PENICILLIN G" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": "2019", "drugenddateformat": "602", "drugindication": "Arthritis infective", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2019", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PENICILLIN G" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DAPTOMYCIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": 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{ "abstract": "BACKGROUND\nClostridium difficile infection (CDI) is the leading infectious cause of nosocomial diarrhea. Hospitalized patients are at increased risk of developing CDI because they are exposed to C. difficile spores through contact with the hospital environment and often receive antibiotics and other medications that can disrupt the integrity of the indigenous intestinal microbiota and impair colonization resistance. Using whole metagenome shotgun sequencing, we examined the diversity and composition of the fecal microbiota in a prospective cohort study of 98 hospitalized patients.\n\n\nRESULTS\nFour patients had asymptomatic C. difficile colonization, and four patients developed CDI. We observed dramatic shifts in the structure of the gut microbiota during hospitalization. In contrast to CDI cases, asymptomatic patients exhibited elevated relative abundance of potentially protective bacterial taxa in their gut at the onset of C. difficile colonization. Use of laxatives was associated with significant reductions in the relative abundance of Clostridium and Eubacterium; species within these genera have previously been shown to enhance resistance to CDI via the production of secondary bile acids. Cephalosporin and fluoroquinolone exposure decreased the frequency of Clostridiales Family XI Incertae Sedis, a bacterial family that has been previously associated with decreased CDI risk.\n\n\nCONCLUSIONS\nThis study underscores the detrimental impact of antibiotics as well as other medications, particularly laxatives, on the intestinal microbiota and suggests that co-colonization with key bacterial taxa may prevent C. difficile overgrowth or the transition from asymptomatic C. difficile colonization to CDI.", "affiliations": "Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada.;Jewish General Hospital, Montréal, Québec, Canada.;Devil's Staircase Consulting, North Vancouver, British Columbia, Canada.;New York Genome Center, New York, NY, USA.;Génome Québec Innovation Centre, McGill University, Montréal, Québec, Canada.;School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada. [email protected].", "authors": "Vincent\|Caroline\|C\|;Miller\|Mark A\|MA\|;Edens\|Thaddeus J\|TJ\|;Mehrotra\|Sudeep\|S\|;Dewar\|Ken\|K\|;Manges\|Amee R\|AR\|", "chemical_list": "D000900:Anti-Bacterial Agents; D001647:Bile Acids and Salts; D002511:Cephalosporins; D024841:Fluoroquinolones; D054368:Laxatives", "country": "England", "delete": false, "doi": "10.1186/s40168-016-0156-3", "fulltext": "\n==== Front\nMicrobiomeMicrobiomeMicrobiome2049-2618BioMed Central London 15610.1186/s40168-016-0156-3ResearchBloom and bust: intestinal microbiota dynamics in response to hospital exposures and Clostridium difficile colonization or infection Vincent Caroline [email protected] Miller Mark A. [email protected] Edens Thaddeus J. [email protected] Mehrotra Sudeep [email protected] Dewar Ken [email protected] Manges Amee R. [email protected] Department of Microbiology and Immunology, McGill University, Montréal, Québec Canada Génome Québec Innovation Centre, McGill University, Montréal, Québec Canada Jewish General Hospital, Montréal, Québec Canada Devil’s Staircase Consulting, North Vancouver, British Columbia Canada New York Genome Center, New York, NY USA Department of Human Genetics, McGill University, Montréal, Québec Canada School of Population and Public Health, University of British Columbia, Vancouver, British Columbia Canada 14 3 2016 14 3 2016 2016 4 124 9 2015 14 2 2016 © Vincent et al. 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nClostridium difficile infection (CDI) is the leading infectious cause of nosocomial diarrhea. Hospitalized patients are at increased risk of developing CDI because they are exposed to C. difficile spores through contact with the hospital environment and often receive antibiotics and other medications that can disrupt the integrity of the indigenous intestinal microbiota and impair colonization resistance. Using whole metagenome shotgun sequencing, we examined the diversity and composition of the fecal microbiota in a prospective cohort study of 98 hospitalized patients.\n\nResults\nFour patients had asymptomatic C. difficile colonization, and four patients developed CDI. We observed dramatic shifts in the structure of the gut microbiota during hospitalization. In contrast to CDI cases, asymptomatic patients exhibited elevated relative abundance of potentially protective bacterial taxa in their gut at the onset of C. difficile colonization. Use of laxatives was associated with significant reductions in the relative abundance of Clostridium and Eubacterium; species within these genera have previously been shown to enhance resistance to CDI via the production of secondary bile acids. Cephalosporin and fluoroquinolone exposure decreased the frequency of Clostridiales Family XI Incertae Sedis, a bacterial family that has been previously associated with decreased CDI risk.\n\nConclusions\nThis study underscores the detrimental impact of antibiotics as well as other medications, particularly laxatives, on the intestinal microbiota and suggests that co-colonization with key bacterial taxa may prevent C. difficile overgrowth or the transition from asymptomatic C. difficile colonization to CDI.\n\nElectronic supplementary material\nThe online version of this article (doi:10.1186/s40168-016-0156-3) contains supplementary material, which is available to authorized users.\n\nKeywords\nClostridium difficile infectionWhole metagenome shotgun sequencingIntestinal microbiotaAntimicrobialsMedicationshttp://dx.doi.org/10.13039/501100000024Canadian Institutes of Health Research (CA)GSD-113375Vincent Caroline http://dx.doi.org/10.13039/100004319Pfizer (US)WS1954106Manges Amee R. issue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nClostridium difficile infection (CDI) is the leading cause of infectious diarrhea in hospitalized patients. In the USA alone, there are an estimated 453,000 cases and 29,300 deaths from CDI each year [1]. CDI is associated with a wide range of syndromes, from asymptomatic colonization to mild diarrhea or more severe pseudomembranous colitis that may progress to toxic megacolon, intestinal perforation, sepsis, and death [2]. Despite advances in infection control practices and the development of new treatment options, there has been a steady increase in the incidence and severity of CDI in the last decade and outbreaks continue to occur in hospitals and health-care institutions worldwide [3, 4].\n\nHospitalized patients are at increased risk of developing CDI because they are exposed to C. difficile spores through contact with the hospital environment and often receive broad-spectrum antimicrobials that disrupt the integrity of the indigenous intestinal microbiota and impair colonization resistance (i.e., the ability of the microbiota to prevent the establishment of enteropathogens like C. difficile in the gut). Nearly all classes of antibiotics have been associated with CDI, but clindamycin, penicillins, cephalosporins, and fluoroquinolones seem to pose the greatest risk [5–7]. Additional risk factors for CDI include advanced age, underlying diseases, gastrointestinal surgery, nasogastric tube feeding, and use of proton pump inhibitors (PPIs, a class of medications that inhibit the production of gastric acid in the stomach) [2, 8].\n\nAmong patients who acquire C. difficile in their gut, some will remain asymptomatically colonized while others may go on to develop diarrhea or more severe forms of CDI. Differences in pathogen or host factors like the immune status or the integrity of the intestinal microbiota may affect the clinical presentation of CDI. In hospitals and health-care facilities, asymptomatic carriers often outnumber symptomatic patients and may represent a considerable reservoir of C. difficile that contributes to environmental contamination and disease transmission among patients [9, 10]. It has been suggested that patients with asymptomatic C. difficile colonization are at decreased risk of developing CDI, but a recent meta-analysis has suggested this may not be the case [11, 12]. Previously, we showed that patients who have higher levels of Clostridiales Family XI Incertae Sedis were at a decreased risk of developing CDI [13], and others have demonstrated that the presence of secondary bile acid-producing bacteria such as Clostridium scindens was associated with resistance to CDI [14].\n\nDespite the strong relationship between the intestinal microbiota and CDI susceptibility, the impact of non-antimicrobial medications on the microbiota has not been examined in detail.\n\nIn this study, we prospectively examined the intestinal microbiota of hospitalized patients at-risk for CDI. Using whole metagenome shotgun (WMGS) DNA sequencing, we specifically assessed (i) the changes in the relative abundance of microbial taxa in patients who were identified as colonized or infected with C. difficile and (ii) the impact of antibiotics and other medications on the diversity and composition of the intestinal microbiota among patients who were neither colonized nor infected with C. difficile. We postulated that protective microbiota members which are thought to mediate competitive inhibition against C. difficile (such as Clostridiales Family XI Incertae Sedis and non-toxigenic C. difficile) [13, 15] or limit the germination and growth of C. difficile via the production of secondary bile acids (Clostridium and Eubacterium genera) [14, 16] are present in colonized but not in infected patients. We also hypothesized that not only antibiotics but also other medications such as PPIs will decrease the overall diversity of the intestinal microbiota and increase the relative abundance of opportunistic microorganisms such as enterococci and yeasts [17–20]. We report that the relative abundance of Clostridiales Family XI Incertae Sedis, Clostridium, and Eubacterium is higher in asymptomatically colonized patients than in CDI cases. Moreover, antibiotics and other medications such as laxatives have substantial effects on the intestinal microbiota of hospitalized patients and reduce the relative abundance of these potentially protective bacterial taxa. Even though the term “infected” is sometimes used to designate people who are asymptomatically colonized with C. difficile, in this report, we will use the term “infected” (or CDI) to describe patients who are symptomatic and “colonized” to describe patients who are asymptomatically colonized with C. difficile.\n\nResults\nSubject characteristics\nA total of 104 patients were enrolled in the study. Four patients did not provide any stool sample, and six stool samples were excluded because of poor library quality or sequencing results; this left a total of 98 patients and 229 fecal samples in the study. We analyzed a median of two fecal samples per patient (range, 1–15). Patient characteristics are shown in Table 1. The majority of patients (63 %) suffered from osteoarthritis and were admitted for orthopedic surgery; most of them (89 %) received cefazolin (a first-generation cephalosporin) as perioperative antimicrobial prophylaxis. One patient (1.0 %) had asymptomatic C. difficile colonization on admission, three patients (3.1 %) became asymptomatically colonized during hospitalization, and four patients (4.1 %) developed hospital-acquired CDI. All of the CDI cases had diarrhea during their initial episode but none of them developed recurrent CDI.Table 1 Characteristics of the study patients\n\nVariable\tNeither C. difficile infection nor colonization (n = 90)\t\nC. difficile infection (n = 4)\t\nC. difficile colonization (n = 4)\t\nAge, mean years (range)\t74 (61–91)\t71 (66–80)\t74 (71–78)\t\nMale sex\t44 (49)\t2 (50)\t2 (50)\t\nHorn’s indexa, median (range)\t1 (1–2)\t1 (1–1)\t1 (1–2)\t\nDuration of hospitalizationb, median days (range)\t5 (1–69)\t21 (2–61)\t5 (1–15)\t\nHospitalization in past 12 monthsc\n\t11 (12)\t0\t0\t\nFecal specimens analyzed, median (range)\t2 (1–12)\t4 (1–15)\t2 (1–4)\t\nReason for hospital admission\t\t\t\t\n Osteoarthritis/Rheumatoid arthritis\t62 (69)\t0\t1 (25)\t\n Pneumonia\t8 (9)\t1 (25)\t1 (25)\t\n Cellulitis\t4 (4)\t1 (25)\t1 (25)\t\n Fever\t2 (2)\t0\t0\t\n Chronic obstructive pulmonary disease\t3 (3)\t0\t0\t\n Othersd\n\t11 (12)\t2 (50)\t1 (25)\t\nMedication useb\n\t\t\t\t\n Non-steroidal anti-inflammatory drugs\t33 (37)\t4 (100)\t2 (50)\t\n Proton pump inhibitors\t26 (29)\t2 (50)\t2 (50)\t\n Glucocorticoids\t12 (13)\t2 (50)\t1 (25)\t\n Opioids\t25 (28)\t3 (75)\t1 (25)\t\n Laxatives\t16 (18)\t3 (75)\t0\t\n Propulsive agents\t3 (3)\t0\t0\t\n Antipropulsive agents\t1 (1)\t1 (25)\t0\t\n Chemotherapeutic agents\t0\t0\t1 (25)\t\n Any antibiotic\t80 (89)\t4 (100)\t4 (100)\t\n Cephalosporins\t60 (67)\t1 (25)\t1 (25)\t\n Fluoroquinolones\t13 (14)\t2 (50)\t0\t\n Penicillin with β-lactamase inhibitors\t12 (13)\t3 (75)\t1 (25)\t\n Vancomycin (intravenous)\t7 (8)\t2 (50)\t0\t\n Carbapenems\t6 (7)\t2 (50)\t2 (50)\t\n Penicillins\t5 (6)\t0\t0\t\n Azithromycin\t4 (4)\t1 (25)\t0\t\n Metronidazole\t3 (3)\t1 (25)\t0\t\n Cotrimoxazole\t2 (2)\t0\t0\t\n Otherse\n\t2 (2)\t3 (75)\t0\t\nData are number (%) of subjects unless otherwise specified\n\n\naEvaluated at study enrollment\n\n\nbFrom admission until diagnosis of C. difficile infection or colonization (for infected and colonized patients, respectively) or until discharge (for patients with neither infection nor colonization)\n\n\ncInformation about prior hospitalization was unknown for one of the 90 patients with neither C. difficile infection nor colonization\n\n\ndOther reasons include bladder/kidney/urinary tract infection, closed fracture, urosepsis, cholecystitis, chronic stasis dermatitis, perinephric infection, diverticulitis, abdominal pain, abdominal hernia, ureteral stone, gangrene, and hip pain\n\n\neOther antimicrobial agents include oral vancomycin, clindamycin, daptomycin, gentamicin, Tigecycline, antivirals, and antifungals\n\n\n\nWMGS sequencing\nFecal samples were evaluated by WMGS sequencing to assess the diversity and composition of the intestinal microbiota. We obtained a median of 6.1 million high-quality reads per sample (range, 0.6–41.9 million). The proportion of human DNA reads was highly variable (range, 0.1–94.9 %) but half of the samples contained <20 % of human reads. After removing the host DNA, we computed the frequency of 16S ribosomal RNA (rRNA) genes in each sample as a measure of bacterial DNA content. The mean frequency of 16S rRNA genes per megabase (Mb) of sequence data was 0.39 (standard deviation 0.18). Across all samples, we obtained a median of 2.1 % of reads (range, 0.1–4.8 %) with a hit to MetaPhlAn2’s taxonomic marker database, with at least 2700 hits per sample. Bacteroides (99.0 %), Prevotella (98.0 %), and Subdoligranulum (98.0 %) were the most common genera, and Porphyromonadaceae (100 %), Bacteroidaceae (99.0 %), Enterobacteriaceae (98.0 %), Prevotellaceae (98.0 %), and Ruminococcaceae (98.0 %) were the most common families detected across patients (percentage of patients in which the corresponding taxa was detected).\n\nC. difficile detection\nResults from the detection of C. difficile or its toxins in eight patients who developed C. difficile colonization (n = 4) or infection (n = 4) are provided in Table 2. Out of these eight patients, six had a positive C. difficile culture result (two of the four CDI cases did not have C. difficile detected by toxigenic culture but rather with an enzyme immunoassay). All patients with a positive C. difficile culture result had a single isolate recovered and characterized. Two of the four asymptomatic carriers were colonized with a toxigenic strain. C. difficile was also detected by WMGS sequencing in two of the four asymptomatically colonized patients as well as in two CDI patients with a positive C. difficile culture result. No other patients had C. difficile detected by culture or sequencing.Table 2 Detection of C. difficile and its toxins in four asymptomatically colonized and four CDI patients\n\nPatient ID\tSample type\tToxigenic culturea\n\tEnzyme immunoassayc\n\tWMGS sequencing\t\nCulture\tToxinb\n\tNo. of reads\tRelative abundance of C. difficile (%)\t\nAsymptomatically colonized\t\t\t\t\t\t\t\n 30\tRectal swab\tPositive\tNegative\tND\t8,487,324\t0.000\t\n 63\tRectal swab\tPositive\tPositive\tND\t10,366,360\t0.000\t\n 87\tRectal swab\tPositive\tNegative\tND\t4,489,956\t0.363\t\n 99\tStool\tPositive\tPositive\tND\t14,952,432\t0.064\t\nCDI\t\t\t\t\t\t\t\n 35\tStoold\n\tNegative\tND\tPositive\t5,926,081\t0.000\t\n 36\tStoold\n\tPositive\tPositive\tND\t7,068,998\t0.017\t\n 55\tStool\tPositive\tPositive\tPositive\t9,950,687\t0.003\t\n 98\tStool\tNegative\tND\tPositive\t4,337,018\t0.000\t\n\nWMGS whole-metagenome shotgun, ND not done\n\n\naPerformed by Dale N. Gerding’s laboratory\n\n\nbDetected by restriction endonuclease analysis or cytotoxicity assay\n\n\ncPerformed on a stool sample at the Jewish General Hospital\n\n\ndA rectal swab was used for WMGS sequencing\n\n\n\nIntestinal microbiota dynamics in patients with C. difficile colonization or infection\nFigure 1 shows variations in the relative abundance of microbial taxa, overall microbial diversity, as well as bacterial and human DNA proportions in relation to hospital exposures and length of stay for patients who became colonized (Fig. 1a–d) or infected (Fig. 1e–h) with C. difficile. The human DNA content and the composition and diversity of the intestinal microbiota were highly variable during patient hospitalization. In contrast, the proportion of bacterial DNA (measured after the exclusion of human DNA) was more stable.Fig. 1 Intestinal microbiota dynamics in patients with C. difficile colonization or infection. The figure shows changes in intestinal microbiota composition (area charts or bar charts for patients with a single measurement), Shannon diversity (dash-dotted line), bacterial DNA content (dotted line), and human DNA content (solid line) during hospitalization for patients who developed C. difficile colonization (a–d) or infection (e–h). Only those microbial taxa with a relative abundance of ≥10 % in at least one sample are depicted. The y-axis on the left shows the relative abundance of microbial taxa or human DNA proportions, while the y-axis on the right shows the Shannon diversity index or bacterial DNA content (expressed as number of 16S rRNA genes per Mb). The x-axis shows the number of days after hospital admission (day 0). The figures only display information for the period from hospital admission until the last stool collection. The bars underneath the graphs indicate hospital exposures: Azithro azithromycin, Ceph cephalosporin, Chemo chemotherapeutic agent, Metro metronidazole, NSAID nonsteroidal anti-inflammatory drug, Penicillin combination penicillin with β-lactamase inhibitor, PPI proton pump inhibitor, Steroid, glucocorticoid, Vanco IV intravenous vancomycin, Vanco PO oral vancomycin. The day on which a patient had a positive C. difficile culture (Culture+), the presence of C. difficile infection symptoms, but a negative C. difficile enzyme immunoassay (CDI symptoms) or a diagnosis of C. difficile infection (CDI diagnosis) is also indicated\n\n\n\nWe specifically looked at the relative abundance of potentially protective bacterial taxa, including Clostridiales Family XI Incertae Sedis, Clostridium, and Eubacterium. A few days prior to or at the time of C. difficile colonization, three out of four asymptomatic patients exhibited high relative abundance of these taxa in their intestinal microbiota: the relative abundance of Eubacterium was 24.3 % in patient 30 on the day C. difficile colonization was detected, the relative abundance of Anaerococcus (a Clostridiales Family XI Incertae Sedis member) was 31.3 % in patient 87 on the day C. difficile colonization was detected, and the relative abundance of Clostridium spp. other than C. difficile (mainly Clostridium bolteae) was 22.2 % in patient 99 4 days prior to C. difficile colonization. We also observed transient increases in the relative abundance of Clostridium spp. other than C. difficile (31.0 % [mainly C. bolteae and Clostridium hathewayi] 13 days prior to CDI diagnosis, patient 55) or Clostridiales Family XI Incertae Sedis (17.4 % 37 days prior to CDI diagnosis, patient 98; data not shown) in two of the four patients who developed CDI. However, these increases occurred several days prior to CDI onset and the corresponding bacterial taxa had a relative abundance of less than 5 % upon CDI diagnosis. In the fecal samples (n = 196) from the 90 patients who were neither colonized nor infected with C. difficile, the median abundance (range) of Clostridiales Family XI Incertae Sedis, Clostridium, and Eubacterium was 3.1 (0.0–62.3 %), 0.4 (0.0–67.6 %), and 0.2 % (0.0–37.0 %), respectively.\n\nWe observed transient but large increases of Microvirus (reaching a relative abundance of ≥50 % in patients 30, 98, and 99), Candida (reaching a relative abundance of >30 % in patients 98 and 99), and Leuconostoc (reaching a relative abundance of >15 % in patients 98 and 99). In patients 98 and 99, the increase in the relative abundance of Microvirus was concomitant with an increase of human read proportions and a decrease of microbial diversity. In patient 98, striking blooms of Enterococcus occurred on days 16 (98.0 %), 31 (60.8 %), and 47–62 (64.8–97.5 %) after admission and appeared to follow the administration of intravenous vancomycin. In the fecal samples (n = 196) from the 90 patients who were neither colonized nor infected with C. difficile, the median abundance (range) of Microvirus, Candida, Leuconostoc, and Enterococcus was 0.0 (0.0–95.6 %), 0.0 (0.0–3.5 %), 0.0 (0.0–51.0 %), and 0.1 % (0.0–91.7 %), respectively.\n\nMedication use and intestinal microbiota diversity and composition\nWe examined the effect of antibiotics as well as other medications on the diversity and composition of the gut microbiota. To avoid confounding the results, we excluded patients who were colonized or infected with C. difficile (n = 8) from these analyses; therefore, the Clostridium genera does not include C. difficile. Utilization of fluoroquinolone was moderately correlated with the use of metronidazole (ρ = 0.45), as were use of penicillin with use of gentamicin (ρ = 0.57), and use of opioids with use of laxatives (ρ = 0.41).\n\nAmong patients who were neither infected nor colonized with C. difficile, we obtained a mean Shannon diversity index of 2.0 (standard deviation 0.6). Exposure to fluoroquinolones and intravenous vancomycin was associated with a significant decrease in intestinal microbiota diversity, while use of opioids was associated with an increase in diversity (Table 3).Table 3 Associations between medication use and intestinal microbiota diversity\n\nMedicationa\n\tNo. of patients exposed\tNo. of samples exposed\tEstimateb\n\tStandard error\t\nP valuec\n\t\nAntibiotics\t\t\t\t\t\t\n Cephalosporins\t57\t81\t−0.06\t0.07\t0.3764\t\n Fluoroquinolones\t8\t15\t−0.20\t0.10\t\n0.0367\n\t\n Penicillin with β-lactamase inhibitors\t7\t12\t−0.17\t0.19\t0.3805\t\n Carbapenems\t5\t11\t−0.30\t0.26\t0.2417\t\n Intravenous vancomycin\t6\t12\t−0.41\t0.15\t\n0.0080\n\t\nOther medications\t\t\t\t\t\t\n Glucocorticoids\t7\t13\t−0.02\t0.17\t0.8977\t\n Laxatives\t13\t24\t−0.05\t0.09\t0.5976\t\n Non-steroidal anti-inflammatory drugs\t30\t57\t0.08\t0.08\t0.3264\t\n Opioids\t23\t38\t0.13\t0.06\t\n0.0202\n\t\n Proton pump inhibitors\t21\t54\t−0.11\t0.10\t0.2738\t\nAmong patients who were neither colonized nor infected with C. difficile\n\n\n\naReceived within 3 days prior to stool collection\n\n\nbA positive value indicates that intestinal microbiota diversity was higher among patients exposed to the medication, while a negative value indicates that intestinal microbiota diversity was lower\n\n\nc\nP values were determined by using the GEE-derived robust z scores\n\n\n\nA large number of microbial taxa were affected by common hospital exposures; out of a total of 125 genera and 59 families identified in at least 5 % of the patients, 88 genera (70.4 %) and 42 families (71.2 %) were associated with a statistically significant increase or decrease in relative abundance in univariable analyses (Additional file 1: Table S1 and Additional file 2: Table S2). With the exception of non-steroidal anti-inflammatory drugs (NSAIDs) and opioids, most medications tended to decrease, rather than increase, the relative abundance of affected microbial taxa. Carbapenems (33 genera and 13 families) and intravenous vancomycin (34 genera and 15 families) influenced the largest number of microbial taxa.\n\nIn multivariable analyses, we specifically looked at the impact of medications on the relative abundance of microbial taxa that are thought to be protective against CDI (Clostridiales Family XI Incertae Sedis, Clostridium, and Eubacterium) as well as opportunistic microorganisms that can overgrow as a result of antimicrobial use (Enterococcus and Candida) (Table 4). Use of laxatives was associated with significant reductions in the relative abundance of Clostridium and Eubacterium. Administration of cephalosporins, fluoroquinolones, or penicillin with β-lactamase inhibitor was associated with significant reductions in the frequency of Clostridiales Family XI Incertae Sedis. Exposure to fluoroquinolones significantly increased the relative abundance of Enterococcus, while intravenous vancomycin was of borderline significance. None of the medications were associated with significant variations in the relative abundance of Candida in multivariable analyses.Table 4 Multivariable analysis of medications associated with selected microbial taxa\n\nTaxa (outcome)\tMedicationa\n\tEstimateb\n\tStandard error\t\nP valuec\n\t\n\nClostridium\n\tGlucocorticoids\t3.72\t1.65\t0.0239\t\nLaxatives\t−2.46\t0.99\t0.0126\t\nNon-steroidal anti-inflammatory drugs\t−2.11\t0.90\t0.0197\t\n\nEubacterium\n\tFluoroquinolones\t−0.99\t0.44\t0.0237\t\nLaxatives\t−1.21\t0.48\t0.0115\t\nClostridiales Family XI Incertae Sedis\tCephalosporins\t−5.78\t2.08\t0.0055\t\nFluoroquinolones\t−5.95\t2.21\t0.0071\t\nNon-steroidal anti-inflammatory drugs\t3.76\t1.99\t0.0580\t\nPenicillin with β-lactamase inhibitors\t−5.70\t2.54\t0.0248\t\n\nEnterococcus\n\tFluoroquinolones\t215.43\t102.34\t0.0353\t\nIntravenous vancomycin\t181.32\t95.02\t0.0564\t\nAmong patients who were neither colonized nor infected with C. difficile. All of the multivariable models were adjusted for age, sex, and duration of hospitalization\n\n\naReceived within 3 days prior to stool collection\n\n\nbA positive value indicates that the relative abundance of the corresponding taxa was higher among patients exposed to the medication, while a negative value indicates that the relative abundance was lower\n\n\nc\nP values were determined by using the GEE-derived robust z scores\n\n\n\nDiscussion\nWe previously demonstrated that a reduction in Clostridiales Family XI Incertae Sedis is significantly and independently associated with the risk of CDI in a distinct patient population [13]. Certain species within the Eubacterium and Clostridium genera, notably C. scindens, have the ability to convert primary bile acids into secondary bile acids [16] and have been shown to strongly inhibit C. difficile in the intestinal microbiota of antibiotic-treated mice and humans [14]. In this study, asymptomatically colonized patients, but not CDI cases, exhibited elevated relative abundance of Clostridiales Family XI Incertae Sedis, Clostridium, or Eubacterium in their gut shortly prior to or when C. difficile colonization was detected. These observations are in agreement with our initial hypothesis and suggest that co-colonization with any of these potentially protective bacterial taxa might prevent C. difficile overgrowth in colonized subjects or the transition from asymptomatic colonization to a full-blown infection.\n\nPrevious studies have shown that in the absence of gross perturbation, the intestinal microbiota of healthy subjects is relatively stable over time [21, 22]. In contrast, we observed dramatic shifts in the composition and diversity of the intestinal microbiota in patients who developed C. difficile colonization or infection, as well as in other hospitalized patients (data not shown). These observations suggest that single measurements of the intestinal microbiota may be problematic when studying hospitalized patients, in particular, as their microbiota composition is strongly influenced by their illness and medical interventions. This offers one explanation why some studies examining the role of the intestinal microbiota on health outcomes may yield conflicting results.\n\nIn a previous study, we showed that fecal excretion of human DNA was significantly increased in patients with CDI or having other gastrointestinal problems and appeared to be an outcome of intestinal inflammation [23]. In this study, the proportion of human DNA was highly variable over time but was observed to be higher prior to CDI development in two of the four cases. In some of our patients, increases in the proportion of human DNA were concomitant with a reduction of microbial diversity and increases in the relative abundance of Microvirus. Microviruses are single-stranded DNA bacteriophages that infect enterobacteria and are commonly found in human gut samples [24]. High levels of human DNA excretion have been associated with a reduction of intestinal microbiota diversity [23].\n\nOne of the patients who developed CDI (patient 98) exhibited striking blooms of Enterococcus (with frequencies reaching 98 %) on multiple occasions during his hospitalization. These blooms appeared to follow the administration of intravenous vancomycin and may represent an overgrowth of vancomycin-resistant Enterococcus (VRE). Studies have shown that the use of intravenous vancomycin is significantly associated with VRE colonization or infection [25]. Although we do not know whether this patient actually carried VRE or developed sepsis, Ubeda et al. have previously shown that intestinal domination by VRE typically precedes bloodstream infection in hospitalized patients [26]. In the cohort of patients who were neither colonized nor infected with C. difficile, we confirm that the use of intravenous vancomycin is associated with increases in the relative abundance of Enterococcus.\n\nReceipt of opioids was associated with significant increases in microbial diversity. This medication typically delays gastrointestinal transit time and may facilitate microbial growth in the colon, thereby increasing diversity. Significant reductions in intestinal microbiota diversity were only associated with the use of fluoroquinolones and intravenous vancomycin. Surprisingly, exposure to other antibiotics and PPIs did not reduce overall microbiota diversity in our cohort but did influence the relative abundance of numerous microbial taxa. The association between PPIs and CDI development is still a controversial issue [27]. The notion of reduced microbiota diversity may suggest that the number and relative abundance of microbial taxa are both declining. However, our study suggests that microbiota dynamics are much more complex; many taxa are being depleted while others are blooming. Therefore, measurement of the overall diversity is masking important distortions in the composition of the microbial community.\n\nIn multivariable analyses, we showed that the use of laxatives is associated with significant reductions in the relative abundance of Clostridium and Eubacterium; certain species among these genera may confer protection against CDI via the production of secondary bile acids. However, in a post hoc analysis, the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway corresponding to secondary bile acid biosynthesis (ko00121) was not detected in any our metagenomic samples. Laxatives accelerate gastrointestinal transit time and may have detrimental effects on the intestinal microbiota. van der Wulp et al. previously showed that treatment with polyethylene glycol (an osmotic laxative) changes the composition of the intestinal microbiota and decreases the production of secondary bile acids in rats [28]. We also demonstrated that the use of cephalosporins, fluoroquinolones, and penicillin with β-lactamase inhibitors is significantly and independently associated with reductions in the relative abundance of Clostridiales Family XI Incertae Sedis representatives. Since cephalosporin and fluoroquinolone exposure, as well as depletions of Clostridiales Family XI Incertae Sedis, have been associated with CDI risk [13], this provides a potential explanation for why these antibiotics increase the susceptibility to CDI in hospitalized patients.\n\nWe observed discrepancies in the detection of C. difficile or its toxins by culture, WMGS sequencing, and enzyme immunoassay. In two of the four asymptomatically colonized patients, C. difficile was detected by culture but not by WMGS sequencing. In two of the four CDI cases, C. difficile could not be detected, either by culture or sequencing (their CDI diagnosis was based on a positive enzyme immunoassay performed at the hospital). This may be due to a low organism load, the lack of biomass collected with the rectal swabs, or insufficient sequencing depth. One patient (patient 98) received vancomycin and metronidazole treatment for presumptive CDI prior to the actual diagnosis by enzyme immunoassay, which may have reduced the quantity of C. difficile organisms available for detection.\n\nThe number of patients who developed C. difficile colonization or infection was limited in our study; therefore, we could not perform statistical analyses to assess the role of hospital exposures and microbial taxa for patients with these outcomes. In all of the four patients who developed asymptomatic colonization, C. difficile was detected by culture in the last stool collected prior to patient discharge. Therefore, we could not determine whether C. difficile colonization was transient (present in only one occasion) or not in these patients. In the full cohort, insufficient numbers of patients exposed to certain medications (e.g., metronidazole and cotrimoxazole) or colonized by specific microbial taxa (e.g., Aerococcus and Microbacteriaceae) precluded statistical analyses. Diet and other factors such as underlying disease state can affect the intestinal microbiota and could still confound the associations identified in our study.\n\nConclusions\nThe integrity of the intestinal microbiota is intricately related to the health of the host. In this study, we show that the diversity and composition of the intestinal microbiota in hospitalized patients is highly dynamic. Use of antibiotics, as well as other non-antimicrobial medications, particularly laxatives, has a profound and rapid effect on the structure of the intestinal microbiota and significantly decreased the relative abundance of key bacterial taxa that may be involved in CDI protection. Our results also support the hypothesis that co-colonization with key bacterial taxa such as Clostridiales Family XI Incertae Sedis, Clostridium, or Eubacterium may prevent C. difficile overgrowth or the transition from asymptomatic C. difficile colonization to CDI. A better understanding of CDI pathogenesis, including the medical exposures that undermine the effectiveness of colonization resistance and the specific microbiota alterations that allow C. difficile to infect the gut, will contribute to our ability to develop novel clinical strategies to prevent or treat this life-threatening infection.\n\nMethods\nPatient recruitment and follow-up\nResearch subjects were recruited as part of a prospective cohort study conducted at the Jewish General Hospital (JGH) in Montréal between October 2009 and April 2011. Patients ≥60 years of age, who were expected to stay more than 2 days in the hospital at the time of study enrolment, and who had received antimicrobials in the previous 48 h or were expected to receive some in the next 24 h were eligible to participate in the study. Patients admitted to the hospital for CDI were excluded. Subjects were enrolled in the study within 5 days after admission to selected medical wards or surgical units. Patients were followed for 60 days after study enrolment or 30 days after hospital discharge (whichever came first) to ascertain the development of CDI. CDI cases were followed for 60 days after successfully completing CDI treatment to monitor the development of recurrent CDI.\n\nEthics, consent, and permissions\nAll study participants provided informed written consent. The Research Ethics Boards of the JGH (08-118A) and the McGill University Health Centre (11-205 GEN) approved the research protocol.\n\nSample and epidemiologic data collection\nFecal specimens were obtained from each patient at study enrollment, every 3 days during hospitalization, at the onset of diarrhea (if applicable), and at discharge. The samples were collected as bulk stool or with the use of a rectal swab if the patient was not producing stool. Rectal swabs are a convenient means of sampling the human gut and give highly reproducible microbiota profiles that can closely resemble that of fecal samples [29]. Epidemiologic information was extracted from the patients’ medical charts and included patient demographics, previous hospitalizations, reason of admission, disease severity index, dates of admission and discharge, CDI diagnosis, and the use of antimicrobials and other medications during hospitalization (with corresponding start and stop dates).\n\nToxigenic C. difficile culture\nToxigenic culture test results were provided as a courtesy of Dr. Dale N. Gerding (Hines VA Hospital and Loyola University Chicago Stritch School of Medicine, IL). Briefly, stool or rectal swab specimens were streaked onto selective pre-reduced cefoxitin-cycloserine-fructose agar supplemented with taurocholate (TCCFA) and incubated anaerobically for 48 h. Presumptive identification of C. difficile was based on typical colony morphology. If colony morphologies suggested that a mixture of C. difficile strains were present, multiple colonies were picked and saved individually. All rectal swabs were also inoculated onto non-selective blood agar to detect the growth of intestinal microbiota and confirm proper sampling technique, thereby excluding the possibility of false-negative results on the TCCFA. Purified isolates were characterized by restriction endonuclease analysis (REA) to determine their toxin classification [30]. The Bartels Cytotoxicity Assay (Trinity Biotech) was performed to determine the presence of toxin B in C. difficile isolates with an undetermined REA group.\n\nStudy definitions\nCDI was defined as follows: (i) the presence of symptoms (diarrhea, fever, abdominal pain, or ileus) and a positive C. difficile enzyme immunoassay (ImmunoCard Toxins A&B, Meridian Bioscience, Inc.) or toxigenic culture, (ii) an endoscopic diagnosis of pseudomembranes, or (iii) a pathological/histological diagnosis of CDI. Diarrhea was defined as the passage of ≥3 new unformed stools within 24 h. Recurrent CDI was defined as a CDI diagnosis that occurs within 60 days after successfully completing the treatment for the initial episode of CDI. Asymptomatic C. difficile colonization was defined as a positive stool culture for C. difficile and the absence of a CDI diagnosis during follow-up. Colonization or infection was considered hospital-acquired if the diagnosis was made ≥48 h after hospital admission and during the study follow-up period.\n\nWMGS sequencing and data analysis\nTotal DNA was extracted from rectal swabs with use of the DNA IQ System (Promega) and from bulk stool aliquots with the use of the QIAamp DNA Stool Mini Kit (Qiagen). Multiplexed DNA libraries were prepared according to a previously described protocol that allows the generation of libraries from low amounts of input DNA [31]. WMGS sequencing was performed with 150-nucleotide read lengths on the Illumina HiSeq 2000 and 2500 platforms at the McGill University and Génome Québec Innovation Centre. Up to 14 samples were multiplexed in each sequencing lane. Reads derived from the human genome were identified and removed with BMTagger [32]. Additional quality filtering steps included the trimming of sequencing adapters and low-quality bases from the 3′ end of reads as well as the removal of short (<60 bases) and duplicate reads [33, 34]. We retrieved all reads containing the V1–V3 reverse primer sequence (which targets a segment of the 16S rRNA gene) [35] and their 3′ sequences in order to obtain 55-mers originating with the primer sequence. The frequency of 16S rRNA genes (55-mers) per Mb of sequence data was used as a measure of bacterial DNA content in each sample. High-quality reads were also analyzed by MetaPhlAn2 [36] in order to determine the family, genus, and species level relative abundances. Diversity was calculated at the genus level with the Shannon index. HUMAnN version 0.99 [37] was used in conjunction with RAPSearch2 [38] and the KEGG database [39] to evaluate the presence of the pathway for secondary bile acid biosynthesis (ko00121) in each metagenomic sample.\n\nStatistical analyses\nWe provide a descriptive analysis of microbiota composition for patients who were either colonized or infected by C. difficile; we specifically examined changes in the relative abundance of potential CDI-protecting microorganisms (i.e., Clostridiales Family XI Incertae Sedis, Clostridium, and Eubacterium). In order to assess the relationship between hospital exposures (e.g., antibiotics and other medications) and either overall microbiota diversity or relative abundance of microbiota members, we used generalized estimating equation (GEE) analyses with a Gaussian link. GEE takes into account the multiple samples per subject and the likelihood that the microbiota profiles are correlated over time within patients. Microbial diversity and relative abundances were modeled using a log transformation. In these analyses, we excluded patients who were colonized or infected with C. difficile and considered only those microbial taxa and medications that were present in or administered to at least 5 % of the patients (i.e., cephalosporins, fluoroquinolones, penicillin with β-lactamase inhibitors, carbapenems, intravenous vancomycin, glucocorticoids, laxatives, NSAIDs, opioids, and PPIs). Use of medication was treated as a binary variable with “1” indicating exposure within 1 to 3 days prior to stool collection and “0” indicating otherwise. We included exposure to intravenous vancomycin in our analyses, as evidence suggests that substantial amounts of the drug can be excreted in the bowel and may therefore affect the intestinal microbiota [40]. Multivariable analyses were used in order to take into account the correlation in the use of certain medications. In addition to the medications mentioned above, all multivariable models included adjustment for age, sex, and duration of hospitalization. Final multivariable models retained significant exposure variables at a p value of <0.05. A positive estimate value indicates that the corresponding exposure is associated with an increase in either overall microbiota diversity or relative abundance of the given microbial taxa. All statistical analyses were performed in R [41]; GEE was performed using the geepack package. P values were determined by using the GEE-derived robust z scores.\n\nAvailability of supporting data\nThe sequence data supporting the results of this article are available in the National Center for Biotechnology Information Sequence Read Archive under accession number SRP064400 (http://www.ncbi.nlm.nih.gov/sra/SRP064400).\n\nAdditional files\nAdditional file 1: \n Table S1. Significant associations between medication use and intestinal microbiota genera (univariable analysis). (XLSX 433 KB)\n\nAdditional file 2: \n Table S2. Significant associations between medication use and intestinal microbiota families (univariable analysis). (XLSX 385 KB)\n\n\n\nAbbreviations\nCDIClostridium difficile infection\n\nPPIproton pump inhibitors\n\nWMGSwhole metagenome shotgun\n\nTCCFAcefoxitin-cycloserine-fructose agar supplemented with taurocholate\n\nREArestriction endonuclease analysis\n\nGEEgeneralized estimating equations\n\nrRNAribosomal RNA\n\nVREvancomycin-resistant Enterococcus\n\nJGHJewish General Hospital\n\nNSAIDnon-steroidal anti-inflammatory drug\n\nCompeting interests\n\nMAM has been an employee of bioMerieux since October 2012. The other authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nCV prepared the sequencing libraries, performed the bioinformatic analyses, participated in data analysis and interpretation, and drafted the manuscript. MAM provided patient epidemiologic information and clinical samples and participated in data analysis and interpretation. TJE performed the statistical analyses. SM assisted with bioinformatic analyses. KD participated in data analysis and interpretation. ARM conceived and designed the study, participated in data analysis and interpretation, and helped to draft the manuscript. All authors read and approved the final manuscript.\n\nAcknowledgements\nThe authors would like to thank Dr. Dale N. Gerding for the toxigenic C. difficile culture, REA typing, and cytotoxicity assays done as part of a parallel study on the same patient cohort. They also thank the clinical research staff at the JGH, Jennifer Eastmond, Romina Gheorghe, and Sophie Florencio, for their valuable help with the collection of clinical samples and the chart reviews. This work was supported by a Pfizer ASPIRE Award in Antibacterial Research [WS1954106 to A.R.M.], a Studentship from the Research Institute of the McGill University Health Centre [C.V.], as well as a Frederick Banting and Charles Best Canada Graduate Scholarship (Doctoral Award) from the Canadian Institutes of Health Research [GSD-113375 to C.V.]. The funding bodies had no role in the study design, in the collection, analysis, and interpretation of data, in the writing of the manuscript, and in the decision to submit the manuscript for publication.\n==== Refs\nReferences\n1. Lessa FC Mu Y Bamberg WM Beldavs ZG Dumyati GK Dunn JR Burden of Clostridium difficile infection in the United States N Engl J Med 2015 372 9 825 34 10.1056/NEJMoa1408913 25714160 \n2. Surawicz CM Brandt LJ Binion DG Ananthakrishnan AN Curry SR Gilligan PH Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections Am J Gastroenterol 2013 108 4 478 98 10.1038/ajg.2013.4 23439232 \n3. 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Vincent C Mehrotra S Loo VG Dewar K Manges AR Excretion of host DNA in feces is associated with risk of Clostridium difficile infection J Immunol Res. 2015 2015 246203 10.1155/2015/246203 26090486 \n24. Fane BA Brentlinger KL Burch AD Chen M Hafenstein S Moore E The Microviridae. The Bacteriophages 2011 2 Oxford Oxford University Press \n25. Gerding DN Is there a relationship between vancomycin-resistant enterococcal infection and Clostridium difficile infection? Clin Infect Dis. 1997 25 Suppl 2 S206 10 10.1086/516247 9310680 \n26. Ubeda C Taur Y Jenq RR Equinda MJ Son T Samstein M Vancomycin-resistant Enterococcus domination of intestinal microbiota is enabled by antibiotic treatment in mice and precedes bloodstream invasion in humans J Clin Invest 2010 120 12 4332 41 10.1172/JCI43918 21099116 \n27. Canadian Agency for Drugs and Technologies in Health. 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Meyer M Kircher M Illumina sequencing library preparation for highly multiplexed target capture and sequencing Cold Spring Harb Protoc 2010 2010 6 pdb prot5448 10.1101/pdb.prot5448 20516186 \n32. BMTagger. ftp://ftp.ncbi.nlm.nih.gov/pub/agarwala/bmtagger/.\n33. Niu B Fu L Sun S Li W Artificial and natural duplicates in pyrosequencing reads of metagenomic data BMC Bioinformatics 2010 11 187 10.1186/1471-2105-11-187 20388221 \n34. Martin M Cutadapt removes adapter sequences from high-throughput sequencing reads EMBnet J 2011 17 1 10 2 10.14806/ej.17.1.200 \n35. Jumpstart Consortium Human Microbiome Project Data Generation Working Group. 16S 454 sequencing protocol. 2010. http://hmpdacc.org/doc/16S_Sequencing_SOP_4.2.2.pdf.\n36. Truong DT Franzosa EA Tickle TL Scholz M Weingart G Pasolli E MetaPhlAn2 for enhanced metagenomic taxonomic profiling Nat Methods 2015 12 10 902 3 10.1038/nmeth.3589 26418763 \n37. Abubucker S Segata N Goll J Schubert AM Izard J Cantarel BL Metabolic reconstruction for metagenomic data and its application to the human microbiome PLoS Comput Biol 2012 8 6 e1002358 10.1371/journal.pcbi.1002358 22719234 \n38. Zhao Y Tang H Ye Y RAPSearch2: a fast and memory-efficient protein similarity search tool for next-generation sequencing data Bioinformatics 2012 28 1 125 6 10.1093/bioinformatics/btr595 22039206 \n39. Kanehisa M Goto S KEGG: kyoto encyclopedia of genes and genomes Nucleic Acids Res 2000 28 1 27 30 10.1093/nar/28.1.27 10592173 \n40. Currie BP Lemos-Filho L Evidence for biliary excretion of vancomycin into stool during intravenous therapy: potential implications for rectal colonization with vancomycin-resistant enterococci Antimicrob Agents Chemother 2004 48 11 4427 9 10.1128/AAC.48.11.4427-4429.2004 15504873 \n41. The R project for statistical computing. http://www.r-project.org/.\n\n", "fulltext_license": "CC BY", "issn_linking": "2049-2618", "issue": "4()", "journal": "Microbiome", "keywords": "Antimicrobials; Clostridium difficile infection; Intestinal microbiota; Medications; Whole metagenome shotgun sequencing", "medline_ta": "Microbiome", "mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D001647:Bile Acids and Salts; D002511:Cephalosporins; D016360:Clostridioides difficile; D003428:Cross Infection; D003967:Diarrhea; D004761:Enterocolitis, Pseudomembranous; D005051:Eubacterium; D005260:Female; D024841:Fluoroquinolones; D000069196:Gastrointestinal Microbiome; D006801:Humans; D054368:Laxatives; D008297:Male; D054892:Metagenome; D008875:Middle Aged; D011446:Prospective Studies", "nlm_unique_id": "101615147", "other_id": null, "pages": "12", "pmc": null, "pmid": "26975510", "pubdate": "2016-03-14", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": "16206099;11136263;10592173;23439232;20516186;25337874;8394378;25437605;26090486;22441775;21099116;23828941;23868407;17879913;16965399;15504873;18971494;9310680;24066741;25020051;22719234;9500319;24450844;25942722;22039206;18177218;11871461;26418763;25732416;25426290;21829582;20388221;25714160;21119612;26164495", "title": "Bloom and bust: intestinal microbiota dynamics in response to hospital exposures and Clostridium difficile colonization or infection.", "title_normalized": "bloom and bust intestinal microbiota dynamics in response to hospital exposures and clostridium difficile colonization or infection" }	[ { "companynumb": "CA-MYLANLABS-2016M1050742", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "VANCOMYCIN" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": "065397", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CLOSTRIDIUM DIFFICILE INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VANCOMYCIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Enterococcal infection", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VINCENT C, MILLER MA, EDENS TJ, MEHROTRA S, DEWAR K, MANGES AR. BLOOM AND BUST: INTESTINAL MICROBIOTA DYNAMICS IN RESPONSE TO HOSPITAL EXPOSURES AND CLOSTRIDIUM DIFFICILE COLONIZATION OR INFECTION. MICROBIOME 2016;4:12.", "literaturereference_normalized": "bloom and bust intestinal microbiota dynamics in response to hospital exposures and clostridium difficile colonization or infection", "qualification": "3", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20161128", "receivedate": "20161128", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 12979098, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" } ]
{ "abstract": "METHODS\nTo present a case of photopsia resulting from digoxin intoxication brought about by dehydration in a 72-year-old woman.\n\n\nCONCLUSIONS\nOphthalmologists may be the first clinicians to notice the symptoms of digitalis intoxication, which is potentially a life-threatening condition.", "affiliations": "Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Japan. [email protected]", "authors": "Oishi\|Akio\|A\|;Miyamoto\|Kazuaki\|K\|;Kashii\|Satoshi\|S\|;Yoshimura\|Nagahisa\|N\|", "chemical_list": "D002316:Cardiotonic Agents; D004077:Digoxin", "country": "England", "delete": false, "doi": "10.1016/S0008-4182(06)80031-1", "fulltext": null, "fulltext_license": null, "issn_linking": "0008-4182", "issue": "41(5)", "journal": "Canadian journal of ophthalmology. Journal canadien d'ophtalmologie", "keywords": null, "medline_ta": "Can J Ophthalmol", "mesh_terms": "D000368:Aged; D002316:Cardiotonic Agents; D003681:Dehydration; D004077:Digoxin; D005260:Female; D005440:Fluid Therapy; D006212:Hallucinations; D006801:Humans; D010719:Phosphenes", "nlm_unique_id": "0045312", "other_id": null, "pages": "603-4", "pmc": null, "pmid": "17016533", "pubdate": "2006-10", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Photopsia as a manifestation of digitalis toxicity.", "title_normalized": "photopsia as a manifestation of digitalis toxicity" }	[ { "companynumb": "JP-CONCORDIA PHARMACEUTICALS INC.-GSH201706-003336", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DIGOXIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "020405", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".125", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIGOXIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "FUROSEMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FUROSEMIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "SPIRONOLACTONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SPIRONOLACTONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CARVEDILOL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARVEDILOL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LOSARTAN POTASSIUM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOSARTAN POTASSIUM." } ], "patientagegroup": null, "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "52", "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Photopsia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "OISHI A,MIYAMOTO K,KASHII S,YOSHIMURA N. PHOTOPSIA AS A MANIFESTATION OF DIGITALIS TOXICITY.. CAN J OPHTHALMOL. 2006 OCT;41(5):603-604.", "literaturereference_normalized": "photopsia as a manifestation of digitalis toxicity", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "CH", "receiptdate": "20170621", "receivedate": "20170606", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13615183, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20170830" } ]
{ "abstract": "This report describes a case of lung cancer with sarcoid reaction following chemoradiotherapy, showing false-positive accumulation of (18)F-fluorodeoxyglucose on positron-emission tomography in a 55-year-old man. Treatment-related sarcoid reaction should be considered when the accumulation of (18)F-fluorodeoxyglucose shows rapid extension in the course of treatment.", "affiliations": "Department of General Thoracic Surgery, Kawasaki Medical School, Okayama, Japan.", "authors": "Yukawa\|Takuro\|T\|;Shimizu\|Katsuhiko\|K\|;Hirami\|Yuji\|Y\|;Maeda\|Ai\|A\|;Yasuda\|Koichiro\|K\|;Nakata\|Masao\|M\|", "chemical_list": "D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D000077146:Irinotecan; D002945:Cisplatin; D002166:Camptothecin", "country": "England", "delete": false, "doi": "10.1177/0218492312468592", "fulltext": null, "fulltext_license": null, "issn_linking": "0218-4923", "issue": "21(6)", "journal": "Asian cardiovascular & thoracic annals", "keywords": "Adenocarcinoma; Lung neoplasms; Lymphatic metastasis; Positron-emission tomography; Sarcoidosis", "medline_ta": "Asian Cardiovasc Thorac Ann", "mesh_terms": "D000230:Adenocarcinoma; D000077192:Adenocarcinoma of Lung; D000971:Antineoplastic Combined Chemotherapy Protocols; D002166:Camptothecin; D059248:Chemoradiotherapy; D002945:Cisplatin; D005189:False Positive Reactions; D019788:Fluorodeoxyglucose F18; D006801:Humans; D000077146:Irinotecan; D008175:Lung Neoplasms; D008198:Lymph Nodes; D008297:Male; D008875:Middle Aged; D049268:Positron-Emission Tomography; D011237:Predictive Value of Tests; D011829:Radiation Dosage; D019275:Radiopharmaceuticals; D012507:Sarcoidosis; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D047368:Tumor Burden", "nlm_unique_id": "9503417", "other_id": null, "pages": "732-4", "pmc": null, "pmid": "24569337", "pubdate": "2013-12", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Lung cancer with sarcoid reaction in the lymph nodes following chemoradiotherapy.", "title_normalized": "lung cancer with sarcoid reaction in the lymph nodes following chemoradiotherapy" }	[ { "companynumb": "JP-PFIZER INC-2014306160", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "IRINOTECAN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "020571", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG/M2, ON DAYS 1 AND 8", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG ADENOCARCINOMA STAGE III", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IRINOTECAN HCL" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "60 MG/M2, ON DAY 1", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG ADENOCARCINOMA STAGE III", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN." } ], "patientagegroup": null, "patientonsetage": "55", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Sarcoidosis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "YUKAWA, T.. LUNG CANCER WITH SARCOID REACTION IN THE LYMPH NODES FOLLOWING CHEMORADIOTHERAPY. 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LUNG CANCER WITH SARCOID REACTION IN THE LYMPH NODES FOLLOWING CHEMORADIOTHERAPY. 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{ "abstract": "Background - Pre-existing pathology, the development of acute new one strictly dependent of the pregnancy or an independent acute or chronic medical problems generate a highly complex disease that requires a nuanced interpretation of the pregnant women in an attempt to identify the most favorable solutions for evaluation and treatment. Case report - 26-28 weeks pregnant women, 23 years old, known epilepsy, HIV encephalitis and pulmonary TB in inconsistent treatment with prolonged seizure status. Emergency air evacuation from a third degree medical center to regional center ( first level) under general anesthesia. After 24 hours, conscious, without focal signs. Favorable ongoing pregnancy. Conclusions - Considering the medical history, we analyzed several possibly triggering and maintenance of the crisis elements so that clarification of them constituted the main challenges. Finding an imaging examination solution with minimal harming effect on the fetus was a key decision points. Tocography and excluding eclampsia as the etiology were the main reasons to refrain from practicing cesarean section and magnesium sulphate administration. Paralytic agents use, in particular succinylcholine was a decisional key point, considering the variation in serum cholynesterase activity in peripartum period. The phenytoin administration was also a difficult choice because of the risk of bradycardia to the fetus. No any adverse event as effects of the crisis and medical intervention on the mother reported to the newborn during the first 8 months of life, but cerebral palsy continues to concern before 24 months.", "affiliations": "Emergency & First Aid Department, University of Medicine and Pharmacy of Craiova, Emergency Department - SMURD, University County Hospital Craiova.;University of Medicine and Pharmacy of Craiova.;University of Medicine and Pharmacy of Târgu - Mureș, Emergency Department - SMURD, University County Hospital Târgu - Mureș.", "authors": "Rotaru\|L T\|LT\|;Popescu\|R M\|RM\|;Boeriu\|C\|C\|", "chemical_list": null, "country": "Romania", "delete": false, "doi": "10.12865/CHSJ.41.01.09", "fulltext": "\n==== Front\nCurr Health Sci JCurr Health Sci JCHSJCurrent Health Sciences Journal2067-06562069-4032Medical University Publishing House Craiova 2015.01.0910.12865/CHSJ.41.01.09Case Report Plurietiologyc Possibilities and Difficulties of Seizures Management in Pregnancy\n ROTARU L.T. 1POPESCU R.M. 2BOERIU C 31 Emergency & First Aid Department, University of Medicine and Pharmacy of Craiova, Emergency Department – SMURD, University County Hospital Craiova2 University of Medicine and Pharmacy of Craiova3 University of Medicine and Pharmacy of Târgu – Mureș, Emergency Department – SMURD, University County Hospital Târgu – MureșCorresponding Author: Dr. Luciana Rotaru\nAssociate Professor Emergency & First Aid DepartmentUniversity of Medicine and Pharmacy Craiova, Medical Director Emergency Department – SMURD, University County Hospital Craiova\nTabaci St. No. 1Craiova [email protected] Jan-Mar 2015 15 3 2015 41 1 67 69 27 2 2015 15 3 2015 Copyright © 2015, Medical University Publishing\nHouse Craiova2015This is an open-access article distributed under the terms of a\nCreative Commons Attribution-NonCommercial-ShareAlike 4.0 International\nPublic License, which permits unrestricted use, adaptation, distribution and\nreproduction in any medium, non-commercially, provided the new creations are\nlicensed under identical terms as the original work and the original work is\nproperly cited.Background - Pre-existing pathology, the development of acute new one strictly dependent of the pregnancy or an independent acute or chronic medical problems generate a highly complex disease that requires a nuanced interpretation of the pregnant women in an attempt to identify the most favorable solutions for evaluation and treatment. Case report - 26-28 weeks pregnant women, 23 years old, known epilepsy, HIV encephalitis and pulmonary TB in inconsistent treatment with prolonged seizure status. Emergency air evacuation from a third degree medical center to regional center ( first level) under general anesthesia. After 24 hours, conscious, without focal signs. Favorable ongoing pregnancy. Conclusions - Considering the medical history, we analyzed several possibly triggering and maintenance of the crisis elements so that clarification of them constituted the main challenges. Finding an imaging examination solution with minimal harming effect on the fetus was a key decision points. Tocography and excluding eclampsia as the etiology were the main reasons to refrain from practicing cesarean section and magnesium sulphate administration. Paralytic agents use, in particular succinylcholine was a decisional key point, considering the variation in serum cholynesterase activity in peripartum period. The phenytoin administration was also a difficult choice because of the risk of bradycardia to the fetus. No any adverse event as effects of the crisis and medical intervention on the mother reported to the newborn during the first 8 months of life, but cerebral palsy continues to concern before 24 months.\n\nseizurespregnancytocographycesarean sectioneclampsia\n==== Body\nIntroduction\nEmergency management of pregnancy is always a challenge because of the risk of fetal damage induced by generating condition, medications, procedures and physiological changes that pregnancy induces to the maternal body. \n\nPre-existing pathology, the development of acute new one strictly dependent of the pregnancy or an independent acute or chronic medical problems generate a highly complex disease that requires a nuanced interpretation in an attempt to identify the most favorable solutions for evaluation and treatment [1].\n\nCase report\nWe present a 23 years old woman case known epilepsy treated with carbamazepine and phenobarbitalum, 26-28 weeks pregnant brought by the ordinary ambulance to a level III medical center in epileptic status since 1 hour. The patient was out with HIV encephalitis and pulmonary TB in inconsistent treatment. BP 96/68mmHg. HR - 134/min. Normal blood glucose level and ECG, negative toxicological report. Fetal HR 100-115/min. Normal uterine tone. \n\nAfter repeated diazepam administration with no significant response in crisis suppression, the patient was air evacuated (HEMS resuscitation team) to the regional medical center (general anesthesia, endotracheal intubation, mechanical ventilation / volume IPPV cycled) with IV. benzodiazepine dose supplementation and IV. Phenytoin administration - 15mg/kg. \n\nFig. 1a and 2b Air evacuation to County University Hospital Craiova\n\nFig.1a Fig.1b Initial crush induction sequence (succinylcholine) sustained by deep sedation (fentanyl, etomidate, diazepam). Under general anesthesia (maintained over 6 hours by the anesthesiologist) has cupped seizures but maintained tachycardia. At 7 hours, she has been extubated without further medical events.\n\n At 24 hours conscious, without focal signs or subsequent seizures. Favorable ongoing pregnancy. \n\nAfter 5 weeks – natural delivery of a 1936 grams, male newborn. No any signs of abnormal brain electrical activity or seizures to the baby related to the mother medical problems during the first 8 months of life, but considering the severe event and therapy cerebral palsy remains under suspicion until 24 months. \n\nDiscussions\nThe main key decision points were the etiology of seizure status, differentiation eclampsia, brain imaging investigation options, anticonvulsant and anesthetics medications, and the decision to perform caesarean section. Each of these assumptions could have an impact on subsequent management decisions regarding caesarean section of necessity, type and level of anesthesia, child monitoring:\n\nThe etiology of seizure status. We have considered several possibilities possibly triggering and maintenance of the crisis: eclampsia, epilepsy, HIV encephalitis outbreak, septic or other opportunist, or any intracranial process (including posttraumatic related to previous seizures), hypoglycemia, intoxication, overdose or withdrawal of anticonvulsant medication. Since toxicological examination was negative, with high probability one of the causes triggering or at least favoring, was constituted by suppressing their medication. \n\nDifferentiation eclampsia. Under normal uterine tone, normal blood count (platelet count 211x106.l), no proteinuria confirmed, normal liver and renal function, LDH and creatinine and coagulation status, no haemolysis, normal and D dimmers level, BP progress and tocography s - decided that determinism is conceivable excluding eclampsia[2].That was the reason of do not attempt magnesium sulphate administration even if, a probability of eclamptic development assumed, very low gestational age and possible delivery needs considered in short horizon of time. In worst-case scenario of imposed hurry delivery, the fetal cerebral risks in this situation were appreciated as very high but the probability of this development of the situation was appreciated as being low. In the same time the cumulative effect of bradycardia induced by magnesium sulphate on the fetus would be reasonable to refrain of that and keep it as a backup solution in eventuality of repeated seizures [3].\n\nBrain imaging investigation. The options were related to performing brain CT (abdominal protection) or MRI (more acceptable to the fetus), considered mandatory to exclude certain items that require special intervention (as brain hemorrhagic event). S - Decided and performed MRI even if CT perhaps more reliant in view of acute minor bleeding. No acute pathological elements showed.\n\nAnticonvulsant and anesthetics medications. Concern was generated by using of succinylcholine, followed by rocuronium (serum cholinesterase activity decreases 30% during pregnancy and remains depressed postpartum [4] and subsequently the need of phenytoin administration. However, is not evidenced prolonged recovery in term-pregnant patients related succinylcholine [5] but cardiac effects on the fetus are not well known. There were no reported any disrhythmias or bradycardia to the fetus following conjugate administration of this drug to the mother.\n\nFigure 2 Abdominal echography - ED Craiova - normal ongoing pregnancy\n\nThe decision to perform caesarean section was related to potential fetal distress caused by prolonged hypoxia, induction and maintenance of long term general anesthesia and phenytoin administration [2] Being small gestational age, management to ensure acceptable adaptation and aggression already exercised on the fetus - considered that keeping it into the ,,natural incubator”, army expectative, tocography and mother observation is more profitable to improve prognosis.\n\nGiven to the patient history is never easy to determine the cause of the current crisis and decide further management, it may be necessary invasive investigations, over which the decision must be nuanced and custom. In the same time, the age of the pregnancy could induce confusion with eclampsia, and the specific management was sensible different. Using antihypertensive therapy administration and volume replacement in attempt of pressure and under perfusion of the placental bed control (which determine uterine ischemia and worsening of the fetus outcome) could induce interstitial pulmonary oedema [6] or rising intracranial pressure especially if preexisting damages, but eclampsia is an acute life-threatening complication of pregnancy and rapid identification and therapeutic decision (including assuming cesarean section) is crucial.\n\nThe existence of brain damage and a previous seizure induced background assumption as at least maintenance factors of the crisis but the imaging examination decision was a difficult one, in attempt to choose the minimal harming effect on the fetus and an acceptable sensitivity and accuracy of the result. \n\nConcerns about the cumulative effects of phenytoin on succinylcholine on fetal heart rate and rhythm - no confirmed, no any bradycardia or other cardiac dysrhythmia was reported and waiting on decision of cesarean section was beneficial.\n\nConclusion\nAlthough it supported increasing the frequency and duration of epilepsy seizures during pregnancy, treatment neglect condition requires exclusion documented as another cerebral etiology (HIV, trauma, toxic context, acute hemorrhagic event) and particularly eclampsia. \n\nCrush induction decision imposed in the context of a very prolonged, severe seizures, air evacuation and anticipating an extended brain imaging investigation. Mivacurium could be an alternative to succinylcholine, but succiniycholine was an option that has not generated any adverse elements from mother to fetus. \n\nPhenytoin administration was mandatory to stop seizures and has not caused either bradycardia or other cumulative adverse effects to the fetus\n\nRefrain from opening delivery was a favorable decision to the fetus, allowing growth to continue, although it may be controversial given mother's medication type and dosage administered [7]. \n\nSevere flightiness could rather be a trigger-to-trigger brain suffering (and hence to seizures in children) than the continuation of anticonvulsant treatment with maximum load.\n\nComplex pathologic and evolutionary context imposes upon the practitioner in emergency medicine at the systematic evaluation of both the mother and fetus to systematic approach and maximal emergency management providing to ensure and improvement vital functions, to prevent of secondary brain injury and several systemic side effects problems (induced by hypoxia, agitation, hyperthermia) and a multidisciplinary decision for the benefit of well weighed both, even if the risk of maternal plurimedicalisation apparaently exhibits risky on the fetus.\n==== Refs\nReferences\n1 Schachter SC Management of epilepsy and pregnancy 2014 \nAvailable from: http://www.uptodate.com/home/index.html \n2 Harden CL Management issues for women with epilepsy - Focus on pregnancy (an evidence-based review): I. Obstetrical complications and change in seizure frequency: Report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the American Epilepsy Society Epilepsia 2009 50 1229 1229 19496807 \n3 Altman D Carroli G Duley L Farrell B Moodley J Nelson J Do women with preeclampsia and their babies benefit from magnesium sulphate? The MAGPLE trial: a randomized placebo - controlled trial Lancet 2002 359 1877 1890 12057549 \n4 Leighton BL Cheek TG Gross JB Apfelbaum JL Shantz BB Gutsche BB Rosenberg H Succinylcholine pharmacodynamics in peripartum patients Anesthesiology 1986 2 64 202 205 3946807 \n5 Mohd Asim Rasheed Urmila Palaria Umesh K Bhadani Abdul Quadir Determination of optimal dose of succinylcholine to facilitate endotracheal intubation in pregnant females undergoing elective cesarean section Journal of Obstetric Anaesthesia and Critical Care 2012 2 2 86 91 \n6 Engelhardt T MacLennan FM Fluid management in pre-eclampsia International Journal of Obstetric Anesthesia 1999 8 253 259 15321120 \n7 Haddad B Deis S Goffnet F Paniel BJ Cabrol D Siba BM Maternal and perinatal outcomes during expectant management of 239 severe preeclamptic women between 24 and 33 weeks gestation Am. J. Obstet. Gynecol. 2004 190 1590 1597 15284743\n\n", "fulltext_license": "CC BY-NC-SA", "issn_linking": null, "issue": "41(1)", "journal": "Current health sciences journal", "keywords": "cesarean section; eclampsia; pregnancy; seizures; tocography", "medline_ta": "Curr Health Sci J", "mesh_terms": null, "nlm_unique_id": "101597164", "other_id": null, "pages": "67-69", "pmc": null, "pmid": "30151252", "pubdate": "2015", "publication_types": "D016428:Journal Article", "references": "12057549;15284743;3946807;19496807;15321120", "title": "Plurietiologyc Possibilities and Difficulties of Seizures Management in Pregnancy.", "title_normalized": "plurietiologyc possibilities and difficulties of seizures management in pregnancy" }	[ { "companynumb": "PHHY2015RO048621", "fulfillexpeditecriteria": "1", "occurcountry": "RO", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARBAMAZEPINE" }, "drugadditional": null, "drugadministrationroute": "064", 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{ "abstract": "Background Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) are two rare headache syndromes classified broadly as Trigeminal Autonomic Cephalalgias (TACs). Methods Here, 65 SUNCT (37 males) and 37 SUNA (18 males) patients were studied to describe their clinical manifestations and responses to treatment. Results Pain was almost always unilateral and side-locked. There were three types of attack: Single stabs, stab groups, and a saw-tooth pattern, with some patients experiencing a mixture of two types. As to cranial autonomic symptoms, SUNA patients mainly had lacrimation (41%) and ptosis (40%). Most cases of the two syndromes had attack triggers, and the most common triggers were touching, chewing, or eating for SUNCT, and chewing/eating and touching for SUNA. More than half of each group had a personal or family history of migraine that resulted in more likely photophobia, phonophobia and persistent pain between attacks. For short-term prevention, both syndromes were highly responsive to intravenous lidocaine by infusion; for long-term prevention, lamotrigine and topiramate were effective for SUNCT, and lamotrigine and gabapentin were efficacious in preventing SUNA attacks. A randomized placebo-controlled cross-over trial of topiramate in SUNCT using an N-of-1 design demonstrated it to be an effective treatment in line with clinical experience. Conclusions SUNCT and SUNA are rare primary headache disorders that are distinct and very often tractable to medical therapy.", "affiliations": "1 Department of Neurology, Wan Fang Hospital, Taipei Medical University, and Department of Neurology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.;3 Clinical Neurosciences, Royal Free Hospital, London, UK.;2 University of California, San Francisco, San Francisco, San Francisco CA, USA.;2 University of California, San Francisco, San Francisco, San Francisco CA, USA.", "authors": "Weng\|Hsing-Yu\|HY\|;Cohen\|Anna S\|AS\|;Schankin\|Christoph\|C\|;Goadsby\|Peter J\|PJ\|", "chemical_list": "D000700:Analgesics; D000927:Anticonvulsants; D000077236:Topiramate; D000077206:Gabapentin; D000077213:Lamotrigine", "country": "England", "delete": false, "doi": "10.1177/0333102417739304", "fulltext": "\n==== Front\nCephalalgiaCephalalgiaCEPspcepCephalalgia0333-10241468-2982SAGE Publications Sage UK: London, England 10.1177/033310241773930410.1177_0333102417739304Original ArticlesPhenotypic and treatment outcome data on SUNCT and SUNA, including a randomised placebo-controlled trial Weng Hsing-Yu 12Cohen Anna S 3Schankin Christoph 24Goadsby Peter J 251 Department of Neurology, Wan Fang Hospital, Taipei Medical University, and Department of Neurology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan2 University of California, San Francisco, San Francisco, San Francisco CA, USA3 Clinical Neurosciences, Royal Free Hospital, London, UK4 Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland5 NIHR-Wellcome Trust King’s Clinical Research Facility, King’s College London, UKPeter J Goadsby, Wellcome Foundation Building, King’s College Hospital, London SE5 9PJ, UK. Email: [email protected] 11 2017 8 2018 38 9 1554 1563 27 12 2016 24 8 2017 2 10 2017 6 10 2017 © International Headache Society 20172017International Headache SocietyThis article is distributed under the terms of the Creative Commons Attribution 4.0 License (http://www.creativecommons.org/licenses/by/4.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Background\nShort-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) are two rare headache syndromes classified broadly as Trigeminal Autonomic Cephalalgias (TACs).\n\nMethods\nHere, 65 SUNCT (37 males) and 37 SUNA (18 males) patients were studied to describe their clinical manifestations and responses to treatment.\n\nResults\nPain was almost always unilateral and side-locked. There were three types of attack: Single stabs, stab groups, and a saw-tooth pattern, with some patients experiencing a mixture of two types. As to cranial autonomic symptoms, SUNA patients mainly had lacrimation (41%) and ptosis (40%). Most cases of the two syndromes had attack triggers, and the most common triggers were touching, chewing, or eating for SUNCT, and chewing/eating and touching for SUNA. More than half of each group had a personal or family history of migraine that resulted in more likely photophobia, phonophobia and persistent pain between attacks. For short-term prevention, both syndromes were highly responsive to intravenous lidocaine by infusion; for long-term prevention, lamotrigine and topiramate were effective for SUNCT, and lamotrigine and gabapentin were efficacious in preventing SUNA attacks. A randomized placebo-controlled cross-over trial of topiramate in SUNCT using an N-of-1 design demonstrated it to be an effective treatment in line with clinical experience.\n\nConclusions\nSUNCT and SUNA are rare primary headache disorders that are distinct and very often tractable to medical therapy.\n\nSUNCTSUNAtrigeminal autonomic cephalalgiacranial autonomic symptomstriggerslidocainelamotriginetopiramategabapentin\n==== Body\nIntroduction\nShort-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) is a rare form of primary headache (1,2). It is clear in tertiary headache practice that many patients do not manifest both conjunctival injection and tearing (3). The current terminology has evolved to respect the initial description and acronym, and acknowledge the underlying physiological principle of co-existent cranial autonomic activation (4). SUNCT syndrome was initially included in the second edition of the International Headache Classification and SUNA in the appendix (5). In the latest version, ICHD-3 beta (6), SUNCT and SUNA are included in the main body.\n\nAt least two unresolved issues arise in these syndromes. First, should they be collapsed under an umbrella or left distinct? Given their rarity, substantial series have not been available to explore the phenotypes. Previously, we reported on 43 SUNCT and nine SUNA patients (3); in the following decade, we have seen more patients with these syndromes and sought here to examine whether the syndromes are sufficiently distinct to maintain their separation. Moreover, we had noted in previous work that migraine features in the phenotype appeared to be associated with an underlying migrainous biology (3); we, therefore, wished to test the question as to whether having underlying migrainous biology influenced the phenotypic expression of these syndromes with our expanded cohort. Secondly, while there are treatment guidelines (7), the body of evidence for the guidance is minimal. We have been able to collect substantial treatment response data, and uniquely have conducted a randomized placebo-controlled trial of SUNCT to test whether topiramate is an effective treatment. We therefore set out to provide experience as an evidence base (8) for treatment recommendations.\n\nMaterial and methods\nClinical material\nAll patients attended outpatient clinics at either the National Hospital for Neurology and Neurosurgery (NHNN), London, UK, between 2002 and 2007; the Headache Center, University of California, San Francisco (UCSF), San Francisco, CA, USA, from 2007 to 2013, or as outpatients at King’s College Hospital, London, UK from 2013 to 2015. Patients were diagnosed as having SUNCT or SUNA as defined by the International Classification of Headache Disorders, Second Edition (ICHD-2) (5) and were consistent with proposed ICHD-3 beta criteria (6). Every patient was seen by at least one of us (PJG). The cohort represents those previously reported (3) whose clinical data were re-reviewed, and additional cases. The study was approved by the NHNN Institute of Neurology Joint Research Ethics Committee (reference 00/N072), by the UCSF Committee for Human Research, and is presented as an audit of practice at King’s College Hospital, London.\n\nIn every patient, detailed and standardised history-taking was carried out, including the side, location, frequency, duration, and character of their headaches, types of attacks, accompanying symptoms, triggering factors, personal and family histories, and their responses to medicines or other treatments. The study focuses on lateralization and type of attacks, cranial autonomic symptoms, and treatment outcomes.\n\nClinical data analysis\nAll data were recorded using Microsoft Excel. All descriptive calculations were performed in Excel. Summary measures are reported for the cohort as n’s with percentages. To test whether the SUNCT and SUNA are different based on phenotype as a surrogate for biology, apart from the cranial autonomic symptom distinction, we used a multinomial logistic model, with a logit link function, and diagnosis as the dependent variable (IBM SPSS Statistics v 22). To test the relationship of background migrainous biology, defined as a personal or family history of migraine, to the presence of a clinical phenotype, we used a binary logistic model, with a logit link function, and the presence of migrainous biology as a binary dependent variable. To test single phenotype questions, a chi squared test was employed. For all analyses, significance was set as p < 0.05. The clinical effect from preventives is recorded as patients subjectively reported their effects, and as it was recorded in the documentation.\n\nClinical trial\nFive male patients (aged 51–72, mean 59 years) with SUNCT were recruited from the Outpatient department at the National Hospital for Neurology and Neurosurgery (NHNN), London, between 2003 and 2004 (Figure 1). They were initially diagnosed with SUNCT using operational criteria later incorporated into ICHD-2 (5). Inclusion criteria were: Diagnosis of SUNCT; willingness to stop any current treatments; and willingness to comply with a diary of attacks as they occurred. Exclusion criteria were: Previous exposure to topiramate; being pregnant or lactating; having a history of renal calculi; and any contraindications to the use of topiramate according to the Summary of Product Characteristics (Medicines and Healthcare products Regulatory Agency- MHRA, UK). The subjects gave their informed consent and were free to withdraw from the study at any time. The study was conducted before trial registration became commonplace (9).\nFigure 1. CONSORT flow diagram.\n\n\n\nDesign\nThe design of the study was a randomised, double-blind, placebo-controlled crossover trial of topiramate. The treatments were topiramate tablets and matching placebo, supplied by Janssen UK; and labelled Treatment 1 and Treatment 2, to be taken in the first and second arm of the study, respectively. The order of active treatment and placebo was randomised by NHNN pharmacy, and each participant was assigned a randomisation number. The code was held by the pharmacy until study completion and database locking.\n\nConduct\nPatients were required to withdraw from preventive medications prior to commencement of the study. After an initial washout drug-free period of 10 days, treatment was started at topiramate 12.5 mg at night and increased every five days to a maximum of 50 mg twice daily for 10 days, after which the dose was reduced over the next 10 days, or the same regimen with matched placebo. A 10-day washout drug-free period followed, after which the patients commenced the second arm of the study in the same paradigm. The patients with episodic SUNCT started the 10-day washout period at the start of their bout.\n\nThe patients were instructed to keep a diary for the duration of the study, which documented the date, time, severity, and duration of each attack.\n\nClinical trial data analysis\nThe primary endpoint was the reduction of attack frequency, as measured by the mean daily number of attacks during the 10 days at maximum dose compared to the 10 drug free days pre-treatment, comparing active and placebo treatment arms. A secondary endpoint, ‘attack load’, was calculated as the number of minutes of pain per day for each patient, to take account of longer attacks, such as saw-tooth patterns (3). The results are presented on an N-of-1 basis. A positive result was declared for the endpoint in each patient, if the outcome was reduced by 50% or more compared to placebo. Given SUNCT attack frequency can vary considerably from week to week, we converted changes to percentages and calculated:%therapeutic effect = (topiramate change) minus (placebo change).\n\n\n\nResults\nClinical data\nSubjects\nOne hundred and two cases were identified: 65 with SUNCT, and 37 with SUNA. There were 37 male and 28 female SUNCT patients, and 18 male and 19 female SUNA patients. The mean age of onset of SUNCT patients was 46 ± 13 (mean ± SD; range: 13–75) years, and that of SUNA was 45 ± 16 (range 15–92).\n\nLaterality of attacks\nOf all the SUNCT and SUNA patients, 48 (47%) cases had only left-side attacks, and 52 (51%) cases had attacks exclusively on the right side; 12 (12%) cases had unilateral attacks with side variance; one case had a unilateral attack with nearly equal possibility of left or right side; only one case had experienced bilateral attacks.\n\nCranial autonomic symptoms\nBy definition, every SUNCT patient had attacks with both an ipsilateral conjunctival injection and lacrimation, while less than half of SUNA patients had either. SUNCT is generally more feature-full in terms of cranial autonomic symptoms than is SUNA. SUNA is dominated by lacrimation, nasal symptoms, and ptosis (Table 1).\nTable 1. Cranial autonomic features.\n\nFeature\tSUNCT n (%)\tSUNA n (%)\t\nConjunctival injection\t65 (100)\t7 (24)\t\nLacrimation\t65 (100)\t14 (48)\t\nNasal: Blocking or rhinorrhea\t44 (67)\t12 (36)\t\nAural fullness\t12 (50)\t5 (17)\t\nPeriorbital oedema\t25 (41)\t8 (29)\t\nForehead/facial:\t\t\t\n Sweating\t4 (7)\t1 (3)\t\n Flushing\t11 (18)\t5 (17)\t\nSympathetic:\t\t\t\n Ptosis\t31 (51)\t11 (38)\t\n Miosis\t1 (2)\t0\t\n\n\nComparing the phenotypes\nTriggering\nAmong SUNCT patients, one patient had only triggered attacks, with no spontaneous ones. Eight (12%) SUNCT patients had only spontaneous attacks with no triggered ones. All the other patients had both spontaneous and triggered attacks. In SUNA patients, 10 (27%) patients had only spontaneous attacks with no triggers, and the remainder had more triggered attacks than spontaneous ones. Of all SUNCT patients, 56 (86%) cases had pain attacks with a cutaneous trigger. The most common triggers included touch (39 cases, 60%), chewing or eating (35 cases, 54%), the wind (24 cases, 37%) and brushing the teeth (23 cases, 35%). Among SUNA patients, 32 (86%) cases had pain with triggers. The most frequent triggers of SUNA cases were chewing or eating (12 cases) and touch (10 cases).\n\nRefractory period\nOf SUNCT cases for whom we had data, 1/52 had a refractory period to cutaneous triggering. Of SUNA cases, 4/32 had a refractory period after cutaneous triggering.\n\nTypes of attacks\nAttacks of SUNCT and SUNA take one or more of three forms: Single stabs, a group of stabs, or a saw-tooth pattern of stabs. In this cohort, SUNCT patients had more single stabs, while SUNA had more groups of stabs (χ2 = 23.4, p < 0.0001). The saw-tooth pattern was comparable in both conditions (Table 2).\nTable 2. Pattern of attacks.\n\n\tSUNCT n (%)\tSUNA n (%)\t\nSingle stabs\t41 (64)\t8 (37)\t\nGroups of stabs\t23 (36)\t23 (62)\t\nSaw-tooth pattern\t22 (34)\t9 (24)\t\nSingle stabs + groups of stabs\t10 (18)\t2 (9)\t\nSingle stabs + saw-tooth pattern\t5 (9)\t1 (5)\t\nGroups of stabs + saw-tooth pattern\t1 (2)\t1 (5)\t\nSingle stabs + groups of stabs + saw-tooth pattern\t3 (5)\t0\t\n* p < 0.0001\n\n\n\nMigrainous background\nBoth SUNCT and SUNA patients had a background migrainous biology in 57 % of cases for which we had data. In a model examining the pain features, a migrainous background was strongly associated with background pain between attacks (Wald χ2 = 6.5, p = 0.01) and worsening of pain during the attack (Wald χ2 = 8.2, p = 0.004). In a model examining the canonical migraine features, the presence of nausea was not associated with migrainous biology (Wald χ2 = 1.04, p = 0.307), whereas the presence of either photophobia or phonophobia was associated (Wald χ2 = 6.8, p = 0.009). Worsening of background pain with movement was seen in 26% (n = 55) of SUNCT cases and in 46% (n = 28) of SUNA cases. Nausea was seen in 27% (n = 64) of SUNCT cases and 29% (n = 35) of SUNA cases. Similarly, for photophobia or phonophobia, 61% (n = 64) of SUNCT and 58% (n = 36) of SUNA cases had one, or both, symptoms.\n\nTreatment effects\nShort-term prevention\nSumatriptan was used in 14 SUNCT and nine SUNA patients, and the attacks lessened in only one of each. High-flow oxygen was tried, but neither SUNCT nor SUNA cases were responsive. Placebo-controlled indomethacin injections (10) had no effect on either SUNCT or SUNA. Intravenous lidocaine had a very good effect in reducing attacks of SUNCT (100%) and SUNA (88%), when it could be tolerated. Dihydroergotamine (11) and corticosteroids seem generally unhelpful in both SUNCT and SUNA. Greater occipital nerve (GON) injections (12) were beneficial in 50% (6 of 12 cases) of SUNCT patients, but had no reliable effect in SUNA cases (Table 3).\nTable 3. Effect of acute treatments of TACs on SUNCT and SUNA.\n\n\tSUNCT\tSUNA\t\nTotal n\tEffective n\tTotal n\tEffective n\t\nSumatriptan 6 mg sc\t14\t1\t9\t1\t\nOxygen 12–15 L/min 100%\t14\t0\t7\t0\t\nIndomethacin 100 mg imi\t13\t0\t6\t0\t\nLidocaine (iv)\t15\t15\t9\t8\t\nDihydroergotamine, iv over 5 days\t5\t0\t5\t0\t\nCorticosteroids – oral high dose\t20\t2\t6\t0\t\nGreater occipital nerve injection*\t12\t6\t4\t3\t\n Placebo controlled (10); over five days (11); with lidocaine and depomethylprednisolone ipsilateral to pain (12).\n\n\n\nLong-term prevention\nLamotrigine had a good effect in reducing the frequency or severity of the attacks in 62% of SUNCT and 31% of SUNA patients at doses of about 100 to 600 mg/day (Table 4).\nTable 4. Effectiveness of preventive.\n\n\tSUNCT\tSUNA\t\n\tTotal n\tEffectiveness n (%)\tTotal n\tEffectiveness n (%)\t\nLamotrigine\t29\t18 (62)\t16\t5 (31)\t\nTopiramate\t27\t13 (48)\t9\t1\t\nGabapentin\t29\t11 (38)\t18\t7 (39)\t\nCarbamazepine\t43\t16 (36)\t20\t4 (20)\t\nOxcarbazepine\t7\t1 (14)\t6\t0\t\nPregabalin\t7\t1 (14)\t16\t1\t\nVerapamil\t16\t2 (13)\t5\t0\t\nValproate\t13\t0\t4\t0\t\nBeta-blocker\t7\t0\t4\t0\t\nTricylic\t36\t3\t17\t3\t\n* Effectiveness: Reported to be useful in reducing frequency or severity of attacks by the patient.\n\n\n\nTopiramate had a good effect in 48% of SUNCT patients at doses of 50–500 mg/day. However, no SUNA case had a good or better response to topiramate.\n\nGabapentin was used in 18 SUNA patients at a dose of 1800–2400 mg/day; seven cases had good to moderate improvement (39%). In addition, gabapentin was also beneficial in 11 of 29 SUNCT cases.\n\nCarbamazepine also had a good to moderate effect in 36% of SUNCT patients at doses of 100–1200 mg/day. Carbamazepine was effective in 20% of SUNA cases.\n\nBrain imaging\nThere were 55 SUNCT (85%) and 33 SUNA (89%) patients with brain imaging, which were almost all magnetic resonance (MR). No abnormal findings on brain images were identified in 42 SUNCT (76%) and 31 SUNA (94%) cases, and apart from pituitary changes, none were SUNCT or SUNA related. There were four SUNCT patients with pituitary lesions. Two of them had macroadenomas, which resolved after treatment of the tumors. The other two had microadenomas, and one of them became pain-free for eight months after resection of the tumor. Vascular loops were found in the brain MR of five SUNCT (10%) and two SUNA (8%) patients. Among them, three SUNCT and two SUNA cases had vascular loops compressing the trigeminal nerves, one was ipsilateral to the pain, one had bilateral loops but unilateral pain only, and one had a vessel loop at one side but had bilateral pain. One SUNCT and two SUNA cases received microvascular decompression: One SUNA case was pain-free for only three months after the surgery, and the operation had no effect in improving the attacks of the SUNCT and the other SUNA cases.\n\nClinical trial\nAll five patients completed the trial (Figure; Table 5).\nTable 5. Clinical trial: Demographics and outcomes.\n\n\tPatient\t\n\t#1\t#2\t#3\t#4\t#5\t\nAge (years)\t72\t54\t60\t59\t51\t\nDuration of SUNCT attacks\t120–1800 s\t1 s stabs, 3600 s groups\t5 s\t1 s stabs, 300 s groups\t60 s\t\nDaily frequency of attacks pre-placebo\t7\t13\t140\t13\t10\t\n% change in frequency on placebo\t−100\t+52\t−15\t+22\t−10\t\nDaily frequency of attacks pre-topiramate\t2\t23\t138\t10\t6\t\n% effect – frequency topiramate\t+2063\t−19\t−100\t+27\t−18\t\nPrimary endpoint %gain Topiramate − placebo\t+2163\t−71\t−85\t+5\t−8\t\nDaily attack load (minutes) pre-placebo\t3\t5\tNA\t93\t11\t\n% change in attack load on placebo\t−100\t+178\tNA\t+192\t+45\t\nDaily attack load pre-topiramate\t57\t33\tNA\t197\t3\t\n% change in attack load on topiramate\t+920\t−71\tNA\t−17\t+160\t\nSecondary endpoint %effect Topiramate − placebo\t+1020\t−249\tNA\t−209\t+115\t\n\n\nPatient #1 had a good effect whilst on placebo, with complete cessation of his attacks. On topiramate, there was an increase of both attack frequency and attack load. He was classified as a topiramate failure; indeed, it appeared to worsen his problem.\n\nPatient #2 had a reduced frequency of attacks by 71% compared to placebo; he was classified a success. He also had a substantial reduction in attack load compared to the placebo period.\n\nPatient #3 had complete cessation of his attacks on topiramate, and a milder 15% reduction on placebo. He was classified as a success. He did not provide attack length data.\n\nPatient #4 had a 5% difference between placebo and topiramate arms in terms of frequency, and was classified as a topiramate failure. On the secondary measure, there was a greater than 200% reduction in attack load.\n\nPatient #5 had an 8% reduction in frequency on the placebo arm when compared to the topiramate arm. He was classified as a failure. On the secondary endpoint of attack load, he worsened by 115 %.\n\nOverall, on the primary endpoint, two patients had improvement, two patients had no change and one worsened.\n\nClinical trial – adverse events\nOne patient (#4) reported peripheral paraesthesiae on topiramate. One patient (#5) reported peripheral paraesthesiae on both treatments and also had dull headache attacks whilst on both treatments, which were not related to his SUNCT or migraine, and not recorded as such. He had one episode of diplopia lasting an hour on placebo, and reported indigestion whilst on topiramate.\n\nDiscussion\nIn this substantial cohort of patients with SUNCT and SUNA, we have been able to explore similarities and differences between the conditions, and explore treatment outcomes. The data suggest sufficient differences in core phenotypes to maintain the current classification. Cranial autonomic symptoms are distributed differently, even allowing for the definitional constraint in SUNCT. Attack pain features show SUNCT being more likely to have single stabs and SUNA more likely to have groups of stabs. In terms of preventive treatments, SUNA is generally less responsive, being most likely to be improved by gabapentin or lamotrigine, while SUNCT is more likely to be improved by lamotrigine and topiramate. Our small randomised placebo-controlled trial of topiramate in SUNCT supports the clinical data and, since SUNA seems much less likely to respond, provides another hint that the conditions have some difference. While the data certainly do not settle the issue of whether SUNCT is on a continuum with SUNA, they do suggest it is reasonable from both a clinical and research perspective to maintain the distinction until more data can be collected.\n\nThe outcome of treatments is instructive as to the biology of SUNCT/SUNA. The conditions respond very well, almost invariably, to intravenous lidocaine, if it is tolerated. There is no effect of oxygen, which although open label, was administered in a dose effective for cluster headache (13). Similarly, while cluster headache is very likely to respond to sumatriptan by injection (14), one only in each group responded here. Again corticosteroids, which can certainly be helpful in the short term in many patients with cluster headache (15), were not useful in most patients with SUNCT or SUNA. In contrast to paroxysmal hemicrania, where an indomethacin effect is diagnostic (16), no such effect is seen in SUNCT or SUNA. One outcome shared with all the TACs, indeed with migraine (12), is a useful effect of greater occipital nerve injection (GONi) with local anesthetic and corticosteroid. The distinction between that effect and the lack of effect of high dose corticosteroids alone suggests the GONi has more than an effect of corticosteroid dose.\n\nAn interesting issue that has arisen in the literature is the relationship between SUNCT/SUNA and trigeminal neuralgia (17). The distribution of pain seems clearly different: SUNCT/SUNA much more often involves the ophthalmic division of the trigeminal nerve, in more than two-thirds of cases (3), while trigeminal neuralgia only involves this division in 4% of cases (18). Cranial autonomic symptoms are the rule in SUNCT/SUNA, with more than 99% of SUNCT/SUNA we have reviewed having one or more, and all SUNCT patients having at least two, while, depending on what cases are accepted, the rate is considerably less in trigeminal neuralgia (18). Less than 5% of SUNCT/SUNA patients presented in our cohort had a refractory period to re-triggering, while almost all trigeminal neuralgia patients have a refractory period. The pain of trigeminal neuralgia is classically described as short electric-shock like pains, whereas up to one-third of our SUNCT/SUNA cohort had the saw-tooth pattern, which is invariably longer than a less than one second stab. Interestingly, both conditions have background pain in about half of patients (19); this would fit well to a common basis for that pain, i.e. associated migrainous biology rather than a common mechanism for trigeminal neuralgia and SUNCT/SUNA. The treatment recommendations for SUNCT/SUNA, and our data, differ considerably to those for trigeminal neuralgia. Carbamazepine and oxcarbazepine are preferred treatments for trigeminal neuralgia, with lamotrigine and gabapentin having insufficient evidence for recommendation (20). In contrast, lamotrigine emerges as the most useful treatment for SUNCT, next topiramate, which now has randomised placebo-controlled trial data, while gabapentin emerges as the most useful treatment of SUNA. Remarkably, topiramate is not listed in the top tier treatments of trigeminal neuralgia (20). The finding of an abnormal vascular loop is common in classical trigeminal neuralgia (21,22). We report these loops in 10% of cases. An important limitation of our data is that they were not collected with this question in mind, scanners used were not uniform, and we only had clinically noted reporting. We remain impressed by the indifferent effects of surgery beyond what would be expected after manipulation in this region and anaesthetic. Lastly, functional imaging studies have established changes in the posterior hypothalamic region in SUNCT (23,24), whereas no such changes have been reported in trigeminal neuralgia. Taken together, the evidence to differentiate between SUNCT/SUNA and trigeminal neuralgia is strong. One possible issue is under-diagnosis of SUNA in what is, in our experience, often called atypical trigeminal neuralgia (25). This issue certainly deserves further attention.\n\nA family history in SUNCT is reported in only one cohort (26). Regarding other trigeminal autonomic cephalalgias, there are reports of familial cluster headache (27–30), familial paroxysmal hemicrania (31) and familial hemicrania continua (32), as well as twins with cluster headache (33–35). Whether the rarity of familial cases reflects a non-genetic basis to the condition or simply the rarity of the problem remains an important unresolved issue.\n\nThe majority of SUNCT and SUNA cases were idiopathic in previous reports. SUNCT syndrome was delineated in patients with microprolactinomas (36) and macroprolactinomas (37,38), with attacks appearing on the same side as the tumors. A further five SUNCT cases were reported with pituitary adenomas, all with attacks ipsilateral to the side of the tumor (39); among the five patients, two of them did not improve after surgical removal of the tumor, one case was pain-free after surgery, one case was pain-free for 1 year then the pain relapsed with tumor recurrence, and one patient had a major reduction in headaches. In our cohort, there were four SUNCT and no SUNA cases with pituitary lesions (two macroadenomas and two microadenomas). When one considers TAC presentations and pituitary tumours (40) in the context of population-based pituitary tumour presentations (41), and the subsequent concordant course of the disorders, there does seem to be a relationship between TACs and acromegaly/prolactinoma not accounted for by chance.\n\nIn the literature, SUNCT patients were reported to be responsive to topiramate at doses of between 75 and 300 mg/day (42,43). The data from our reported cohort suggest about half of SUNCT patients find topiramate useful whereas few patients with SUNA find it useful. The open label SUNCT data are now supported by the placebo-controlled data that we report. SUNCT is rare, and doing large controlled trials in SUNCT prevention is challenging. The N-of-1 crossover approach is appropriate for this patient group. The finding that two of the five patients clearly benefitted on the primary endpoint and one on an important secondary endpoint of reducing time spent in pain, supports the open label experience and offers a clear mandate to continue to offer topiramate to SUNCT patients.\n\nThe issue of inter-paroxysmal pain in SUNCT/SUNA, and more broadly in trigeminal autonomic cephalalgias, is an important pathophysiological issue. It can confuse clinicians and certainly can be an important part of the disability of these conditions. In these patients, a little more than half had some identified migrainous biology, which we defined operationally as a personal or family history of migraine. While this seems considerable, if one reviews the cumulative lifetime migraine incidence for episodic migraine, it is 43% in females (44). If one adds in patients with probable migraine and chronic migraine, it could be easily seen that the gene pool for migraine in females is about 50%. It could be argued that the rates we see here are a combination of that gene pool and the diagnostic bias of seeing a physician. Interestingly, inter-paroxysmal background pain was strongly associated with migrainous biology, as was a worsening of pain with movement, and the presence of photophobia and phonophobia. It may be argued that SUNCT and SUNA facilitate the expression of migrainousness, which expresses itself in these other features. Interestingly, nausea did not seem to be associated, which may be because it is relatively less common or because the SUNCT/SUNA effect on migraine pathways is not universal.\n\nIn summary, a very substantial cohort of patients with SUNCT and SUNA is presented. Based on the phenotypic presentation of the pain features and the distribution of cranial autonomic symptoms, the two seem different. This is supported by differences in response to preventive therapies, particularly topiramate, for which we supply data from a randomised placebo-controlled trial. An analysis of the clinical, therapeutic, and pathophysiological findings in SUNCT/SUNA supports their differentiation from classical trigeminal neuralgia. The findings of associations between background migrainous biology and features such as inter-paroxysmal pain and aggravation of pain with movement, suggest SUNCT and SUNA can trigger the expression of an underlying migrainous process that colours the clinical presentation. SUNCT and SUNA seem well placed as trigeminal autonomic cephalalgias (TACs), and our clinical data offer both directions for new work and consolidate what is known about these rare and highly disabling conditions.\n\nClinical implications\n\nShort-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) are two rare headache syndromes classified broadly as trigeminal autonomic cephalalgias (TACs).\n\nRegarding cranial autonomic features, SUNA patients were most likely to have lacrimation and ptosis.\n\nPatients with SUNCT and SUNA who had had a personal or family history of migraine were more likely to have photophobia, phonophobia and persistent pain between attacks.\n\nA randomized placebo-controlled cross-over trial of topiramate in SUNCT using an N-of-1 design supports offering this therapy to patients with SUNCT.\n\n\n\n\nAuthor contributions\nHsing-Yu Weng: Saw patients and compiled the data into a summary sheet, and did the analyses.\n\nAnna S Cohen: Saw patients, compiled data from the patients into the results spreadsheet and conducted the randomised controlled trial.\n\nChristophe Schankin: Saw patients and helped compile the data summary sheet.\n\nPeter J Goadsby: Saw all the patients, checked the spreadsheet and the trial calculations and edited the final manuscript.\n\nDeclaration of conflicting interests\nThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Hsing-Yu Weng reports no conflicts of interest.\n\nAnna S Cohen reports no conflicts of interest.\n\nChristoph Schankin reports no conflicts of interest.\n\nPeter J Goadsby reports no conflicts of interest in this paper.\n\nFor completeness, in the three years prior to submission, Dr Goadsby also reports grants and personal fees from Allergan, Amgen, Eli-Lilly and Company, and eNeura Inc., and personal fees from Akita Biomedical, Alder Biopharmaceuticals, Autonomic Technologies Inc, Avanir Pharma, Cipla Ltd, Colucid Pharmaceuticals, Ltd, Dr Reddy’s Laboratories, Electrocore LLC, Novartis, Pfizer Inc, Scion, Teva Pharmaceuticals, Trigemina Inc., MedicoLegal work, Journal Watch, Up-to-Date and Oxford University Press outside the submitted work. 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Cephalalgia \n2008 ; 28 : 1170 –1178 .18644028\n\n", "fulltext_license": "CC BY", "issn_linking": "0333-1024", "issue": "38(9)", "journal": "Cephalalgia : an international journal of headache", "keywords": "SUNA; SUNCT; cranial autonomic symptoms; gabapentin; lamotrigine; lidocaine; topiramate; trigeminal autonomic cephalalgia; triggers", "medline_ta": "Cephalalgia", "mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000700:Analgesics; D000927:Anticonvulsants; D018592:Cross-Over Studies; D005260:Female; D005500:Follow-Up Studies; D000077206:Gabapentin; D006261:Headache; D006801:Humans; D000077213:Lamotrigine; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D050798:SUNCT Syndrome; D000077236:Topiramate; D016896:Treatment Outcome; D055815:Young Adult", "nlm_unique_id": "8200710", "other_id": null, "pages": "1554-1563", "pmc": null, "pmid": "29096522", "pubdate": "2018-08", "publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't", "references": "26453658;25501956;10027765;15888539;20558416;16905753;1647496;12058109;18644028;24842632;15356289;2743414;10554000;2027500;25767102;18252775;1097222;12453028;16527404;20956404;15910571;25231219;8666537;1603361;23771276;16987158;11971110;1620353;22049203;11342697;14984234;11701590;23197348;8496062;12603293;19996400;26423473;25541189;14617728", "title": "Phenotypic and treatment outcome data on SUNCT and SUNA, including a randomised placebo-controlled trial.", "title_normalized": "phenotypic and treatment outcome data on sunct and suna including a randomised placebo controlled trial" }	[ { "companynumb": "TW-MYLANLABS-2018M1069661", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TOPIRAMATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "076314", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "12.5 MG/AT NIGHT; THE DOSE WAS INCREMENTED EVERY FIVE DAYS", "drugenddate": null, "drugenddateformat": null, "drugindication": "SUNCT SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "12.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOPIRAMATE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TOPIRAMATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "076314", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG/MAXIMUM DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOPIRAMATE." } ], "patientagegroup": null, "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "SUNCT syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WENG H-Y, COHEN AS, SCHANKIN C, GOADSBY PJ. PHENOTYPIC AND TREATMENT OUTCOME DATA ON SUNCT AND SUNA, INCLUDING A RANDOMISED PLACEBO-CONTROLLED TRIAL. CEPHALALGIA 2018?38(9):1554-1563.", "literaturereference_normalized": "phenotypic and treatment outcome data on sunct and suna including a randomised placebo controlled trial", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "TW", "receiptdate": "20181001", "receivedate": "20181001", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15451308, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190204" } ]
{ "abstract": "Therapy-related myelodysplasticsyndrome(t-MDS)has been reported to occur after treatment with cytotoxic agents and radiation. Here, we report a case of t-MDS following oxaliplatin(L-OHP)exposure, which was successfully treated with azacitidine(AZA). A 71-year-old man was referred to our department because of pancytopenia. He had been diagnosed with rectal cancer(cT4aNXM0, stage II B-III C, RAS gene status wild-type)3 years ago and had received 8 courses of capecitabine(CAP)and L-OHP(XELOX regimen), followed by 48 courses of CAP and bevacizumab. Before referral, recurrence of rectal cancer was detected using CT after the last course of chemotherapy. A bone marrow examination revealed multilineage dysplasia and 9.0%myeloblasts. Cytogenetic analysis disclosed a chromosome 7 abnormality. The diagnosis of t- MDS was made and treatment with AZA was initiated. Subsequently, temporary but significant hematological improvements were observed, which enabled the patient to receive additional palliative radiation therapy against the locally relapsed rectal cancer. AZA might be useful in t-MDS because of its efficacy and low toxicity.", "affiliations": "Dept. of Oncology, Japan Labour Health and Welfare Organization Kanto Rosai Hospital.", "authors": "Matsui\|Tomoharu\|T\|;Sakamoto\|Nami\|N\|;Doi\|Ayako\|A\|;Fujii\|Tomoki\|T\|;Ohno\|Nobuhiro\|N\|;Sahara\|Naohi\|N\|;Irie\|Seiji\|S\|", "chemical_list": "D000964:Antimetabolites, Antineoplastic; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D001374:Azacitidine; D002955:Leucovorin", "country": "Japan", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0385-0684", "issue": "45(8)", "journal": "Gan to kagaku ryoho. Cancer & chemotherapy", "keywords": null, "medline_ta": "Gan To Kagaku Ryoho", "mesh_terms": "D000368:Aged; D000964:Antimetabolites, Antineoplastic; D001374:Azacitidine; D003131:Combined Modality Therapy; D017809:Fatal Outcome; D006801:Humans; D002955:Leucovorin; D008297:Male; D009190:Myelodysplastic Syndromes; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D012004:Rectal Neoplasms", "nlm_unique_id": "7810034", "other_id": null, "pages": "1201-1203", "pmc": null, "pmid": "30158420", "pubdate": "2018-08", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Azacitidine for Therapy-Related Myelodysplastic Syndrome Following Oxaliplatin (L-OHP)Therapy for Metastatic Rectal Cancer.", "title_normalized": "azacitidine for therapy related myelodysplastic syndrome following oxaliplatin l ohp therapy for metastatic rectal cancer" }	[ { "companynumb": "JP-MYLANLABS-2018M1088195", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091358", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "8 COURSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "COLORECTAL CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CAPECITABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "8 COURSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "COLORECTAL CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CAPECITABINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ACLARUBICIN" }, "drugadditional": "2", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "14 MILLIGRAM(S)/SQ. METER,DAYS 1-4; EVERY FOUR WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE MYELOID LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACLARUBICIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "AZACITIDINE" }, "drugadditional": "2", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "D75 MILLIGRAM(S)/SQ. METER ,DAY 1-7 OF EVERY 4 WEEKS CYCLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYELODYSPLASTIC SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZACITIDINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": "2", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM(S)/SQ. METER,DAYS 1-13", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE MYELOID LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." } ], "patientagegroup": null, "patientonsetage": "71", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bone marrow failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Acute myeloid leukaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "MATSUI T, SAKAMOTO N, DOI A, FUJII T, OHNO N, SAHARA N, ET AL.. AZACITIDINE FOR THERAPY-RELATED MYELODYSPLASTIC SYNDROME FOLLOWING OXALIPLATIN (L-OHP)THERAPY FOR METASTATIC RECTAL CANCER.. GAN-TO-KAGAKU-RYOHO. 2018?45(8):1201-1203.", "literaturereference_normalized": "azacitidine for therapy related myelodysplastic syndrome following oxaliplatin l ohp therapy for metastatic rectal cancer", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20181204", "receivedate": "20181128", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15666077, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "JP-SA-2018SA259049", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021759", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTASES TO ADRENALS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021759", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "COLORECTAL CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN." } ], "patientagegroup": "6", "patientonsetage": "71", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Acute myeloid leukaemia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Bone marrow failure", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "MATSUI T., SAKAMOTO N., DOI A., FUJII T., OHNO N., SAHARA N. ET AL.. AZACITIDINE FOR THERAPY?RELATED MYELODYSPLASTIC SYNDROME FOLLOWING OXALIPLATIN (L?OHP)THERAPY FOR METASTATIC RECTAL CANCER. GAN TO KAGAKU RYOHO. 2018?45(8):1201?1203", "literaturereference_normalized": "azacitidine for therapy related myelodysplastic syndrome following oxaliplatin l ohp therapy for metastatic rectal cancer", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20180919", "receivedate": "20180919", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15404269, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20181010" }, { "companynumb": "JP-TEVA-2018-JP-980154", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "CAPECITABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "8 COURSES; TREATMENT COMPLETED; XELOX REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "RECTAL CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CAPECITABINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "022160", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "8 COURSES; TREATMENT COMPLETED; XELOX REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "RECTAL CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN (L-OHP)" } ], "patientagegroup": null, "patientonsetage": "71", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Myeloid leukaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Bone marrow failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "MATSUI T, SAKAMOTO N, DOI A, FUJII T, OHNO N, SAHARA N, ET AL. AZACITIDINE FOR THERAPY-RELATED MYELODYSPLASTIC SYNDROME FOLLOWING OXALIPLATIN (L-OHP)THERAPY FOR METASTATIC RECTAL CANCER. GAN-TO-KAGAKU-RYOHO 2018?45(8):1201-1203.", "literaturereference_normalized": "azacitidine for therapy related myelodysplastic syndrome following oxaliplatin l ohp therapy for metastatic rectal cancer", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190115", "receivedate": "20181129", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15668852, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "PHHY2018JP157914", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CAPECITABINE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "RECTAL CANCER METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CAPECITABINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "78817", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "RECTAL CANCER METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "BEVACIZUMAB" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "RECTAL CANCER METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BEVACIZUMAB." } ], "patientagegroup": null, "patientonsetage": "71", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Metastases to adrenals", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dysplasia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Metastases to peritoneum", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rectal cancer metastatic", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Malignant neoplasm progression", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pancytopenia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MATSUI T, SAKAMOTO N, DOI A,FUJII T, OHNO N, SAHARA N ET AL.. AZACITIDINE FOR THERAPY-RELATED MYELODYSPLASTIC SYNDROME FOLLOWING OXALIPLATIN (L-OHP) THERAPY FOR METASTATIC RECTAL CANCER. JAPANESE JOURNAL OF CANCER AND CHEMOTHERAPY. 201/?45(8):1201-3", "literaturereference_normalized": "azacitidine for therapy related myelodysplastic syndrome following oxaliplatin l ohp therapy for metastatic rectal cancer", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20181121", "receivedate": "20181121", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15645755, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2018RR-192151", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "202922", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "COLORECTAL CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN." } ], "patientagegroup": null, "patientonsetage": "71", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MATSUI T, SAKAMOTO N, DOI A, FUJII T, OHNO N, SAHARA N, ET AL. AZACITIDINE FOR THERAPY-RELATED MYELODYSPLASTIC SYNDROME FOLLOWING OXALIPLATIN (L-OHP) THERAPY FOR METASTATIC RECTAL CANCER. JPN J CANCER CHEMOTHER. 2018?AUG? 45(8):1201-1203", "literaturereference_normalized": "azacitidine for therapy related myelodysplastic syndrome following oxaliplatin l ohp therapy for metastatic rectal cancer", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20181128", "receivedate": "20181128", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15663585, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "JP-PFIZER INC-2018356459", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "CAPECITABINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK (48 COURSES)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CAPECITABINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BEVACIZUMAB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK (48 COURSES)", "drugenddate": null, "drugenddateformat": null, "drugindication": "RECTAL CANCER STAGE II", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BEVACIZUMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "078813", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK (8 COURSES)", "drugenddate": null, "drugenddateformat": null, "drugindication": "RECTAL CANCER STAGE II", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CAPECITABINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK (8 COURSES)", "drugenddate": null, "drugenddateformat": null, "drugindication": "RECTAL CANCER STAGE II", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CAPECITABINE." } ], "patientagegroup": null, "patientonsetage": "71", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Second primary malignancy", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "MATSUI, T.. AZACITIDINE FOR THERAPY?RELATED MYELODYSPLASTIC SYNDROME FOLLOWING OXALIPLATIN (L?OHP) THERAPY FOR METASTATIC RECTAL CANCER. GAN TO KAGAKU RYOHO [JAPANESE JOURNAL OF CANCER + CHEMOTHERAPY]. 2018?45 (8):1201?1203", "literaturereference_normalized": "azacitidine for therapy related myelodysplastic syndrome following oxaliplatin l ohp therapy for metastatic rectal cancer", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20180920", "receivedate": "20180906", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15357681, "safetyreportversion": 4, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" } ]
{ "abstract": "BACKGROUND\nStandard-of-care antiretroviral therapy (ART) uses a combination of drugs deemed essential to minimise treatment failure and drug resistance. Protease inhibitors are potent, with a high genetic barrier to resistance, and have potential use as monotherapy after viral load suppression is achieved with combination treatment. We aimed to assess clinical risks and benefits of protease inhibitor monotherapy in long-term clinical use: in particular, the effect on drug resistance and future treatment options.\n\n\nMETHODS\nIn this pragmatic, parallel-group, randomised, controlled, open-label, non-inferiority trial, we enrolled adults (≥18 years of age) positive for HIV attending 43 public sector treatment centres in the UK who had suppressed viral load (<50 copies per mL) for at least 24 weeks on combination ART with no change in the previous 12 weeks and a CD4 count of more than 100 cells per μL. Participants were randomly allocated (1:1) to maintain ongoing triple therapy (OT) or to switch to a strategy of physician-selected ritonavir-boosted protease inhibitor monotherapy (PI-mono); we recommended ritonavir (100 mg)-boosted darunavir (800 mg) once daily or ritonavir (100 mg)-boosted lopinavir (400 mg) twice daily, with prompt return to combination treatment if viral load rebounded. All treatments were oral. Randomisation was with permuted blocks of varying size and stratified by centre and baseline ART; we used a computer-generated, sequentially numbered randomisation list. The primary outcome was loss of future drug options, defined as new intermediate-level or high-level resistance to one or more drugs to which the patient's virus was deemed sensitive at trial entry (assessed at 3 years; non-inferiority margin of 10%). We estimated probability of rebound and resistance with Kaplan-Meier analysis. Analyses were by intention to treat. This trial is registered with the International Standard Randomised Controlled Trial Number registry, number ISRCTN04857074.\n\n\nRESULTS\nBetween Nov 4, 2008, and July 28, 2010, we randomly allocated 587 participants to OT (291) or PI-mono (296). At 3 years, one or more future drug options had been lost in two participants (Kaplan-Meier estimate 0·7%) in the OT group and six (2·1%) in the PI-mono group: difference 1·4% (-0·4 to 3·4); non-inferiority shown. 49 (16·8%) participants in the OT group and 65 (22·0%) in the PI-mono group had grade 3 or 4 clinical adverse events (difference 5·1% [95% CI -1·3 to 11·5]; p=0·12); 45 (six treatment related) and 56 (three treatment related) had serious adverse events.\n\n\nCONCLUSIONS\nProtease inhibitor monotherapy, with regular viral load monitoring and prompt reintroduction of combination treatment for rebound, preserved future treatment options and did not change overall clinical outcomes or frequency of toxic effects. Protease inhibitor monotherapy is an acceptable alternative for long-term clinical management of HIV infection.\n\n\nBACKGROUND\nNational Institute for Health Research.", "affiliations": "Medical Research Council Clinical Trials Unit at University College London, London, UK; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Electronic address: [email protected].;Medical Research Council Clinical Trials Unit at University College London, London, UK.;Medical Research Council Clinical Trials Unit at University College London, London, UK.;Brighton and Sussex University Hospitals NHS Trust, Brighton, UK.;Research Department of Infection and Population Health, University College London, London, UK.;Royal Free Hospital, London, UK.;Barts and the Royal London Hospital NHS Trust, London, UK.;Royal Berkshire Hospital, Reading, UK.;Manchester Royal Infirmary, Manchester, UK.;St Mary's Hospital, London, UK.;Southmead Hospital, Bristol, UK.;Guy's and St Thomas' Hospital, London, UK.;Medical Research Council Clinical Trials Unit at University College London, London, UK.;Medical Research Council Clinical Trials Unit at University College London, London, UK.", "authors": "Paton\|Nicholas I\|NI\|;Stöhr\|Wolfgang\|W\|;Arenas-Pinto\|Alejandro\|A\|;Fisher\|Martin\|M\|;Williams\|Ian\|I\|;Johnson\|Margaret\|M\|;Orkin\|Chloe\|C\|;Chen\|Fabian\|F\|;Lee\|Vincent\|V\|;Winston\|Alan\|A\|;Gompels\|Mark\|M\|;Fox\|Julie\|J\|;Scott\|Karen\|K\|;Dunn\|David T\|DT\|;\|\|\|", "chemical_list": "D017320:HIV Protease Inhibitors", "country": "Netherlands", "delete": false, "doi": null, "fulltext": "\n==== Front\nLancet HIVLancet HIVThe Lancet. HIV2352-3018Elsevier B.V S2352-3018(15)00176-910.1016/S2352-3018(15)00176-9ArticlesProtease inhibitor monotherapy for long-term management of HIV infection: a randomised, controlled, open-label, non-inferiority trial Paton Nicholas I [email protected]Stöhr Wolfgang PhDaArenas-Pinto Alejandro PhDaFisher Martin ProfMBBScWilliams Ian FRCPdJohnson Margaret ProfFRCPeOrkin Chloe MBBChfChen Fabian FRCPgLee Vincent MBChBhWinston Alan MDiGompels Mark MBBSjFox Julie MDkScott Karen BAaDunn David T ProfPhDafor the Protease Inhibitor Monotherapy Versus Ongoing Triple Therapy (PIVOT) Trial Team†a Medical Research Council Clinical Trials Unit at University College London, London, UKb Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singaporec Brighton and Sussex University Hospitals NHS Trust, Brighton, UKd Research Department of Infection and Population Health, University College London, London, UKe Royal Free Hospital, London, UKf Barts and the Royal London Hospital NHS Trust, London, UKg Royal Berkshire Hospital, Reading, UKh Manchester Royal Infirmary, Manchester, UKi St Mary's Hospital, London, UKj Southmead Hospital, Bristol, UKk Guy's and St Thomas' Hospital, London, UK Correspondence to: Prof Nicholas I Paton, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228Correspondence to: Prof Nicholas I PatonDepartment of MedicineYong Loo Lin School of MedicineNational University of SingaporeSingapore119228 [email protected]† Members listed at end of paper\n\n14 9 2015 10 2015 14 9 2015 2 10 e417 e426 © 2015 Paton et al. Open Access article published under the terms of CC BY2015This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Summary\nBackground\nStandard-of-care antiretroviral therapy (ART) uses a combination of drugs deemed essential to minimise treatment failure and drug resistance. Protease inhibitors are potent, with a high genetic barrier to resistance, and have potential use as monotherapy after viral load suppression is achieved with combination treatment. We aimed to assess clinical risks and benefits of protease inhibitor monotherapy in long-term clinical use: in particular, the effect on drug resistance and future treatment options.\n\nMethods\nIn this pragmatic, parallel-group, randomised, controlled, open-label, non-inferiority trial, we enrolled adults (≥18 years of age) positive for HIV attending 43 public sector treatment centres in the UK who had suppressed viral load (<50 copies per mL) for at least 24 weeks on combination ART with no change in the previous 12 weeks and a CD4 count of more than 100 cells per μL. Participants were randomly allocated (1:1) to maintain ongoing triple therapy (OT) or to switch to a strategy of physician-selected ritonavir-boosted protease inhibitor monotherapy (PI-mono); we recommended ritonavir (100 mg)-boosted darunavir (800 mg) once daily or ritonavir (100 mg)-boosted lopinavir (400 mg) twice daily, with prompt return to combination treatment if viral load rebounded. All treatments were oral. Randomisation was with permuted blocks of varying size and stratified by centre and baseline ART; we used a computer-generated, sequentially numbered randomisation list. The primary outcome was loss of future drug options, defined as new intermediate-level or high-level resistance to one or more drugs to which the patient's virus was deemed sensitive at trial entry (assessed at 3 years; non-inferiority margin of 10%). We estimated probability of rebound and resistance with Kaplan-Meier analysis. Analyses were by intention to treat. This trial is registered with the International Standard Randomised Controlled Trial Number registry, number ISRCTN04857074.\n\nFindings\nBetween Nov 4, 2008, and July 28, 2010, we randomly allocated 587 participants to OT (291) or PI-mono (296). At 3 years, one or more future drug options had been lost in two participants (Kaplan-Meier estimate 0·7%) in the OT group and six (2·1%) in the PI-mono group: difference 1·4% (−0·4 to 3·4); non-inferiority shown. 49 (16·8%) participants in the OT group and 65 (22·0%) in the PI-mono group had grade 3 or 4 clinical adverse events (difference 5·1% [95% CI −1·3 to 11·5]; p=0·12); 45 (six treatment related) and 56 (three treatment related) had serious adverse events.\n\nInterpretation\nProtease inhibitor monotherapy, with regular viral load monitoring and prompt reintroduction of combination treatment for rebound, preserved future treatment options and did not change overall clinical outcomes or frequency of toxic effects. Protease inhibitor monotherapy is an acceptable alternative for long-term clinical management of HIV infection.\n\nFunding\nNational Institute for Health Research.\n==== Body\nIntroduction\nCurrent HIV treatment guidelines recommend a combination of two drug classes for initiation and maintenance of antiretroviral therapy (ART).1, 2 The principle of combining drugs with different mechanisms of action to increase potency and reduce selection of drug-resistant mutants is common to the treatment of many infectious diseases. However, in HIV, the need for combination treatment might decrease once viral load has been suppressed.\n\nProtease inhibitors are potent, with a high genetic barrier to resistance, and are the only drugs that act at many steps of the HIV lifecycle, thus having potential for use alone as monotherapy.3 Protease inhibitor monotherapy could be an attractive therapeutic option because of its potential to reduce renal, CNS, and other toxic effects associated with drugs widely used in standard ART combinations. The high genetic barrier to resistance might reduce the risk of resistance during periods of suboptimum treatment adherence. Furthermore, use of a single drug might decrease treatment costs. Although inadequate for initial treatment,4 findings from previous randomised trials of maintenance protease inhibitor monotherapy5, 6, 7, 8, 9 have shown high levels of short-term viral load suppression. However, these trials have not been of sufficient size and duration to address definitively the effects on long-term drug resistance, clinical disease progression, and drug toxic effects in clinical practice.5, 6, 7, 8, 9 Furthermore, investigators have mostly restricted the standard-of-care treatment to a specific protease inhibitor regimen and mandated use of a particular protease inhibitor for monotherapy, neither of which takes account of the diversity of regimen selection in routine clinical practice.\n\nResearch in context\nEvidence before this study\n\nWe searched PubMed for reports published between Jan 1, 1998, and Jan 1, 2008, with no language restrictions, using terms including “protease inhibitors”, “monotherapy”, and the individual drug names, and reviewed relevant HIV conference abstracts to identify randomised controlled trials that compared protease inhibitor monotherapy with triple antiretroviral therapy (ART) in patients who had previously achieved viral load suppression. We identified three trials, all investigating lopinavir monotherapy, and, overall, these trials supported the hypothesis of virological non-inferiority of monotherapy to triple therapy. Since then, authors of a meta-analysis of ten trials noted an overall risk ratio of 0·94 for viral load suppression at 48 weeks with protease inhibitor monotherapy compared with triple ART, with, at most, a 13% increase in the absolute risk of virological failure with protease inhibitor monotherapy.\n\nAdded value of this study\n\nTo our knowledge, this trial is the largest and longest-duration protease inhibitor monotherapy trial done so far, with more than three times the randomly allocated person follow-up time of previous trials, and thus it provides more precise estimates of important but uncommon efficacy and safety outcomes than did previous trials. By contrast with previous studies that restricted the choice of drugs in both the monotherapy (single specified protease inhibitor) and combination ART (usually to a protease-inhibitor-containing combination, and with the same protease inhibitor as specified for monotherapy) groups, this trial used a pragmatic design representative of routine clinical care, with flexibility of drug selection in both treatment groups. Also, whereas previous trials compared predefined regimens with short-term viral load endpoints, this trial compared treatment strategies with a primary efficacy endpoint (preservation of drug options) relevant to long-term clinical management. In this trial we noted an increase of about 32% in absolute risk of virological failure with protease inhibitor monotherapy (much greater than that previously reported), but all patients with rebound resuppressed spontaneously or with reintroduction of combination ART. Findings from this trial showed that the protease inhibitor monotherapy strategy was non-inferior to triple ART in preservation of future treatment options and did not change overall clinical outcomes or frequency of toxic effects.\n\nImplications of all the available evidence\n\nProtease inhibitor monotherapy does not increase the risk of drug resistance and is an acceptable alternative for long-term clinical management of HIV infection. Clinical benefits, if any, seem slight, and some patients might need to switch back to combination ART. Nevertheless, this approach could appeal to patients who are stable on treatment but who wish to minimise their exposure to specific drugs or more than one drug class.\n\n\n\nWe did a pragmatic randomised controlled trial comparing a protease inhibitor monotherapy treatment strategy with clinician-selected standard combination treatment, aiming to assess effects on drug resistance, future treatment options, and other, long-term, clinically relevant outcomes.\n\nMethods\nStudy design and patients\nIn this pragmatic, parallel-group, randomised, controlled, open-label, non-inferiority trial, we enrolled participants attending 43 public sector hospital-based HIV treatment centres in the UK. Eligible participants were adults aged 18 years or older who were HIV positive, had been on ART consisting of two nucleoside reverse transcriptase inhibitors (NRTIs) and one non-NRTI (NNRTI) or protease inhibitor for at least 24 weeks with no change in the previous 12 weeks, had a viral load of less than 50 copies per mL at screening and for at least 24 weeks before screening (one blip to less than 200 copies per mL allowed during this period if followed by at least two results less than 50 copies per mL), had a CD4 count of more than 100 cells per μL at screening, and who were willing to continue current ART or change according to the randomised allocation. Exclusion criteria were known major protease inhibitor resistance mutations at previous resistance testing (if done; not mandated), previous ART change for unsatisfactory virological response (ie, slow initial virological suppression, incomplete suppression, or rebound; change for convenience or toxic effect prevention or management allowed), protease inhibitor allergy, concomitant drugs with protease inhibitor interactions, present or anticipated need for radiotherapy or cytotoxic chemotherapy, treatment for acute opportunistic infection within the previous 3 months, present or planned pregnancy, active substance misuse or psychiatric illness, history of HIV encephalopathy with a present deficit of more than 1 in any domain of the Neuropsychiatric AIDS Rating Scale,10, 11 history of cardiovascular disease or a 10 year absolute coronary heart disease risk of more than 30% or more than 20% with diabetes or a family history of premature ischaemic heart disease or stroke,12 insulin-dependent diabetes mellitus, active or planned hepatitis C virus treatment, hepatitis B surface antigen positive at screening or since HIV diagnosis (unless hepatitis B DNA of less than 1000 copies per mL taken while off drugs active against hepatitis B), or a fasting plasma glucose of more than 7·0 mmol/L at screening.\n\nThe protocol was approved by the Cambridgeshire 4 Research Ethics Committee and Medicines and Healthcare Products Regulatory Agency. All participants provided written informed consent.\n\nRandomisation and masking\nParticipants were randomly assigned (1:1) to maintain ongoing triple therapy (OT) or switch to a protease inhibitor monotherapy strategy (PI-mono). Randomisation was stratified by centre (nine groups, based on the eight largest sites and one group for the remaining sites) and baseline ART regimen (protease inhibitor or NNRTI). The computer-generated, sequentially numbered randomisation list (random permuted blocks of varying size) was preprepared by WS. Sites faxed screening forms to the trial coordinating centre, where trial staff confirmed eligibility and did the randomisation (they could access the next number on the list, but not the whole list). Treatment allocation was open label.\n\nProcedures\nIn the OT group, we managed patients using triple combination treatment. In the PI-mono group, we switched patients to a single ritonavir-boosted protease inhibitor selected by the physician: we recommended darunavir (800 mg) boosted with ritonavir (100 mg) once daily or lopinavir (400 mg) boosted with ritonavir (100 mg) twice daily. Drugs were taken orally. Patients switching from NNRTI-based regimens continued NRTIs for the first 2 weeks. Protease inhibitor substitution was allowed in the event of toxic effects or for convenience. The strategy required prompt reintroduction of NRTIs (switch of protease inhibitor to NNRTI optional) for protocol-defined confirmed viral load rebound and management with combination treatment for the remainder of the trial (subsequent switches for toxic effects, convenience, and viral load failure allowed, as in OT group).\n\nStudy visits at baseline, weeks 4 and 8 (PI-mono group only), week 12, and every 12 weeks thereafter included assessment of clinical status, drug adherence (standardised questions), viral load, CD4 cell count, and safety blood tests (measured at site laboratory). Visits at baseline, week 12, week 48, and every 48 weeks thereafter included additional assessments of cardiovascular disease risk (Framingham equation),13 neurocognitive function (standard five-test battery),14, 15 symptomatic peripheral neuropathy (Brief Peripheral Neuropathy Screen),16 and quality of life (self-completed Medical Outcomes Study HIV Health Survey questionnaire17, 18). We classified clinical and laboratory events with protocol-defined diagnostic criteria (on the basis of Centers for Disease Control and Prevention criteria for AIDS,19 INSIGHT criteria for serious non-AIDS events,20 and Division of AIDS criteria for adverse events21), and an independent physician at the coordinating centre reviewed them. We calculated estimated glomerular filtration rate (eGFR) with the Chronic Kidney Disease Epidemiology Collaboration equation.22\n\nIf viral load was detectable at 50 copies per mL or higher at any visit, we repeated the test (on the same sample if available or a fresh sample draw if not). If viral load was less than 50 copies per mL on the repeat test, we continued routine follow-up, but if higher, we did adherence counselling and patients returned for a confirmatory test at least 4 weeks from the date that the first sample was taken. If viral load was less than 50 copies per mL with the confirmatory test, we resumed routine follow-up, but if higher (ie, on the third consecutive test), this result met the protocol definition of confirmed rebound and so the patient was required to change treatment, and we did a repeat test 4 weeks later.\n\nWe did genotypic resistance testing on all viral load rebound samples that were confirmed or preceded treatment switch. We did genotypic testing at site laboratories, repeated at the central laboratory if local sequencing was unsuccessful. We used the Stanford algorithm for drug susceptibility prediction. If we identified resistance mutations, we compared them with any genotypic testing reports from before the trial.\n\nOutcomes\nThe primary outcome was loss of future drug options, defined as new intermediate-level or high-level resistance to one or more drugs in contemporary use to which we deemed patient's virus to be sensitive at trial entry (assessed at 3 years). We defined contemporary use on the basis of inclusion in present UK treatment guidelines,1 with saquinavir added because this drug was taken by some participants during the trial.\n\nSecondary outcomes were occurrence of serious drug-related or disease-related complications, including death or serious AIDS-defining (excluding oesophageal candidiasis or chronic mucocutaneous herpes simplex virus infection) or non-AIDS-defining illness; total number of grade 3 and 4 adverse events; confirmed virological rebound; CD4 cell count change from baseline; neurocognitive function change from baseline; cardiovascular risk change from baseline; and health-related quality of life change from baseline (mental and physical health summary scores). Additional specified safety outcomes were facial lipoatrophy, abdominal fat accumulation, peripheral neuropathy, and estimated glomerular filtration rate.\n\nStatistical analysis\nWe defined non-inferiority of the PI-mono group by the upper limit of the two-sided 95% CI for the difference in proportions of patients who maintain all future drug options during 3 years (OT group minus the PI-mono group) being less than 10%. We chose the 10% non-inferiority margin on the basis of US Food and Drug Administration guidance 23, 24 and with reference to other protease inhibitor monotherapy trials.9 Using a survival analysis approach (on a hazard ratio scale) to allow inclusion of all follow-up data for estimation of the primary endpoint, and assuming that 97% of patients in the OT group would meet the primary endpoint,7, 25, 26 with an 85% power and a 10% loss to follow-up, we estimated that about 280 patients per group would be needed to show non-inferiority. This approach gives a conservative estimate of the sample size, which has the additional advantage of allowing precise estimates of important secondary safety outcomes. On the basis of a conventional analysis of proportions, the power of the study to show non-inferiority for the primary endpoint with use of the same parameters would be more than 99%.\n\nAll comparisons were as randomised (intention to treat). We deemed a per-protocol analysis not relevant for this pragmatic trial in view of the fact that a switch back to combination treatment in the PI-mono group was an intrinsic element of the clinical strategy being assessed. Statistical tests are two-sided and test the hypotheses of no difference between randomised groups. We estimated the absolute difference between groups in reduction of future drug options using Kaplan-Meier analysis, with the 95% CI (two-sided) derived with bootstrap methods. In this analysis and other time-to-event analyses, we censored participants at the time of death, loss to follow-up, or withdrawal. The primary analysis included all new resistance mutations noted that conferred intermediate-level or high-level drug resistance. We predefined a sensitivity analysis in which we restricted loss of drug options to classes to which the patient was exposed during the trial, thus excluding mutations that were probably archived (ie, acquired at transmission or during treatment before enrolment, but unknown at trial entry).\n\nFor secondary endpoints, we compared binary outcome variables between groups using χ2 or Fisher's exact tests, with conventional or Agresti-Caffo 95% CIs for the risk difference and logistic regression models for adjusted analyses. For continuous variables, we compared groups by use of mean change from baseline and t tests or linear regression; we estimated change from baseline to the last available visit at which a measurement was done at or after week 144 (we did not include patients without such data). We estimated the proportion of patients who had viral load rebound with Kaplan-Meier analysis and compared groups by use of a log-rank test. We compared incidence rates with Poisson regression. We compared adherence during the entire follow-up period between groups with generalised estimating equations (independent correlation structure; binomial distribution).\n\nWe used Stata version 12.1 for all analyses. A data monitoring committee reviewed interim data annually. This trial is registered with the International Standard Randomised Controlled Trial Number registry, number ISRCTN04857074.\n\nRole of the funding source\nThe funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.\n\nResults\nBetween Nov 4, 2008, and July 28, 2010, we randomly allocated 587 participants to OT (291) or PI-mono (296; figure 1). One (<1%) died and 11 (4%) withdrew or were lost to follow-up in the OT group, whereas six (2%) died and five (2%) withdrew or were lost to follow-up in the PI-mono group. Study visits ended on Nov 1, 2013. The median duration of trial follow-up was 44 months (maximum 59 months). Participant characteristics were similar between groups (table 1).\n\nIn the PI-mono group, initial drug choices were darunavir in 233 (80%) of patients, lopinavir in 40 (14%), atazanavir in 16 (6%), and saquinavir in 1 (<1%); 58% were still taking monotherapy at trial end. Combination treatment was reintroduced for the following reasons: 69 (23%) for protocol-defined confirmed viral rebound (appendix p 8), 11 (4%) for viral rebound not meeting protocol criteria, 16 (5%) for toxic effects, and 22 (7%) for other or unknown reasons; 6 (2%) never started monotherapy. Overall, 72% of follow-up time was spent on monotherapy. Self-reported adherence to study drugs was high: participants reported not missing any ART doses in the past 2 weeks at 4301 (93%) of 4635 visits in the OT group and 4376 (92%) of 4748 visits in the PI-mono group (p=0·52).\n\nThe number of patients with loss of future drug options at 3 years (the primary outcome) was two patients (Kaplan-Meier estimate 0·7%) in the OT group and six (2·1%) in the PI-mono group (difference 1·4% [95% CI −0·4 to 3·4]), therefore meeting the non-inferiority criterion. PI-mono was also non-inferior with prespecified analyses of loss of future drug options during the full trial follow-up period (OT 1·8%; PI-mono 2·1%; difference 0·2% [–2·5% to 2·6]) and loss of future drug options during the full trial period but excluding mutations that were probably archived (OT 1·5%; PI-mono 1·0%; difference −0·4% [–2·9% to 1·4%]). One (<1%) participant on atazanavir monotherapy developed the Ile50Leu mutation (as a mixture with wild-type), conferring predicted high-level atazanavir resistance. We detected an isolated Leu90Met mutation in two (<1%) patients on darunavir monotherapy; both resuppressed with reintroduction of NRTIs. This mutation, possibly archived, does not affect darunavir sensitivity, but confers resistance to saquinavir and thus meets the endpoint definition. Three (1%) patients in the PI-mono group had NRTI or NNRTI mutations detected, probably archived from previous treatment. In the OT group, three (1%) patients had loss of future drug options to drug classes that they were taking and one (<1%) taking a protease-inhibitor-based regimen had NNRTI mutations that were probably archived (table 2; appendix p 2–3).\n\nWe noted one or more episodes of confirmed viral load rebound in eight (Kaplan-Meier estimate 3·2%) patients in the OT group and 95 (35·0%) in the PI-mono group during all follow-up: absolute risk difference 31·8% (95% CI 24·6–39·0; p<0·0001). Rebound while actually on monotherapy (occurred in 93 patients) was more common in the first year (24 per 100 person-years) than in subsequent years (six per 100 person-years; figure 2). Findings were similar with use of an extended definition of viral load rebound (appendix, p 9) and across the different protease inhibitors used as monotherapy. The median peak viral load at first episode of rebound on monotherapy was 526 copies per mL (peak was less than 400 copies per mL in 39 [42%] of 93 patients); of the 91 (98%) patients with subsequent tests available, 22 (24%) had resuppressed spontaneously and 69 (76%) resuppressed after changing ART: 47 (68%) by adding NRTIs only, 18 (26%) by adding NRTIs and changing the protease inhibitor to an NNRTI, two (3%) by changing the protease inhibitor monotherapy drug, and two (3%) other changes (appendix p 8). Viral load was resuppressed to less than 50 copies per mL after a median of 3·5 weeks (figure 2).\n\nWe noted no differences in serious drug-related or disease-related complications (death, AIDS, or serious non-AIDS) between groups (table 3). Causes of the one death in the OT group and six in the PI-mono group were diverse, and we did not deem any to be related to treatment strategy (appendix p 4). CD4 cell count increased similarly in both groups (table 3). Serious adverse events and clinical grade 3 and 4 adverse events did not differ between groups (table 3, appendix p 5–7). Fewer patients in the PI-mono group had a serum phosphate concentration of less than 0·65 mmol/L (p<0·0001, appendix p 6) and an eGFR of less than 60 mL/min per 1·73 m2 during follow-up (table 3). However, mean change in eGFR did not differ between groups (table 3), and only one case of end-stage renal failure occurred: a patient in the PI-mono group with pre-existing chronic renal impairment. Proportions of patients with symptomatic peripheral neuropathy, facial lipoatrophy, or abdominal fat accumulation during follow-up, and changes in neurocognitive function summary, cardiovascular disease risk, or quality of life summary scores did not differ between groups (table 3).\n\nDiscussion\nIn patients who have achieved viral load suppression with combination treatment, a maintenance strategy of protease inhibitor monotherapy, with reintroduction of combination treatment in the event of viral load rebound, was non-inferior to continuous combination treatment for preservation of future treatment options during 3–5 years. Furthermore, and perhaps more relevant than is non-inferiority for understanding of the clinical implications of this approach, the findings showed that the absolute number of patients who lost future drug options with protease inhibitor monotherapy was very low. Only one patient developed clinically significant resistance to a protease inhibitor taken as monotherapy, an Ile50Leu mutation with atazanavir monotherapy; clinical negative effects are mitigated by an increase in sensitivity to other protease inhibitors conferred by this mutation.27 None of the 277 patients taking darunavir or lopinavir (the recommended options for monotherapy in this trial, taken by almost all patients) developed resistance affecting their efficacy. The very low amount of resistance concurs with previous trials of monotherapy (and trials with protease-inhibitor-based combinations),5, 6, 7, 8, 9 but extend findings from these trials to provide the crucial long-term randomised outcome data from a large pragmatic trial needed to provide confidence in use of protease inhibitor monotherapy in clinical practice.\n\nWe sought resistance fastidiously, testing confirmed viral rebound samples irrespective of level of viraemia with standard population sequence genotypic testing. Although protease inhibitor resistance could occur in other regions of the virus, such as gag or env genes, or in minority species that are not detected by population assays,3 previous minority species sequencing in patients with viral rebound on monotherapy has shown only a small excess of resistance compared with that detected by population sequencing.28, 29 Furthermore, our finding that patients with viral load rebound in the PI-mono group, without exception, achieved full viral load suppression when switched to combination treatment (usually by reintroduction of NRTIs) provides an important assurance that any mutations that were not detected by population sequencing did not affect subsequent treatment efficacy. The follow-up period of 3–5 years, long for an HIV treatment trial, is sufficient to have confidence that preservation of treatment options is likely to be durable in the long term.\n\nA higher proportion of patients in the PI-mono group had viral rebound, as expected, although the difference was much greater than the 10–13% noted in a previous systematic review.9 Viral suppression is the traditional outcome variable for comparison of treatment regimens in clinical trials, but is less informative in long-term strategy trials such as this one, especially in view of the different effect of viral rebound on risk of drug resistance for different drug classes. Aside from risk of resistance (shown to be negligible in this study), these brief episodes of low-level viraemia, rapidly reversed by reintroduction of combination treatment, are unlikely to have adverse long-term clinical effects: much higher levels of viraemia are needed than those noted in this study to drive HIV disease progression,30 and CD4 cell count increases and total HIV disease-related clinical events were similar between the two groups. Risk of transmission to others arising from such short episodes of low-level viraemia is also likely to be negligible in view of the fact that transmission is exceedingly rare in patients with a low viral load, whether on or off ART.31, 32 Although more deaths occurred in the PI-mono group, the difference was not statistically significant and the causes were diverse, without a plausible link to the drugs taken or HIV disease progression. This finding is probably a chance imbalance, and follow-up of the cohort continues. Further analyses of predictive factors are planned that might enable identification of patients at low risk of rebound. However, selection factors are unlikely to be able to remove the excess risk entirely, and rebound and resuppression should be viewed as an integral part of the strategy for some patients. After the first year of suppression on monotherapy, the risk of rebound is much reduced, and this factor might increase acceptability for patients.\n\nWe noted fewer episodes of renal impairment in the PI-mono group as expected in view of the well-recognised renal toxic effects of NRTIs (especially tenofovir). However, the risk of serious drug toxic effects can be minimised by close laboratory monitoring and pre-emptive treatment changes, and no patients in the OT group developed end-stage renal disease.33 This pragmatic trial in which clinicians were allowed to switch drugs at clinical discretion (rather than being restricted to single-protocol-mandated regimens) provides a realistic estimate of the effect of protease inhibitor monotherapy in routine clinical practice, suggesting that benefits in terms of renal toxic effects would be small. We did not find any other clinical advantages of the monotherapy strategy. Treatment costs might be reduced, partly offset by increased monitoring costs, but considerations are complex, and detailed cost-effectiveness analyses will be reported in a separate paper.\n\nA concern with protease inhibitor monotherapy is that suboptimum drug penetration into the CNS might lead to harm.34, 35 However, we noted no difference in neurocognitive function between groups, nor any significant excess of neurological events in the PI-mono group. We used a small battery of neurocognitive tests (for feasibility in view of the large numbers of patients and repeated assessments), possibly less sensitive than a comprehensive neurocognitive assessment would be. Although we cannot rule out delayed effects on neurocognitive function or neurological events after longer periods on monotherapy than those in this study, the size and duration of our trial nevertheless provides reassurance that even if monotherapy were to have less brain penetration, this factor is unlikely to have important clinical negative effects.\n\nThe strengths of this trial are its size and duration (more than three times the randomly allocated person follow-up time of previous studies, allowing precise estimates of important but uncommon efficacy and safety outcomes); low withdrawal and loss-to-follow-up; pragmatic design set in routine clinical care, with flexibility in drug selection in both treatment groups; and use of a primary efficacy endpoint relevant to long-term management. The open-label design, a possible limitation, is unlikely to have affected detection of viral rebound or resistance (and hence the primary endpoint) because the protocol-mandated frequency of viral load testing was identical in the two groups (apart from two extra tests at weeks 4 and 8 in the monotherapy group), and we did resistance testing in everyone with viral rebound. Likewise, the open-label design is unlikely to have affected adverse event detection because the frequency of laboratory safety monitoring was standardised and adverse events were graded with standardised diagnostic criteria. Another possible limitation is the absence of before-treatment resistance tests that would help rule out resistance acquired before the trial. Although entry criteria were broad, patients entering this trial were established for years on a stable effective regimen, yet needed to be willing to change to an alternative regimen (in some cases adding new drugs with risk of side-effects or increased pill burden) if randomly allocated to do so. In view of the absence of any certainty of benefit, only a few eligible patients would therefore have been likely to be prepared to participate. Such motivated patients might have better outcomes (perhaps mediated by adherence) than the general clinic population would have, and this notion is consistent with the very low amount of rebound and resistance noted in the OT group. The main study finding that, despite high levels of viral load rebound, protease inhibitor monotherapy does not jeopardise future treatment options is likely to be generalisable internationally to settings where treatment is individualised and regular viral load monitoring done. However, protease inhibitor monotherapy is not appropriate for resource-limited settings delivering treatment without regular viral load monitoring.36\n\nProtease inhibitor monotherapy is an acceptable alternative to standard combination ART for long-term HIV management, with a slight benefit in terms of a reduction of renal toxic effects. The need for regular viral load monitoring and a possible switch back to combination treatment might be perceived as drawbacks, but this approach could nevertheless appeal to patients who are stable on treatment but wish to minimise their exposure to specific drugs or more than one drug class. Broadly, the trial challenges the notion that combination treatment is essential for management of chronic HIV infection.\n\nSupplementary Material\nSupplementary appendix\n \n\nAcknowledgments\nThis study was funded by the National Institute for Health Research Health Technology Assessment programme (project number 06/403/90). The views and opinions expressed herein are those of the authors and do not necessarily reflect those of the Health Technology Assessment programme, National Institute for Health Research, National Health Service, or the Department of Health. We thank all patients and staff from all the centres participating in the Protease Inhibitor Monotherapy Versus Ongoing Triple Therapy trial, and the UK Community Advisory Board and African Eye for community support.\n\nContributors\nNIP and DTD designed the study. AA-P, MF, IW, MJ, CO, FC, VL, AW, MG, and JF enrolled participants into the study. NIP, WS, AA-P, KS, and DTD coordinated and oversaw the study. WS and DTD did the statistical analysis. All authors interpreted data. NIP, WS, AA-P, and DTD drafted the report. All authors provided input into the report and approved the final version of the report.\n\nProtease Inhibitor Monotherapy Versus Ongoing Triple Therapy (PIVOT) Trial Team\nParticipating UK sites: M Fisher, A Clarke, W Hadley, D Stacey (Elton John Centre, Brighton). M Johnson, P Byrne (Royal Free Hospital, London). I Williams, N De Esteban, P Pellegrino, L Haddow, A Arenas-Pinto (Mortimer Market Centre, London). C Orkin, J Hand, C De Souza, L Murthen, A Crawford-Jones (Barts & the London Hospital, London). F Chen, R Wilson, E Green, J Masterson (Royal Berkshire Hospital, Reading). V Lee, K Patel, R Howe (Manchester Royal Infirmary, Manchester). A Winston, S Mullaney (St Mary's Hospital, London). M Gompels, L Jennings (Southmead Hospital, Bristol). N Beeching, R Tamaklo (Royal Liverpool University Hospital, Liverpool). J Fox, A Teague, I Jendrulek, J Tiraboschi (Guy's and St Thomas' Hospital, London). E Wilkins, Y Clowes, A Thompson (North Manchester General Hospital, Manchester). G Brook, M Trivedi (Central Middlesex Hospital, London). K Aderogba, M Jones (Avenue House Clinic, Eastbourne). A DeBurgh-Thomas, L Jones (Gloucester Royal Hospital, Gloucester). I Reeves, S Mguni (Homerton University Hospital, London). D Chadwick, P Spence, N Nkhoma (James Cook University Hospital, Middlesbrough). Z Warwick, S Price, S Read (Derriford Hospital, Plymouth). E Herieka, J Walker, R Woodward (Royal Bournemouth Hospital, Bournemouth). J Day, L Hilton (Southend University Hospital, Westcliff-on-Sea). V Harinda, H Blackman (St Mary's Hospital, Portsmouth). P Hay, W Mejewska, O Okolo (St George's Hospital, London). E Ong, K Martin, L Munro (Royal Victoria Infirmary, Newcastle). D Dockrell, L Smart (Royal Hallamshire Hospital, Sheffield). J Ainsworth, A Waters (North Middlesex University Hospital, London). S Kegg, S McNamara (Queen Elizabeth Hospital, Woolwich). S Taylor, G Gilleran (Birmingham Heartlands Hospital, Birmingham). B Gazzard, J Rowlands (Chelsea and Westminster Hospital, London). S Allan, R Sandhu (University Hospital of Coventry, Coventry). N O'Farrell, S Quaid (Ealing Hospital, London). F Martin, C Bennett (Harrogate District Hospital, Harrogate). M Kapembwa (Northwick Park Hospital, Harrow). J Minton, J Calderwood (St James' Hospital, Leeds). F Post, L Campbell, E Wandolo (King's College Hospital, London). A Palfreeman, L Mashonganyika (Leicester Royal Infirmary, Leicester). T Balachandran, M Kakowa (Luton and Dunstable Hospital, Luton). R O'Connell, C Tanawa (Newham University Hospital, London). S Jebakumar, L Hagger (Edith Cavell Hospital, Peterborough). S Quah, S McKernan (Royal Victoria Hospital, Belfast). C Lacey, S Douglas, S Russell-Sharpe, C Brewer (York Teaching Hospital, York). C Leen, S Morris (Western General Hospital, Edinburgh). S Obeyesekera, S Williams (Barking Hospital, London). N David (Norfolk and Norwich University Hospital, Norwich). M Roberts, J Wollaston (Worcester Royal Hospital, Worcester).\n\nMedical Research Council Clinical Trials Unit at University College London: N Paton, W Stöhr, A Arenas-Pinto, K Scott, D Dunn, E Beaumont, S Fleck, M Hall, S Hennings, I Kummeling, S Martins, E Owen-Powell, K Sanders, F van Hooff, L Vivas, E White.\n\nIndependent event reviewer: B Angus.\n\nTrial Steering Committee: A Freedman (chair), B Cromarty, D Mercey, S Fidler, E Torok, A Babiker, B Gazzard, C Orkin, N Paton.\n\nData Monitoring Committee: T Peto (chair), D Lalloo, A Phillips, R James.\n\nDeclaration of interests\nNIP, WS, KS, and DTD report grants from the National Institute of Health Research Health Technology Assessment programme during the conduct of this study. AA-P, MF, IW, MJ, CO, FC, VL, AW, MG, and JF report non-financial support from the UK Clinical Research Network during the conduct of this study. NIP reports grants, personal fees, and non-financial support from AbbVie and Janssen; personal fees and non-financial support from Merck and Roche; grants and non-financial support from GlaxoSmithKline; and non-financial support from Gilead Sciences, all outside the submitted work. AA-P reports grants from Janssen and ViiV Healthcare outside the submitted work. MF reports personal fees from AbbVie, Bristol-Myers Squibb, and Janssen; and grants and personal fees from Gilead Sciences, all outside the submitted work. IW reports grants and personal fees from Gilead Sciences; and grants from Pfizer, Merck Sharp & Dohme, and Bristol-Myers Squibb, all outside the submitted work. CO reports grants, personal fees, and non-financial support from Gilead Sciences, Janssen, ViiV Healthcare, and Bristol-Myers Squibb; and grants from Abbvie and Boehringer Ingelheim, all outside the submitted work. VL reports grants from Gilead Sciences, Merck Sharp & Dohme, ViiV Healthcare, Abbvie, Boehringer Ingelheim, and Janssen, all during the conduct of this study. AW reports honoraria or research grants from or engagement as a consultant or investigator in clinical trials sponsored by Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Janssen-Cilag, Roche, Pfizer, and ViiV Healthcare. MG reports speakers fees, meeting sponsorship, and educational grants from Bristol-Myers Squibb, Boehringer Ingelheim, and Janssen.\n\nFigure 1 Trial profile\n\nART=antiretroviral therapy. PI=protease inhibitor. NNRTI=non-nucleoside reverse transcriptase inhibitor. NRTI=nucleoside reverse transcriptase inhibitor. VL=viral load. Six patients had more than one reason for ineligibility.\n\nFigure 2 Viral load rebound and resuppression\n\n(A) Time to viral rebound. (B) Time to viral resuppression after change of ART in the PI-mono group. The time to first viral load of less than 50 copies per mL (midpoint between last test 50 copies per mL or more and first test of less than 50 copies per mL) for patients at the time of first rebound who were taking protease inhibitor monotherapy (excluding two patients in the PI-mono group who rebounded while not on monotherapy) is shown. Outcomes by type of treatment switch are shown in the appendix (p 8). ART=antiretroviral therapy. HR=hazard ratio. OT=ongoing triple therapy. PI-mono=protease inhibitor monotherapy. VL=viral load.\n\nTable 1 Baseline characteristics\n\n\t\tOT (n=291)\tPI-mono (n=296)\tTotal (n=587)\t\nDemographic and clinical characteristics\t\nAge (years)\t43 (37–49, 23–75)\t45 (39–50, 23–67)\t44 (38–49, 23–75)\t\nRoute of infection\t\n\tHomosexual\t175 (60%)\t176 (59%)\t351 (60%)\t\n\tHeterosexual\t108 (37%)\t108 (36%)\t216 (37%)\t\n\tOther\t8 (3%)\t12 (4%)\t20 (3%)\t\nFemale\t64 (22%)\t73 (25%)\t137 (23%)\t\nEthnic origin\t\n\tWhite\t206 (71%)\t195 (66%)\t401 (68%)\t\n\tBlack\t73 (25%)\t90 (30%)\t163 (28%)\t\n\tOther\t12 (4%)\t11 (4%)\t23 (4%)\t\nHepatitis C virus antibody positive\t7 (2%)\t14 (5%)\t21 (4%)\t\nHIV disease status\t\nPrevious AIDS-defining illness\t59 (20%)\t57 (19%)\t116 (20%)\t\nNadir CD4 count (cells per μL)\t181 (90–258)\t170 (80–239)\t178 (86–250)\t\nBaseline CD4 count (cells per μL)\t512 (386–658)\t516 (402–713)\t513 (392–682)\t\nUndetectable baseline HIV viral load\t276 (95%)\t279 (94%)\t555 (95%)\t\nDuration of undetectable viral load (months)\t36 (17–62)\t38 (22–66)\t37 (20–63)\t\nART history\t\nYears since ART started\t3·9 (2·0–6·4)\t4·2 (2·4–6·9)\t4·0 (2·2–6·7)\t\nOn first ART combination\t91 (31%)\t96 (32%)\t187 (32%)\t\nNumber of drugs ever received\t5 (3–6)\t4 (3–6)\t4 (3–6)\t\nNNRTI at entry\t\n\tAny\t157 (54%)\t157 (53%)\t314 (53%)\t\n\tEfavirenz\t115 (40%)\t115 (39%)\t230 (39%)\t\n\tNevirapine\t42 (14%)\t39 (13%)\t81 (14%)\t\n\tEtravirine\t0\t3 (1%)\t3 (1%)\t\nProtease inhibitor at entry\t\n\tAny\t134 (46%)\t139 (47%)\t273 (47%)\t\n\tAtazanavir\t59 (20%)\t59 (20%)\t118 (20%)\t\n\tLopinavir\t28 (10%)\t49 (17%)\t77 (13%)\t\n\tDarunavir\t24 (8%)\t13 (4%)\t37 (6%)\t\n\tSaquinavir\t16 (5%)\t15 (5%)\t31 (5%)\t\n\tFosamprenavir\t7 (2%)\t3 (1%)\t10 (2%)\t\nNRTIs at entry\t\n\tAny\t291 (100%)\t296 (100%)\t587 (100%)\t\n\tEmtricitabine and tenofovir\t190 (65%)\t180 (61%)\t370 (63%)\t\n\tLamivudine and abacavir\t80 (27%)\t82 (28%)\t162 (28%)\t\n\tOther\t21 (7%)\t34 (11%)\t55 (9%)\t\nResistance\t\nResistance test result available before trial\t181 (62%)\t165 (56%)\t346 (59%)\t\nIntermediate-level or high-level resistance to NRTI or NNRTI before trial\t4 (2%)\t7 (4%)\t11 (3%)\t\nData are median (IQR, range), median (IQR), or n (%). OT=ongoing triple therapy. PI-mono=protease inhibitor monotherapy. ART=antiretroviral therapy. NNRTI=non-nucleoside reverse transcriptase inhibitor. NRTI=nucleoside reverse transcriptase inhibitor.\n\n* Percentages are of the numbers of patients with resistance test results available before the trial.\n\nTable 2 Individual patients with loss of future drug options by end of trial\n\n\tDrugs received during trial\tReverse transcriptase mutations\tProtease mutations\tLost drug options\t\nOT\t\n1\tABC, 3TC, ATV\tVal118Ile, Val179Asp, Met184Val\tIle84Val\t3TC, FTC, ATV, SQV, FPV, TPV\t\n2\tTDF, FTC, RPV, DRV\tLeu100Ile, Lys103Asn, Met184Val\tAla71Val\t3TC, FTC, NVP, EFV, ETV, RPV\t\n3\tTDF, FTC, ETV, NVP, EFV, DRV\tLys65Arg, Glu138Ala, Tyr181Cys, Met184Val/Ile, His221Tyr, Met230Leu\t..\t3TC, FTC, ABC, TDF, NVP, EFV, ETV, RPV\t\n4\tTDF, FTC, DRV\tVal106Ala\t..\tNVP,‡ EFV‡\t\nPI-mono\t\n5\tATV\t..\tLys20Thr, Ile50Leu/Ile, Ala71Thr\tATV\t\n6\tDRV\t..\tLeu90Met\tSQV†\t\n7\tDRV\t..\tAla71Thr, Leu90Met\tSQV†\t\n8\tDRV\tLys103Asn\t..\tNVP,‡ EFV‡\t\n9\tDRV\tLys103Asn\t..\tNVP,‡ EFV‡\t\n10\tDRV\tMet41Leu, Thr215Asp\t..\tZDV‡\t\nOT=ongoing triple therapy. ABC=abacavir. 3TC=lamivudine. ATV=atazanavir. FTC=emtricitabine. SQV=saquinavir. FPV=fosamprenavir. TPV=tipranavir. TDF=tenofovir. RPV=rilpivirine. NVP=nevirapine. EFV= efavirenz. ETV=etravirine. DRV=darunavir. PI-mono=protease inhibitor monotherapy. ZDV=zidovudine.\n\n* Met primary outcome at 3 years.\n\n† Possibly archived resistance.\n\n‡ Probably archived resistance (excluded in sensitivity analysis).\n\nTable 3 Secondary outcomes\n\n\t\tOT (n=291)\tPI-mono (n=296)\tDifference (95% CI)\tp value\t\nSerious drug-related or disease-related complications\t\n\tTotal\t8 (2·7%)\t15 (5·1%)\t2·3% (−0·8 to 5·4)\t0·15\t\n\tDeath†\t1 (0·3%)\t6 (2·0%)\t1·7% (−0·3 to 3·6)\t0·12\t\n\tAIDS-defining event\t1 (0·3%)\t1 (0·3%)\t0·0% (−1·3 to 1·3)\t1·00\t\n\tSerious non-AIDS event\t7 (2·4%)\t12 (4·1%)\t1·6% (−1·2 to 4·5)\t0·26\t\nCD4 change (cells per mm3)\t93 (10)\t109 (9)\t16 (−11 to 42)\t0·30\t\nSerious adverse event\t45 (15·5%)\t56 (18·9%)\t3·5% (−2·6 to 9·6)\t0·27\t\nTotal grade 3 or 4 adverse event\t159 (54·6%)\t137 (46·3%)\t−8·4% (−16·4 to −0·3)\t0·043\t\nClinical grade 3 or 4 adverse event\t49 (16·8%)\t65 (22·0%)\t5·1% (−1·3 to 11·5)\t0·12\t\nEGFR\t\n\t<60 mL/min per 1·73 m2‡\t28/290 (9·7%)\t15/296 (5·1%)\t−4·6% (−8·8 to −0·4)\t0·033\t\n\tChange (mL/min per 1·73 m2)\t−5·13 (0·67)\t−3·83 (0·66)\t1·30% (−0·55 to 3·15)\t0·092\t\nSymptomatic peripheral neuropathy§\t44/283 (15·5%)\t46/289 (15·9%)\t0·4% (−5·6 to 6·3)\t0·90\t\nFacial lipoatrophy¶\t23/282 (8·2%)\t35/289 (12·1%)\t4·0% (−1·0 to 8·9)\t0·12\t\nAbdominal fat accumulation¶\t47/274 (17·2%)\t57/277 (20·6%)\t3·4% (−3·1 to 10·0)\t0·30\t\n10 year cardiovascular disease risk change\t1·32 (0·31)\t1·59 (0·31)\t0·27 (−0·58 to 1·12)\t0·52\t\nNeurocognitive function change (NPZ-5 score)\t0·53 (0·04)\t0·52 (0·04)\t−0·01 (−0·11 to 0·09)\t0·94\t\nQuality of life change\t\n\tMental health score\t−0·75 (0·57)\t−1·82 (0·54)\t−1·07 (−2·61 to 0·47)\t0·17\t\n\tPhysical health score\t−0·76 (0·53)\t−1·17 (0·46)\t−0·41 (−1·79 to 0·98)\t0·56\t\nData are n (%), n/N (%), or mean (SE). Means are predicted means adjusted for baseline values. The numbers of patients are the numbers of patients having the specified event during the entire trial follow-up period. OT=ongoing triple therapy. PI-mono=protease inhibitor monotherapy. EGFR=estimated glomerular filtration rate.\n\n Difference between PI-mono and OT. Absolute differences for binary outcomes or mean differences for continuous outcomes shown.\n\n† Causes of death were metastatic adenocarcinoma in the OT group and suicide, pulmonary embolism, breast carcinoma (recurrent), small-cell lung carcinoma, glioblastoma, and anal carcinoma in the PI-mono group (details in appendix p 4).\n\n‡ New episodes after baseline.\n\n§ Symptomatic peripheral neuropathy at one or more of the post-baseline-scheduled follow-up assessments (irrespective of status at baseline).\n\n¶ Facial lipoatrophy present at one or more of the post-baseline-scheduled follow-up assessments (irrespective of status at baseline), assessed by a doctor or nurse; abdominal fat accumulation at last available assessment compared with baseline (irrespective of status at baseline), self-assessed by the patient.\n==== Refs\nReferences\n1 Williams I Churchill D Anderson J British HIV Association guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy 2012 HIV Med 13 suppl 2 2012 1 85 \n2 Thompson MA Aberg JA Hoy JF Antiretroviral treatment of adult HIV infection: 2012 recommendations of the International Antiviral Society-USA panel JAMA 308 2012 387 402 22820792 \n3 Rabi SA Laird GM Durand CM Multi-step inhibition explains HIV-1 protease inhibitor pharmacodynamics and resistance J Clin Invest 123 2013 3848 3860 23979165 \n4 Ghosn J Flandre P Cohen-Codar I Long-term (96-week) follow-up of antiretroviral-naïve HIV-infected patients treated with first-line lopinavir/ritonavir monotherapy in the MONARK trial HIV Med 11 2010 137 142 19682100 \n5 Arribas JR Delgado R Arranz A Lopinavir-ritonavir monotherapy versus lopinavir-ritonavir and 2 nucleosides for maintenance therapy of HIV: 96-week analysis J Acquir Immune Defic Syndr 51 2009 147 152 19349870 \n6 Cameron DW da Silva BA Arribas JR A 96-week comparison of lopinavir-ritonavir combination therapy followed by lopinavir-ritonavir monotherapy versus efavirenz combination therapy J Infect Dis 198 2008 234 240 18540803 \n7 Katlama C Valantin MA Algarte-Genin M Efficacy of darunavir/ritonavir maintenance monotherapy in patients with HIV-1 viral suppression: a randomized open-label, noninferiority trial, MONOI-ANRS 136 AIDS 24 2010 2365 2374 20802297 \n8 Arribas JR Clumeck N Nelson M Hill A van Delft Y Moecklinghoff C The MONET trial: week 144 analysis of the efficacy of darunavir/ritonavir (DRV/r) monotherapy versus DRV/r plus two nucleoside reverse transcriptase inhibitors, for patients with viral load <50 HIV-1 RNA copies/mL at baseline HIV Med 13 2012 398 405 22413874 \n9 Mathis S Khanlari B Pulido F Effectiveness of protease inhibitor monotherapy versus combination antiretroviral maintenance therapy: a meta-analysis PLoS One 6 2011 e22003 21811554 \n10 Hughes CP Berg L Danziger WL Coben LA Martin RL A new clinical scale for the staging of dementia Br J Psychiatry 140 1982 566 572 7104545 \n11 Price RW Brew BJ The AIDS dementia complex J Infect Dis 158 1988 1079 1083 3053922 \n12 Wilson PW D'Agostino RB Levy D Belanger AM Silbershatz H Kannel WB Prediction of coronary heart disease using risk factor categories Circulation 97 1998 1837 1847 9603539 \n13 D'Agostino RB Sr Vasan RS Pencina MJ General cardiovascular risk profile for use in primary care: the Framingham Heart Study Circulation 117 2008 743 753 18212285 \n14 Winston A Arenas-Pinto A Stohr W Neurocognitive function in HIV infected patients on antiretroviral therapy PLoS One 8 2013 e61949 23646111 \n15 Arenas-Pinto A Winston A Stohr W Neurocognitive function in HIV-infected patients: comparison of two methods to define impairment PLoS One 9 2014 e103498 25078406 \n16 Evans SR Ellis RJ Chen H Peripheral neuropathy in HIV: prevalence and risk factors AIDS 25 2011 919 928 21330902 \n17 Wu AW Rubin HR Mathews WC A health status questionnaire using 30 items from the Medical Outcomes Study. Preliminary validation in persons with early HIV infection Med Care 29 1991 786 798 1875745 \n18 Wu AW Hanson KA Harding G Responsiveness of the MOS-HIV and EQ-5D in HIV-infected adults receiving antiretroviral therapies Health Qual Life Outcomes 11 2013 42 23497257 \n19 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults MMWR Recomm Rep 41 1992 1 19 \n20 Lifson AR Belloso WH Davey RT Development of diagnostic criteria for serious non-AIDS events in HIV clinical trials HIV Clin Trials 11 2010 205 219 20974576 \n21 National Institutes of Health Division of AIDS Division of AIDS table for grading the severity of adult and pediatric adverse events http://rsc.tech-res.com/document/safetyandpharmacovigilance/table_for_grading_severity_of_adult_pediatric_adverse_events.pdf (accessed Jan 1, 2008). \n22 Levey AS Stevens LA Schmid CH A new equation to estimate glomerular filtration rate Ann Intern Med 150 2009 604 612 19414839 \n23 US Department of Health and Human Services Guidance for industry. Non-inferiority clinical trials 2010 US Department of Health and Human Services Washington, DC \n24 US Department of Health and Human Services Guidance for industry. Human Immunodeficiency Virus-1 infection: developing antiretroviral drugs for treatment 2013 US Department of Health and Human Services Washington, DC \n25 Pulido F Arribas JR Noninferiority and lopinavir/ritonavir monotherapy trials AIDS 22 2008 1696 1697 18670240 \n26 Arribas JR Horban A Gerstoft J The MONET trial: darunavir/ritonavir with or without nucleoside analogues, for patients with HIV RNA below 50 copies/ml AIDS 24 2010 223 230 20010070 \n27 Sista P Wasikowski B Lecocq P Pattery T Bacheler L The HIV-1 protease resistance mutation I50L is associated with resistance to atazanavir and susceptibility to other protease inhibitors in multiple mutational contexts J Clin Virol 42 2008 405 408 18472298 \n28 McKinnon JE Delgado R Pulido F Shao W Arribas JR Mellors JW Single genome sequencing of HIV-1 gag and protease resistance mutations at virologic failure during the OK04 trial of simplified versus standard maintenance therapy Antivir Ther 16 2011 725 732 21817194 \n29 Lambert-Niclot S Flandre P Valantin MA Resistant minority species are rarely observed in patients on darunavir/ritonavir monotherapy J Antimicrob Chemother 67 2012 1470 1474 22396434 \n30 Raffanti SP Fusco JS Sherrill BH Effect of persistent moderate viremia on disease progression during HIV therapy J Acquir Immune Defic Syndr 37 2004 1147 1154 15319674 \n31 Quinn TC Wawer MJ Sewankambo N Viral load and heterosexual transmission of human immunodeficiency virus type 1. Rakai Project Study Group N Engl J Med 342 2000 921 929 10738050 \n32 Supervie V Viard JP Costagliola D Breban R Heterosexual risk of HIV transmission per sexual act under combined antiretroviral therapy: systematic review and Bayesian modeling Clin Infect Dis 59 2014 115 122 24723286 \n33 Ryom L Mocroft A Kirk O Predictors of advanced chronic kidney disease and end-stage renal disease in HIV-positive persons AIDS 28 2014 187 199 24361680 \n34 Gutmann C Cusini A Gunthard HF Randomized controlled study demonstrating failure of LPV/r monotherapy in HIV: the role of compartment and CD4-nadir AIDS 24 2010 2347 2354 20802298 \n35 Paton NI Meynard JL Pulido F Arenas-Pinto A Girard PM Arribas J Inappropriate claim of ‘failure of ritonavir-boosted lopinavir monotherapy in HIV’ in the Monotherapy Switzerland/Thailand (MOST) trial AIDS 25 2011 393 394 21239897 \n36 Paton NI Kityo C Hoppe A Assessment of second-line antiretroviral regimens for HIV therapy in Africa N Engl J Med 371 2014 234 247 25014688\n\n", "fulltext_license": "CC BY", "issn_linking": "2352-3018", "issue": "2(10)", "journal": "The lancet. HIV", "keywords": null, "medline_ta": "Lancet HIV", "mesh_terms": "D000328:Adult; D000368:Aged; D018791:CD4 Lymphocyte Count; D024882:Drug Resistance, Viral; D005260:Female; D006678:HIV; D015658:HIV Infections; D017320:HIV Protease Inhibitors; D006801:Humans; D060046:Maintenance Chemotherapy; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D006113:United Kingdom; D019562:Viral Load; D055815:Young Adult", "nlm_unique_id": "101645355", "other_id": null, "pages": "e417-26", "pmc": null, "pmid": "26423649", "pubdate": "2015-10", "publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't", "references": "15319674;22396434;21817194;7104545;3053922;22830364;23497257;23646111;23979165;24361680;25014688;25078406;24723286;22820792;10738050;22413874;1875745;1361652;9603539;18212285;18540803;18472298;18670240;19414839;19349870;20010070;19682100;20802297;20802298;20974576;21239897;21330902;21811554", "title": "Protease 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{ "abstract": "Pemetrexed is a multitargeted antifolate that has demonstrated antitumor activity in non-small cell lung cancer. A 70-year-old male presented with a stage IV non-small cell lung cancer. The patient was treated with pemetrexed as third-line chemotherapy. However, a pneumothorax occurred 16 days after the administration of the second cycle of pemetrexed. The pneumothorax was slight and the patient was observed without undergoing any additional treatment. Twenty-four days after its initial occurrence, the pneumothorax had improved. This is the first case of pneumothorax that has been observed during pemetrexed treatment. Pneumothorax during chemotherapy is rare; however, it is a life-threatening complication and should not be overlooked.", "affiliations": "Department of Respiratory Medicine, Kitasato University School of Medicine, Sagamihara, Japan.;Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.;Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.;Department of Respiratory Medicine, Kitasato University School of Medicine, Sagamihara, Japan.;Research and Development Center for New Medical Frontiers, Kitasato University School of Medicine, Sagamihara, Japan.;Department of Respiratory Medicine, Kitasato University School of Medicine, Sagamihara, Japan.", "authors": "Nakahara\|Yoshiro\|Y\|;Mikura\|Shinichiro\|S\|;Nagamata\|Makoto\|M\|;Fukui\|Tomoya\|T\|;Sasaki\|Jiichiro\|J\|;Masuda\|Noriyuki\|N\|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.1159/000471479", "fulltext": "\n==== Front\nCase Rep OncolCase Rep OncolCROCase Reports in Oncology1662-6575S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, [email protected] 10.1159/000471479cro-0010-0428Case ReportPneumothorax during Pemetrexed Treatment in a Patient with Non-Small Cell Lung Cancer: A Case Report and Literature Review Nakahara Yoshiro abMikura Shinichiro bNagamata Makoto bFukui Tomoya aSasaki Jiichiro cMasuda Noriyuki aaDepartment of Respiratory Medicine, Kitasato University School of Medicine, Sagamihara, JapanbDepartment of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, JapancResearch and Development Center for New Medical Frontiers, Kitasato University School of Medicine, Sagamihara, JapanYoshiro Nakahara, Department of Respiratory Medicine, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-Ku, Sagamihara, Kanagawa 252-0374 (Japan), E-Mail [email protected] 2017 9 5 2017 9 5 2017 10 2 428 432 14 3 2017 15 3 2017 Copyright © 2017 by S. Karger AG, Basel2017This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Pemetrexed is a multitargeted antifolate that has demonstrated antitumor activity in non-small cell lung cancer. A 70-year-old male presented with a stage IV non-small cell lung cancer. The patient was treated with pemetrexed as third-line chemotherapy. However, a pneumothorax occurred 16 days after the administration of the second cycle of pemetrexed. The pneumothorax was slight and the patient was observed without undergoing any additional treatment. Twenty-four days after its initial occurrence, the pneumothorax had improved. This is the first case of pneumothorax that has been observed during pemetrexed treatment. Pneumothorax during chemotherapy is rare; however, it is a life-threatening complication and should not be overlooked.\n\nKeywords\nPemetrexedPneumothoraxNon-small cell lung cancer\n==== Body\nIntroduction\nPemetrexed is a multitargeted antifolate that has demonstrated antitumor activity in non-small cell lung cancer. It has several notable adverse effects including myelosuppression, nausea, vomiting, diarrhea, and skin toxicity. However, the occurrence of pneumothorax during pemetrexed chemotherapy has not been previously reported [1]. Herein, we present a case of pneumothorax that was observed during pemetrexed chemotherapy.\n\nCase Report\nAn asymptomatic 70-year-old man was referred to the Department of Respiratory Diseases because of abnormal shadows found during a chest computed tomography scan. The scan revealed bilateral infiltrative shadows in the lower lung lobes (Fig. 1). Transbronchial lung biopsy was performed and the patient was diagnosed with non-small cell lung cancer classified as stage IV (T3N3M1a). The patient was treated every 3 weeks with 3 cycles of first-line chemotherapy, including carboplatin (AUC 5) on day 1 and gemcitabine (1,000 mg/m2) on days 1 and 8. After 3 cycles of chemotherapy, the bilateral infiltrative shadows had progressed. Consequently, the patient was treated every 3 weeks with 3 cycles of docetaxel (60 mg/m2) monotherapy as second-line chemotherapy. However, after the third cycle, the infiltrative shadows had progressed again. Subsequently, the patient was treated with pemetrexed (500 mg/m2) as third-line chemotherapy, every 3 weeks. In the first cycle of the chemotherapy, there were no grade 3 or 4 adverse events. However, the patient experienced sudden onset of cough and dyspnea 16 days after the administration of the second cycle of pemetrexed. Physical examination showed decreased breathing sounds in the right chest, and a chest radiograph revealed a pneumothorax (Fig. 2, Fig. 3). Because the pneumothorax was slight, the patient was observed without any treatment, and pemetrexed therapy was stopped. The pneumothorax had improved 24 days after the occurrence of the pneumothorax (Fig. 4). However, the patient died 2 months after the occurrence of pneumothorax because of disease progression.\n\nDiscussion\nSecondary spontaneous pneumothorax after chemotherapy is rare; however, well-documented occurrence is associated with primary or metastatic lung lesions. Lai et al. [2] reported that pneumothorax appeared in 18 out of 5,567 (0.32%) lung cancer patients, and 2 out of 18 patients experienced pneumothorax during chemotherapy. Maniwa et al. [3] reported that pneumothorax associated with the treatment for pulmonary malignancy (primary and metastatic) tends to require chest tube drainage over a long period, and sometimes requires surgical treatment; this is associated with increased perioperative morbidity and mortality because of the dense adhesions or anatomical changes in the thoracic cavity caused by treatment or the progression of the tumors [3].\n\nRecently, molecular targeted therapies have also been linked with the occurrence of pneumothorax. Mori et al. [4] reported a case of simultaneous bilateral spontaneous pneumothorax that occurred during gefitinib treatment for lung adenocarcinoma with multiple lung metastases. A case of pneumothorax after bevacizumab-containing chemotherapy for colorectal cancer with lung metastases was reported by Yang et al. [5]. In addition, Gennatas et al. [6] reported a case of pneumothorax during crizotinib therapy in a patient with anaplastic lymphoma kinase-rearranged lung adenocarcinoma. In contrast, pneumothorax during cytotoxic chemotherapy treatment is rare, and secondary spontaneous pneumothorax during pemetrexed has not been previously reported in the available literature.\n\nThe mechanism of secondary pneumothorax from pulmonary malignancy is unclear, although several theories have been proposed. The proposed mechanisms are as follows: accidental rupture of the subpleural bulla or bleb during chemotherapy; the formation of a bronchopleural fistula as a result of direct tumor invasion or necrosis of the peripheral tumor after effective chemotherapy; a check-valve mechanism associated with airway compression by the tumor; and an air leak caused by pulmonary infarction from tumor emboli [7].\n\nIn the present case, there was no clinical response to pemetrexed treatment, and tumor necrosis was not observed. Furthermore, neither progression of airway compression or signs of pulmonary infarction were observed. In addition, there were no subpleural bullae or blebs on chest computed tomography before pemetrexed treatment. We believe that the pneumothorax was possibly caused by the formation of a bronchopleural fistula as a result of direct tumor invasion of the peripheral tumor.\n\nIn summary, ours is the first reported case of pneumothorax to have occurred during pemetrexed treatment. Pneumothorax during chemotherapy is rare; however, it is a life-threatening complication that should not be overlooked. It is important to observe the patients’ symptoms during chemotherapy treatment.\n\nStatement of Ethics\nThe authors have no ethical conflicts to disclose.\n\nDisclosure Statement\nThe authors state that they have no conflict of interest.\n\nFig. 1 Chest computed tomography demonstrating bilateral infiltrative shadows. These lesions were diagnosed as non-small cell lung cancer by transbronchial lung biopsy.\n\nFig. 2 Chest X-ray demonstrating right pneumothorax.\n\nFig. 3 Chest computed tomography demonstrating right pneumothorax, and bilateral infiltrative shadows had progressed.\n\nFig. 4 The pneumothorax had improved 24 days after the occurrence of the pneumothorax.\n==== Refs\nReferences\n1 Hanna N Shepherd FA Fossella FV Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy J Clin Oncol 2004 22 1589 1597 15117980 \n2 Lai RS Perng RP Chang SC Primary lung cancer complicated with pneumothorax Jpn J Clin Oncol 1992 22 194 197 1518168 \n3 Maniwa T Nakagawa K Isaka M Pneumothorax associated with treatment for pulmonary malignancy Interact Cardiovasc Thorac Surg 2011 13 257 261 21700592 \n4 Mori M Nakagawa M Fujikawa T Simultaneous bilateral spontaneous pneumothorax observed during the administration of gefitinib for lung adenocarcinoma with multiple lung metastases Intern Med 2005 44 862 864 16157988 \n5 Yang SH Lin JK Chen WS Pneumothorax after bevacizumab-containing chemotherapy: a case report Jpn J Clin Oncol 2011 41 269 271 21030401 \n6 Gennatas S Stanway SJ Thomas R Early pneumothorax as a feature of response to crizotinib therapy in a patient with ALK rearranged lung adenocarcinoma BMC Cancer 2013 13 207 23617826 \n7 Srinivas S Varadhachary G Spontaneous pneumothorax in malignancy: a case report and review of the literature Ann Oncol 2000 11 887 889 10997821\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1662-6575", "issue": "10(2)", "journal": "Case reports in oncology", "keywords": "Non-small cell lung cancer; 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{ "abstract": "Elizabethkingia anophelis, originally discovered from Anopheles mosquito gut, is an emerging pathogen, especially in immunocompromised patients. We isolated two strains of E. anophelis from two separate patients with multiple organ dysfunction syndrome and lower respiratory tract infection. In this paper, we reviewed the status of E. anophelis infection and its antibiotics resistance from reported cases.", "affiliations": "Yun Leung Laboratory for Molecular Diagnostics, School of Biomedical Sciences, Huaqiao University Xiamen, China.;Yun Leung Laboratory for Molecular Diagnostics, School of Biomedical Sciences, Huaqiao University Xiamen, China.;Department of Medical Laboratory, Institute of Nanomedicine Technology, Weifang Medical University Weifang, China.;Yun Leung Laboratory for Molecular Diagnostics, School of Biomedical Sciences, Huaqiao University Xiamen, China.;Department of Medical Laboratory, Institute of Nanomedicine Technology, Weifang Medical University Weifang, China.;Department of Information, Quanzhou First Hospital Affiliated to Fujian Medical University Fujian, China.;Department of Information, Quanzhou First Hospital Affiliated to Fujian Medical University Fujian, China.;Yun Leung Laboratory for Molecular Diagnostics, School of Biomedical Sciences, Huaqiao UniversityXiamen, China; Department of Medical Laboratory, Institute of Nanomedicine Technology, Weifang Medical UniversityWeifang, China.;Department of Clinical Laboratory, Quanzhou First Hospital Affiliated to Fujian Medical University Fujian, China.;Department of Microbiology and Molecular Genetics, Michigan State University East Lansing, MI, USA.", "authors": "Hu\|Shaohua\|S\|;Jiang\|Tao\|T\|;Zhang\|Xia\|X\|;Zhou\|Yajun\|Y\|;Yi\|Zhengjun\|Z\|;Wang\|Youxi\|Y\|;Zhao\|Sishou\|S\|;Wang\|Mingxi\|M\|;Ming\|Desong\|D\|;Chen\|Shicheng\|S\|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.3389/fmicb.2017.00382", "fulltext": "\n==== Front\nFront MicrobiolFront MicrobiolFront. Microbiol.Frontiers in Microbiology1664-302XFrontiers Media S.A. 10.3389/fmicb.2017.00382MicrobiologyCase ReportElizabethkingia anophelis Isolated from Patients with Multiple Organ Dysfunction Syndrome and Lower Respiratory Tract Infection: Report of Two Cases and Literature Review Hu Shaohua 1†Jiang Tao 1†Zhang Xia 2Zhou Yajun 1Yi Zhengjun 2Wang Youxi 3Zhao Sishou 3Wang Mingxi 12Ming Desong 4Chen Shicheng 51Yun Leung Laboratory for Molecular Diagnostics, School of Biomedical Sciences, Huaqiao UniversityXiamen, China2Department of Medical Laboratory, Institute of Nanomedicine Technology, Weifang Medical UniversityWeifang, China3Department of Information, Quanzhou First Hospital Affiliated to Fujian Medical UniversityFujian, China4Department of Clinical Laboratory, Quanzhou First Hospital Affiliated to Fujian Medical UniversityFujian, China5Department of Microbiology and Molecular Genetics, Michigan State UniversityEast Lansing, MI, USAEdited by: Leonard Peruski, US Centers for Disease Control and Prevention, USA\n\nReviewed by: Peter Bergman, Karolinska Institutet, Sweden; Marquita Vernescia Gittens-St.Hilaire, University of the West Indies, Barbados\n\nCorrespondence: Mingxi Wang [email protected] Ming [email protected] Chen [email protected] article was submitted to Infectious Diseases, a section of the journal Frontiers in Microbiology\n\n†These authors have contributed equally to this work.\n\n08 3 2017 2017 8 38220 11 2016 23 2 2017 Copyright © 2017 Hu, Jiang, Zhang, Zhou, Yi, Wang, Zhao, Wang, Ming and Chen.2017Hu, Jiang, Zhang, Zhou, Yi, Wang, Zhao, Wang, Ming and ChenThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Elizabethkingia anophelis, originally discovered from Anopheles mosquito gut, is an emerging pathogen, especially in immunocompromised patients. We isolated two strains of E. anophelis from two separate patients with multiple organ dysfunction syndrome and lower respiratory tract infection. In this paper, we reviewed the status of E. anophelis infection and its antibiotics resistance from reported cases.\n\nE. anophelisemerging pathogenmultiple organ dysfunction syndromelower respiratory tract infectionantibiotics resistance\n==== Body\nBackground\nElizabethkingia, a Gram-negative, aerobic, rod-shaped bacterium, belongs to the family Flavobacteriaceae within the phylum Bacteroidetes. Four species are assigned to this genus, including Elizabethkingia meningoseptica, E. anophelis, Elizabethkingia miricola, and Elizabethkingia endophytica, with the first three being considered to be medically important (Kukutla et al., 2013, 2014; Lau et al., 2015; Breurec et al., 2016). E. anophelis was initially isolated from the midgut of mosquito Anopheles gambiae in 2011 (Kämpfer et al., 2011). Later, it was found in the environment (water and soil) and health care settings (Balm et al., 2013; Teo et al., 2013). It rarely causes infections in healthy people while it is pathogenic to immunocompromised patients with a high mortality rate (Teo et al., 2013; Lau et al., 2016; https://www.cdc.gov/elizabethkingia/outbreaks/). The first reported case of E. anophelis infection was meningitis in an 8-day-old girl delivered by cesarean section in the Central African Republic in 2011 (Frank et al., 2013). It also caused nosocomial outbreak in two intensive-care units from a hospital in Singapore in 2012 (Teo et al., 2013). By conventional phenotypic test, an epidemiological survey of bacteremia from five regional hospitals in Hong Kong (from 2004 to 2013) identified 17 cases of E. anophelis bacteremia (Lau et al., 2016). E. anophelis was implicated in recent outbreaks of infections in the Midwest regions. In Wisconsin, 63 confirmed and 4 possible infections were reported between November 1, 2015 and January 11, 2017. Among these cases, a total of 19 deaths (estimated mortality rate, 28%) were found (https://www.dhs.wisconsin.gov/disease/elizabethkingia.htm). At least 10 E. anophelis infections were reported in Illinois (between January 2014 and April 2016) and one in Michigan in March 2016 (https://www.cdc.gov/elizabethkingia/outbreaks/). Most patients were over 65 years old with serious underlying diseases (https://www.cdc.gov/elizabethkingia/outbreaks/). We report here two cases of E. anophelis infection at Quanzhou First Hospital, Fujian, China.\n\nCase presentation\nCase 1\nAn 82-year-old male patient presenting with lethargy in consciousness, malnutrition, multiple bedsores [an 8 × 10 cm2 at level I (containing a 5 × 6 cm2 at level II) on the sacrococcygeal region, two 5 × 5 cm2 at level I on the both heel, two 2 × 2 cm2 at level I on both external malleolus] was admitted on December 14, 2009. He had a history of surgery for esophagus cancer at 73 years old, hypertension at level III, two hospitalizations due to lower respiratory tract infections (treated by azithromycin, cefoperazone/tazobactam, levofloxacin, meropenem, linezolid, piperacillin/tazobactam, and ciprofloxacin) 4 months before this final hospitalization. He demonstrated expectoration and shortness of breath for 7 days before admission. The blood gas analysis and blood biochemical test at admission showed respiratory acidosis (pCO2 97 mm Hg, pO2 122 mm Hg), metabolic alkalosis (pH 7.48, HCO3- > 60 mmol/L, CO2 36.8 mmol/L), very low blood K+ (2.1 mmol/L), renal dysfunction (BUN 23.9 mmol/L), and extremely low Cl− (68.6 mmol/L). He came into deep coma with BP 58/34 mmHg within 2 h after admission. Emergency salvage was given, including assisted ventilation, raising BP by dopamine and L-noradrenaline, supplement of potassium chloride, and anti-infection treatment with piperacillin/tazobactam and ciprofloxacin. In the subsequent 2 days, he recovered from coma gradually, but presented clear sign of lung infection (fever, moist rale sound in both sides of lower lung lobes, blood WBC 9.8 × 109/L, NEUT 94.61%, CRP 146 mg/L). Diagnoses of shock, multiple organ dysfunction syndrome (MODS), and lower respiratory tract infection were made. The infection and the respiratory acidosis combined with metabolic alkalosis lasted for nearly the whole 52 day-hospitalization. On the 45th day of hospitalization, a fistula between the esophagus and trachea was found through gastroscopy and further verified by bronchoscopy. It was treated with tracheal stenting 2 days later. However, 5 h after post-tracheal stenting, sudden cardiac arrest occurred, complicated with a loss of spontaneous breathing, then he went into coma (combined with dilated pupils and disappeared light reflex of both sides) again. BP and SpO2 could not be measured while his pulse and spontaneous breathing returned 5 min after salvage. BP, SpO2, and light reflex of both pupils returned to normal gradually within the subsequent 5 h. However, the patient was still in coma and was discharged after 7 days at his family's request to terminate treatment.\n\nDuring the hospitalization, the separately or jointed isolated pathogenic microbes for the lung infection included Acinetobacter calcoaceticus–Acinetobacter baumannii complex (7 times isolated from sputum, 7 TIFS), Acinetobacter baumannii (4 TIFS), Enterobacter cloacae (3 TIFS), Pseudomonas aeruginosa (2 TIFS), Serratia marcescens (2 TIFS), molds (2 TIFS), and E. anophelis (7 TIFS) (named as 12012 PRCM). E. anopheles 12012 PRCM was verified by 16S rRNA gene sequencing (GenBank accession no. KR349263) of the genomic DNA with the forward primer 27F (5′-AGAGTTTGATCCTGGCTCAG-3′) and the reverse primer 1492R (5′-GGTTACCTTGTTACGACTT-3′; Lane, 1991). It was resistant to all the 20 antibiotics in the antibiotic susceptibility tests (AST) panel, including β-lactams (ampicillin, piperacillin, ampicillin-sulbactam, piperacillin-tazobactam, ceftazidime, cefotaxime, cephazolin, cefepime, aztreonam, imipenem, and meropenem), aminoglycosides (amikacin, gentamicin), tetracycline, chloramphenicol, and polymyxin, quinolones (ciprofloxacin, levofloxacin, moxifloxacin), and sulfamethoxazole-trimethoprim. The strain was also resistant to another antibiotic amoxicillin-clavulanate tested. To investigate the resistance mechanisms, extended spectrum β-lactamase (ESBL) detection was performed on the E. anophelis 12012 PRCM using BD's PhoenixTM-100 Automated Microbiology System with the NMIC/ID-4 panel (Becton, Dickinson, and Company; Stefaniuk et al., 2003; Liu et al., 2005). The cephalosporin test was positive and the carbapenem-hydrolyzing β-lactamases and carbapenemases (CHBLs) were detected. In addition, we found this strain was co-positive between EDTA (Ethylenediaminetetraacetic acid) and imipenem. These laboratory findings indicated strain 12012 PRCM could produce metal-beta-lactamase, possibly conferring the β-lactamases resistance.\n\nCase 2\nA 47-year-old male with hypotension (BP 95/55 mmHg) was admitted to our hospital on August 21, 2015. He had history of exacerbated abdominal pain and abdominal distension for more than 10 days, shortness of breath for 3 days, complicated with stagnated exhaust and defecation. Before admission, his pressure was maintained by continuous pumping of L-noradrenaline and dopamine. Physical examination found weak breath sounds in both sides of lung lobes and severe subcutaneous edema on whole body. The arterial blood gas analysis displayed acidosis (pH 7.20, pCO2 11.1 mmHg, pO2 99 mmHg, HCO3- −8.6 mmol/L, BE −23.3 mmol/L). He had a low white blood cell count (WBC) (2.35 × 109/L). Blood biochemical test showed several abnormal results (glucose 8.86 mmol/L, BUN 18.93 mmol/L, creatinine 271 μmol/L, GFR 24.20 ml/min, AST 827 U/L, ALT 197 U/L, albumin 30.5 g/L, T-BIL 29.5 μmol/L, D-BIL 12.8 μmol/L, total osmotic pressure 280 mOsm/L). Ultrasound imaging demonstrated liver cirrhosis, echo enhancement in parenchyma of both kidneys and effusion around left renal. Computed tomography scanning revealed inflammatory changes within both sides of the lower lung lobes, severe effusion within bilateral pleural, abdominal, and pelvic cavity, edema within subcutaneous soft tissue of chest and abdominal wall. Diagnoses of shock, MODS, electrolyte imbalances (low sodium, low calcium), diabetes and pulmonary infection were made. Within 16 h after admission, the patient further presented oliguria and aggravated during the 12-day hospitalization. On the 3rd day, hepatic virus infection [with positive HBsAg, anti-HBe antibody, and anti-HBc antibody (IgG)], abnormal blood coagulation [prothrombin time (PT) 16.7 s, partial prothrombin time (APTT) 67.8 s, fibrinogen (FIB) 1.75 g/L, D-dimer 8.32 mg/L, international normalized ratio (INR) 1.43], and thrombocytopenia (84 × 109/L) were diagnosed, with the latter lasting for the remaining hospitalization. The treatment strategies included drainage of bilateral pleural effusion, maintaining blood pressure as previously, improving liver function, daily hemodialysis, management of electrolyte, insulin injection and improving nutrition. The empirical antimicrobial therapy was started with IV piperacillin and tazobactam during the first 3 days of hospitalization, then changed to IV imipenem and cilastatin sodium for 1 day and further combined with vancomycin; the latter lasted for the remaining 8 days of hospitalization. The patient died of sudden cardiac arrest.\n\nBy using BD's Phoenix™-100 Automated Microbiology System with the NMIC/ID-4 panel as Case 1, we repeatedly isolate E. meningoseptica (on the 7th and 9th day of hospitalization respectively) and Stenotrophomonas maltophilia (on the 8th and 9th day of hospitalization respectively) from sputum cultures. Later, E. meningoseptica was verified as E. anophels (named as N107618, GenBank accession No. KX775952) by 16S rRNA gene sequencing as Case 1. E. anophelis N107618 was resistant to 16 out of 20 antibiotics in the same AST panel used to test the E. anophelis 12012 PRCM, and was only susceptible to ciprofloxacin, levofloxacin, moxifloxacin, and sulfamethoxazole-trimethoprim.\n\nDiscussion\nE. anophelis was an opportunistic pathogen but it could result in a high mortality rate (Teo et al., 2013; Lau et al., 2016; https://www.cdc.gov/elizabethkingia/outbreaks/). The number of E. anophelis infections was possibly underestimated because E. anophelis were often misidentified as E. meningoseptica by conventional identification methods (Kämpfer et al., 2011; Teo et al., 2013, 2014; Nicholson et al., 2016). Identification of E. anophelis by the matrix assisted laser desorption-ionization time-of-flight (MALDI-TOF) mass spectrometry will be helpful if E. anophelis reference is added in the database (Teo et al., 2013; Lau et al., 2016). 16S rRNA gene sequencing should be performed as a routine bacterial identification tool in the medical laboratories without MALDI-TOF mass spectrometry (Teo et al., 2013; Lau et al., 2016).\n\nThe high mortality rate of E. anophelis infection was partly due to its property of multidrug-resistance. E. anophelis N107618 was resistant to 16 out of 20 antibiotics while strain 12012 PRCM was resistant to all the 20 antibiotics in the AST panel, indicating that our two clinical E. anophelis isolates were multidrug-resistant. Furthermore, our tests showed that the isolate E. anophelis 12012 PRCM produced metallo-beta-lactamase(s). β-lactams resistance has been shown in many clinical important Elizabethkingia isolates (Frank et al., 2013; Lau et al., 2015, 2016). Notably, all clinical E. anophelis isolates, except for our strain 12012 PRCM, were susceptible to one or more quinolones such as ciprofloxacin or moxifloxacin (Frank et al., 2013; Lau et al., 2015). Therefore, ciprofloxacin or moxifloxacin might be considered as empirical antibiotic therapy of E. anophelis infections. For example, Frank et al. reported that a clinical isolate was resistant to all β-lactams tested (amoxicillin, cefotaxime, ceftazidime, cefepime, and imipenem) except for piperacillin and aminoglycosides (amikacin, tobramycin, and gentamicin) while it was susceptible to moxifloxacin (Frank et al., 2013). Similarly, three clinical E. anophelis strains were resistant to β-lactams aminoglycosides, tetracycline, and chloramphenicol while they were susceptible to pipercillin, cefoperazone-sulbactam, trimethoprim-sulfamethoxazole, ciprofloxacin, moxifloxacin, and rifampin (Lau et al., 2015). Moreover, the survey of 17 E. anophelis bacteremia demonstrated that they were resistant or intermediate-resistant to imipenem, amikacin, gentamicin, and tobramycin, but they were susceptible to ceftazidime, piperacillin, and rifampicin (Lau et al., 2016).\n\nNext generation sequencing (NGS) techniques greatly contribute to our understanding of drug resistance and infectivity of E. anophelis. For example, 16 and 19 antibiotic resistance genes were found from the core and accessory genomes of E. anophelis, respectively (Teo et al., 2014). The genome of E. anophelis NUHP1 contained 14 antibiotic resistant genes that correlated to its multi-drug resistance (Li et al., 2015). Breurec et al. reported that at least 17 antimicrobial resistance genes in E. anophelis consisted of metallo-beta-lactamase genes blablaB and blaGOB (conferring β-lactams resistance), subclass B1 beta-lactamase gene, efflux systems, conserved chloramphenicol acetyltransferase (CAT and AAC3-I) gene, a tetX gene (encoding for a tetracycline inactivating enzyme) and LinF gene (encoding lincosamide resistance protein; Breurec et al., 2016). Genome sequencing analysis showed that E. anophelis processed virulence genes encoding cell wall hydrolase A, listeriolysin O (LLO), phospholipase (PlcA), virulence cluster protein B (VclB), and arylsulfatase (Lau et al., 2015; Breurec et al., 2016). These virulence factors possibly contribute to the invading of the host, escape from phagocytosis, surviving in the secondary vacuole of macrophages, and propagating in bloodstreams (Lau et al., 2015; Breurec et al., 2016).\n\nConclusion\nE. anophelis is an emerging opportunistic pathogen. It often leads to a high mortality rate because of its multiple antibiotic resistance. Therefore, E. anophelis infections should be considered clinically significant. Investigation of antibiotic resistance mechanisms are warranted.\n\nEthics statement\nThe written informed consents were obtained from the patients or their relatives/guardians. This work was already approved by the Ethics Committee of Quanzhou First Hospital.\n\nAuthor contributions\nSH and TJ contributed equally to this work. All of authors wrote the papers. SH conducted the test. MW, DM, and SC guided the testing and experiments.\n\nConflict of interest statement\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nThis work was supported by Huaqiao University Graduate Student Scientific Research Innovation Ability Cultivation Plan Projects, the Fong Shu Fook Tong and Fong Yun Wah Foundations (14X30127), the Xiamen Southern Oceanographic Center (14GYY008NF08), the Natural Science Fund Project of Fujian Province (2015J01514), the Technology Planning Projects of Quanzhou Social Development Fields (2014Z24), and the Major Support Research Project of National Key Colleges Construction of Quanzhou Medical College (2013A13).\n==== Refs\nReferences\nBalm M. N. Salmon S. Jureen R. Teo C. Mahdi R. Seetoh T. . (2013 ). 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Steritz M. . (2013 ). Draft genome sequences of Elizabethkingia anophelis strains R26T and Ag1 from the midgut of the malaria mosquito Anopheles gambiae . Genome Announc. \n1 , e01030 –e01013 . 10.1128/genomeA.01030-13 24309745 \nKukutla P. Lindberg B. G. Pei D. Rayl M. Yu W. Steritz M. . (2014 ). Insights from the genome annotation of Elizabethkingia anophelis from the malaria vector Anopheles gambiae . PLoS ONE \n9 :e97715 . 10.1371/journal.pone.0097715 24842809 \nLane D. J. (1991 ). 16S/23S rRNA sequencing , in Nucleic Acid Techniques in Bacterial Systematics , eds Stackebrandt E. Goodfellow M. (Chichester : John Wiley & Sons ), 115 –175 .\nLau S. K. Chow W. N. Foo C. H. Curreem S. O. Lo G. C. Teng J. L. . (2016 ). Elizabethkingia anophelis bacteremia is associated with clinically significant infections and high mortality . Sci. Rep. \n6 :26045 . 10.1038/srep26045 27185741 \nLau S. K. Wu A. K. Teng J. L. Tse H. Curreem S. O. Tsui S. K. . (2015 ). Evidence for Elizabethkingia anophelis transmission from mother to infant, Hong Kong . Emerg. Infect. Dis. \n21 , 232 –241 . 10.3201/eid2102.140623 25625669 \nLi Y. Liu Y. Chew S. C. Tay M. Salido M. M. Teo J. . (2015 ). Complete genome sequence and transcriptomic analysis of the novel pathogen Elizabethkingia anophelis in response to oxidative stress . Genome Biol. Evol. \n7 , 1676 –1685 . 10.1093/gbe/evv101 26019164 \nLiu Z. K. Ling T. K. Cheng A. F. (2005 ). Evaluation of the BD phoenix automated microbiology system for identification and antimicrobial susceptibility testing of common clinical isolates . Med. Princ. Pract. \n14 , 250 –254 . 10.1159/000085744 15961935 \nNicholson A. C. Whitney A. M. Emery B. D. Bell M. E. Gartin J. T. Humrighouse B. W. . (2016 ). Complete genome sequences of four strains from the 2015-2016 Elizabethkingia anophelis outbreak . Genome Announc. \n4 , e00563 –00564 . 10.1128/genomeA.00563-16 27313304 \nStefaniuk E. Baraniak A. Gniadkowski M. Hryniewicz W. (2003 ). Evaluation of the BD Phoenix automated identification and susceptibility testing system in clinical microbiology laboratory practice . Eur. J. Clin. Microbiol. Infect. Dis. \n22 , 479 –485 . 10.1007/s10096-003-0962-y 12884060 \nTeo J. Tan S. Y. Liu Y. Tay M. Ding Y. Li Y. . (2014 ). Comparative genomic analysis of malaria mosquito vector-associated novel pathogen Elizabethkingia anophelis . Genome Biol. Evol. \n6 , 1158 –1165 . 10.1093/gbe/evu094 24803570 \nTeo J. Tan S. Y. Tay M. Ding W. Kjelleberg S. Givskov M. . (2013 ). First case of E. anophelis outbreak in an intensive-care unit . Lancet \n382 , 855 –856 . 10.1016/S0140-6736(13)61858-9 24012265\n\n", "fulltext_license": "CC BY", "issn_linking": "1664-302X", "issue": "8()", "journal": "Frontiers in microbiology", "keywords": "E. anophelis; antibiotics resistance; emerging pathogen; lower respiratory tract infection; multiple organ dysfunction syndrome", "medline_ta": "Front Microbiol", "mesh_terms": null, "nlm_unique_id": "101548977", "other_id": null, "pages": "382", "pmc": null, "pmid": "28337189", "pubdate": "2017", "publication_types": "D002363:Case Reports", "references": "12884060;24803570;24309745;15961935;23706804;24842809;23958153;27185741;21169462;24012265;25625669;27461509;27313304;26019164", "title": "Elizabethkingia anophelis Isolated from Patients with Multiple Organ Dysfunction Syndrome and Lower Respiratory Tract Infection: Report of Two Cases and Literature Review.", "title_normalized": "elizabethkingia anophelis isolated from patients with multiple organ dysfunction syndrome and lower 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"reactionmeddraversionpt": "19.1", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "HU S, JIANG T, ZHANG X, ZHOU Y, YI Z, WANG Y, ZHAO S, WANG M, MING D, CHEN S. ELIZABETHKINGIA ANOPHELIS ISOLATED FROM PATIENTS WITH MULTIPLE ORGAN DYSFUNCTION SYNDROME AND LOWER RESPIRATORY TRACT INFECTION: REPORT OF TWO CASES AND LITERATURE REVIEW. FRONTIERS IN MICROBIOLOGY. 2017;8:XX", "literaturereference_normalized": "elizabethkingia anophelis isolated from patients with multiple organ dysfunction syndrome and lower respiratory tract infection report of two cases and literature review", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20170321", "receivedate": "20170321", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13356174, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20170429" } ]
{ "abstract": "We describe our experience, gained over the past 3 years, in the treatment of gastroesophageal junction adenocarcinoma, whose incidence has been increasing in recent years. In our series, we present the results to a follow-up of about 2 years for a total of 18 patients, treated with a particularly intensive combination treatment. It consists of neoadjuvant induction chemotherapy with the protocol docetaxel-cisplatin-5-fluorouracil for four cycles, before a concomitant chemoradiotherapy treatment. During combined phase, patients received an intensity-modulated radiotherapy and a weekly cisplatin. We will present the data to a long follow-up time and we will discuss the literature, the integration with thoracoabdominal surgery and other specific issues of this pathology.", "affiliations": "UOC Radiodiagnostica e Radioterapia, AOU Policlinico-VE di Catania, 95125, Italy.;UOC Radiodiagnostica e Radioterapia, AOU Policlinico-VE di Catania, 95125, Italy.;UOC Radiodiagnostica e Radioterapia, AOU Policlinico-VE di Catania, 95125, Italy.;UOC Radiodiagnostica e Radioterapia, AOU Policlinico-VE di Catania, 95125, Italy.;UOC Radiodiagnostica e Radioterapia, AOU Policlinico-VE di Catania, 95125, Italy.;UOC Radiodiagnostica e Radioterapia, AOU Policlinico-VE di Catania, 95125, Italy.;UOC Radiodiagnostica e Radioterapia, AOU Policlinico-VE di Catania, 95125, Italy.;UOC Chirurgia Toracica, AOU Policlinico-VE Catania, Italy.;UOC Radiodiagnostica e Radioterapia, AOU Policlinico-VE di Catania, 95125, Italy.;UOC Chirurgia Digerente e colo-rettale, AOU Policlinico-VE Catania, Italy.;UOC Radioterapia AOE Cannizzaro Catania, Italy.;UOC Radiodiagnostica e Radioterapia, AOU Policlinico-VE di Catania, 95125, Italy.", "authors": "Spatola\|Corrado\|C\|;Tocco\|Alessandra\|A\|;Pagana\|Antonio\|A\|;Milazzotto\|Roberto\|R\|;Luigi\|Raffaele\|R\|;Salamone\|Vincenzo\|V\|;Militello\|Carmelo\|C\|;Migliore\|Marcello\|M\|;Foti\|Pietro Valerio\|PV\|;Cataldo\|Antonio Di\|AD\|;Acquaviva\|Grazia\|G\|;Privitera\|Giuseppe\|G\|", "chemical_list": "D043823:Taxoids", "country": "England", "delete": false, "doi": "10.2217/fon-2017-0342", "fulltext": null, "fulltext_license": null, "issn_linking": "1479-6694", "issue": "14(6s)", "journal": "Future oncology (London, England)", "keywords": "gastroesophageal junction adenocarcinoma; intensity-modulated radiotherapy; simultaneous integrated boost", "medline_ta": "Future Oncol", "mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D059248:Chemoradiotherapy; D018572:Disease-Free Survival; D004938:Esophageal Neoplasms; D004943:Esophagogastric Junction; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D011829:Radiation Dosage; D050397:Radiotherapy, Intensity-Modulated; D013274:Stomach Neoplasms; D043823:Taxoids; D014057:Tomography, X-Ray Computed", "nlm_unique_id": "101256629", "other_id": null, "pages": "47-51", "pmc": null, "pmid": "29664354", "pubdate": "2018-03", "publication_types": "D016428:Journal Article", "references": null, "title": "Combined taxane-based chemotherapy and intensity-modulated radiotherapy with simultaneous integrated boost for gastroesophageal junction adenocarcinoma.", "title_normalized": "combined taxane based chemotherapy and intensity modulated radiotherapy with simultaneous integrated boost for gastroesophageal junction adenocarcinoma" }	[ { "companynumb": "PHHY2018IT006802", 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"drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SPATOLA C, TOCCO A, PAGANA A, MILAZZOTTO R, LUIGI R, SALAMONE V ET AL.. COMBINED TAXANE-BASED CHEMOTHERAPY AND INTENSITY-MODULATED RADIOTHERAPY WITH SIMULTANEOUS INTEGRATED BOOST FOR GASTROESOPHAGEAL JUNCTION ADENOCARCINOMA. 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{ "abstract": "Lung is the most common site of distant metastasis for patients with head and neck squamous cell carcinoma (HNSCC). However, differentiating second primary lung cancers from metastasis may be difficult for p16 negative HNSCC.\n\n\n\nWe describe a case of oral cavity squamous cell carcinoma (SCC) who was found to have lung nodule and hilar lymphadenopathy (LAD) after surgery and radiation therapy. Hilar node was consistent with SCC however, it was difficult to differentiate second primary lung cancer and metastasis from oral cavity SCC. Next-generation sequencing was done for the primary oral cavity and the hilar node. Both samples had the same type of TP53 mutation and variants of unknown significance suggesting metastatic HNSCC. He was treated with a chemotherapy regimen for metastatic HNSCC.\n\n\n\nMolecular studies can help to differentiate metastasis from second primary lung cancers for p16 negative HNSCC.", "affiliations": "Department of Hematology and Medical Oncology, Cleveland Clinic, Cleveland, Ohio, USA.;Department of Radiation Oncology, University of Kansas Medical Center, Kansas City, Kansas, USA.;University of New Mexico Comprehensive Cancer Center, University of New Mexico, Albuquerque, New Mexico, USA.;University of New Mexico Comprehensive Cancer Center, University of New Mexico, Albuquerque, New Mexico, USA.;Department of Pathology, University of New Mexico, Albuquerque, New Mexico, USA.", "authors": "Yilmaz\|Emrullah\|E\|0000-0003-2308-713X;Gan\|Gregory N\|GN\|;Schroeder\|Thomas M\|TM\|;Cowan\|Andrew\|A\|;Joste\|Nancy\|N\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1002/cnr2.1363", "fulltext": "\n==== Front\nCancer Rep (Hoboken)\nCancer Rep (Hoboken)\n10.1002/(ISSN)2573-8348\nCNR2\nCancer Reports\n2573-8348\nJohn Wiley and Sons Inc. Hoboken\n\n34161676\n10.1002/cnr2.1363\nCNR21363\nCase Report\nCase Reports\nRole of molecular signature to differentiate second primary lung cancer from metastasis in a patient with squamous cell carcinoma of oral cavity\nYilmaz et al.\nYilmaz Emrullah https://orcid.org/0000-0003-2308-713X\n1 [email protected]\n\nGan Gregory N. 2\nSchroeder Thomas M. 3\nCowan Andrew 3\nJoste Nancy 4\n1 Department of Hematology and Medical Oncology Cleveland Clinic Cleveland Ohio USA\n2 Department of Radiation Oncology University of Kansas Medical Center Kansas City Kansas USA\n3 University of New Mexico Comprehensive Cancer Center University of New Mexico Albuquerque New Mexico USA\n4 Department of Pathology University of New Mexico Albuquerque New Mexico USA\n* Correspondence\nEmrullah Yilmaz, MD, PhD, Department of Hematology and Medical Oncologt, Cleveland Clinic, Cleveland, OH.\nEmail: [email protected]\n\n23 6 2021\n8 2021\n4 4 10.1002/cnr2.v4.4 e136331 1 2021\n09 10 2020\n22 2 2021\n© 2021 The Authors. Cancer Reports published by Wiley Periodicals LLC.\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.\n\nAbstract\n\nBackground\n\nLung is the most common site of distant metastasis for patients with head and neck squamous cell carcinoma (HNSCC). However, differentiating second primary lung cancers from metastasis may be difficult for p16 negative HNSCC.\n\nCase\n\nWe describe a case of oral cavity squamous cell carcinoma (SCC) who was found to have lung nodule and hilar lymphadenopathy (LAD) after surgery and radiation therapy. Hilar node was consistent with SCC however, it was difficult to differentiate second primary lung cancer and metastasis from oral cavity SCC.\n\nNext‐generation sequencing was done for the primary oral cavity and the hilar node. Both samples had the same type of TP53 mutation and variants of unknown significance suggesting metastatic HNSCC. He was treated with a chemotherapy regimen for metastatic HNSCC.\n\nConclusion\n\nMolecular studies can help to differentiate metastasis from second primary lung cancers for p16 negative HNSCC.\n\nhead and neck cancer\nlung cancer\nlung metastasis\nmolecular signature\nsource-schema-version-number2.0\ncover-dateAugust 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.6 mode:remove_FC converted:26.08.2021\nYilmazE, GanGN, SchroederTM, CowanA, JosteN. Role of molecular signature to differentiate second primary lung cancer from metastasis in a patient with squamous cell carcinoma of oral cavity. Cancer Reports. 2021;4 :e1363. 10.1002/cnr2.1363\n==== Body\n1 INTRODUCTION\n\nHead and neck squamous cell carcinoma (HNSCC) patients are at risk for developing both lung metastasis and second primary lung squamous cell carcinoma.1, 2 P16 immunohistochemistry (IHC) can help to differentiate the metastasis vs the second primary if the primary HNSCC is human papilloma virus (HPV) related.3 However, diagnosis is more challenging for HPV‐unrelated, p16 negative HNSCC. The role of the IHC is limited to distinguish second primary lung SCC. Thyroid transcription factor 1 (TTF‐1) can be positive in 7%‐10% of primary lung carcinoma, and not found in head and neck cancer.4 An algorithm using cytokeratin 19 (CK19), matrix metallopeptidase 3 (MMP3), and peptidase inhibitor 3 (PI3) IHC was suggested to help differentiate metastasis from second lung primary SCC.5 Loss of heterozygosity and TP53 mutations were found to be stable during tumor progression in HNSCC.6 Therefore LOH and TP53 status were suggested as markers to diagnose metastasis in retrospective studies.6, 7, 8 In the era of molecular studies, we suggest that molecular profiling can help to differentiate metastasis vs the second primary for HPV negative cancers for these cancers. Here, we present the use of comprehensive molecular profiling in a patient with squamous cell carcinoma (SCC) of the oral cavity.\n\n2 CASE REPORT\n\nA 67‐year‐old male presented with an ulcer in the right ventral tongue, approximately 2 cm in the greatest dimension. He was then found to have SCC of the tongue, which immunohistochemical staining showed to be p16 negative. (Figure 1) He underwent right partial glossectomy with skin graft reconstruction and selective neck dissection, pathology was pT1N2b with negative margins and no extranodal extension. He then received adjuvant radiotherapy. His post‐treatment positron emission tomography (PET) showed a metabolic response in the neck, but a new spiculated right lower lobe mass and hilar and subcarinal nodes were found. (Figure 2) Fine needle aspiration (FNA) from the hilar node showed malignant squamous cells. IHC demonstrated strong staining of the tumor with cytokeratin 5 and p40 and no staining with TTF‐1, napsin A, and p16, Therefore cytology was consistent squamous cell carcinoma, however unable to exclude a second primary right lung SCC with hilar node involvement. Next‐generation sequencing (NGS) with FoundationOne was performed for both primary tongue tumor and hilar lymph node.\n\nFIGURE 1 Invasive squamous cell carcinoma involving the tongue. A, infiltrating nests of squamous cell carcinoma (H&E, ×200); B, p16 immunostain with negative staining (×200)\n\nFIGURE 2 PET/CT showing right lung nodule A, and right hilar lymph node B. CT imaging of the spiculated lung nodule C\n\nBoth specimens had the same TP53 (R273H) and BRCA2 (W563) mutations. The specimen from the hilar lymph node had FAT1 (Q1138) and TERT promoter (−124C > T) mutations in addition to TP53 and BRCA2. BRCA2 allele frequency was 50% suggesting germline mutation. His family history of cancer included his mother with multiple myeloma and his father with lung cancer and melanoma. So, the patient was referred to genetics and a blood test confirmed germline BRCA2 mutation. The variants of unknown significance (VUS) were also identical in both specimens. (Table 1) Having the identical TP53 mutation and VUS in both specimens was consistent with metastatic disease from SCC of the tongue. The patient was treated with carboplatin/5‐Fluorouracil (5‐FU) and cetuximab with initial partial response in lung nodule and hilar lymph node however, he subsequently had progression with bone metastasis. He was briefly on olaparib, and then pembrolizumab without response so he transitioned to hospice.\n\nTABLE 1 Genomic alterations and variants of unknown significance found in primary tongue lesion and hilar lymph node\n\n\tTongue lesion\tHilar lymph node\t\nGenomic alteration\tTP53 R273H\n\nBRCA2 W563\n\n\tTP53 R273H\n\nBRCA2 W563\n\nFAT1 Q1138\n\nTERT promoter −124C > T\n\n\t\nVariants of unknown significance\tJUN T239I\n\nMYST3 I729L\n\nNOTCH3 C1222G\n\nRAF1 A237G\n\nSRC K106R\n\nSUFU R289Q\n\n\tJUN T239I\n\nMYST3 I1729L\n\nNOTCH3 C1222G\n\nRAF1 A237G\n\nSRC K106R\n\nSUFU R289Q\n\n\t\n\n3 DISCUSSION\n\nLung is the most common site of distant metastasis in HNSCC. Given the high incidence of second primary lung squamous cell carcinoma in patients with HNSCC, differentiating the second primary from metastasis helps to identify the next line of treatment. Clinical features can help to guide the treatment. Lung metastasis from HNSCC usually presents as smoothly defined multiple lesions whereas lung cancer is usually a single spiculated lung nodule.9 Our patient had a spiculated lung nodule with associated hilar LAD suspicious for second primary lung cancer. On the other hand, his lung finding was seen within 6 months of the initial surgery and he had no tobacco smoking or alcohol history. Recurrence risk in HNSCC is higher in the first year of the initial treatment.10 Tobacco smoking increases the risk of the second primary malignancies in HNSCC patients.11 However, a recent study using the TP53 mutation status to differentiate metastasis from second primary lung malignancies suggested that 55% of the patients received incorrect treatments based on clinical and immunohistochemical data.8 Molecular alterations in pathways affecting the cell cycle, cell death, DNA repair mechanism, and cell differentiation are common in HNSCC.12 Incorporation of molecular profiling of the HPV negative HNSCC can help to distinguish second primary lung cancer from metastasis. (Figure 3) Molecular signature with clinical presentation supporting the metastasis from HNSCC, our patient received systemic treatment for metastatic HNSCC.\n\nFIGURE 3 A suggested approach to biopsy from suspicious lung nodule or mediastinal lymph node biopsy in head and neck squamous cell carcinoma\n\nInterestingly, our patient had FAT1 and TERT promoter mutations in the metastatic tumor, while they were not observed in the primary tumor FAT1 mutation was observed in 21.7% of the HNSCC samples in The Cancer Genome Atlas (TCGA) database.12 FAT1 is known to have a role in cell migration and EMT.13, 14 TERT promoter mutations are common in solid tumors and associated with metastasis and poor survival.15, 16 Although the tumor heterogeneity could have played a role in the lack of FAT1 and TERT promoter mutations in the primary tumor; similar allele frequency with the TP53 mutation in both samples suggests the same clone with the primary tumor. As FAT1 and TERT are both known to be associated with cell migration and metastasis; the subclones with these two mutations could have been selected following radiation to drive the metastasis. Analysis of larger cohorts to differentiate the molecular characteristics of primary tumor and metastasis for HNSCC might help to identify mechanisms of metastasis.\n\nSomatic mutations of the BRCA2 gene can be seen in up to 9% of HNSCC.17 However, germline mutations can also be identified using NGS.18, 19 This also brings ethical considerations to share with patients incidental findings from NGS. Our patient knew about the risk of BRCA2 and hereditary cancer risk and since he had 50% BRCA2 allele frequency, he consented for genetics counseling which confirmed germline BRCA2 mutations. Germline BRCA2 mutation has been identified in SCC of the esophagus and lung.20, 21 Poly (ADP‐ribose) polymerase (PARP) inhibitors are used in ovarian, breast, and pancreatic cancer patients with germline BRCA mutations.22, 23, 24 However, the role of the PARP inhibitors in other solid tumors with uncommon germline BRCA mutations is not well known. Our patient was briefly on PARP inhibitor without response.\n\nTo summarize, the molecular signature of primary HNSCC tumor and hilar node led to three observations in our patient: (a) Molecular signature may help to identify metastasis from second primary lung cancer for p16 negative HNSCC, (b) Further studies needed to identify differences in molecular signatures of primary tumor and metastasis of HNSCC, which may help to better understanding and therapeutics strategies for metastasis, (c) Increased use of NGS may increase identification of germline mutations.\n\nCONFLICT OF INTEREST\n\nNone of the authors have a conflict of interest to declare.\n\nAUTHOR CONTRIBUTIONS\n\nGregory N Gan: Conceptualization; writing‐review and editing. Thomas M Schroeder: Conceptualization; writing‐review and editing. Andrew Cowan: Conceptualization; writing‐review and editing. Nancy Joste: Conceptualization; data curation; formal analysis; writing‐review and editing.\n\nETHICS STATEMENT\n\nThe patient was not alive at the time of the manuscript submission and he did not have contact information for next of kin documented in his medical records, therefore we were unable to obtain a written informed consent. This case study was reviewed by the University of New Mexico Human Research Review Committee (HRRC). The HRRC determined that the proposed activity is not research involving human subjects. HRRC review and approval is not required.\n\nDATA AVAILABILITY STATEMENT\n\nThe data that support the findings of this study are available from the corresponding author upon reasonable request.\n==== Refs\nREFERENCES\n\n1 BudnikJ, DeNunzioNJ, SinghDP, MilanoMT. Second primary non‐small‐cell lung cancer after head and neck cancer: a population‐based study of clinical and pathologic characteristics and survival outcomes in 3597 patients. 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N Engl J Med. 2019;381 (4 ):317‐327.31157963\n\n", "fulltext_license": "CC BY", "issn_linking": "2573-8348", "issue": "4(4)", "journal": "Cancer reports (Hoboken, N.J.)", "keywords": "head and neck cancer; lung cancer; lung metastasis; molecular signature", "medline_ta": "Cancer Rep (Hoboken)", "mesh_terms": null, "nlm_unique_id": "101747728", "other_id": null, "pages": "e1363", "pmc": null, "pmid": "34161676", "pubdate": "2021-08", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "31400079;26614708;23354438;29749098;31481248;26723501;27597287;28578601;31565484;15536619;30914310;11793443;28949800;25631445;34161676;29522268;21617878;10679659;31157963;16847186;26350882;17724471;18318581;30170373", "title": "Role of molecular signature to differentiate second primary lung cancer from metastasis in a patient with squamous cell carcinoma of oral cavity.", "title_normalized": "role of molecular signature to differentiate second primary lung cancer from metastasis in a patient with squamous cell carcinoma of oral cavity" }	[ { "companynumb": "US-009507513-2112USA005639", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PEMBROLIZUMAB" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "125514", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Powder for injection", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Squamous cell carcinoma of the oral cavity", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KEYTRUDA" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OLAPARIB" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Tablet", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Squamous cell carcinoma of the oral cavity", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLAPARIB" } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Therapy non-responder", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Yilmaz E, Gan GN, Schroeder TM ,Cowan A, Joste N. Role of molecular signature to differentiate second primary lung cancer from metastasis in a patient with squamous cell carcinoma of oral cavity. Cancer Reports. 2021;4:e1363", "literaturereference_normalized": "role of molecular signature to differentiate second primary lung cancer from metastasis in a patient with squamous cell carcinoma of oral cavity", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20211218", "receivedate": "20211218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20202572, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220303" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-330096", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "77926", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Chemotherapy", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Chemotherapy", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUOROURACIL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CETUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Chemotherapy", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CETUXIMAB" } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Metastases to bone", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Yilmaz E, Gan GN, Schroeder TM, Cowan A, Joste N. Role of molecular signature to differentiate second primary lung cancer from metastasis in a patient with squamous cell carcinoma of oral cavity. Cancer Rep. 2021;4(4):e1363", "literaturereference_normalized": "role of molecular signature to differentiate second primary lung cancer from metastasis in a patient with squamous cell carcinoma of oral cavity", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220325", "receivedate": "20220325", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20636560, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220424" } ]
{ "abstract": "A longer duration of untreated psychosis (DUP) has been linked with poor clinical outcomes and variation in resting-state striatal connectivity with central executive regions. However, the link between DUP and task-based activation of executive neurocognition has not previously been examined. This functional magnetic resonance imaging study examined the association between DUP and both activation and frontostriatal functional connectivity during a visual working memory (WM) paradigm in patients with first-episode psychosis.\n\n\n\nPatients with first-episode psychosis (n = 37) underwent functional magnetic resonance imaging scanning while performing a visual WM task. At the single-subject level, task conditions were modeled; at the group level, each condition was examined along with DUP. Activation was examined within the dorsolateral prefrontal cortex, a primary region supporting visual WM activation. Frontostriatal functional connectivity during the WM was examined via psychophysical interaction between the dorsal caudate and the dorsolateral prefrontal cortex. Results were compared with a reference range of connectivity values in a matched group of healthy volunteers (n = 25). Task performance was also examined in relation to neuroimaging findings.\n\n\n\nNo significant association was observed between DUP and WM activation. Longer DUP showed less functional frontostriatal connectivity with the maintenance of increasing WM load. Results were not related to task performance measures, consistent with previous work.\n\n\n\nOur data suggest that DUP may affect frontostriatal circuitry that supports executive functioning. Future work is necessary to examine if these findings contribute to the mechanism underlying the relationship between DUP and worsened clinical outcomes.", "affiliations": "Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania.;Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania.;Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania.;Department of Psychology, Temple University, Philadelphia, Pennsylvania.;Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania.;Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania.;Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Psychology, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania.;Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania. Electronic address: [email protected].", "authors": "Manivannan\|Ashwinee\|A\|;Foran\|William\|W\|;Jalbrzikowski\|Maria\|M\|;Murty\|Vishnu P\|VP\|;Haas\|Gretchen L\|GL\|;Tarcijonas\|Goda\|G\|;Luna\|Beatriz\|B\|;Sarpal\|Deepak K\|DK\|", "chemical_list": "D014150:Antipsychotic Agents", "country": "United States", "delete": false, "doi": "10.1016/j.bpsc.2019.01.007", "fulltext": null, "fulltext_license": null, "issn_linking": "2451-9022", "issue": "4(5)", "journal": "Biological psychiatry. Cognitive neuroscience and neuroimaging", "keywords": "Duration of untreated psychosis; Frontostriatal connectivity; Psychosis; Schizophrenia; Working memory; fMRI", "medline_ta": "Biol Psychiatry Cogn Neurosci Neuroimaging", "mesh_terms": "D000293:Adolescent; D000328:Adult; D014150:Antipsychotic Agents; D002648:Child; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008570:Memory, Short-Term; D009434:Neural Pathways; D017397:Prefrontal Cortex; D011618:Psychotic Disorders; D061665:Time-to-Treatment; D055815:Young Adult", "nlm_unique_id": "101671285", "other_id": null, "pages": "454-461", "pmc": null, "pmid": "30852127", "pubdate": "2019-05", "publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't", "references": "27386561;18971297;26315980;25300902;14992973;25471062;25651194;26873890;18400794;19042912;29137828;16448803;19675535;26831091;16343792;24559680;22378170;12271790;28320846;29748629;23337947;25649287;12505813;1503130;25251486;22569188;19042105;16199825;21596142;21914644;19897178;28294137;15231551;27056754;23034655;25588418;17306506;11581115;26558708;24067164;24657353;19652121;3387514;11231835;19196494;21706013;25372846;28634088;25252316", "title": "Association Between Duration of Untreated Psychosis and Frontostriatal Connectivity During Maintenance of Visuospatial Working Memory.", "title_normalized": "association between duration of untreated psychosis and frontostriatal connectivity during maintenance of visuospatial working memory" }	[ { "companynumb": "US-OTSUKA-2020_000515", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ARIPIPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021436", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Tablet", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ABILIFY" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "No adverse event", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Manivannan A, Foran W, Jalbrzikowski M, Murty VP, Haas GL, Tarcijonas G, Luna B, Sarpal DK.. Association Between Duration of Untreated Psychosis and Frontostriatal Connectivity During Maintenance of Visuospatial Working Memory. Biol Psychiatry Cogn Neurosci Neuroimaging.. 2019;4(5):454-61", "literaturereference_normalized": "association between duration of untreated psychosis and frontostriatal connectivity during maintenance of visuospatial working memory", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20211004", "receivedate": "20211004", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19916356, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220303" } ]
{ "abstract": "Drug-induced immune hemolytic anemia (DIIHA) is an uncommon side effect of pharmacologic intervention. A rare mediator of DIIHA, carboplatin is an agent used to treat many pediatric cancers. We describe here, the first case of fatal carboplatin induced DIIHA in a pediatric patient and a brief review of the literature. Our patient developed acute onset of multi-organ failure with evidence of complement activation, secondary to a drug induced red cell antibody. Early recognition of the systemic insult associated with carboplatin induced hemolytic anemia may allow for future affected patients to receive plasmapheresis, a potentially effective therapy.", "affiliations": "Division of Pediatric Hematology/Oncology, Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA.;Division of Pediatric Hematology/Oncology, Department of Pediatrics, Wake Forest Baptist Health, Medical Center Blvd, Winston-Salem, NC, USA.;Departments of Pathology, Medicine and Pediatrics, Oregon Health and Science University, Portland, OR, USA.;American Red Cross Blood Services, Pomona, CA, USA.;American Red Cross Blood Services, Pomona, CA, USA.;Division of Pediatric Hematology/Oncology, Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA.;Division of Pediatric Hematology/Oncology, Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA.", "authors": "Haley\|Kristina M\|KM\|;Russell\|Thomas B\|TB\|;Boshkov\|Lynn\|L\|;Leger\|Regina M\|RM\|;Garratty\|George\|G\|;Recht\|Michael\|M\|;Nazemi\|Kellie J\|KJ\|", "chemical_list": null, "country": "New Zealand", "delete": false, "doi": "10.2147/JBM.S59192", "fulltext": "\n==== Front\nJ Blood MedJ Blood MedJournal of Blood Medicine1179-2736Dove Medical Press 10.2147/JBM.S59192jbm-5-055Case ReportFatal carboplatin-induced immune hemolytic anemia in a child with a brain tumor Haley Kristina M 1Russell Thomas B 2Boshkov Lynn 3Leger Regina M 4Garratty George 4†Recht Michael 1Nazemi Kellie J 11 Division of Pediatric Hematology/Oncology, Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA2 Division of Pediatric Hematology/Oncology, Department of Pediatrics, Wake Forest Baptist Health, Medical Center Blvd, Winston-Salem, NC, USA3 Departments of Pathology, Medicine and Pediatrics, Oregon Health and Science University, Portland, OR, USA4 American Red Cross Blood Services, Pomona, CA, USACorrespondence: Kristina M Haley, Division of Pediatric Hematology/Oncology, Department of Pediatrics, Oregon Health & Science University, 3181 SW Gaines Street, Mail code: CDRCP, Portland, OR 97239, USA, Tel +1 503 494 0829, Fax +1 503 494 2721, Email [email protected]† George Garratty passed away March 2014\n\n2014 15 5 2014 5 55 58 © 2014 Haley et al. This work is published by Dove Medical Press Ltd, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License2014The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Ltd, provided the work is properly attributed.Drug-induced immune hemolytic anemia (DIIHA) is an uncommon side effect of pharmacologic intervention. A rare mediator of DIIHA, carboplatin is an agent used to treat many pediatric cancers. We describe here, the first case of fatal carboplatin induced DIIHA in a pediatric patient and a brief review of the literature. Our patient developed acute onset of multi-organ failure with evidence of complement activation, secondary to a drug induced red cell antibody. Early recognition of the systemic insult associated with carboplatin induced hemolytic anemia may allow for future affected patients to receive plasmapheresis, a potentially effective therapy.\n\nKeywords\nhemolytic anemiacarboplatingliomacomplement fixationdrug-induced hemolysis\n==== Body\nCase\nAn 11-year-old female was being treated for low-grade astrocytoma with carboplatin and vincristine. The patient was also receiving levothyroxine for central hypothyroidism, ondansetron for chemotherapy-induced nausea, omeprazole for gastrointestinal reflux, and trimethoprim-sulfamethoxazole for Pneumocystis jirovecii pneumonia prophylaxis. Notably, she was not receiving any steroids. On day 15 of cycle five (carboplatin dose number 22), the patient reported acute lower back pain prior to receiving chemotherapy. Her physical exam was unremarkable. She had a stable macrocytic anemia and normal platelet count (Table 1). Thought to be of musculoskeletal origin, the back pain resolved with hydromorphone and ibuprofen. Vincristine 2 mg (max dose) and carboplatin 294 mg (175 mg/m2) were administered. She developed abdominal pain, diarrhea, chills, and tachypnea within approximately 8 hours of chemotherapy administration. The following morning, upon arrival at the local emergency room, she was afebrile, tachycardic, hypertensive, tachypneic, and hypoxemic. She had diffuse abdominal tenderness, delayed capillary refill time, and a normal neurologic exam. She had worsening anemia (with rouleaux formation but without schistocytes) and had acute renal failure and hepatitis (Table 1). Transfusion support and broad-spectrum antibiotics were initiated. She was started on continuous positive airway pressure, and remained alert and interactive.\n\nPossible explanations of the patient’s acute presentation include; hemolytic uremic syndrome (HUS), atypical HUS, viral hepatitis, autoimmune hemolytic anemia, sepsis with disseminated intravascular coagulation (DIC), and toxic exposure. Concurrent with this patient’s presentation, there was an epidemic of HUS occurring in her community. She denied similar exposures to those reported by the affected patients. Review of the peripheral smear did not demonstrate the typical significant schistocytosis found in HUS. Furthermore, stool cultures were negative. While the patient presented acutely with multi-organ failure, she was not febrile and did not have the characteristic distributive shock associated with bacterial sepsis. Blood culture at the time of admission grew non-typable Haemophilis influenzae; repeat cultures after 24 hours of cefepime were negative. It seemed that her severe illness could not be primarily attributed to this positive culture because she was not neutropenic, non-typeable H. influenzae is not typically associated with severe infection, and the culture cleared quickly with appropriate antibiotics.\n\nComputed tomography (CT) of the chest, abdomen, and pelvis done on hospital day 2, demonstrated a small right pleural effusion, multi-focal nodular ground glass and tree-in-bud opacities in both lungs concerning for atypical infections or diffuse alveolar injury, hepatic steatosis versus edema, and edematous kidneys. An endotracheal aspirate culture grew Aspergillus. As she was not neutropenic and had not been on steroids previously, this appeared to be consistent with laboratory contaminant. Furthermore, her chest CT did not reveal the typical findings associated with invasive pulmonary aspergillosis. Serum viral studies were negative except for Epstein–Barr virus (EBV polymerase chain reaction: 320 copies/mL). Serum cortisol was normal at 46 μg/dL. Acetaminophen level was less than 10 μg/mL.\n\nWhile undergoing dialysis on hospital day 2 the patient complained of severe headache, became lethargic, and required intubation. Her pupils became fixed and dilated. Head CT demonstrated diffuse cerebral and cerebellar edema (Figure 1). An external ventricular drain was placed. Approximately 40 hours into the hospitalization, she had no brain or brainstem activity. She was pronounced dead 64 hours after initial presentation to our hospital.\n\nThe temporal relationship between the patient’s acute deterioration and the administration of carboplatin and vincristine suggested that one of these agents or the fluids accompanying them was the cause for multi-organ failure and death. The hospital’s carboplatin and vincristine stock concentrations and the patient’s doses were verified. The patient had received the only dose of carboplatin from a specific manufacturer on that day, while many patients had received vincristine from the same supplier. The stock of carboplatin was quarantined. Evaluation for organismal and toxic contamination was unrevealing. An US Food and Drug Administration (FDA) MedWatch alert was placed. No other reports of hemolytic anemia or multi-organ failure were reported in patients receiving carboplatin from this specific manufacturer.\n\nAn initial direct anti-globulin test (DAT) at our institution was negative. Evidence of intravascular hemolysis associated with acute renal failure, hepatitis, and coagulopathy, plus concern that the other findings did not fully explain her severe clinical presentation prompted repeat DAT and collection of multiple samples for investigation of carboplatin drug-induced immune hemolytic anemia (DIIHA), by the American Red Cross in Pomona, CA, USA. The repeat DAT was strongly positive for immunoglobulin (Ig) G (3+) and C3 (3+) as well as weakly positive (1+) for IgM. The patient’s serum was found to contain strongly reactive carboplatin-dependent IgG and IgM antibodies that agglutinated (titer =2) and sensitized (titer =32) carboplatin-treated red cells but not untreated red cells. The patient’s serum also agglutinated (titer =16) and sensitized (titer =128) untreated red cells in the presence of a solution of carboplatin; there was no reactivity in the control without drug added. A weak drug-independent antibody was also found in an acid eluate prepared from the patient’s red cells. This testing confirmed carboplatin-induced immune hemolytic anemia.\n\nA post-mortem exam was requested for the patient by our institution, but the family declined.\n\nDiscussion\nDIIHA is a rare cause of hemolytic anemia with an estimated incidence of one per million individuals.2 Over 125 drugs have been implicated in DIIHA, with additional drugs reported to be associated with hemolysis but not meeting the full criteria for DIIHA.2 The mechanism and severity of hemolysis varies among different drugs. Approximately 15% of the implicated drugs are anti-neoplastic agents.2,3\n\nThese drugs cause immune hemolysis through drug-dependent and drug-independent mechanisms. Drug-dependent antibodies can result in hemolytic anemia through two mechanisms.3 In the first, a drug binds covalently to proteins on the red cell membrane, then anti-drug antibodies bind to the drug-red blood cell (RBC) membrane complex, resulting in extravascular hemolysis. Two hypotheses have been proposed to explain the second mechanism.3 According to the immune complex hypothesis; anti-drug antibody combines with the drug to form an immune complex. This immune complex then attaches to the RBC membrane and activates complement. Alternatively, the neoantigen hypothesis suggests that the drug binds to the RBC membrane and changes the membrane forming a novel antigen that is part red cell membrane and part drug. Specific anti-drug antibodies then bind to the neoantigen, which may fix complement.\n\nThe mechanism of antibody formation in drug-independent hemolytic anemia is poorly understood but has been attributed to molecular mimicry, drug adsorption causing red cell membrane alteration, or immune dysregulation.3 The antibody reacts in vitro in the absence of drug. Laboratory and clinical findings are identical to RBC autoantibodies and autoimmune hemolytic anemia (AIHA). The treatment of choice for DIIHA is supportive care and immediate withdrawal of the causative agent. Steroids or intravenous IgG are not indicated for drug-dependent DIIHA. However, these therapies may provide some benefit in treatment of drug-independent DIIHA given the similarities to AIHA.3,4 Hence, DIIHA may result in life-threatening or fatal hemolytic anemia.2,3\n\nPlatinum-based chemotherapies result in cytopenias through marrow suppression but may also cause cytopenias through immune mediated mechanisms.5,6 IgE mediated hypersensitivity reactions occur with platinum-based chemotherapies as well, but likely through a separate mechanism from immune-mediated cytopenias.7 There have been several reports of oxaliplatin-induced immune cytopenias in the literature;5,6,8–10 however, only three case reports of carboplatin-induced immune hemolytic anemia exist. Marani et al12 described an 8-year-old boy, treated with a carboplatin-based chemotherapy regimen, who complained of low back pain during his 26th dose of carboplatin with subsequent overt intravascular hemolysis with his 27th dose. His anemia responded to blood transfusion, and the hemolysis ceased without further intervention.11,12 Maloisal et al13 reported a 44-year-old female developing hemolytic anemia following carboplatin administration. Interestingly, her hemolysis did not worsen with additional doses. Dacha et al14 described a 72-year-old female who developed acute onset intravascular hemolysis during infusion of carboplatin and subsequently died of multi-organ failure. In our patient, carboplatin-dependent antibodies were identified. The clinical picture and laboratory evidence support the pathophysiologic mechanism of drug-dependent immune hemolytic anemia resulting in complement fixation and intravascular hemolysis prompting a systemic inflammatory response, resulting in acute multi-organ failure and death.\n\nConclusion\nAlthough uncommon, DIIHA is often responsive to drug withdrawal and supportive care.3 Select drugs have been implicated in a more serious, often fatal form of DIIHA. Here we report the second case of fatal carboplatin-induced immune hemolytic anemia, the first in a pediatric patient. Despite its rarity, DIIHA must be included in the differential diagnosis of any patient receiving platinum-based chemotherapy that presents with overt hemolysis, sudden changes in serum chemistry values, or unexplained back pain. Along with supportive care, clearing the offending antibodies via plasma exchange may control the underlying cause and prevent the brisk and efficient complement fixation that characterizes this form of severe DIIHA.1 Due to the rapidity of clinical deterioration, plasma exchange was not performed in this case.\n\nAcknowledgments\nThe authors wish to acknowledge the contributions of our colleague, Dr George Garratty, to the fields of immunohematology, hematology, and transfusion medicine. Dr Garratty sadly passed away during the preparation of this manuscript. Dr Garratty’s work and research propelled the field of immunohematology to new fronts, and his persistent curiosity and pure appreciation for the complex nature of transfusion medicine and immune hemolytic anemia was infectious and inspiring. Always available to clinicians and scientists across the world, Dr Garratty was the consummate teacher –guiding us through the complex and sometimes confusing answers to our clinical problems. Dr Garratty was always just a phone call or email away and always willing to help us explain our particular clinical conundrum while simultaneously shedding light on how we could apply the information to the next scenario. He will surely be missed.\n\nDisclosure\n\nThe authors have no conflicts of interest to disclose.\n\nFigure 1 An axial, non-contrast enhanced view of the brain shows severe diffuse cerebral and cerebellar edema.\n\nNotes: The normal definition between gray and white matter tissue is poor because of the edema. The quadrigeminal and ambient basal cisterns (white arrows) are no longer seen due to upward transtentorial herniation. The fourth ventricle (black circle) is not seen as edematous cerebellum displaces the CSF. The cystic (asterisk) and calcified suprasellar mass is seen.\n\nTable 1 Vital signs and laboratory values before acute decompensation, on the day of therapy, at the referring hospital, and at our institution\n\n\tClinic visit for chemotherapy 2 weeks prior to acute decompensation\tDay of clinic visit (1 day prior to acute decompensation)\tAt presentation to referring hospital\tAt presentation to our institution\t\nHeart rate (bpm)\t91\t109\t122\t125\t\nBlood pressure (mmHg)\t111/70\t149/90\t134/82\t156/91\t\nRespiratory rate (bpm)\t18\t22\t44\t45\t\nWhite blood cell count (μL)\t4.8\t7.2\t9.3\t8.4\t\nAbsolute neutrophil count (μL)\t2,300\t2,900\t4,950\t3,700\t\nHemoglobin (g/dL)\t12.2\t9.9\t7.2\t6.2\t\nMean corpuscular volume (fL)\t101.1\t98.1\t90.7\tInterfering substances\t\nPlatelet count (μL)\t224\t241\t181\t92\t\nBlood urea nitrogen (mg/dL)\t11\tNA\t47\t50\t\nCreatinine (mg/dL)\t0.49\tNA\t3.2\t4.23\t\nAspartate aminotransferase (U/L)\t23\tNA\t1,636\t3,977\t\nAlanine aminotransferase (U/L)\t27\tNA\t1,263\t3,029\t\nTotal bilirubin (mg/dL)\t0.4\tNA\t5.6\t7.7\t\nDirect bilirubin (mg/dL)\tNA\tNA\tNA\t3\t\nAbbreviations: NA, not available; bpm, beats or breaths per minute.\n==== Refs\nReferences\n1 Doratota S Recht M Garratty G Krupicka M Thomas GA Boshkov L Successful treatment of life-threatening ceftriaxone-induced hemolysis by plasmapheresis Transfusion 2009 49 S 13A abtr 18954397 \n2 Garratty G Arndt PA Review: drug-induced immune hemolytic anemia – the last decade Immunohematology 2004 20 3 138 146 15373645 \n3 Garratty G Immune hemolytic anemia associated with drug therapy Blood Rev 2010 24 4–5 143 150 20650555 \n4 Pierce A Nester T Pathology consultation on drug-induced hemolytic anemia Am J Pathol 2011 136 1 7 12 \n5 Cobo F De Celis G Pereira A Latorre X Pujadas J Albiol S Oxaliplatin-induced immune hemolytic anemia: a case report and review of the literature Anticancer Drugs 2007 18 8 973 976 17667605 \n6 Arndt PA Garratty G Isaak E Bolger M Lu Q Positive direct and indirect anti-globulin tests associated with oxaliplatin can be due to drug antibody and/or drug-induced nonimmunologic protein adsorption Transfusion 2009 49 4 711 718 19192254 \n7 Makrilia N Syrigou E Kaklamanos I Manolopoulos L Saif MW Hypersensitivity reactions associated with platinum antineoplastic agents: a systematic review Met Based Drugs Epub 9 20 2010 \n8 Hofheinz RD Nguyen XD Buchheidt D Kerowgan M Hehlmann R Hochhaus A Two potential mechanisms of oxaliplatin-induced haemolytic anemia in a single patient Cancer Chemother Pharmacol 2004 53 276 277 14676977 \n9 Sorbye H Bruserud O Dahl O Oxaliplatin-induced haematological emergency with an immediate severe thrombocytopenia and haemolysis Acta Oncol 2001 40 7 882 883 11859992 \n10 Teng CJ Hsieh YY Chen KW Chao TC Tzeng CH Wang WS Sudden-onset pancytopenia with intracranial hemorrhage after oxaliplatin treatment: a case report and literature review Jpn J Clin Oncol 2011 41 1 125 129 20826449 \n11 Marani T Leatherbarrow HB Armstrong KS Carboplatin-induced immune hemolytic anemia (CIHA) due to an antibody reaction with features of both the immune complex (IC) and drug-adsorption (DA) mechanisms [abstract] Transfusion 1994 34 20S \n12 Marani TM Trich MB Armstrong KS Carboplatin-induced immune hemolytic anemia Transfusion 1996 36 11–12 1016 1018 8937414 \n13 Maloisal F Kurtz JE Andres E Gorodetsky C Dufour P Oberling F Platin salts-induced hemolytic anemia: cisplatin- and the 2nd case of carboplatin-induced hemolysis Anticancer Drugs 1995 6 2 324 326 7795280 \n14 Dacha S Reddivan AK Latta S Devidi M Iroegbu N Carboplatin-induced fatal autoimmune hemolytic anemia: first reported case World J Oncol 2010 1 4 173 175\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1179-2736", "issue": "5()", "journal": "Journal of blood medicine", "keywords": "carboplatin; complement fixation; drug-induced hemolysis; glioma; hemolytic anemia", "medline_ta": "J Blood Med", "mesh_terms": null, "nlm_unique_id": "101550884", "other_id": null, "pages": "55-8", "pmc": null, "pmid": "24868179", "pubdate": "2014", "publication_types": "D002363:Case Reports", "references": "17667605;8937414;19192254;15373645;21685026;20826449;20650555;11859992;14676977;7795280;20886011;29147201", "title": "Fatal carboplatin-induced immune hemolytic anemia in a child with a brain tumor.", "title_normalized": "fatal carboplatin induced immune hemolytic anemia in a child with a brain tumor" }	[ { "companynumb": "US-PFIZER INC-2399606", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROOESOPHAGEAL REFLUX DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LEVOTHYROXINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "NOT REPORTED", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPOTHYROIDISM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOTHYROXINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "NOT REPORTED", "drugenddate": null, "drugenddateformat": null, "drugindication": "BACK PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBUPROFEN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "076517", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "294 MG, CYCLICAL (175 MG/M2)", "drugenddate": null, "drugenddateformat": null, "drugindication": "ASTROCYTOMA, LOW GRADE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "294", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROMORPHONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "NOT REPORTED", "drugenddate": null, "drugenddateformat": null, "drugindication": "BACK PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROMORPHONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 MG, CYCLICAL (MAX DOSE)", "drugenddate": null, "drugenddateformat": null, "drugindication": "ASTROCYTOMA, LOW GRADE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ONDANSETRON" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "NOT REPORTED", "drugenddate": null, "drugenddateformat": null, "drugindication": "NAUSEA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ONDANSETRON" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "NOT REPORTED", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIFUNGAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRIMETHOPRIM SULFAMETHOXAZOLE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "NOT REPORTED", "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROOESOPHAGEAL REFLUX DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." } ], "patientagegroup": null, "patientonsetage": "11", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemolytic anaemia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "HALEY, K.. FATAL CARBOPLATIN?INDUCED IMMUNE HEMOLYTIC ANEMIA IN A CHILD WITH A BRAIN TUMOR.. JOURNAL OF BLOOD MEDICINE.. 2014?5:55?58", "literaturereference_normalized": "fatal carboplatin induced immune hemolytic anemia in a child with a brain tumor", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180720", "receivedate": "20180720", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15173132, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" } ]
{ "abstract": "Concurrent chemoradiotherapy (CCRT) with three-weekly high-dose cisplatin (100 mg/m2) is a standard treatment for locally advanced head and neck squamous cell carcinoma (HNSCC), but compliance with cisplatin is often poor due to various adverse events. The aim of this prospective, observational study was to determine the predictors of achievement of full-dose cisplatin.\n\n\n\nA prospective, observational study was conducted involving 60 patients who received CCRT with three-weekly high-dose cisplatin (100 mg/m2) for locally advanced HNSCC. Possible predictors affecting compliance with cisplatin were subjected to univariate and multivariate logistic regression analyses. Age, sex, primary site, clinical stage, treatment intent, history of hypertension, diabetes mellitus, smoking and drinking habits, body mass index, creatinine clearance, serum albumin, controlling nutrition status, trace elements (Fe, Zn, Cu, Se), acute kidney injury, white blood cell count decrease, neutrophilia, and weight loss were the variables evaluated.\n\n\n\nTwenty-seven patients achieved full-dose cisplatin (300 mg/m2), and the other 33 patients did not. Multivariate logistic regression analysis showed that both mild renal dysfunction and selenium deficiency before treatment independently had negative impacts on achievement of full-dose cisplatin.\n\n\n\nAs well as renal function, selenium deficiency is a potential therapeutic target for CCRT with high-dose cisplatin in HNSCC patients.", "affiliations": "Department of Otorhinolaryngology, Head and Neck Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan. Electronic address: [email protected].;Department of Otorhinolaryngology, Head and Neck Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan.;Department of Otorhinolaryngology, Head and Neck Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan.;Department of Otorhinolaryngology, Head and Neck Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan.;Department of Otorhinolaryngology, Head and Neck Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan.;Department of Otorhinolaryngology, Head and Neck Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan.;Department of Otorhinolaryngology, Head and Neck Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan.;Department of Otolaryngology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu City 501-1193, Japan.;Department of Otorhinolaryngology, Head and Neck Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan.", "authors": "Ohkoshi\|Akira\|A\|;Ishii\|Ryo\|R\|;Wakamori\|Shun\|S\|;Nakayama\|Yuki\|Y\|;Yoshida\|Takuya\|T\|;Higashi\|Kenjiro\|K\|;Nakanome\|Ayako\|A\|;Ogawa\|Takenori\|T\|;Katori\|Yukio\|Y\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1016/j.oraloncology.2021.105475", "fulltext": null, "fulltext_license": null, "issn_linking": "1368-8375", "issue": "121()", "journal": "Oral oncology", "keywords": "Cisplatin; Concurrent chemoradiotherapy; Head and neck cancer; Renal insufficiency; Selenium; Trace elements", "medline_ta": "Oral Oncol", "mesh_terms": null, "nlm_unique_id": "9709118", "other_id": null, "pages": "105475", "pmc": null, "pmid": "34364132", "pubdate": "2021-10", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Serum selenium predicts achievement of full-dose cisplatin in concurrent chemoradiotherapy for locally advanced head and neck squamous cell carcinoma: A prospective, observational study.", "title_normalized": "serum selenium predicts achievement of full dose cisplatin in concurrent chemoradiotherapy for locally advanced head and neck squamous cell carcinoma a prospective observational study" }	[ { "companynumb": "JP-HQ SPECIALTY-JP-2021INT000236", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "018057", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG/M2, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Squamous cell carcinoma of head and neck", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RADIATION THERAPY" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Squamous cell carcinoma of head and neck", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RADIATION THERAPY" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Septic shock", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute respiratory distress syndrome", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Ohkoshi A., Ishii R., Wakamori S., Nakayama Y., Yoshida T., Higashi K., et al. Serum selenium predicts achievement of full-dose cisplatin in concurrent chemoradiotherapy for locally advanced head and neck squamous cell carcinoma: A prospective, observational study. Oral Oncology. 2021;121:Number: 105475", "literaturereference_normalized": "serum selenium predicts achievement of full dose cisplatin in concurrent chemoradiotherapy for locally advanced head and neck squamous cell carcinoma a prospective observational study", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20211215", "receivedate": "20211215", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20187287, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220303" }, { "companynumb": "JP-HQ SPECIALTY-JP-2021INT000237", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "018057", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG/M2, ON DAYS 1, 22, AND 43 DURING CCRT", "drugenddate": null, "drugenddateformat": null, "drugindication": "Squamous cell carcinoma of head and neck", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RADIATION THERAPY" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Squamous cell carcinoma of head and neck", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RADIATION THERAPY" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hyperglycaemic hyperosmolar nonketotic syndrome", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Ohkoshi A., Ishii R., Wakamori S., Nakayama Y., Yoshida T., Higashi K., et al. Serum selenium predicts achievement of full-dose cisplatin in concurrent chemoradiotherapy for locally advanced head and neck squamous cell carcinoma: A prospective, observational study. Oral Oncology. 2021;121:Number: 105475", "literaturereference_normalized": "serum selenium predicts achievement of full dose cisplatin in concurrent chemoradiotherapy for locally advanced head and neck squamous cell carcinoma a prospective observational study", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20211215", "receivedate": "20211215", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20187267, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220303" } ]
{ "abstract": "OBJECTIVE\nMethotrexate (MTX) can cause significant clinical neurotoxicity and asymptomatic leukoencephalopathy. We sought to identify clinical, pharmacokinetic, and genetic risk factors for these MTX-related toxicities during childhood acute lymphoblastic leukemia (ALL) therapy and provide data on safety of intrathecal and high-dose MTX rechallenge in patients with neurotoxicity.\n\n\nMETHODS\nProspective brain magnetic resonance imaging was performed at four time points for 369 children with ALL treated in a contemporary study that included five courses of high-dose MTX and 13 to 25 doses of triple intrathecal therapy. Logistic regression modeling was used to evaluate clinical and pharmacokinetic factors, and a genome-wide association study (GWAS) was performed to identify germline polymorphisms for their association with neurotoxicities.\n\n\nRESULTS\nFourteen patients (3.8%) developed MTX-related clinical neurotoxicity. Of 13 patients rechallenged with intrathecal and/or high-dose MTX, 12 did not experience recurrence of neurotoxicity. Leukoencephalopathy was found in 73 (20.6%) of 355 asymptomatic patients and in all symptomatic patients and persisted in 74% of asymptomatic and 58% of symptomatic patients at the end of therapy. A high 42-hour plasma MTX to leucovorin ratio (measure of MTX exposure) was associated with increased risk of leukoencephalopathy in multivariable analysis (P = .038). GWAS revealed polymorphisms in genes enriched for neurodevelopmental pathways with plausible mechanistic roles in neurotoxicity.\n\n\nCONCLUSIONS\nMTX-related clinical neurotoxicity is transient, and most patients can receive subsequent MTX without recurrence of acute or subacute symptoms. All symptomatic patients and one in five asymptomatic patients develop leukoencephalopathy that can persist until the end of therapy. Polymorphisms in genes related to neurogenesis may contribute to susceptibility to MTX-related neurotoxicity.", "affiliations": "All authors: St Jude Children's Research Hospital; and Deepa Bhojwani, Jun J. Yang, Hiroto Inaba, Jeffrey E. Rubnitz, Monika L. Metzger, Scott C. Howard, Raul C. Ribeiro, Sima Jeha, John T. Sandlund, and Ching-Hon Pui, University of Tennessee Health Sciences Center, College of Medicine, Memphis, TN.", "authors": "Bhojwani\|Deepa\|D\|;Sabin\|Noah D\|ND\|;Pei\|Deqing\|D\|;Yang\|Jun J\|JJ\|;Khan\|Raja B\|RB\|;Panetta\|John C\|JC\|;Krull\|Kevin R\|KR\|;Inaba\|Hiroto\|H\|;Rubnitz\|Jeffrey E\|JE\|;Metzger\|Monika L\|ML\|;Howard\|Scott C\|SC\|;Ribeiro\|Raul C\|RC\|;Cheng\|Cheng\|C\|;Reddick\|Wilburn E\|WE\|;Jeha\|Sima\|S\|;Sandlund\|John T\|JT\|;Evans\|William E\|WE\|;Pui\|Ching-Hon\|CH\|;Relling\|Mary V\|MV\|", "chemical_list": "D000964:Antimetabolites, Antineoplastic; D002955:Leucovorin; D008727:Methotrexate", "country": "United States", "delete": false, "doi": "10.1200/JCO.2013.53.0808", "fulltext": null, "fulltext_license": null, "issn_linking": "0732-183X", "issue": "32(9)", "journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", "keywords": null, "medline_ta": "J Clin Oncol", "mesh_terms": "D000293:Adolescent; D000964:Antimetabolites, Antineoplastic; D000971:Antineoplastic Combined Chemotherapy Protocols; D001921:Brain; D002648:Child; D002675:Child, Preschool; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D018095:Germ-Line Mutation; D006801:Humans; D002955:Leucovorin; D056784:Leukoencephalopathies; D016015:Logistic Models; D008279:Magnetic Resonance Imaging; D008297:Male; D008727:Methotrexate; D020258:Neurotoxicity Syndromes; D011110:Polymorphism, Genetic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011446:Prospective Studies; D012307:Risk Factors", "nlm_unique_id": "8309333", "other_id": null, "pages": "949-59", "pmc": null, "pmid": "24550419", "pubdate": "2014-03-20", "publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't", "references": "19404257;21646343;22683712;21091140;19553647;19068252;15569732;16568441;18285545;6693915;15527894;1734087;19006245;1525778;22927505;22586486;21545793;9697870;14576448;12714818;19193882;20182759;23650422;12915598;7776773;16219848;20732627;21832240;23049924;19901119;11070477;17170721;23760811;20573900;9586883;21148812;10835412;17264302;12761601;17947226;11493634;21064136;21444869;18367627;18056785;15891195", "title": "Methotrexate-induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia.", "title_normalized": "methotrexate induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia" }	[ { "companynumb": "US-PFIZER INC-2014090767", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." } ], "patientagegroup": null, "patientonsetage": "14", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Confusional state", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Headache", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukoencephalopathy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BHOJWANI, D.. METHOTREXATE-INDUCED NEUROTOXICITY AND LEUKOENCEPHALOPATHY IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA.. 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"patientagegroup": null, "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Leukoencephalopathy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Cerebrovascular accident", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "BHOJWANI, D.. METHOTREXATE-INDUCED NEUROTOXICITY AND LEUKOENCEPHALOPATHY IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA. 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"drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." } ], "patientagegroup": null, "patientonsetage": "11", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Generalised tonic-clonic seizure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukoencephalopathy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BHOJWANI, D.. METHOTREXATE-INDUCED NEUROTOXICITY AND LEUKOENCEPHALOPATHY IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA.. JOURNAL OF CLINICAL ONCOLOGY.. 2014?32(9):949-959", "literaturereference_normalized": "methotrexate induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190311", "receivedate": "20190311", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16056614, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "US-PFIZER INC-2373784", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "NOT REPORTED", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": "3", "drugadministrationroute": "041", "drugauthorizationnumb": "011719", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 G/M^2", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": "3", "drugadministrationroute": "041", "drugauthorizationnumb": "011719", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 G/M^2", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROCORTISONE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "NOT REPORTED", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCORTISONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG/M2, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEUCOVORIN /00566701/" } ], "patientagegroup": null, "patientonsetage": "5", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Leukoencephalopathy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Generalised tonic-clonic seizure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CHENG C., PUI C., BHOJWANI D., PEI D., INABA H., RUBNITZ JE., PANETTA J., SANDLUND JT., YANG JJ., KRULL KR., RELLING MV., METZGER ML., SABIN ND., KHAN RB., RIBEIRO RC., HOWARD SC., JEHA S., REDDICK. METHOTREXATE-INDUCED NEUROTOXICITY AND LEUKOENCEPHALOPATHY IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA. J CLIN ONCOL. 2014?32(9):949-959", "literaturereference_normalized": "methotrexate induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190314", "receivedate": "20190314", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16073067, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "US-PFIZER INC-2014090788", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG/M2, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEUCOVORIN [FOLINIC ACID]" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROCORTISONE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCORTISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 G/M2 OVER 24 HOURS, ADJUSTED TO 65 UMOL/L", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." } ], "patientagegroup": null, "patientonsetage": "18", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cerebrovascular accident", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Leukoencephalopathy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "BHOJWANI, D.. METHOTREXATE-INDUCED NEUROTOXICITY AND LEUKOENCEPHALOPATHY IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA.. JOURNAL OF CLINICAL ONCOLOGY.. 2014?32(9):949-959", "literaturereference_normalized": "methotrexate induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190208", "receivedate": "20190208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15937147, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "US-PFIZER INC-2373834", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "3", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": null, "drugadministrationroute": "041", "drugauthorizationnumb": "011719", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 G/M^2", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": null, "drugadministrationroute": "041", "drugauthorizationnumb": "011719", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 G/M^2", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "NOT REPORTED", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG/M2, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEUCOVORIN /00566701/" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROCORTISONE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "NOT REPORTED", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCORTISONE." } ], "patientagegroup": null, "patientonsetage": "18", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cerebrovascular accident", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukoencephalopathy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CHENG C., PUI CH., BHOJWANI D., PEI D., INABA H., RUBNITZ JE., PANETTAJC., SANDLUND JT., YANG JJ., KRULL KR., RELLING MV., METZGER ML., SABIN ND., KHAN RB., RIBEIRO RC., HOWARD SC., JEHA S., REDDICK W. METHOTREXATE-INDUCED NEUROTOXICITY AND LEUKOENCEPHALOPATHY IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA. J CLIN ONCOL. 2014?32(9):949-949", "literaturereference_normalized": "methotrexate induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190208", "receivedate": "20190208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15939187, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "US-PFIZER INC-2014090696", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "5 G/M2 OVER 24 HOURS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROCORTISONE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCORTISONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG/M2, CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEUCOVORIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEUCOVORIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": "3", "drugadministrationroute": "041", "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "1 G/M2", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." } ], "patientagegroup": null, "patientonsetage": "5", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Generalised tonic-clonic seizure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukoencephalopathy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BHOJWANI, D.. METHOTREXATE-INDUCED NEUROTOXICITY AND LEUKOENCEPHALOPATHY IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA. JOURNAL OF CLINICAL ONCOLOGY. 2014?32(9):949-959", "literaturereference_normalized": "methotrexate induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190314", "receivedate": "20190314", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16071988, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "US-PFIZER INC-2014090785", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG/M2, CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEUCOVORIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AMINOPHYLLINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMINOPHYLLINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROCORTISONE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCORTISONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEUCOVORIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": null, "drugadministrationroute": "041", "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 G/M2", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "METHOTREXATE SODIUM 5 G/M2 OVER 24 HOURS, ADJUSTED TO 65 UMOL/L", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." } ], "patientagegroup": null, "patientonsetage": "12", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukoencephalopathy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cerebrovascular accident", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BHOJWANI, D.. METHOTREXATE-INDUCED NEUROTOXICITY AND LEUKOENCEPHALOPATHY IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA.. JOURNAL OF CLINICAL ONCOLOGY.. 2014?32(9):949-959", "literaturereference_normalized": "methotrexate induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190304", "receivedate": "20190304", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16029646, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "US-PFIZER INC-2373799", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": "3", "drugadministrationroute": "041", "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 G/ M^2", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": "3", "drugadministrationroute": "041", "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 G/ M^2", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROCORTISONE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCORTISONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG/M2", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEUCOVORIN /00566701/" } ], "patientagegroup": null, "patientonsetage": "10", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Focal dyscognitive seizures", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukoencephalopathy", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BHOJWANI, D.. METHOTREXATE-INDUCED NEUROTOXICITY AND LEUKOENCEPHALOPATHY IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA. JOURNAL OF CLINICAL ONCOLOGY.. 2014?32(9):949-959", "literaturereference_normalized": "methotrexate induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190408", "receivedate": "20190408", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16170836, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "US-PFIZER INC-2014090762", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "AMINOPHYLLINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMINOPHYLLINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROCORTISONE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCORTISONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG/M2, CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEUCOVORIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEUCOVORIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": "3", "drugadministrationroute": "041", "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "1 G/M2", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "5 G/M2 OVER 24 HOURS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." } ], "patientagegroup": null, "patientonsetage": "14", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukoencephalopathy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Headache", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cerebrovascular accident", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Confusional state", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BHOJWANI, D.. METHOTREXATE-INDUCED NEUROTOXICITY AND LEUKOENCEPHALOPATHY IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA.. JOURNAL OF CLINICAL ONCOLOGY.. 2014?32(9):949-959", "literaturereference_normalized": "methotrexate induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190329", "receivedate": "20190329", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16135196, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "US-PFIZER INC-2014090731", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG/M2, CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEUCOVORIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROCORTISONE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCORTISONE." }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "5 G/M2 OVER 24 HOURS, CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": null, "drugadministrationroute": "041", "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "1 G/M2", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": null, "drugadministrationroute": "041", "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "5 G/M2", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEUCOVORIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." } ], "patientagegroup": null, "patientonsetage": "4", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukoencephalopathy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ataxia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BHOJWANI, D.. METHOTREXATE-INDUCED NEUROTOXICITY AND LEUKOENCEPHALOPATHY IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA.. JOURNAL OF CLINICAL ONCOLOGY.. 2014?32(9):949-959", "literaturereference_normalized": "methotrexate induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190321", "receivedate": "20190321", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16100369, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": 1, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "US-PFIZER INC-2014090775", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "5 G/M2 OVER 24 HOURS, ADJUSTED TO 65 UMOL/L", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROCORTISONE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCORTISONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG/M2, CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEUCOVORIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." } ], "patientagegroup": null, "patientonsetage": "5", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Focal dyscognitive seizures", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukoencephalopathy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BHOJWANI, D.. METHOTREXATE-INDUCED NEUROTOXICITY AND LEUKOENCEPHALOPATHY IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA.. JOURNAL OF CLINICAL ONCOLOGY.. 2014?32(9):949-959", "literaturereference_normalized": "methotrexate induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190314", "receivedate": "20190314", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16071989, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "US-PFIZER INC-2373789", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROCORTISONE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "NOT REPORTED", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCORTISONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "NOT REPORTED", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG/M2, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEUCOVORIN /00566701/" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": "3", "drugadministrationroute": "041", "drugauthorizationnumb": "011719", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 G/M^2", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": "3", "drugadministrationroute": "041", "drugauthorizationnumb": "011719", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 G/M^2", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." } ], "patientagegroup": null, "patientonsetage": "15", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Leukoencephalopathy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cerebrovascular accident", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CHENG C., PUI C.H., BHOJWANI D., PEI D., INABA H., RUBNITZ JE., PANETTA JC., SANDLUND JT., YANG JJ., KRULL KR., RELLING MV., METZGER ML., SABIN ND., KHAN RB., RIBEIRO RC., HOWARD SC., JEHA S., REDDICK. METHOTREXATE-INDUCED NEUROTOXICITY AND LEUKOENCEPHALOPATHY IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA. J CLIN ONCOL. 2014?32(9):949-959", "literaturereference_normalized": "methotrexate induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190219", "receivedate": "20190215", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15967089, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "US-PFIZER INC-2014090718", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROCORTISONE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCORTISONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG/M2, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEUCOVORIN [FOLINIC ACID]" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "5 G/M2 OVER 24 HOURS, CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." } ], "patientagegroup": null, "patientonsetage": "15", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cerebrovascular accident", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukoencephalopathy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BHOJWANI, D.. METHOTREXATE-INDUCED NEUROTOXICITY AND LEUKOENCEPHALOPATHY IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA.. JOURNAL OF CLINICAL ONCOLOGY.. 2014?32(9):949-959", "literaturereference_normalized": "methotrexate induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190215", "receivedate": "20190215", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15966182, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "US-PFIZER INC-2014090819", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MG/M2, WEEKLY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROCORTISONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCORTISONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG/M2, CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEUCOVORIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK MG/M2, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEUCOVORIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MG/M2, WEEKLY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." } ], "patientagegroup": null, "patientonsetage": "17", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukoencephalopathy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CHENG C., PUI C., BHOJWANID., PEI D., INABA H., RUBNITZ J., PANETTA J., SANDLUND J., YANG J., KRULL K., RELLING M., METZGER M., SABIN N., KHAN R., RIBEIRO R., HOWARD S., JEHA S., REDDICK W., EVANS W.. METHOTREXATE-INDUCED NEUROTOXICITY AND LEUKOENCEPHALOPATHY IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA.. JOURNAL OF CLINICAL ONCOLOGY.. 2014?32(9):949-959", "literaturereference_normalized": "methotrexate induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190328", "receivedate": "20190328", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16127710, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "US-PFIZER INC-2014090660", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "3", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": null, "drugadministrationroute": "041", "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "2.5 G/M^2", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": null, "drugadministrationroute": "041", "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "1 G/M^2", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROCORTISONE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCORTISONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "2.5 G/M2 INFUSED OVER 24 HOURS FOR FOUR DOSES,ADJUSTED TO PLASMA CONCENTRATION OF 33 UMOL/L", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG/M2", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEUCOVORIN /00566701/" } ], "patientagegroup": null, "patientonsetage": "3", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Focal dyscognitive seizures", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Leukoencephalopathy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CHENG C.,PUI C.,BHOJWANI D.,PEI D.,INABA H.,RUBNITZ J.,PANETTA J.,SANDLUND J.,YANG J.,KRULL K.,RELLING M.,METZGER M.,SABIN N.,KHAN R.,RIBEIRO R.,HOWARD S.,JEHA S.,REDDICK W.,EVANS W.. METHOTREXATE-INDUCED NEUROTOXICITY AND LEUKOENCEPHALOPATHY IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA.. JOURNAL OF CLINICAL ONCOLOGY.. 2014?32(9):949-959", "literaturereference_normalized": "methotrexate induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190321", "receivedate": "20190321", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16100421, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "US-PFIZER INC-2014090647", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG/M2, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEUCOVORIN [FOLINIC ACID]" }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 G/M2 OVER 24 HOURS, ADJUSTED TO 65 UMOL/L", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROCORTISONE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCORTISONE." }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": null, "drugadministrationroute": "041", "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 G/M 2", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." } ], "patientagegroup": null, "patientonsetage": "13", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Generalised tonic-clonic seizure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukoencephalopathy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BHOJWANI, D.. METHOTREXATE-INDUCED NEUROTOXICITY AND LEUKOENCEPHALOPATHY IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA.. JOURNAL OF CLINICAL ONCOLOGY.. 2014?32(9):949-959", "literaturereference_normalized": "methotrexate induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190304", "receivedate": "20190304", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16029133, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" } ]
{ "abstract": "BACKGROUND\nWe aimed to improve the outcomes for locoregionally advanced nasopharyngeal carcinoma by testing the feasibility and safety of the addition of bevacizumab to chemoradiotherapy.\n\n\nMETHODS\nWe enrolled patients older than 18 years with stage IIB-IVB nasopharyngeal carcinoma from 19 centres in North America and Hong Kong. Treatment consisted of three cycles of bevacizumab (15 mg/kg) and cisplatin (100 mg/m(2)) both given on days 1, 22, and 43 of radiation (70 Gy) with intensity-modulated radiation therapy delivered over 33 days on a daily basis, Monday through Friday. Patients then received three cycles of bevacizumab (15 mg/kg) and cisplatin (80 mg/m(2)), both given on days 64, 85, and 106 after radiation, and three cycles of fluorouracil (1000 mg/m(2) per day), given on days 64-67, 85-88, and 106-109 after radiation. The primary endpoint was the occurrence of treatment-related grade 4 haemorrhage or any grade 5 adverse event in the first year. Analyses were done with all eligible patients who started protocol treatment. The trial is registered at ClinicalTrials.gov, number NCT00408694.\n\n\nRESULTS\nFrom Dec 13, 2006, to Feb 5, 2009, we enrolled 46 patients, of whom 44 were eligible for analysis. We recorded no grade 3-4 haemorrhages or grade 5 adverse events; nine patients (20%) had a treatment-related grade 1-2 haemorrhage. Nine patients had one or more grade 4 blood or bone marrow-related complication (grade 4 leucopenia was noted in six patients, grade 4 lymphopenia in five, grade 4 neutrophils in five, and grade 4 anaemia in one). One patient had two grade 4 infections with grade 3-4 neutrophils. One patient reported grade 4 tinnitus, one patient reported grade 4 thrombosis, one reported grade 4 radiation mucositis, and two reported grade 4 pharyngolaryngeal pain. With a median follow-up of 2·5 years (IQR 2·1-2·9), the estimated 2 year locoregional progression-free interval was 83·7% (95% CI 72·6-94·9), the 2 year distant metastasis-free interval was 90·8% (82·2-99·5), the 2 year progression-free survival was 74·7% (61·8-87·6), and 2 year overall survival was 90·9% (82·3-99·4).\n\n\nCONCLUSIONS\nThe addition of bevacizumab to standard chemoradiation treatment for patients with nasopharyngeal carcinoma is feasible, and might delay the progression of subclinical distant disease.\n\n\nBACKGROUND\nNational Cancer Institute, USA.", "affiliations": "Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. [email protected]", "authors": "Lee\|Nancy Y\|NY\|;Zhang\|Qiang\|Q\|;Pfister\|David G\|DG\|;Kim\|John\|J\|;Garden\|Adam S\|AS\|;Mechalakos\|James\|J\|;Hu\|Kenneth\|K\|;Le\|Quynh T\|QT\|;Colevas\|A Dimitrios\|AD\|;Glisson\|Bonnie S\|BS\|;Chan\|Anthony Tc\|AT\|;Ang\|K Kian\|KK\|", "chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab", "country": "England", "delete": false, "doi": "10.1016/S1470-2045(11)70303-5", "fulltext": null, "fulltext_license": null, "issn_linking": "1470-2045", "issue": "13(2)", "journal": "The Lancet. Oncology", "keywords": null, "medline_ta": "Lancet Oncol", "mesh_terms": "D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D002277:Carcinoma; D059248:Chemoradiotherapy; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms; D009367:Neoplasm Staging", "nlm_unique_id": "100957246", "other_id": null, "pages": "172-80", "pmc": null, "pmid": "22178121", "pubdate": "2012-02", "publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural", "references": "20103659;15746043;12586799;10554016;15378492;16904519;9552031;10096545;19564532;15542811;17167137;15175435;10640954;15190138;15920746;15042677;12419787;20950416;12890841;7082756;20930754;17971582;10974445;20667969;15936155;18472356;20634482;10811107;15284255;12948418;19201650;10334236;11156384;20971520;16192584;19470921;16139912;11708497;10884741;19464823;12007936;16170180;17145528", "title": "Addition of bevacizumab to standard chemoradiation for locoregionally advanced nasopharyngeal carcinoma (RTOG 0615): a phase 2 multi-institutional trial.", "title_normalized": "addition of bevacizumab to standard chemoradiation for locoregionally advanced nasopharyngeal carcinoma rtog 0615 a phase 2 multi institutional trial" }	[ { "companynumb": "US-MYLANLABS-2017M1007229", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": "3", "drugadministrationroute": "065", 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"drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BEVACIZUMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "091062", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "THREE CYCLES OF 80 MG/M2 GIVEN ON DAYS 64, 85 AND 106 AFTER RADIATION", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, 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ADDITION OF BEVACIZUMAB TO STANDARD CHEMORADIATION FOR LOCOREGIONALLY ADVANCED NASOPHARYNGEAL CARCINOMA (RTOG 0615): A PHASE 2 MULTI-INSTITUTIONAL TRIAL. LANCET-ONCOL 2012;13(2):172-80.", "literaturereference_normalized": "addition of bevacizumab to standard chemoradiation for locoregionally advanced nasopharyngeal carcinoma rtog 0615 a phase 2 multi institutional trial", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170208", "receivedate": "20170208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13200375, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" } ]
{ "abstract": "To perform a meta-analysis of available cohort studies on the association between sertraline use by pregnant women in the first trimester and the findings of congenital anomalies in infants.\n\n\n\nA comprehensive search of articles published from the index date up to 31st December 2015 investigating the aforementioned associations was conducted on PubMed and Web of Science. Mesh headings used included the terms \"serotonin reuptake inhibitor,\" \"sertraline,\" \"congenital anomalies\" and \"obstetrical outcome.\"\n\n\n\nTwelve cohort studies that involved 6 468 241 pregnant women were identified. We summarized odds ratios (ORs) and 95% confidence intervals (CIs) of congenital anomalies using the random-effects model. Pregnant women who used sertraline in the first trimester had a statistically significant increased risk of infant cardiovascular-related malformations (OR = 1.36; 95% CI = 1.06-1.74; I2 = 64.4%; n = 12) as well as atrial and/or ventricular septal defects (OR = 1.36, 95% CI = 1.06-1.76; I2 = 62.2%; n = 8). Additionally, positive but nonsignificant associations between sertraline use and congenital anomalies of the nervous system (OR = 1.39; 95% CI = 0.83-2.32; I2 = 0%; n = 5), digestive system (OR = 1.23; 95% CI = 0.76-1.98; I2 = 0%; n = 5), eye, ear, face and neck (OR = 1.08; 95% CI = 0.33-3.55; I2 = 32.1%; n = 3), urogenital system (OR = 1.03; 95% CI = 0.73-1.46; I2 = 0%; n = 5), and musculoskeletal system (OR = 0.97; 95% CI = 0.69-1.36; I2 = 0%; n = 5) were observed.\n\n\n\nThis meta-analysis suggested that the use of sertraline use by pregnant women in the first trimester had an increased risk of cardiovascular-related malformations as well as atrial and/or ventricular septal defects in infants. Meanwhile, nonsignificant associations between sertraline use and other congenital anomalies were found. More cohort studies are warranted to provide detailed results of other congenital anomalies.", "affiliations": "Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.;Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China.;International Education College, China Medical University, Shenyang, China.;Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China.;Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.;Department of Cardiology, First Affiliated Hospital of Dalian Medical University, Dalian, China.;Department of Emergency, Shengjing Hospital of China Medical University, Shenyang, China.;Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.;Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China.;Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China.;Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China.;Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.", "authors": "Shen\|Zi-Qi\|ZQ\|;Gao\|Shan-Yan\|SY\|;Li\|Shawn Xiang\|SX\|;Zhang\|Tie-Ning\|TN\|;Liu\|Cai-Xia\|CX\|;Lv\|Hai-Chen\|HC\|;Zhang\|Yuan\|Y\|;Gong\|Ting-Ting\|TT\|;Xu\|Xin\|X\|;Ji\|Chao\|C\|;Wu\|Qi-Jun\|QJ\|;Li\|Da\|D\|", "chemical_list": "D017367:Serotonin Uptake Inhibitors; D020280:Sertraline", "country": "England", "delete": false, "doi": "10.1111/bcp.13161", "fulltext": null, "fulltext_license": null, "issn_linking": "0306-5251", "issue": "83(4)", "journal": "British journal of clinical pharmacology", "keywords": "antidepressive agents; cohort studies; congenital anomalies; meta-analysis; pregnancy; sertraline", "medline_ta": "Br J Clin Pharmacol", "mesh_terms": "D000014:Abnormalities, Drug-Induced; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007223:Infant; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D012306:Risk; D017367:Serotonin Uptake Inhibitors; D020280:Sertraline", "nlm_unique_id": "7503323", "other_id": null, "pages": "909-922", "pmc": null, "pmid": "27770542", "pubdate": "2017-04", "publication_types": "D016428:Journal Article; D017418:Meta-Analysis; D016454:Review; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't", "references": "25899043;22190957;14659992;26727146;20865100;24612301;10789670;17676579;17905176;25098615;3802833;10944220;26118971;26568366;12450956;25359305;25229932;16137987;18948314;19622511;10413337;17697910;26515595;8367830;25888213;23797870;17216624;25991012;7786990;21646927;22710132;14618156;20447455;22367660;26075658;25637841;19691085;26373341;27770542;26650439;16896784;23638179;17519397;9310563;26462150;23175139;23966430;23553059;21963886;21381184;26498356;23211939;22393202;26464438;18293409;21042552;17565615;26940835;12958120", "title": "Sertraline use in the first trimester and risk of congenital anomalies: a systemic review and meta-analysis of cohort studies.", "title_normalized": "sertraline use in the first trimester and risk of congenital anomalies a systemic review and meta analysis of cohort studies" }	[ { "companynumb": "AU-CIPLA LTD.-2016AU22119", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "SERTRALINE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "77397", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SERTRALINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Threatened labour", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SHEN ZQ, WU QJ, LI D, GAO SY, LI SX, ZHANG TN, ET.. 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{ "abstract": "A 64-year-old asymptomatic man had an incidental finding of a giant left circumflex artery (LCX) aneurysm, with the distal LCX draining into a confluence receiving terminal portions of all coronary arteries and communicating with the left ventricle through a transmural fistulous tract. We believe that this is the first case reported with such a complex LCX abnormality. (Level of Difficulty: Beginner.).", "affiliations": "Division of Cardiology, John D. Dingell VA Medical Center, Detroit, Michigan.;Division of Cardiology, Department of Medicine, Wayne State University School of Medicine, Detroit, Michigan.;Henry Ford Health System, Detroit, Michigan.;Division of Cardiology, John D. Dingell VA Medical Center, Detroit, Michigan.;Division of Cardiology, John D. Dingell VA Medical Center, Detroit, Michigan.", "authors": "Touma\|Rabih\|R\|;Palla\|Mohan\|M\|;Alam\|Khurshaid\|K\|;Mastromatteo\|James F\|JF\|;Abidov\|Aiden\|A\|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.jaccas.2020.04.059", "fulltext": "\n==== Front\nJACC Case Rep\nJACC Case Rep\nJACC Case Reports\n2666-0849\nElsevier\n\nS2666-0849(20)30632-X\n10.1016/j.jaccas.2020.04.059\nCase Report\nClinical Case\nGiant Calcified Left Circumflex Coronary Artery Aneurysm With Complex Coronary-to–Left Ventricular Communication\nTouma Rabih MD a\nPalla Mohan MD b\nAlam Khurshaid MD c\nMastromatteo James F. MD a\nAbidov Aiden MD, PhD [email protected]\nab∗\na Division of Cardiology, John D. Dingell VA Medical Center, Detroit, Michigan\nb Division of Cardiology, Department of Medicine, Wayne State University School of Medicine, Detroit, Michigan\nc Henry Ford Health System, Detroit, Michigan\n∗ Address for correspondence: Dr. Aiden Abidov, Division of Cardiology, John D. Dingell VA Medical Center, 4646 John R, Detroit, Michigan 48201. [email protected]\n22 7 2020\n9 2020\n22 7 2020\n2 11 18121817\n19 11 2019\n21 4 2020\n29 4 2020\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nA 64-year-old asymptomatic man had an incidental finding of a giant left circumflex artery (LCX) aneurysm, with the distal LCX draining into a confluence receiving terminal portions of all coronary arteries and communicating with the left ventricle through a transmural fistulous tract. We believe that this is the first case reported with such a complex LCX abnormality. (Level of Difficulty: Beginner.)\n\nGraphical abstract\n\nA 64-year-old asymptomatic man had an incidental finding of a giant left circumflex artery (LCX) aneurysm, with the distal LCX draining into a confluence…\n\nKey Words\n\ncoronary artery aneurysm\ncoronary fistula\nleft ventricular fistula\nAbbreviations and Acronyms\n\nCT, computed tomography\nCTA, computed tomography angiogram\nLCX, left circumflex artery\nLV, left ventricle\n==== Body\nHistory of Presentation\n\nA 64-year-old asymptomatic man underwent a computed tomography (CT) scan of the abdomen and pelvis for evaluation of hematuria. The scan revealed an incidental finding of left circumflex artery (LCX) aneurysm. His physical examination was unremarkable for any acute or chronic cardiovascular findings. Upon admission, his vital signs were as follows: blood pressure, 136/89 mm Hg; pulse, 74 beats/min and regular; respiratory rate, 18 breaths/min; temperature, 98.1°F; and pulse oximetry, 97% on room air.Learning Objectives\n\n• LCX aneurysm is an extremely rare clinical condition. Careful evaluation of the coronary anatomy is needed to identify any additional coronary anomalies in these patients. Our case represents a unique anatomy, with a giant LCX aneurysm and the distal LCX draining into a confluence receiving terminal portions of all coronary arteries and communicating with the LV through a transmural fistulous tract.\n\n• Complex coronary anomalies require in-depth evaluation, including multimodality imaging to assess the patients for presence of myocardial ischemia and significant left-to-right shunt. Cardiac CTA is a very helpful diagnostic tool in establishing definitive anatomy in these cases.\n\n• The treatment should be individualized on the basis of the patients’ symptoms, objective prediction of risk (presence of ischemia, progression of the lesion), and the presence of associated coronary and cardiac anomalies.\n\n• With a careful work-up and follow-up, this coronary anomaly may have a benign short-term clinical outcome.\n\nPast Medical History\n\nThe patient had history of well-controlled hypertension and no other modifiable or nonmodifiable risk factors or clinical markers of coronary artery disease.\n\nDifferential Diagnosis\n\nBecause of the incidental CT findings in this asymptomatic patient, the possibility of congenital versus acquired coronary aneurysm was raised. Given that the patient had not undergone any coronary interventions, the possibility of past iatrogenic causes or coronary manipulation was excluded.\n\nInvestigations\n\nSubsequent coronary CT angiography (CTA) showed a giant (3.7-cm), calcified proximal LCX aneurysm with a small thromboatheroma (Figure 1). An additional smaller, noncalcified distal LCX aneurysm was present. Furthermore, the distal LCX drained into a confluent structure receiving terminal portions of the remainder of the coronary arteries (Figures 2 and 3). This confluence communicated with the left ventricle (LV) through a moderate-caliber transmural fistulous tract (Figures 3 and 4). The left anterior descending artery was markedly enlarged and tortuous proximally, and it appeared to drain into the arterial confluence distally. The right coronary artery was dominant, with a normal caliber, and it terminated distally into the confluence. Increased trabeculation was present in the LV at the anterolateral segment. A transthoracic echocardiogram (Figure 5) showed normal left ventricular and right ventricular systolic function without any wall motion abnormalities or valvular heart disease. Cardiac magnetic resonance revealed normal resting myocardial perfusion, normal biventricular function, a normal pulmonary-to-systemic flow ratio, and no evidence of delayed gadolinium enhancement (Figures 6A and 6B). An exercise single-photon emission computed tomography myocardial perfusion imaging study demonstrated no inducible ischemia, with normal left ventricular ejection fraction. We could not identify any additional congenital abnormalities or signs of infection or vasculitis in the past medical history or during the index evaluation.Figure 1 3D VR CTA Image\n\nA 3-dimensional (3D) volume-rendered (VR) image of the lateral cardiac surface that shows a giant left circumflex (LCX) coronary artery aneurysm, left anterior descending artery (LAD), obtuse marginal branch, and part of the left ventricular (LV) transmural fistula. CTA = computed tomography angiography; LA = left atrium.\n\nFigure 2 3D VR and MPR CTA Images\n\nThese 3D VR images of the inferior and lateral cardiac surface show a giant LCX coronary artery aneurysm, an LV transmural fistula, and confluence receiving terminal portions of all the coronary arteries. Multiplanar reconstruction (MPR) images show a giant left circumflex coronary artery aneurysm and confluence receiving terminal portions of all the coronary arteries. RA = right atrium; RV = right ventricle; other abbreviations as in Figure 1.\n\nFigure 3 3D VR and MPR CTA Images\n\nThese 3D VR images of the apical and lateral cardiac surface show the LAD, LCX, LV transmural fistula, and confluence receiving terminal portions of all the coronary arteries. MPR images show an LV transmural fistula and confluence receiving terminal portions of all the coronary arteries. Abbreviations as in Figures 1 and 2.\n\nFigure 4 3D VR and MPR CTA Images\n\nThese 3D VR and MPR images show a giant LCX coronary artery aneurysm, an LV transmural fistula, and the LCX. Abbreviations as in Figure 1.\n\nFigure 5 Apical 4-Chamber Echocardiogram\n\nThis apical 4-chamber echocardiogram shows normal-size cardiac chambers, normal valves, and a calcified LCX aneurysm. Abbreviations as in Figures 1 and 2.\n\nFigure 6 CMR SSFP Images in Systole and Diastole\n\nImages obtained in (A) systole and (B) diastole demonstrate findings similar to those seen in the echocardiogram in Figure 5. A mild increase in the LCX aneurysm dimension in diastole is noted. CMR = cardiac magnetic resonance; SSFP = steady-state free precession; other abbreviations as in Figures 1, 2, and 5.\n\nManagement\n\nThe patient was managed conservatively using dual antiplatelet therapy (aspirin and clopidogrel) and a statin because coronary artery thrombosis and progressive stenosis within the aneurysm may cause myocardial ischemia, which increases the risk of myocardial infarction and sudden cardiac death in these patients. The patient took warfarin for a month, but it was stopped because of hematuria and hematospermia. He also underwent yearly coronary CTA for surveillance without significant change in the size of the aneurysm, and he has remained without cardiac complications to date for a total of 3 years. At present, nonradiation modalities such as cardiac magnetic resonance are not beneficial in this case because of the need in a 3-dimensional imaging modality with excellent all-axis spatial resolution (isometric voxels) for depiction of such a complex coronary anatomy.\n\nDiscussion\n\nThe incidence of coronary artery aneurysms is 0.02% to 0.04%, and these aneurysms are usually seen in the right coronary artery. To our knowledge, there has been no case reported of a patient with an LCX aneurysm communicating with a distal coronary arterial confluence, and this confluence further connected to the LV through a fistulous track. LCX aneurysms with fistulous communication have rarely been reported; among the reported aneurysms, most communicated with the coronary sinus (1). Only 1 case report described LCX aneurysm with a fistulous communication to the LV myocardium through several small vessels (2).\n\nCoronary artery aneurysms may represent a potentially life-threatening condition with important complications including thrombosis or rupture. Of note, our patient was asymptomatic. The available treatment options for coronary artery aneurysm with fistula are surgical or endovascular interventions (1). However, treatment depends on the complexity of the anomalous anatomy. Furthermore, the follow-up duration and treatment with surgical or endovascular interventions in asymptomatic patients are unknown. A systematic approach with possible multicenter registries, development of a specific diagnostic approach, and prognostic estimates in patients with this complex anatomy, requires further research.\n\nFollow-Up\n\nThe patient underwent yearly coronary CTA for surveillance without significant change in the size of the LCX aneurysm, and he has remained without cardiac complications to date for a total of 3 years.\n\nConclusions\n\nLCX aneurysm is an extremely rare clinical condition. Careful assessment of the coronary anatomy is needed to identify any additional coronary anomalies in these patients. Evaluation of such a unique anomaly as giant LCX aneurysm combined with distal LCX draining into a confluence receiving terminal portions of all coronary arteries and communicating with left ventricle through a transmural fistulous tract requires implementation of advanced 3-dimensional imaging methods.\n\nThe authors have reported that they have no relationships relevant to the contents of this paper to disclose.\n\nThe authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Case Reportsauthor instructions page.\n==== Refs\nReferences\n\n1 Gupta V. Truong Q.A. Okada D.R. Images in cardiovascular medicine. Giant left circumflex coronary artery aneurysm with arteriovenous fistula to the coronary sinus Circulation 118 2008 2304 2307 19029479\n2 Suh S.Y. Kim J.W. Yong H.S. Aneurysm of circumflex coronary artery caused by cardiac vein and fistulous connection to the left ventricle identified on MDCT Int J Cardiol 114 2007 e3 e4 16893576\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2666-0849", "issue": "2(11)", "journal": "JACC. Case reports", "keywords": "CT, computed tomography; CTA, computed tomography angiogram; LCX, left circumflex artery; LV, left ventricle; coronary artery aneurysm; coronary fistula; left ventricular fistula", "medline_ta": "JACC Case Rep", "mesh_terms": null, "nlm_unique_id": "101757292", "other_id": null, "pages": "1812-1817", "pmc": null, "pmid": "34317061", "pubdate": "2020-09", "publication_types": "D002363:Case Reports", "references": "16893576;19029479", "title": "Giant Calcified Left Circumflex Coronary Artery Aneurysm With Complex Coronary-to-Left Ventricular Communication.", "title_normalized": "giant calcified left circumflex coronary artery aneurysm with complex coronary to left ventricular communication" }	[ { "companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2020-081591", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "WARFARIN SODIUM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "009218", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ISCHAEMIC HEART DISEASE PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN SODIUM." } ], "patientagegroup": null, "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haematospermia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haematuria", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOUMA R, PALLA M, ALAM K, MASTROMATTEO JF, ABIDOV A. 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{ "abstract": "To find a remedy for serpiginous choroiditis refractory to oral prednisone and chlorambucil treatment.\nEight eyes of four patients (all female) with advanced macular involvement secondary to serpiginous choroiditis were included in the study. The average age of the patients was 45.2 years. One eye of each patient was legally blind and the lesion was close to the fovea in the other eye. All four patients failed oral prednisone and chlorambucil therapy. However, case 1 responded to chlorambucil treatment after intravitreal dexamethasone implant implantation and discontinuation of oral prednisone. Case 2 responded to chlorambucil therapy when oral prednisone was stopped in combination with infliximab therapy. Due to long follow-up period of more than four years, these two cases are considered to be cured. Case 3 and case 4 were not able to achieve remission with chlorambucil and immunomodulatory therapy. They refused intravitreal steroid implant due to side effects profile.\nThe stability of WBC counts within toxic levels close to normal or lower limits of normal (3000-4500 cells/μl) during treatment with chlorambucil is an essential factor for the success of this therapy. A combination of dexamethasone intravitreal implant with chlorambucil therapy can be an effective and promising regimen in inducing and maintaining remission in refractory serpiginous choroiditis patients who fail a combination of systemic corticosteroid and chlorambucil therapy.", "affiliations": "Massachusetts Eye Research and Surgery Institution, Waltham, MA, United States.;Massachusetts Eye Research and Surgery Institution, Waltham, MA, United States.;Massachusetts Eye Research and Surgery Institution, Waltham, MA, United States.;Massachusetts Eye Research and Surgery Institution, Waltham, MA, United States.;Massachusetts Eye Research and Surgery Institution, Waltham, MA, United States.;Massachusetts Eye Research and Surgery Institution, Waltham, MA, United States.", "authors": "Maleki\|Arash\|A\|;Maldonado Cerda\|Anapatricia\|A\|;Garcia\|Cristina M\|CM\|;Zein\|Mike\|M\|;Manhapra\|Ambika\|A\|;Foster\|C Stephen\|CS\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1016/j.ajoc.2021.101014", "fulltext": "\n==== Front\nAm J Ophthalmol Case Rep\nAm J Ophthalmol Case Rep\nAmerican Journal of Ophthalmology Case Reports\n2451-9936 Elsevier \n\nS2451-9936(21)00005-0\n10.1016/j.ajoc.2021.101014\n101014\nCase Report\nChlorambucil combination therapy in refractory serpiginous choroiditis: A cure?\nMaleki Arash ab Maldonado Cerda Anapatricia ab Garcia Cristina M. ab Zein Mike ab Manhapra Ambika ab Foster C. Stephen [email protected]∗ a Massachusetts Eye Research and Surgery Institution, Waltham, MA, United States\nb The Ocular Immunology and Uveitis Foundation, Waltham, MA, United States\nc Harvard Medical School, Department of Ophthalmology, Boston, MA, United States\n∗ Corresponding author. Massachusetts Eye Research and Surgery Institution, 1440 Main St. Ste. 201, Waltham, MA, USA. [email protected]\n30 1 2021 \n3 2021 \n30 1 2021 \n21 10101427 8 2020 7 12 2020 11 1 2021 © 2021 The Authors2021This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Purpose\nTo find a remedy for serpiginous choroiditis refractory to oral prednisone and chlorambucil treatment.\n\nObservations\nEight eyes of four patients (all female) with advanced macular involvement secondary to serpiginous choroiditis were included in the study. The average age of the patients was 45.2 years. One eye of each patient was legally blind and the lesion was close to the fovea in the other eye. All four patients failed oral prednisone and chlorambucil therapy. However, case 1 responded to chlorambucil treatment after intravitreal dexamethasone implant implantation and discontinuation of oral prednisone. Case 2 responded to chlorambucil therapy when oral prednisone was stopped in combination with infliximab therapy. Due to long follow-up period of more than four years, these two cases are considered to be cured. Case 3 and case 4 were not able to achieve remission with chlorambucil and immunomodulatory therapy. They refused intravitreal steroid implant due to side effects profile.\n\nConclusions and importance\nThe stability of WBC counts within toxic levels close to normal or lower limits of normal (3000–4500 cells/μl) during treatment with chlorambucil is an essential factor for the success of this therapy. A combination of dexamethasone intravitreal implant with chlorambucil therapy can be an effective and promising regimen in inducing and maintaining remission in refractory serpiginous choroiditis patients who fail a combination of systemic corticosteroid and chlorambucil therapy.\n\nHighlights\n• Serpiginous choroiditis may be recurrent or refractory to chlorambucil in conjunction with systemic corticosteroids.\n\n• The stability of WBC counts within lower limits of normal is an essential factor for the success of chlorambucil therapy.\n\n• This can be achieved with dexamethasone intravitreal implant or systemic immunomodulatory without systemic corticosteroid therapy.\n\n\n\nKeywords\nChlorambucilCyclophosphamideDexamethasone implantInfliximabSerpiginous choroiditis\n==== Body\n1 Introduction\nSerpiginous choroiditis (SC) is a rare, chronic, asymmetrically bilateral posterior uveitis with a recurrent course. The exact prevalence of SC is unknown; however, it is estimated between 1.6% and 5.3% of posterior uveitis cases in non-endemic areas for tuberculosis.1 Major features of SC include choriocapillaris occlusive vasculitis, secondary endothelial cell injury, and subsequent atrophy of the retinal pigment epithelium, outer retina, and choroid.2,3 Histopathology studies reveal lymphocytic infiltration in the choroid and, less commonly, around vessels.4 The peripapillary area is classically involved in SC and accounts for 80% of the cases.5 The prognosis of vision is poor when it involves the macula, especially in the macular variant of SC. Moreover, the macular variant has a higher risk of developing choroidal neovascularization in nearly half of the affected patients.6,7 Fluorescein angiography (FA), indocyanine green angiography (ICG), optical coherence tomography (OCT), fundus autofluorescence (FAF), and microperimetry are the ancillary diagnostic tools and tests which help in the diagnosis, follow-up, and monitoring for secondary complications.1\n\nHistorically, the administration of high doses of oral or intravenous steroids was considered as the standard of care for patients with SC.8 However, immunosuppressive agents such as azathioprine, cyclosporine, chlorambucil, and cyclophosphamide emerged as treatment options for steroid-free remission.4,9, 10, 11, 12 Of these, the alkylating agents cyclophosphamide and chlorambucil have been noted to have a high success rate in the treatment of SC.4,10,12 Chlorambucil, being a potent alkylating agent, can interfere with DNA replication and cell division.13 This medication can induce remission, maintain remission, and even cure this disease.12\n\nDespite successful treatment of SC with alkylating agents, in some patients the disease can recur frequently and progress to affect the central vision. This becomes more important in patients with poor vision in the other eye secondary to SC or advanced SC encroaching the fovea in the affected eye. In this case series, we decided to evaluate possible remedies for refractory and recurrent SC in patients who have been treated with chlorambucil and oral or intravenous corticosteroids.\n\n2 4 Cases\nCase 1. A sixty-year-old female was referred to us for the evaluation of macular SC OU. She had noticed blurry vision OS one month before her first visit with us. A geographic lesion with indistinct and irregular borders was observed in both eyes. The lesion was uni-centric OU, temporal to fovea OD and peripapillary with extension to fovea OS. FA and ICG showed the activity of the lesions in both eyes (Fig. 1A). Her best-corrected visual acuity (BCVA) was 20/20 OD and decreased OS to 20/100. Complete blood work-up for uveitis ruled out non-infectious and infectious posterior uveitis, including syphilis and tuberculosis. Based on these findings, she was diagnosed with autoimmune SC OU and was started on a combination of chlorambucil and daily oral prednisone. Chlorambucil was titrated based on her white blood cell (WBC) count. She had another flare-up while she was on 2 mg/day prednisone and had already stopped chlorambucil for three weeks due to WBC 3200 cells/μl. BCVA OS decreased to 20/125, and ICGA confirmed enlargement of the lesion. Chlorambucil was restarted to 2 mg every other day, and oral prednisone was increased to 5 mg/day. With this change in her regimen, the vision increased to the baseline before her last flare, to 20/40. Treatment with chlorambucil was stopped after one year. Her follow-up visit increased to every three months from monthly. Then, six months later, she was started on oral methotrexate 7.5 mg weekly by her rheumatologist because of her joint issues. She was followed every three months for seven months until she noticed a change in OS again. At that time, she was on oral methotrexate 15 mg weekly. BCVA OS decreased to 20/125, and ancillary tests showed activity at the border of the lesions on the foveal side (Fig. 1B). She received one dose of 1 g intravenous methylprednisolone, intravitreal injection of triamcinolone and bevacizumab, and was restarted on oral prednisone 80 mg/day. A week later, her methotrexate dose was boosted to methotrexate 25 mg weekly subcutaneous injections, and we tapered prednisone 10 mg weekly. In three months, oral prednisone was tapered and stopped. Three months later, her lesion became active and she developed choroidal neovascularization (CNV) for which she received a bevacizumab injection. She was restarted on chlorambucil and oral prednisone. The decision for local therapy with dexamethasone implant was made at this point, and she was put back on chlorambucil 2 mg every three days. She was on chlorambucil without oral prednisone, titrating the dose based on WBC for seventeen months, after which she was considered cured (Fig. 1C). In her last visit with us, her BCVA OD and OS were 20/20 and 20/50, respectively. The patient's average WBC count while on chlorambucil with prednisone, chlorambucil without prednisone, and chlorambucil after dexamethasone intravitreal implant were 5500 ± 2900, 4700 ± 1100 and 4100 ± 500 cells/μl, respectively. The total duration of treatment before dexamethasone intravitreal implant was 60 months and 17 months after dexamethasone intravitreal implant. The total length of follow-up is 132 months, and the total duration of remission off medication is 48 months (Table 1).Fig. 1 A patient with bilateral serpiginous choroidopathy. (A) Serpiginous lesions in both eyes, encroaching the fovea in right eye and with foveal involvement in left eye. Fluoresecein angiography shows activity in both eyes. (B) The middle row shows progression towards the fovea with leakage pointing toward the fovea in the right eye. (C) Shows the stability of fundus photos and fluorescein angiography in both eyes at one year after intravitreal dexamethasone implant and chlorambucil treatment.\n\nFig. 1Table 1 Demographics and clinical characteristics of patients with resistant serpiginous choroiditis.\n\nTable 1\tAge years\tSex\tLaterality\tBCVA first visit\tWBC (C + P) cells/μl\n(x 10c)\tWBC (C) cells/μl\n(x 10c)\tWBC (C + IMTor implan cells/μl (*10c)\tDuration of treatment before IMT\tDuration of treatment after IMT\tDuration of follow-up on chlorambucil\tDuration of follow-up off chlorambucil\tBCVA last visit\t\nPatient 1\t60\tF\tBilat\t20/20 20/100\t5.5 ± 2.9\t4.7 ± 1.1\t4.1 ± 0.5\t60a months\t17b months\t60 months\t83 months\t20/20 20/50\t\n OD\t\n OS\t\nPatient 2\t42\tF\tBilat\t1 mcf 20/20\t5.7 ± 2.2\tN/A\t3.8 ± 0.5\t40c months\t19d months\t49 months\t60 months\t1mcf\n20/15\t\n OD\t\n OS\t\nPatient 3\t32\tF\tBilat\tHM 20/20\t8.8 ± 3.4\tN/A\tN/A\t5 + 10 e months\tN/A\t5 months\tN/A\tHM 20/50\t\n OD\t\n OS\t\nPatient 4\t47\tF\tBilat\t20/30 1mcf\t6.2 ± 3.3\tN/A\tN/A\tN/A\tN/A\t12 months\tN/A\t20/50 1mcf\t\n OD\t\n OS\t\nBCVA:best corrected visual acuity; Bilat:bilateral; C:chlorambucil; CF:counting fingers; HM:hand motion; IMT:immunomodulatory therapy; P:prednisone; N/A:not applicable.\n\na Before intravitreal dexamethasone implant.\n\nb After intravitreal dexamethasone implant.\n\nc Before starting infliximab.\n\nd After starting infliximab.\n\ne 5 months chlorambucil and 10 months cyclophosphamide.\n\n\n\nCase 2. A 42-year-old female was referred to us with blurry vision and field distortion OD for ten years and OS for eight years. Her vision was counting fingers at 1 m OD and 20/20 OS. At the time of presentation, the patient had already received multiple intravitreal anti-VEGF (bevacizumab) and triamcinolone injections OD. The geographic lesions were peripapillary OU, with foveal involvement OD. Initial FA revealed chorioretinal scarring with window defects OU and leakage on borders OD (Fig. 2A). On ICG, the area of hypolucency OS extended further into the macula, which was not seen on FA (Fig. 2B). Complete blood work-up for uveitis ruled out non-infectious and infectious posterior uveitis, including syphilis and tuberculosis. Based on these findings, she was diagnosed with autoimmune SC OU and we recommended therapy with chlorambucil. She sought a second opinion elsewhere, where she was started on mycophenolate mofetil (MMF) 1 g daily with infliximab 300 mg IV every four weeks and oral prednisone 80 mg/day with taper. MMF and infliximab were eventually discontinued due to elevated LFTs. On follow up at our clinic eighteen months after the initial consult, chlorambucil was finally started with dose adjustment based on weekly monitoring of WBC count to reach the endpoint of WBC count 3000–4500 cells/μl. While on chlorambucil 20mg and prednisone 40mg daily, the patient became symptomatic OS with new changes and leakage on FA OS, prompting boosting of oral prednisone to 80 mg; she also received one ranibizumab injection OS locally. Six weeks after starting treatment with chlorambucil (20mg at this time) and oral prednisone 80 mg daily, WBC count dropped down to 4900 cells/μl, so we started tapering prednisone. Two months after initiation of chlorambucil therapy, chlorambucil was stopped while tapering prednisone at 30 mg/day with a WBC count of 3300 cells/μl. At this point, FA, FAF, and OCT showed stability and quiescence. On a subsequent visit with her local ophthalmologist, infliximab 600 mg infusions every four weeks was started for activity OS, and eventually increased to 900 mg every four weeks in combination with chlorambucil. WBC count increased to 7900 cells/μl while on prednisone 10 mg with taper, and chlorambucil was restarted at 4 mg daily, eventually going up to 6 mg daily (Fig. 2B). Chlorambucil dose adjustment with weekly WBC count was continued. Meanwhile, she received a bevacizumab injection with her local ophthalmologist due to central vision distortion OD. On her eight-month of treatment, WBC count dipped to 2000 cells/μl, and chlorambucil was stopped. After one week, with WBC count creeping back up to 4800 cells/μl, chlorambucil was restarted at 2 mg/day. Disease activity was then noted at ten months from treatment initiation with no interventions at that time. On follow up at our clinic fourteen months after starting chlorambucil, the activity noted at ten months prompted treatment extension, and the patient was educated on the risks vs. benefits of this decision. Chlorambucil treatment was continued for a total duration of twenty-one months. FA and OCT macula findings were stable and the patient was asymptomatic (Fig. 2C,D). Subsequent consults established disease stability with no new symptoms or activity. Infliximab was eventually tapered by 100 mg every four weeks. On her last consult at our clinic, she was on infliximab 100 mg infusions every four weeks with a final VA of 20/400 OD and 20/15 OS and stable findings on FA and macula OCT. Her average WBC count was 5700 ± 2200 cells/μl while on chlorambucil with prednisone, and 3800 ± 500 cells/μl when she was on chlorambucil after starting infliximab infusions without prednisone. The total duration of treatment before and after beginning infliximab infusions was 40 and 19 months, respectively. The total length of follow-up is 108 months. The total period of remission off chlorambucil is 60 months (Table 1).Fig. 2 (A) Fundus photo and fluorescein angiography of a patient with bilateral serpiginous choroiditis at the primary visit at our clinic. (B) The same patient during a recurrence in the left eye close to the fovea. (C,D) Stability of year after stopping chlorambucil while on infliximab tapering. (E) Macular optical coherence tomography at the first visit (left), during a recurrence (middle), and the last visit (right).\n\nFig. 2\n\nCase 3. A 32-year-old female presented with decreased vision, floaters, and photophobia OS. Vision OD was poor due to retinal detachment after a motor vehicle accident. Before presenting to her initial consultation at our clinic, complete blood work-up for uveitis had ruled out non-infectious and infectious posterior uveitis, including syphilis and tuberculosis and she had already been diagnosed with idiopathic SC. She had been on MMF 2 g daily, cyclosporin 25 mg and prednisone 30 mg daily for fourteen months. Her vision was hand-motion OD and 20/20 OS at presentation. A fundus examination revealed optic atrophy and a horizontal scar OD in addition to diffuse chorioretinal (CR) scarring in both eyes. Given the possibility of the activity of the lesion potentially affecting the fovea OS and her monocular status, chlorambucil and cyclophosphamide were discussed as treatment options.\n\nThe patient was started on chlorambucil 4 mg daily and continued on 25 mg of prednisone daily. A month later, her WBC count dropped from 14,800 to 12,100 cells/μl. However, she felt her vision had decreased once again after two weeks on chlorambucil. She was advised to increase chlorambucil to 6 mg/day from 4 mg/day, as well as increase prednisone to 40 mg daily. After one week at this dose, she reported stable vision OD. Chlorambucil dose adjustment with weekly WBC count and oral prednisone were continued until she reported stable vision and no other symptoms. At this time, she was advised to increase chlorambucil to 12 mg daily.\n\nApproximately four months after her initial visit, the patient presented to our clinic with worsening scotoma and floaters OS. At this point, she was on prednisone 5 mg daily and chlorambucil 10 mg daily. She had stopped chlorambucil for a week due to fever, and the WBC count was at 11,200 cells/μl. FA and ICG showed active choroidal inflammation at the lesion border, especially OS. Later on, she developed a diffuse, itchy rash, and because of this side effect, she was started on bi-weekly cyclophosphamide pulse therapy. She had five doses of cyclophosphamide pulse therapy, and her WBC count was between 4500 and 6300 cells/μl. However, a few days later, she complained of decreased vision OS with more central involvement. Her local ophthalmologist increased her prednisone to 60 mg, and she received her next cyclophosphamide infusion four days later with WBC count at 4000 cells/μl. Cyclophosphamide therapy was finally stopped due to persistent skin rash.\n\nIn the interim, she followed up with her local ophthalmologist while on oral prednisone with different doses based on disease activity. Her next visit with us was seven years later, and vision OS had deteriorated to 20/50. FA showed active inflammation OS in the form of enlarged CR lesions approaching the fovea with multifocal areas of leakage at the margins of the lesions (Fig. 3B). Up to that point, the patient had been off all immunomodulatory therapy (IMT) for seven years, yet only cyclophosphamide appeared to halt the progression of her disease. Monthly cyclophosphamide pulse therapy was resumed but was later stopped after eight months due to low WBC count. After this, she continued with oral prednisone 20 mg daily. At her last follow-up visit, chlorambucil was restarted due to the persistence of symptoms, worsening of vision OS, and the progression of lesion activity on imaging (Fig. 3C). Intravitreal steroid implants were also discussed. The patient was never able to taper off oral prednisone during treatment, and the average WBC count during her course of treatment was 8800 ± 3400 cells/μl. The total duration of treatment with chlorambucil was 5 months, cyclophosphamide was 10 months, and MMF plus cyclosporine was 14 months. The total duration of follow-up is 148 months. She has never been in remission for an extended period off medication (Table 1).Fig. 3 (A) Fundus photo of both eyes of a patient with bilateral serpiginous choroiditis. History of traumatic retinal detachment surgery with legal blindness in the right eye and active serpiginous choroiditis in the left eye. Fluorescein angiography shows an active lesion in the left eye. (B) Optical coherence tomography, fundus autofluorescence, and fluorescein angiography during a recurrence where the patient was started on cyclophosphamide pulse therapy. (C) Progression of the lesion in the left eye with an active lesion in fluorescein angiography at her last visit. Intravitreal dexamethasone and triamcinolone implants were discussed at this visit.\n\nFig. 3\n\nCase 4. A 47-year-old female was referred to our center with decreased vision OU for one month and had been started on prednisone 50 mg daily before her first visit with us. Her vision OD and OS were 20/30 and counting fingers at 1 m, respectively, at presentation. Dilated fundoscopy showed bilateral geographic lesions nasal to the fovea OD and involving the fovea OS (Fig. 4A). Complete blood work-up for uveitis ruled out non-infectious and infectious posterior uveitis, including syphilis and tuberculosis. Based on these findings, and she was diagnosed with autoimmune SC OU. Oral prednisone was increased to 60 mg daily, and due to significant vision loss OS, she was started on chlorambucil 6 mg daily. Chlorambucil treatment with WBC count monitoring and tapering of oral prednisone was continued for a year. Once the oral prednisone taper was completed, she continued with chlorambucil monotherapy for five more months, at which time she had achieved remission. After four months; however, she had a flare-up OD, which was first treated with 1 g IV methylprednisolone infusion and intravenous methotrexate 200 mg/day. Subsequently, she was continued on subcutaneous methotrexate 15 mg weekly along with folic acid 1 mg/day for two years. She developed another flare-up when tapering methotrexate; hence methotrexate dose was boosted, and a combination of chlorambucil and oral prednisone was restarted. The patient was on chlorambucil and oral prednisone for one year, with an average WBC count of 6200 ± 3300 cells/μl. The patient was then on chlorambucil alone for another two months. She had been flare-free for twenty months when she had another episode. This time she was treated with intravenous and subcutaneous methotrexate. She had another flare during tapering of methotrexate and she is currently on a combination of chlorambucil, prednisone, and subcutaneous methotrexate therapy. The total duration of follow-up has been 116 months. She has never been in remission for an extended period (Table 1).Fig. 4 A serpiginous choroiditis patient with multiple recurrences despite treatment with a combination of oral prednisone and chlorambucil therapy. (A) Color fundus photos and fluorescein angiography of both eyes at the first visit, which showed activity around the lesion in both eyes. (B) The second row shows the progression of lesions in both eyes during a recurrence on fundus photos and fundus autofluorescence. (C) Fundus autofluorescence and fluorescein angiography showed reactivation of the supratemporal area of the lesion in the right eye. (D) Optical coherence tomography shows the lesion, edema, and destruction of the supratemporal part of the lesion, compatible with fundus autofluorescence and fluorescein angiography. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)\n\nFig. 4\n\n3 Discussion\nThe pathogenesis of serpiginous choroiditis (SC) is unknown. The course of the disease is indolent and can be asymptomatic until it involves the macula and the central vision. Many patients can have old scars even at the first visit when they are diagnosed with SC.14 Laatikainen and Erkkila et al. reported that new lesions may appear at an interval of 3 months–4 years. They also demonstrated that active lesions resolve in a few weeks; however, signs of activity may last between 1 and 9 months.14 Central vision is involved in 20%–50% of cases, with the likelihood increasing with longer duration of follow-up and disease activity.8,14 Recurrences that affect the macula can cause severe visual loss of less than 20/200, which is typically irreversible and may induce CNV in the macula or around the optic disc.15\n\nThere are no controlled trials for the treatment of SC due to the rarity of the disease. Cytosine arabinoside, azathioprine, and oral prednisone were used with reported improved visual acuity in one month.16 Employment of a combination of cyclosporine and oral prednisone as a treatment of active SC had conflicting results. Hopper and Kaplan reported a triple-agent regimen of azathioprine, cyclosporine, and oral prednisone that resulted in rapid control of the active SC and vision recovery; however, disease recurrence was the study's main problem.9 Akpek et al. employed the same regimen in a more extended study and found that this regimen helped keep the inflammation quiet during treatment; however, it did not maintain remission off medication.17\n\nAlkylating agents can bind to DNA, interfere with DNA replication, and subsequently interfere with cell division. Cyclophosphamide is commonly used because of its predictable, dose-dependent, and reversible adverse effects on WBC count18; nonetheless, it can result in serious side effects, some of which are life-threatening. These side effects include reversible hematuria, hemorrhagic cystitis, reversible alopecia, sterility, bladder cancer, lymphoma, and leukemia. Chlorambucil is another alkylating agent primarily used for the treatment of several lymphoproliferative diseases. It is a stable derivative of the nitrogen mustard.19 Based on its ability to reduce circulating lymphocytes, chlorambucil is effective in the treatment of rheumatologic diseases, including juvenile rheumatoid arthritis, systemic lupus erythematosus, and nephrotic syndrome.20, 21, 22, 23 Given the availability of other conventional immunomodulatory agents and biologic response modifiers that yield better results with fewer unpredictable side effects, ophthalmologists are reluctant to use chlorambucil. Our knowledge about biologic response modifier agents is limited to a few case reports and some of our patients had already failed infliximab, mycophenolate mofetil, methotreaxte before their first presentation to us or during follow-up with us. Palmer et al. studied the side effects of chlorambucil and found that these side effects are related to the total dose and duration of treatment.24 However, Tessler et al. found chlorambucil to be a successful treatment for different types of uveitis with no severe complications during 12 years of follow-up. They also reported complete remission in all patients. Although chlorambucil dose in their study was administered regardless of body weight, it did not exceed 2.2 g per patient during the entire treatment.25 Based on these findings, recent studies still rely on alkylating agents including cyclophosphamide and chlorambucil for classical and macular SC.5,12,32\n\nIt may take more time for chlorambucil to show its therapeutic and toxic effects. Patients on this medication should be monitored with weekly blood counts, specifically WBC and platelet counts, since its side effects are not always dose-related.25 Chlorambucil is administered orally because it has excellent gastrointestinal absorption, and its superiority over cyclophosphamide is related to the absence of associated side effects such as hair loss, hemorrhagic cystitis, and bladder cancer.26\n\nThe recommendation for the daily and total dose of chlorambucil is equal to or less than 0.2 mg/kg and 2.2 g, respectively. These recommendations help avoid late complications such as lymphoma and leukemia.27 Various doses of chlorambucil have been employed in the past in the field of ophthalmology. The use of lower doses of chlorambucil over an extended period, such as more than one year, without provoking bone marrow toxicity is one approach.28, 29, 30, 31 However, it has been demonstrated that sustained remission of the disease is achievable when the WBC count remained depressed for at least six weeks. This finding suggests that effective treatment with chlorambucil requires the induction of a toxic hematologic response.25\n\nThe recent literature shows that alkylating agents are still the most potent and effective treatment in patients with SC.4,12,32 Venkatesh and colleagues showed that intravenous cyclophosphamide pulse therapy provided a rapid resolution of active lesions and helped maintain good functional visual acuity.4 However, they admitted that this treatment might not prevent recurrences in patients with SC.4 Venkatesh et al. also studied intravenous methylprednisolone and cyclophosphamide in macular SC; they, again demonstrated it could be effective in acute macular SC, yet admitted that this treatment had no effects on disease relapses in the long-term.32 Ebrahimiadib et al. retrospectively studied 17 patients on chlorambucil with dose escalation based on weekly WBC count, with the target of 3000–4500 white blood cells/μl. They concluded that chlorambucil was well tolerated by the patients and was effective in preventing recurrences.12 Although all these recent studies provided important facts regarding SC treatment, they did not discuss the next step for the patients who failed these treatments. In the current study, we decided to evaluate the possible causes of chlorambucil treatment failure in patients with resistant SC and to examine possible successful regimens in these patients. To the best of our knowledge, this study is the first one which evaluates the possible remedy for resistance to chlorambucil as one of the most commonly employed medications in SC patients.\n\nHistopathological studies in SC have demonstrated that lymphocytes infiltrate the choroid, and less commonly, vessels, leading to subsequent choriocapillaris occlusive vasculitis. This finding may indicate the important roles of lymphocytes in the pathogenesis of the disease.5 The histopathology in SC is very similar to birdshot chorioretinopathy.33,34 On the other hand, multiple studies have discussed the effects of long-term systemic corticosteroids on lymphocyte proliferation and T-cell population.35,36 Ferrari et al. reported increased lymphocytes, including increased absolute numbers of T cells, CD4+ and CD8+ cells, after four weeks of corticosteroid therapy in idiopathic thrombocytopenic purpura (ITP).35 Moreover, lymphocyte redistribution has been discussed in long-term steroid therapy.36 These changes associated with long-term corticosteroid use may interfere with the aim of chlorambucil treatment, since cells with higher proliferation rates are the target of this therapy. The negative effect of long-term systemic corticosteroids on birdshot chorioretinopathy has been studied in the past.37,38 Due to similarities between birdshot chorioretinopathy and SC in terms of histopathology, these facts can be applied to SC patients as well.\n\nThe target WBC count for chlorambucil therapy for SC is between 3000 and 4500 cells/μl. Chlorambucil dose adjustment is based on a weekly WBC count. In our experience, patients might be considered cured if there is no recurrence during the treatment period, which is around one year. Our observation in this case series showed that patients on high doses of systemic corticosteroids have unstable WBC count during chlorambucil therapy. Keeping this count in the satisfactory range for a reasonable period of at least six weeks can be challenging since it has been shown that induced toxic hematologic response is required for effective treatment with chlorambucil.25 The first two patients in this case series achieved durable remission and were likely cured after employing local corticosteroids or systemic immunomodulatory therapy, which allowed us to stop systemic corticosteroid use during chlorambucil therapy. However, the third and fourth patients are still experiencing recurrences since all systemic immunomodulatory therapies were unable to induce steroid-free remission. Local corticosteroid therapy was also recommended for both of the patients, but its potential side effects and the patients’ monocular statuses made this option unappealing.\n\nWe might be criticized for not employing local corticosteroid monotherapy without any systemic therapy. We believe that, although corticosteroids are the best option for controlling of acute ocular inflammation of any type, they are not potent enough to prime or re-program the immune system12 and not to respond to self-antigens as we expect with immunomodulatory therapy. This is similar to what occurs to pathologic cancer cells especially in blood cancers (lymphoma and leukemia) in patients who achieve remission with chemotherapy which is an advanced and more aggressive form of immunomodulatory therapy. Based on the above mentioned theory, corticosteroids as monotherapy cannot halt the inflammation thoroughly, so the ongoing inflammation can cause more cells destruction and epitopes exposures which might result in more resistant ocular inflammation which is believed to happen in patients with resistant autoimmune SC. we assume that the employment of systemic corticosteroid therapy, along with chlorambucil, is the main obstacle in achieving remission in patients with SC. This combination therapy is mostly seen in monocular patients or in vision-threatening SC where there is a lower threshold for aggressive systemic corticosteroid therapy in these patients.\n\nWe might also be criticized for using different therapies in one patient; however, we follow the strategy of “one change at a time” and this means that any time a conventional IMT is tried, we wait for three months with no changes to assess its effectiveness. For biologic response modifier agents, we wait for two months. This strategy makes interaction between medications unlikely. Moreover, since our mission is systemic steroid free remission, we only consider a medication to be effective if the inflammation stays in remission even after the effects of steroids are gone. Furthermore, none of these therapies induced long term remission in our patients.\n\nDexamethasone intravitreal implants have been employed in the treatment of active SC and serpiginous-like choroiditis.39,40 In these studies, the authors showed the success of this implant in controlling active SC. Based on these studies, dexamethasone can be an alternative to high dose oral or intravenous corticosteroid without systemic side effects including its effects on bone marrow, secondary lymphoid tissues, and peripheral blood regarding WBC counts, especially lymphocytes.\n\nOne common fact between all patients in this case series is the instability of WBC count during chlorambucil therapy plus systemic corticosteroids. This issue was addressed in one patient with dexamethasone intravitreal implant and in another patient with infliximab therapy. Both patients allowed us to taper and stop oral prednisone during chlorambucil therapy. The latter patient has been in remission for four years, which is the time frame during which one would expect a new lesion based on the Laatikainen and Erkkila et al. study.14 Despite this, this patient continues to take infliximab at a dose of 300 mg every four weeks since there is a fear of SC recurrence once infliximab therapy is terminated. However, this concept and hypothesis need further, more sophisticated examination.\n\nThis study had inherent limitations given its retrospective study design with a small sample size due to the rarity of cases of SC. It was even more challenging to find refractory cases with a reasonable follow-up period to expect a recurrence as all of these patients have at least 8 years of follow-up at our center without any serious side effects. Furthermore, all confounding factors cannot be controlled in a retrospective study. Regardless, we believe that confounding factors related to WBC might not interfere in this study since chlorambucil dose is adjusted based on WBC count and in clinical practice, changes in WBC count are typically more related to changes in corticosteroid dosage. Based on all these limitations, the results of this case series should be interpreted with caution and justifies the need for more potent studies.\n\n4 Conclusion\nThe stability of WBC counts within toxic levels close to normal or lower limits of normal (3000–4500 cells/μl) during treatment with chlorambucil is an essential factor for the success of this therapy. A combination of dexamethasone intravitreal implant with chlorambucil therapy can be an effective and promising regimen in inducing and maintaining remission in refractory SC patients who fail a combination of systemic corticosteroid and chlorambucil therapy as the first line therapy. However, this primitive hypothesis should be investigated with more potent studies and larger sample sizes.\n\nPatient consent\nConsent to publish the personal information and cases details was obtained from all the patients.\n\nFinancial supports\nNone.\n\nAll named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.\n\nDisclosures\nDr. C Stephen Foster declares the following: Consultancies with Aldeyra Therapeutics (Lexington, MA), Allakos (Redwood City, CA), Bausch & Lomb Surgical, Inc (Rancho Cucamonga, CA), Eyegate Pharma (Waltham, MA), Genentech (South San Francisco, CA), Novartis (Cambridge, MA), pSivida (Watertown, MA) Grants or grants pending with Aciont (Salt Lake City, UT), Alcon (Aliso Viejo, CA), Aldeyra Therapeutics (Lexington, MA), Bausch & Lomb (Rochester, NY), Clearside Biomedical (Alpharetta, GA), Dompé pharmaceutical (Milan, Italy), Eyegate Pharma (Waltham, MA), Mallinckrodt pharmaceuticals (Staines-upon-Thames, UK), Novartis Pharmaceuticals (Cambridge, MA), pSivida (Watertown, MA), Santen (Osaka, Japan). Payment for lectures including service on speaking bureaus: Alcon (Aliso Viejo, CA), Allergan (Dublin, Ireland), Mallinckrodt pharmaceuticals (Staines-upon-Thames, UK). Stock or Stock Options: Eyegate Pharma (Waltham, MA).\n\nThe other authors have nothing to declare.\n\nCompliance with ethics guidelines\nThis study was approved by the New England Institutional Review Board, which has issued a waiver of informed consent for the retrospective chart review analysis. This study was performed in accordance with the Helsinki Declaration of 1964, and its later amendments. All participants provided consent for publication if any identifying information is included in the manuscript.\n\nData availability\nThe data that support the findings of this study are available from the corresponding author, upon reasonable request.\n\nDeclaration of competing interest\nNo conflicting relationship exists for any author.\n==== Refs\nReferences\n1 Nazari H. Rao N.A. 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Systemic delayed hypersensitivity reaction to chlorambucil: a case report and literature review Contact Dermatitis 78 2 2018 171 173 29341183 \n20 Callis L. Nieto J. Vila A. Rende J. Chlorambucil treatment in minimal lesion nephrotic syndrome: a reappraisal of its gonadal toxicity J Pediatr 97 4 1980 653 656 7420231 \n21 Grupe W.E. Chlorambucil in steroid-dependent nephrotic syndrome J Pediatr 82 1973 598 606 4121460 \n22 Baluarte H.J. Hiner L. Gruskin A.B. Chlorambucil dosage in frequently relapsing nephrotic syndrome: a controlled clinical trial J Pediatr 92 1978 295 298 621612 \n23 Savolainen H.A. Chlorambucil in severe juvenile chronic arthritis: longterm follow-up with special reference to amyloidosis J Rheumatol 26 4 1999 898 903 10229413 \n24 Palmer R.G. Dore C.J. Denman A.M. Chlorambucil-induced chromosome damage to human lymphocytes is dose-dependent and cumulative Lancet 1 8371 1984 246 249 6142995 \n25 Tessler H.H. Jennings T. 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Dexamethasone intravitreal implants in the management of tubercular multifocal serpiginoid choroiditis J Ophthalmic Inflamm Infect 6 1 2016 31 27576870\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2451-9936", "issue": "21()", "journal": "American journal of ophthalmology case reports", "keywords": "Chlorambucil; Cyclophosphamide; Dexamethasone implant; Infliximab; Serpiginous choroiditis", "medline_ta": "Am J Ophthalmol Case Rep", "mesh_terms": null, "nlm_unique_id": "101679941", "other_id": null, "pages": "101014", "pmc": null, "pmid": "33615036", "pubdate": "2021-03", "publication_types": "D002363:Case Reports", "references": "1866149;30777946;27849419;27175923;1165913;12153803;12022010;2458620;29341183;4472398;6336643;12446382;7904272;2378842;6171987;10229413;4121460;27256717;11825825;621612;26383629;26044470;6535326;2483464;6142995;434065;27576870;773421;11815884;23541041;11935432;26807626;15804771;27754769;1794742;4433491;92200;7420231;22402699", "title": "Chlorambucil combination therapy in refractory serpiginous choroiditis: A cure?", "title_normalized": "chlorambucil combination therapy in refractory serpiginous choroiditis a cure" }	[ { "companynumb": "US-CELLTRION INC.-2021US002859", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "INFLIXIMAB" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "115544", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "POWDER FOR SOLUTION FOR INFUSION", "drugdosagetext": "900 MG EVERY 4 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, 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CHLORAMBUCIL COMBINATION THERAPY IN REFRACTORY SERPIGINOUS CHOROIDITIS: A CURE?. 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"reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Metamorphopsia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "White blood cell count decreased", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "FOSTER C. CHLORAMBUCIL COMBINATION THERAPY IN REFRACTORY SERPIGINOUS CHOROIDITIS: A CURE. AMERICAN JOURNAL OF OPHTHALMOLOGY CASE REPORTS. 2021 JAN 30?21:. DOI:10.1016/J.AJOC.2021.101014", "literaturereference_normalized": "chlorambucil combination therapy in refractory serpiginous choroiditis a cure", "qualification": "5", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210311", "receivedate": "20210311", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19000865, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210420" } ]
{ "abstract": "We herein report two cases of myelodysplastic syndrome with rheumatic manifestations. (Case 1) A 70-year-old man presented with fever, arthritis and bone pain and developed cranial nerve palsy caused by an epipharyngeal mass. Steroid therapy led to a prolonged remission of the febrile condition and mass lesion. (Case 2) An 82-year-old male was treated for intractable polyarthritis and fever with steroid therapy, and serious side effects resulted in lethal pneumonia. We herein describe the entire course of steroid therapy in these two cases. Various rheumatic manifestations in myelodyaplastic syndrome often require empirical steroid therapy. It was effective for the soft tissue mass in Case 1, in which indolent lymphoma could not be denied, and was only partially effective for Case 2 of the febrile and putatively benign conditions, suggesting heterogeneous nature of rheumatic complications in myelodysplastic syndrome.", "affiliations": "Division of Rheumatic Diseases, National Center for Global Health and Medicine , Tokyo , Japan.", "authors": "Inoue\|Mariko\|M\|;Kano\|Toshikazu\|T\|;Ozaki\|Takashi\|T\|;Takahashi\|Yuko\|Y\|;Yamashita\|Hiroyuki\|H\|;Kaneko\|Hiroshi\|H\|;Mimori\|Akio\|A\|", "chemical_list": "D005938:Glucocorticoids; D013256:Steroids", "country": "England", "delete": false, "doi": "10.3109/14397595.2013.844300", "fulltext": null, "fulltext_license": null, "issn_linking": "1439-7595", "issue": "25(4)", "journal": "Modern rheumatology", "keywords": "Autoimmune manifestation; Glucocorticoid; Myelodysplastic syndrome", "medline_ta": "Mod Rheumatol", "mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D001168:Arthritis; D001172:Arthritis, Rheumatoid; D001706:Biopsy; D001842:Bone and Bones; D017809:Fatal Outcome; D005334:Fever; D005938:Glucocorticoids; D006801:Humans; D008297:Male; D009190:Myelodysplastic Syndromes; D010243:Paralysis; D010608:Pharyngeal Diseases; D049268:Positron-Emission Tomography; D013256:Steroids; D014057:Tomography, X-Ray Computed", "nlm_unique_id": "100959226", "other_id": null, "pages": "653-6", "pmc": null, "pmid": "24313918", "pubdate": "2015-07", "publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Rheumatic manifestations and an epipharyngeal mass accompanied by myelodysplastic syndrome.", "title_normalized": "rheumatic manifestations and an epipharyngeal mass accompanied by myelodysplastic syndrome" }	[ { "companynumb": "JP-MYLANLABS-2015M1047072", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "202179", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "80 MG/ DAY; REDUCED TO", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "202179", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "CONTINUED WITH 10-20 MG / DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYELODYSPLASTIC SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "202179", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG / DAY; 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RHEUMATIC MANIFESTATIONS AND AN EPIPHARYNGEAL MASS ACCOMPANIED BY MYELODYSPLASTIC SYNDROME. 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null, "patientonsetage": "81", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pneumonia aspiration", "reactionmeddraversionpt": "19.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Pneumocystis jirovecii pneumonia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Systemic candida", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lung abscess", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201104" } }, "primarysource": { "literaturereference": "INOUE M, KANO T, OZAKI T, TAKAHASHI Y, YAMASHITA H, KANEKO H, ET AL. RHEUMATIC MANIFESTATIONS AND AN EPIPHARYNGEAL MASS ACCOMPANIED BY MYELODYSPLASTIC SYNDROME. MOD-RHEUMATOL 2015?25(4):653-656.", "literaturereference_normalized": "rheumatic manifestations and an epipharyngeal mass accompanied by myelodysplastic syndrome", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20160103", "receivedate": "20160103", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11884166, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160526" } ]
{ "abstract": "Outside of clinical trials, experience with daratumumab-based combination therapies (DCTs) using bortezomib (V)/lenalidomide (R)/pomalidomide (P), and dexamethasone (d) in relapsed/refractory multiple myeloma (RRMM) is limited. We reviewed the outcomes of 126 patients who received ≥ 1 cycle of any DCT. Median age at DCT initiation was 67 (range, 43-93) years. High-risk cytogenetics was present in 33% patients. Median number of prior therapies was 4 (range, 1-14) and time to first DCT from diagnosis was 4.3 years (range, 0.4-13.0). Seventeen (13%) patients were refractory to single agent daratumumab. Fifty-two (41%), 34 (27%), 23 (18%), and 17 (14%) received DPd, DRd, DVd and \"other\" DCTs, respectively. Overall response rate was 47%. Median follow-up was 5.5 months (95% CI, 4.2-6.1). Median progression-free survival (PFS) was 5.5 months (95% CI, 4.2-7.8). Median overall survival was not reached (NR) with any regimen. Median PFS (months) was worst for penta-refractory MM (n = 8) vs quadruple refractory MM (n = 18) and others (n = 100) (2.2 [95% CI, 1-2.4] vs 3.1 [95% CI, 2.1-NR] vs 5.9 [95% CI, 5.0-NR]; P < .001); those who were refractory to ≥1 agents used in the DCT vs others (4.9 [95% CI, 3.1-6.0] vs 8.2 [95% CI, 4.6-NR]; P = .02); and those who received >2 prior therapies vs others (5.0 months [95% CI, 3.7-5.9] vs NR [95% CI, NR-NR]; P = .002). Non-hematologic toxicities included infections (38%), fatigue (32%), and infusion reactions (18%). Grade 3 or higher hematological toxicities were seen in 41% of patients. DCTs are effective in RRMM. ORR and PFS in heavily pretreated patients are lower than those reported in clinical trials.", "affiliations": "Division of Hematology, Mayo Clinic, Rochester, Minnesota.;Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota.;Division of Hematology, Mayo Clinic, Rochester, Minnesota.;Division of Hematology, Mayo Clinic, Rochester, Minnesota.;Division of Hematology, Mayo Clinic, Rochester, Minnesota.;Division of Hematology, Mayo Clinic, Rochester, Minnesota.;Division of Hematology, Mayo Clinic, Rochester, Minnesota.;Division of Hematology, Mayo Clinic, Rochester, Minnesota.;Division of Hematology, Mayo Clinic, Rochester, Minnesota.;Division of Hematology, Mayo Clinic, Rochester, Minnesota.;Division of Hematology, Mayo Clinic, Rochester, Minnesota.;Division of Hematology, Mayo Clinic, Rochester, Minnesota.;Division of Hematology, Mayo Clinic, Rochester, Minnesota.;Division of Hematology, Mayo Clinic, Rochester, Minnesota.;Division of Hematology, Mayo Clinic, Rochester, Minnesota.;Division of Hematology, Mayo Clinic, Rochester, Minnesota.;Division of Hematology, Mayo Clinic, Rochester, Minnesota.;Division of Hematology, Mayo Clinic, Rochester, Minnesota.;Division of Hematology, Mayo Clinic, Rochester, Minnesota.;Division of Hematology, Mayo Clinic, Rochester, Minnesota.;Division of Hematology, Mayo Clinic, Rochester, Minnesota.;Division of Hematology, Mayo Clinic, Rochester, Minnesota.;Division of Hematology, Mayo Clinic, Rochester, Minnesota.", "authors": "Lakshman\|Arjun\|A\|;Abeykoon\|Jithma P\|JP\|http://orcid.org/0000-0003-3939-6252;Kumar\|Shaji K\|SK\|;Rajkumar\|S Vincent\|SV\|;Dingli\|David\|D\|;Buadi\|Francis K\|FK\|;Gonsalves\|Wilson I\|WI\|http://orcid.org/0000-0001-6890-969X;Leung\|Nelson\|N\|http://orcid.org/0000-0002-5651-1411;Dispenzieri\|Angela\|A\|;Kourelis\|Taxiarchis V\|TV\|;Go\|Ronald S\|RS\|http://orcid.org/0000-0002-8284-3495;Lacy\|Martha Q\|MQ\|;Hobbs\|Miriam A\|MA\|;Lin\|Yi\|Y\|;Warsame\|Rahma\|R\|http://orcid.org/0000-0003-0240-0326;Lust\|John\|J\|;Fonder\|Amie L\|AL\|;Hwa\|Yi L\|YL\|;Hayman\|Suzanne R\|SR\|;Russell\|Stephen J\|SJ\|;Kyle\|Robert A\|RA\|;Gertz\|Morie A\|MA\|;Kapoor\|Prashant\|P\|", "chemical_list": "D000911:Antibodies, Monoclonal; D015415:Biomarkers; C556306:daratumumab", "country": "United States", "delete": false, "doi": "10.1002/ajh.24883", "fulltext": null, "fulltext_license": null, "issn_linking": "0361-8609", "issue": "92(11)", "journal": "American journal of hematology", "keywords": null, "medline_ta": "Am J Hematol", "mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal; D000971:Antineoplastic Combined Chemotherapy Protocols; D015415:Biomarkers; D002869:Chromosome Aberrations; D019008:Drug Resistance, Neoplasm; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D012008:Recurrence; D019233:Retreatment; D016019:Survival Analysis; D016896:Treatment Outcome", "nlm_unique_id": "7610369", "other_id": null, "pages": "1146-1155", "pmc": null, "pmid": "28799231", "pubdate": "2017-11", "publication_types": "D016428:Journal Article", "references": null, "title": "Efficacy of daratumumab-based therapies in patients with relapsed, refractory multiple myeloma treated outside of clinical trials.", "title_normalized": "efficacy of daratumumab based therapies in patients with relapsed refractory multiple myeloma treated outside of clinical trials" }	[ { "companynumb": "US-TAKEDA-2017MPI009826", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "DARATUMUMAB" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": 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"drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "THALIDOMIDE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Prophylaxis", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neuropathy peripheral", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary oedema", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dyspnoea", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dehydration", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Infection", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Disease progression", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fatigue", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Infusion related reaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KAPOOR P, LAKSHMAN A, DINGLI D, ABEYKOON JP, KUMAR SK, RAJKUMAR SV, ET AL.. EFFICACY OF DARATUMUMAB-BASED THERAPIES IN PATIENTS WITH RELAPSED, REFRACTORY MULTIPLE MYELOMA TREATED OUTSIDE OF CLINICAL TRIALS.. AMERICAN JOURNAL OF HEMATOLOGY 2017. 2017;92(11):1146-1155", "literaturereference_normalized": "efficacy of daratumumab based therapies in patients with relapsed refractory multiple myeloma treated outside of clinical trials", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20171107", "receivedate": "20171107", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14165624, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180321" }, { "companynumb": "US-JNJFOC-20171104837", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": 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"drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "LYOPHILIZED POWDER", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VELCADE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, 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null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "THALIDOMIDE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", 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null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DARATUMUMAB" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CONCENTRATE FOR SOLUTION FOR INFUSION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "16", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DARATUMUMAB" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DOXORUBICIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADRIAMYCIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LENALIDOMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "REVLIMID" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DARATUMUMAB" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CONCENTRATE FOR SOLUTION FOR INFUSION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "2", "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "16", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DARATUMUMAB" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "IXAZOMIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IXAZOMIB" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pneumonia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neuropathy peripheral", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dehydration", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fatigue", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Infection", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Prophylaxis", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary oedema", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dyspnoea", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Disease progression", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Infusion related reaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KAPOOR P, LAKSHMAN A, DINGLI D, ABEYKOON JP, KUMAR SK, RAJKUMAR SV, ET AL. EFFICACY OF DARATUMUMAB-BASED THERAPIES IN PATIENTS WITH RELAPSED, REFRACTORY MULTIPLE MYELOMA TREATED OUTSIDE OF CLINICAL TRIALS. AMERICAN JOURNAL OF HEMATOLOGY 2017;2017:92(11):1146-1155.", "literaturereference_normalized": "efficacy of daratumumab based therapies in patients with relapsed refractory multiple myeloma treated outside of clinical trials", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20171107", "receivedate": "20171107", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14165448, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180321" }, { "companynumb": "US-CELGENEUS-USA-20170805413", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "POMALIDOMIDE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "204026", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULES", "drugdosagetext": "4 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "POMALYST" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DARATUMUMAB" }, "drugadditional": "3", "drugadministrationroute": "041", "drugauthorizationnumb": "127058", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "16 MILLIGRAM/KILOGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "2", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "16", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DARATUMUMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "40 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DARATUMUMAB" }, "drugadditional": "3", "drugadministrationroute": "041", "drugauthorizationnumb": "127058", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "16 MILLIGRAM/KILOGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "802", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DARATUMUMAB" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Infusion related reaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Constipation", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Renal impairment", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Muscle spasms", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Mood altered", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fatigue", 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EFFICACY OF DARATUMUMAB-BASED THERAPIES IN PATIENTS WITH RELAPSED, REFRACTORY MULTIPLE MYELOMA TREATED OUTSIDE OF CLINICAL TRIALS. AMERICAN JOURNAL OF HEMATOLOGY.", "literaturereference_normalized": "efficacy of daratumumab based therapies in patients with relapsed refractory multiple myeloma treated outside of clinical trials", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170827", "receivedate": "20170827", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13908598, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" } ]
{ "abstract": "Hepatic glycogenosis (HG) has been reported after intravenous (IV) dextrose administration to treat insulin overdose. We describe a case of HG in a patient with type 1 diabetes mellitus (T1DM) due to insulin overdose treated with oral glucose administration.\nAn adolescent boy with T1DM on a basal bolus insulin regimen presented with abdominal discomfort, nausea, vomiting, and hypoglycemia of a few hours. His glucose was 71 mg/dL, aspartate transaminase (AST) 119 U/L, and alanine transaminase (ALT) 65 U/L. Hypoglycemia was treated with juice, and 12 hours later AST and ALT were 979 U/L and 700 U/L, respectively. Workup for infectious, autoimmune, metabolic, and toxic causes of hepatitis was negative. The transaminases improved by the next day and normalized within 3 weeks. Two weeks after discharge the patient returned with hypoglycemia, nausea, and right-sided abdominal pain of 13 hours. Hypoglycemia persisted despite multiple courses of glucose tablets and juice. Laboratory studies showed glucose of 58 mg/dL, AST of 776 U/L, ALT of 496 U/L, negative toxicology studies, and normal abdominal ultrasound. His serum insulin level was 249.7 mU/L and, C-peptide was less than 0.1 ng/mL, consistent with insulin overdose. He received IV fluids with dextrose, and insulin was held. Transaminases improved by the following day. Repeat serum insulin while on home regimen was normal.\nAlong with other diagnoses, HG should be considered in patients treated with insulin who present with hypoglycemia and acute hepatitis. HG can occur in cases of insulin overdose treated with repeated oral glucose administration.", "affiliations": "Division of Pediatric Endocrinology, Hasbro Children's Hospital, Providence, Rhode Island 02903, USA.;Division of Pediatric Endocrinology, Hasbro Children's Hospital, Providence, Rhode Island 02903, USA.;Division of Pediatric Endocrinology, Hasbro Children's Hospital, Providence, Rhode Island 02903, USA.", "authors": "Sasidharan Pillai\|Sabitha\|S\|https://orcid.org/0000-0002-0391-3759;Quintos\|Jose Bernardo\|JB\|https://orcid.org/0000-0003-1691-2293;Topor\|Lisa Swartz\|LS\|https://orcid.org/0000-0002-1219-9921", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1210/jendso/bvab142", "fulltext": "\n==== Front\nJ Endocr Soc\nJ Endocr Soc\njes\nJournal of the Endocrine Society\n2472-1972\nOxford University Press US\n\n10.1210/jendso/bvab142\nbvab142\nCase Reports\nAcademicSubjects/MED00250\nAcute Hepatitis due to Hepatic Glycogenosis After Insulin Overdose and Oral Glucose Administration in an Adolescent\nhttps://orcid.org/0000-0002-0391-3759\nSasidharan Pillai Sabitha 12\nhttps://orcid.org/0000-0003-1691-2293\nQuintos Jose Bernardo 12\nhttps://orcid.org/0000-0002-1219-9921\nTopor Lisa Swartz [email protected]\n\n1 Division of Pediatric Endocrinology, Hasbro Children’s Hospital, Providence, Rhode Island 02903, USA\n2 Department of Pediatrics, The Warren Alpert Medical School of Brown University, Providence, Rhode Island 02903, USA\nCorrespondence: Lisa Swartz Topor, MD, MMSc, Department of Pediatrics, The Warren Alpert Medical School of Brown University, 593 Eddy St, Providence, RI 02903, USA. Email: [email protected].\n01 11 2021\n01 9 2021\n5 11 bvab14214 7 2021\n17 8 2021\n23 9 2021\n© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact [email protected]\n\nAbstract\n\nBackground\n\nHepatic glycogenosis (HG) has been reported after intravenous (IV) dextrose administration to treat insulin overdose. We describe a case of HG in a patient with type 1 diabetes mellitus (T1DM) due to insulin overdose treated with oral glucose administration.\n\nCase Presentation\n\nAn adolescent boy with T1DM on a basal bolus insulin regimen presented with abdominal discomfort, nausea, vomiting, and hypoglycemia of a few hours. His glucose was 71 mg/dL, aspartate transaminase (AST) 119 U/L, and alanine transaminase (ALT) 65 U/L. Hypoglycemia was treated with juice, and 12 hours later AST and ALT were 979 U/L and 700 U/L, respectively. Workup for infectious, autoimmune, metabolic, and toxic causes of hepatitis was negative. The transaminases improved by the next day and normalized within 3 weeks. Two weeks after discharge the patient returned with hypoglycemia, nausea, and right-sided abdominal pain of 13 hours. Hypoglycemia persisted despite multiple courses of glucose tablets and juice. Laboratory studies showed glucose of 58 mg/dL, AST of 776 U/L, ALT of 496 U/L, negative toxicology studies, and normal abdominal ultrasound. His serum insulin level was 249.7 mU/L and, C-peptide was less than 0.1 ng/mL, consistent with insulin overdose. He received IV fluids with dextrose, and insulin was held. Transaminases improved by the following day. Repeat serum insulin while on home regimen was normal.\n\nConclusion\n\nAlong with other diagnoses, HG should be considered in patients treated with insulin who present with hypoglycemia and acute hepatitis. HG can occur in cases of insulin overdose treated with repeated oral glucose administration.\n\nadolescent\ntype 1 diabetes mellitus\ninsulin overdose\nhepatic glycogenesis\n==== Body\npmcPierre Mauriac first described hepatic glycogenosis (HG) in 1930, a syndrome in children with poorly controlled type 1 diabetes mellitus (T1DM) characterized by glycogen accumulation in the liver causing hepatomegaly, growth failure, round facies, and delayed puberty [1, 2]. This constellation of symptoms is also referred to as Mauriac syndrome, liver glycogenosis, liver glycogen storage, diabetes mellitus-associated glycogen storage hepatomegaly, and glycogenic hepatopathy [3, 4].\n\nHG occurs when insulin levels are elevated in the presence of high levels of glucose and is typically seen in those with wide fluctuations in glucose and insulin levels. Hyperglycemia leads to increased glucose entry into the hepatocytes, and excess insulin promotes conversion of the glucose into glycogen. Liver injury is mediated by increased glucose uptake, glycogenesis, and inhibition of gluconeogenesis [4], and pathologic glycogen accumulation leads to elevated hepatic transaminases [5]. HG can also occur with isolated liver involvement, without the full phenotype of growth delay and hepatomegaly and has been reported in individuals across the lifespan [6]. Excess glycogenesis reverses rapidly once insulin and glucose levels are stabilized, and hepatic injury is reversible.\n\nMost cases of HG occur in individuals with T1DM, while a small percentage of cases occurs in those with type 2 diabetes mellitus. HG has also been reported in the setting of dumping syndrome following gastrostomy and in cases of hyperglycemia following high-dose glucocorticoid therapy [4, 5], as frequent hypoglycemia and its correction with glucose administration contributes to the pathogenesis.\n\nTransient hepatitis secondary to HG has been reported after intravenous (IV) dextrose administration to treat insulin overdose in adults. We describe an adolescent male with T1DM who developed 2 episodes of acute hepatitis due to HG following insulin overdoses and repeated oral glucose administration to treat hypoglycemia.\n\nCase Presentation\n\nA 16-year-old boy with T1DM for 7 years treated with a basal bolus insulin regimen presented in the evening to an emergency department (ED) of a tertiary care hospital with complaints of abdominal discomfort, nausea, nonbilious nonbloody vomiting, and hypoglycemia for the past 8 hours. Most recent glycated hemoglobin A1c was 9.5%. The abdominal symptoms started in the late afternoon the day of presentation. His blood sugar was in the 40-mg/dL range and was treated with oral glucose tablets. He described taking his usual insulin doses earlier in the day, and denied taking any other medications, substances, or excess insulin. His medications included glargine insulin each night, lispro insulin with meals, sertraline 100 mg daily, guanfacine 1 mg in the morning and 3 mg at night, and melatonin 3 mg nightly as needed. On examination, he was alert, afebrile, with stable vital signs and an exam notable for epigastric and right upper-quadrant tenderness. His initial laboratory workup showed elevated liver enzymes (Table 1) and hypoglycemia. Additional laboratory values including pH (7.36), blood gas, complete blood count with total white blood cell count 6100 cells/mm3, and basic metabolic profile, including bicarbonate 28 mEq/L, were normal. An extended respiratory viral panel and COVID-19 test were all negative. Testing for Epstein-Barr virus and enterovirus was also negative. Urinalysis was negative for ketones. Chest and abdominal plain films were unremarkable. The hypoglycemia was treated with juice, and he was admitted to the hospital for monitoring. He ate dinner and 2 snacks before bed. Overnight, he had 2 additional episodes of hypoglycemia and was treated with juice (total carbohydrate 60 g). The patient did not require IV dextrose to correct the hypoglycemia. Repeat laboratory values 12 hours after admission showed marked elevation in liver enzymes (see Table 1). Given concern for an undisclosed ingestion, infection, or other cause of hepatitis, additional laboratory studies were obtained (Table 2). An abdominal ultrasound showed normal liver size and texture, and Doppler ultrasound of the liver vasculature was also normal. He had normal thyroid function. Owing to the rapid rise in transaminase levels, the patient was treated empirically with a 21-hour NAC (N-acetylcysteine) protocol for presumed ingestion, as per the recommendation of the poison control team. Transaminases began to trend down by 25 hours after admission and normalized by 3 weeks (see Table 1).\n\nTable 1. Glucose and liver enzymes during the first presentation\n\nLaboratory test\tReference range\t0 h\t12 h\t25 h\t37 h\t53 h\tD 22\t\nGlucose, mg/dL\t67-99\t71\t219\t262\t287\t212\t89\t\nAST, U/L\t13-38\t119\t979\t377\t166\t78\t20\t\nALT, U/L\t8-36\t65\t700\t627\t475\t336\t28\t\nAbbreviations: ALT, alanine transaminase; AST, aspartate transaminase.\n\nTable 2. Laboratory evaluation for causes of abdominal pain and hepatitis\n\nVariable\tReference range\tResults\t\nCeliac panel: total IgA, mg/dL\t63-484\t102\t\n TTG IgA, units\t0-20\t4.2\t\nCortisol (7:45 am), μg/dL\t5.5-20\t15.8\t\nAlpha 1 antitrypsin phenotype\t–\tPI*M1N\t\nFerritin, ng/mL\t22-322\t20\t\nCeruloplasmin, mg/dL\t20-60\t34\t\nAcute hepatitis panel (hepatitis A antibody, IgM; hepatitis B core antibody, IgM; hepatitis B surface antigen; hepatitis C virus antibody)\t–\tNegative\t\nAutoimmune hepatitis panel: actin Ab IgG, anti-LKM Ab, anti- smooth muscle actin Ab, ANA\tNegative\tNegative\t\nToxicology (ethchlorvynol and phenothiazine, acetaminophen, salicylate, imipramine/desipramine, GC and MS)\tAcetaminophen: 11-20 mg/dL\nSalicylate: 15-30 mg/dL\tAcetaminophen < 10 μg/dL\nSalicylate: < 2.5 mg/dL\t\nUrine toxicology\t–\tNegative\t\nAbbreviations: Ab, antibody; ANA, antinuclear antibodies; GC, gas chromatography; Ig, immunoglobulin; LKM, liver kidney microsome; MS, mass spectrometry; TTG, tissue transglutaminase.\n\nThe patient was discharged home after a prolonged hospitalization that included a stay in a behavioral health unit because of concern of medication overdose, despite repeated denials. He did not have any hypoglycemia during the admission. Two weeks after his discharge home (30 days after the initial admission), the patient returned to the ED with complaints of nausea, vomiting, abdominal pain, and hypoglycemia. The patient was found to have hypoglycemia (40 mg/dL) the morning of admission, when his school nurse checked his blood sugar before breakfast. He did not receive prandial insulin with breakfast or lunch. He consumed more than 20 glucose tablets and servings of juice (4 ounces) to maintain blood glucose above 70 mg/dL. He developed nausea and right-sided abdominal pain of 8 out of 10 in intensity during the day, and symptoms worsened by late afternoon. He also had an episode of nonbilious, nonbloody emesis. He was brought to the ED about 13 hours after the detection of hypoglycemia. He did not have fever, sick contacts, or recent travel, and denied ingestion of any medications or substances. In the ED, examination was unremarkable except for right upper-quadrant abdominal tenderness. Laboratory evaluation showed elevated liver enzymes (Table 3) and hypoglycemia. He had a normal complete blood count with total white blood cell count 3800/mm3, normal basic metabolic profile (bicarbonate, 24 mEq/L), negative urine ketones, and negative COVID-19 testing. His insulin level was 250 mU/L with a C-peptide level of less than 0.1 ng/mL at the time of hypoglycemia, consistent with excess exogenous insulin (see Table 3). As his serum glucose levels improved, his IV fluids were weaned and then discontinued 22 hours after presentation. The abdominal pain and nausea subsided over 3 days. He resumed his home insulin regimen and did not have further hypoglycemia. Repeat serum insulin when he was receiving his home insulin regimen was 19.5 mU/L (see Table 3). His liver enzymes normalized within 2 months (see Table 3).\n\nTable 3. Glucose and liver enzymes during the second presentation\n\nLaboratory test\tReference range\t0 h\t5 h\t15 h\t26 h\tD 6\t2 mo\t\nGlucose, mg/dL\t67-99\t58\t42\t143\t259\t245\t356\t\nAST, U/L\t13-38\t776\t955\t441\t229\t40\t13\t\nALT, U/L\t8-36\t496\t747\t546\t444\t101\t12\t\nC peptide, ng/mL\t0.8-3.85\t\t< 0.10\t\t\t\t\t\nTotal serum insulin, mU/L\t3-25\t\t249.7\t\t\t19.5\t\t\nAbbreviations: ALT, alanine transaminase; AST, aspartate transaminase.\n\nWith improved supervision of insulin administration, the patient did not have further episodes of hypoglycemia episodes or elevated liver enzymes. He continued to deny insulin overdose.\n\nDiscussion\n\nWe describe HG that occurred after insulin overdose and solely oral glucose treatment of hypoglycemia, without classic features of Mauriac syndrome. Unlike previous case reports of HG in adults treated for insulin overdose with prolonged IV dextrose administration (Table 4), our patient developed HG following insulin overdose managed with repeated courses of oral glucose administration.\n\nTable 4. Case reports of hepatic glycogenosis following insulin overdose\n\nReference y\tDiabetes diagnosis\tAge, y; sex\tInsulin type and units\tPresenting symptoms\tTreatment before development of HG\tOnset of symptoms\t\n2001 [14]\tNondiabetic\t48, female\t1000 units of long-acting insulin along with benzodiazepines and ASA\tComa with severe hypoglycemia, requiring intubation for 3 d\tBoluses of 40% glucose, continuous infusion of 20% glucose (1200-1400 g daily × 3 d)\tOn d 3, nausea, RUQ abdominal pain, hepatomegaly with worsening of liver enzymes\t\n2012 [15]\tType 1\t26, male\t4800 units of glargine\tSevere hypoglycemia\tParenteral 20% glucose, 10% glucose, oral fruit concentrate\tOn d 3, nausea, right-sided abdominal pain and hepatomegaly, elevated liver enzymes, bilirubin elevation\t\n2006 [16]\tType 2\t41, male\t180 units of glargine\tLoss of consciousness\tParenteral glucose and hypercaloric feed\tDeranged hepatic function and hepatomegaly on d 3\t\n2020 [13]\tType 1\t25, male\t3600 units of insulin glargine and 2100 units of insulin lispro\tCold sweat, feeling groggy\tContinuous 17.5% glucose infusion. ~ 900 g of glucose/d × 4 d\tOn d 4 with general fatigue, persistent right hypochondral pain, abdominal discomfort, appetite loss, elevated liver enzymes\t\nOur patient\tType 1\t16, male\tUnknown\tSevere hypoglycemia, abdominal pain, nausea\tMultiple glucose tablets, juice\tAt admission, ~ 18 h after onset of hypoglycemia with pain abdomen, nausea, vomiting, elevated liver enzymes\t\nAbbreviations: ASA, acetylsalicylic acid; RUQ, right upper quadrant.\n\nDuring his second episode, our patient developed hypoglycemia during the school day and was treated repeatedly with glucose tablets and juice. HG may present with nausea, vomiting, abdominal pain, and hepatomegaly with elevated transaminases [5] due to increased glycogen synthesis and deposition in the setting of excess insulin and glucose levels. Increased serum glucose leads to increased glucose entry into the hepatocyte through insulin-independent facilitated diffusion via glucose transporter 2 (GLUT2). The excess insulin promotes conversion of this glucose into glycogen and inhibits glycogenolysis, leading to glycogen deposition. The rapid glycogen deposition causes elevation of liver enzymes, and the sudden increase in liver size with stretching of the liver capsule triggers the abdominal pain [7]. Though hepatomegaly is characteristic of HG in more than 90% of cases, it can occur without hepatomegaly [7-9]. Our patient did not have hepatomegaly on exam or by imaging.\n\nIt is essential to distinguish HG from nonalcoholic fatty liver disease (NAFLD). NAFLD is characterized by triglyceride deposition in hepatocytes due to factors other than alcohol intake and can also present with hepatomegaly and elevated transaminases. Obesity is a driving factor in NAFLD development, and it has been reported in children and adolescents with obesity [10]. NAFLD has also been described in children with T1DM [11]. NAFLD is associated with mild, persistent elevation of liver enzymes [6, 12] and can progress to fibrosis and cirrhosis, while the hepatomegaly and elevated liver enzymes of HG are transient and complete resolution occurs with improvement of glycemic control.\n\nDemonstration of glycogen deposition in hepatocytes by liver biopsy is the gold standard for the diagnosis of HG [6]. The characteristic histologic finding in HG is ballooned hepatocytes with intracytoplasmic glycogen deposition [13]. Other histological features include no or minimal fatty change, portal inflammation, nor necrosis or fibrosis with intact architect of the liver parenchyma [5, 7]. In contrast, liver biopsy in NAFLD typically shows macrovesicular steatosis and mild lobular and portal inflammation and fibrosis of varying degrees [7]. Ultrasound does not help in distinguishing HG from NAFLD as both conditions lead to increased echogenicity of the liver [13]. Computed tomography of the liver demonstrates high density in HG and low density in NAFLD. Magnetic resonance imaging (MRI) shows low density on T2-weighted images for HG. Gradient dual-echo MRI is more helpful in distinguishing between the glycogen and fat deposition by demonstrating low intensity in phase and high intensity out of phase with HG [13].\n\nWe identified 4 case reports in the literature that describe HG in adults following insulin overdose and subsequent IV dextrose administration to manage the profound and prolonged hypoglycemia (see Table 4) [13-16]. All of the cases describe administration of large doses of IV dextrose over multiple days. Three reports describe development of hepatomegaly and hepatitis the third day after insulin administration, and one case reported these symptoms on day 4. All patients had a dramatic recovery of liver enzymes after stabilization of glucose levels.\n\nIn contrast, during his initial presentation, our patient’s hypoglycemia was detected after the development of abdominal symptoms, and during the second admission, he presented with hepatitis the same day that he developed hypoglycemia, after treatment with multiple glucose tablets and juice. Our patient had poorly controlled T1DM, with chronic hyperglycemia and elevations in the glycated hemoglobin A1c over the past few years. One possible explanation for the onset of abdominal symptoms before the detection and treatment of hypoglycemia is that baseline hyperglycemia led to glucose influx into the liver cells via GLUT2 channels with trapping of glucose-6-phosphate in hepatocytes after phosphorylation by glucokinase. The addition of supraphysiological doses of insulin could have promoted glycogenesis from trapped glucose-6-phosphate, leading to HG [7]. Glucose administration to treat hypoglycemia would have further enhanced glycogenesis in the setting of high insulin, with worsening of abdominal symptoms.\n\nOur patient did not acknowledge excess insulin administration, though his markedly elevated plasma insulin and undetectable C-peptide at the time of hypoglycemia (see Table 1) and the return of plasma insulin to a normal level while receiving his typical doses suggested exogenous insulin administration. Infections, ingestions, and metabolic and autoimmune disease were ruled out with various laboratory studies (see Table 2). Two episodes with dramatic recovery of the liver enzymes with improved glycemic control and unremarkable liver ultrasound favors a diagnosis of HG, though he did not have a liver biopsy or MRI performed. Along with other diagnoses, HG should be considered in patients treated with insulin who present with hypoglycemia and acute hepatitis, as HG can develop after repeated administration of oral glucose for treatment of hypoglycemia.\n\nAcknowledgments\n\nFinancial Support: The authors received no financial support for the research, authorship, and/or publication of this article.\n\nAbbreviations\n\nALT alanine transaminase\n\nAST aspartate transaminase\n\nED emergency department\n\nGLUT2 glucose transporter 2\n\nHG hepatic glycogenosis\n\nIV intravenous\n\nMRI magnetic resonance imaging\n\nNAFLD nonalcoholic fatty liver disease\n\nT1DM type 1 diabetes mellitus\n\nAdditional Information\n\nDisclosures: The authors have nothing to disclose.\n\nData Availability\n\nData sharing is not applicable to this article because no data sets were generated or analyzed during the present study.\n==== Refs\nReferences\n\n1. MauriacP. Gros ventre, hepatomegalie, troubles de croissance chez les enfants diabetiques traites depuis plusiers annee par l’insuline. Gaz Hebd Med Bordeaux. 1930;26 :402-4102.\n2. KimMS, QuintosJB. Mauriac syndrome: growth failure and type 1 diabetes mellitus. Pediatr Endocrinol Rev. 2008;5 (Suppl 4 ):989-993.18806715\n3. AbaciA, BekemO, UnuvarT, et al. Hepatic glycogenosis: a rare cause of hepatomegaly in Type 1 diabetes mellitus. J Diabetes Complications. 2008;22 (5 ):325-328.18413182\n4. IkarashiY, KogisoT, HashimotoE, et al. Four cases of type 1 diabetes mellitus showing sharp serum transaminase increases and hepatomegaly due to glycogenic hepatopathy. Hepatol Res. 2017;47 (3 ):E201-E209.27027269\n5. GiordanoS, MartocchiaA, ToussanL, et al. Diagnosis of hepatic glycogenosis in poorly controlled type 1 diabetes mellitus. World J Diabetes. 2014;5 (6 ):882-888.25512791\n6. BuaJ, MarchettiF, FaleschiniE, VenturaA, BussaniR. Hepatic glycogenosis in an adolescent with diabetes. J Pediatr. 2010;157 (6 ):1042.20638077\n7. SherigarJM, CastroJ, YinYM, GussD, MohantySR. Glycogenic hepatopathy: a narrative review. World J Hepatol. 2018;10 (2 ):172-185.29527255\n8. ChatilaR, WestAB. Hepatomegaly and abnormal liver tests due to glycogenosis in adults with diabetes. Medicine (Baltimore). 1996;75 (6 ):327-333.8982149\n9. MukewarS, SharmaA, LackoreKA, et al. Clinical, biochemical, and histopathology features of patients with glycogenic hepatopathy. Clin Gastroenterol Hepatol. 2017;15 (6 ):927-933.28043933\n10. ScapaticciS, D’AdamoE, MohnA, ChiarelliF, GianniniC. Non-alcoholic fatty liver disease in obese youth with insulin resistance and type 2 diabetes. Front Endocrinol (Lausanne). 2021;12 :639548.33889132\n11. RegnellSE, LernmarkÅ. Hepatic steatosis in type 1 diabetes. Rev Diabet Stud. 2011;8 (4 ):454-467.22580727\n12. van den BrandM, ElvingLD, DrenthJP, van KriekenJH. Glycogenic hepatopathy: a rare cause of elevated serum transaminases in diabetes mellitus. Neth J Med. 2009;67 (11 ):394-396.20009116\n13. FujisakiN, KosakiY, NojimaT, et al. Glycogenic hepatopathy following attempted suicide by long-acting insulin overdose in patient with type 1 diabetes. J Am Coll Emerg Physicians Open. 2020;1 (5 ):1097-1100.33145563\n14. JollietP, LeverveX, PichardC. Acute hepatic steatosis complicating massive insulin overdose and excessive glucose administration. Intensive Care Med. 2001;27 (1 ):313-316.11280657\n15. WarrinerD, DebonoM, GandhiRA, ChongE, CreaghF. Acute hepatic injury following treatment of a long-acting insulin analogue overdose necessitating urgent insulin depot excision. Diabet Med. 2012;29 (2 ):232-235.21781150\n16. TsujimotoT, TakanoM, NishiofukuM, et al. Rapid onset of glycogen storage hepatomegaly in a type-2 diabetic patient after a massive dose of long-acting insulin and large doses of glucose. Intern Med. 2006;45 (7 ):469-473.16679704\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2472-1972", "issue": "5(11)", "journal": "Journal of the Endocrine Society", "keywords": "adolescent; hepatic glycogenesis; insulin overdose; type 1 diabetes mellitus", "medline_ta": "J Endocr Soc", "mesh_terms": null, "nlm_unique_id": "101697997", "other_id": null, "pages": "bvab142", "pmc": null, "pmid": "34568710", "pubdate": "2021-11-01", "publication_types": "D002363:Case Reports", "references": "22580727;25512791;28043933;20638077;18413182;18806715;27027269;21781150;16679704;8982149;20009116;29527255;11280657;33889132;33145563", "title": "Acute Hepatitis due to Hepatic Glycogenosis After Insulin Overdose and Oral Glucose Administration in an Adolescent.", "title_normalized": "acute hepatitis due to hepatic glycogenosis after insulin overdose and oral glucose administration in an adolescent" }	[ { "companynumb": "US-MYLANLABS-2021M1083768", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "INSULIN GLARGINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "210605", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, PM, EACH NIGHT", "drugenddate": null, "drugenddateformat": null, "drugindication": "Type 1 diabetes mellitus", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INSULIN GLARGINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "213255", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETAMINOPHEN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "INSULIN LISPRO" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "WITH MEALS", "drugenddate": null, "drugenddateformat": null, "drugindication": "Type 1 diabetes mellitus", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INSULIN LISPRO" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXTROSE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Tablet", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Hypoglycaemia", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXTROSE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SERTRALINE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, 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"003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GUANFACINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "GUANFACINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3 MILLIGRAM, PM (3 MG AT NIGHT)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "3", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GUANFACINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MELATONIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3 MILLIGRAM, PRN, 3 MG NIGHTLY AS NEEDED", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "3", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELATONIN" } ], "patientagegroup": null, "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Glycogen storage disease type VIII", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypoglycaemia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hepatitis acute", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Sasidharan Pillai S, Quintos JB, Topor LS. Acute Hepatitis due to Hepatic Glycogenosis after Insulin Overdose and Oral Glucose Administration in an Adolescent. J-Endocr-Soc 2021;5(11):1-6.", "literaturereference_normalized": "acute hepatitis due to hepatic glycogenosis after insulin overdose and oral glucose administration in an adolescent", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220302", "receivedate": "20211112", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20062036, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220424" } ]
{ "abstract": "BACKGROUND\n5% minoxidil formulations twice daily are effective in treating vertex male androgenetic alopecia (AGA); however, efficacy and safety data in frontotemporal regions are lacking.\n\n\nOBJECTIVE\nTo assess the efficacy of 5% minoxidil topical foam (5% MTF) in the frontotemporal region of male AGA patients after 24 weeks of treatment compared to placebo treatment and to the vertex region.\n\n\nMETHODS\nSeventy males with moderate AGA applied 5% MTF or placebo foam (plaTF) twice daily for 24 weeks in frontotemporal and vertex regions. Target area non-vellus hair count (TAHC) was the primary end point.\n\n\nRESULTS\nFrontotemporal and vertex TAHC and target area cumulative non-vellus hair width (TAHW) showed similar responses to 5% MTF with significant increases up to week 16 compared to baseline (p < 0.001). After 24 weeks of treatment, frontotemporal TAHW increased significantly in the 5% MTF group compared to the plaTF group (p = 0.017), while TAHC showed a similar non-significant increase from baseline in both regions. At 24 weeks, 5% MTF users rated a significant improvement in scalp coverage for the frontotemporal (p = 0.016) and vertex areas (p = 0.027).\n\n\nCONCLUSIONS\n5% MTF twice a day promotes hair density and width in both frontotemporal and vertex regions in men with moderate stages of AGA. © 2015 S. Karger AG, Basel.", "affiliations": "Clinical Research Center for Hair and Skin Science, Department of Dermatology and Allergy, Charité-Universitätsmedizin Berlin, Berlin, Germany.", "authors": "Hillmann\|Kathrin\|K\|;Garcia Bartels\|Natalie\|N\|;Kottner\|Jan\|J\|;Stroux\|Andrea\|A\|;Canfield\|Douglas\|D\|;Blume-Peytavi\|Ulrike\|U\|", "chemical_list": "D014665:Vasodilator Agents; D008914:Minoxidil", "country": "Switzerland", "delete": false, "doi": "10.1159/000375320", "fulltext": null, "fulltext_license": null, "issn_linking": "1660-5527", "issue": "28(5)", "journal": "Skin pharmacology and physiology", "keywords": null, "medline_ta": "Skin Pharmacol Physiol", "mesh_terms": "D000279:Administration, Cutaneous; D000328:Adult; D000368:Aged; D000505:Alopecia; D004311:Double-Blind Method; D006197:Hair; D006801:Humans; D008297:Male; D008875:Middle Aged; D008914:Minoxidil; D013997:Time Factors; D016896:Treatment Outcome; D014665:Vasodilator Agents; D055815:Young Adult", "nlm_unique_id": "101188418", "other_id": null, "pages": "236-44", "pmc": null, "pmid": "25765348", "pubdate": "2015", "publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "A Single-Centre, Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Investigate the Efficacy and Safety of Minoxidil Topical Foam in Frontotemporal and Vertex Androgenetic Alopecia in Men.", "title_normalized": "a single centre randomized double blind placebo controlled clinical trial to investigate the efficacy and safety of minoxidil topical foam in frontotemporal and vertex androgenetic alopecia in men" }	[ { "companynumb": "US-JNJFOC-20150901600", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "MINOXIDIL" }, "drugadditional": null, "drugadministrationroute": "061", "drugauthorizationnumb": "020834", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "030", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MINOXIDIL." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "MINOXIDIL" }, "drugadditional": null, "drugadministrationroute": "061", "drugauthorizationnumb": "021812", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "FOAM", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "030", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MINOXIDIL." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "MINOXIDIL" }, "drugadditional": null, "drugadministrationroute": "061", "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "FOAM", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MINOXIDIL." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "MINOXIDIL" }, "drugadditional": null, "drugadministrationroute": "061", "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MINOXIDIL." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Alopecia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Palpitations", "reactionmeddraversionpt": "18.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "HILLMANN K, BARTELS NG, JAN K, ANDREA S, DOUGLAS C, ULRIKE B. A SINGLE-CENTRE, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED CLINICAL TRIAL TO INVESTIGATE THE EFFICACY AND SAFETY OF MINOXIDIL TOPICAL FOAM IN FRONTOTEMPORAL AND VERTEX ANDROGENETIC ALOPECIA IN MEN. SKIN PHARMACOLOGY AND PHYSIOLOGY 2015?28 (5):236-244.", "literaturereference_normalized": "a single centre randomized double blind placebo controlled clinical trial to investigate the efficacy and safety of minoxidil topical foam in frontotemporal and vertex androgenetic alopecia in men", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20151013", "receivedate": "20151013", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11622141, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160304" } ]
{ "abstract": "OBJECTIVE\nTo explore the safety and tolerability of atacicept in combination with rituximab in patients with active rheumatoid arthritis (RA) receiving rituximab re-treatment.\n\n\nMETHODS\nIn this randomized, double-blind, placebo-controlled pilot trial, 2 infusions (1,000 mg per infusion) of intravenous rituximab, given 2 weeks apart, were followed by once-weekly subcutaneous injections of 150 mg atacicept or placebo for 25 weeks. Primary end points were the nature, incidence, and severity of adverse events (AEs). Secondary end points were the effects on peripheral blood B cells, disease activity biomarkers, and American College of Rheumatology 20% (ACR20), 50% (ACR50), and 70% (ACR70) response rates.\n\n\nRESULTS\nEighteen patients were randomized to receive atacicept and 9 to receive placebo. AEs occurred in 17 atacicept-treated patients (94.4%) and in all 9 placebo-treated patients (100%). There were no infection-related serious adverse events. Hypersensitivity and injection site reactions were more common, and more patients withdrew due to AEs, in the atacicept group. Median reductions in Ig levels from baseline to week 32 were greater with atacicept (median change in IgG -31.2%, IgM -60.9%, and IgA -56.4%) than with placebo (median change in IgG -4.4%, IgM -15.9%, and IgA -8.2%). Peripheral B cell numbers remained low in all patients after rituximab-mediated B cell depletion, limiting comparison of time to recovery between treatment groups. There were no between-group differences in ACR20, ACR50, and ACR70 response rates.\n\n\nCONCLUSIONS\nIn this exploratory trial, atacicept in combination with rituximab showed no new safety issues. Peripheral B cell counts remained too low to determine whether atacicept delayed B cell re-expansion following rituximab-mediated depletion. Despite clear biologic effects, adding atacicept to rituximab in patients with active RA was not associated with clinical benefit.", "affiliations": "Karolinska Institute, Stockholm, Sweden.;EMD Serono, Inc., Rockland, Massachusetts.;EMD Serono, Inc., Rockland, Massachusetts.;Academic Medical Center and University of Amsterdam, Amsterdam, The Netherlands, University of Cambridge, Cambridge, UK, and GlaxoSmithKline, Stevenage, UK.", "authors": "van Vollenhoven\|R F\|RF\|;Wax\|S\|S\|;Li\|Y\|Y\|;Tak\|P P\|PP\|", "chemical_list": "D018501:Antirheumatic Agents; D011993:Recombinant Fusion Proteins; D000069283:Rituximab; C524618:TACI receptor-IgG Fc fragment fusion protein", "country": "United States", "delete": false, "doi": "10.1002/art.39262", "fulltext": "\n==== Front\nArthritis Rheumatol10.1002/(ISSN)2326-5205ARTArthritis & Rheumatology (Hoboken, N.j.)2326-51912326-5205John Wiley and Sons Inc. Hoboken 10.1002/art.39262ART39262Rheumatoid ArthritisRheumatoid ArthritisSafety and Efficacy of Atacicept in Combination With Rituximab for Reducing the Signs and Symptoms of Rheumatoid Arthritis: A Phase II, Randomized, Double‐Blind, Placebo‐Controlled Pilot Trial ATACICEPT IN RHEUMATOID ARTHRITISVAN VOLLENHOVEN ET ALvan Vollenhoven R. F. \n1\n\n†\nWax S. \n2\nLi Y. \n2\nTak P. P. \n3\n\n‡\n1 Karolinska InstituteStockholmSweden2 EMD Serono, Inc.RocklandMassachusetts3 Academic Medical Center and University of Amsterdam, Amsterdam, The Netherlands, University of Cambridge, Cambridge, UK, and GlaxoSmithKlineStevenageUKAddress correspondence to R. F. van Vollenhoven, MD, PhD, Unit for Clinical Therapy Research Inflammatory Diseases, Department of Medicine, Karolinska Institute, 171 76 Stockholm, Sweden. E‐mail: [email protected].† Dr. van Vollenhoven has received consulting fees from AbbVie, Biotest, Bristol‐Myers Squibb, Crescendo Bioscience, GlaxoSmithKline, Janssen, Lilly, Merck Serono, Pfizer, Roche, UCB, and Vertex (less than $10,000 each) and research grant support from AbbVie, Bristol‐Myers Squibb, GlaxoSmithKline, Pfizer, Roche, and UCB.\n\n‡ Dr. Tak has received consulting fees from Roche, Genentech, and Merck Serono (less than $10,000 each) and owns stock or stock options in GlaxoSmithKline.\n\n11 2015 28 10 2015 67 11 10.1002/art.v67.112828 2836 14 1 2015 23 6 2015 © 2015 The Authors. Arthritis & Rheumatology is published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Objective\nTo explore the safety and tolerability of atacicept in combination with rituximab in patients with active rheumatoid arthritis (RA) receiving rituximab re‐treatment.\n\nMethods\nIn this randomized, double‐blind, placebo‐controlled pilot trial, 2 infusions (1,000 mg per infusion) of intravenous rituximab, given 2 weeks apart, were followed by once‐weekly subcutaneous injections of 150 mg atacicept or placebo for 25 weeks. Primary end points were the nature, incidence, and severity of adverse events (AEs). Secondary end points were the effects on peripheral blood B cells, disease activity biomarkers, and American College of Rheumatology 20% (ACR20), 50% (ACR50), and 70% (ACR70) response rates.\n\nResults\nEighteen patients were randomized to receive atacicept and 9 to receive placebo. AEs occurred in 17 atacicept‐treated patients (94.4%) and in all 9 placebo‐treated patients (100%). There were no infection‐related serious adverse events. Hypersensitivity and injection site reactions were more common, and more patients withdrew due to AEs, in the atacicept group. Median reductions in Ig levels from baseline to week 32 were greater with atacicept (median change in IgG −31.2%, IgM −60.9%, and IgA −56.4%) than with placebo (median change in IgG −4.4%, IgM −15.9%, and IgA −8.2%). Peripheral B cell numbers remained low in all patients after rituximab‐mediated B cell depletion, limiting comparison of time to recovery between treatment groups. There were no between‐group differences in ACR20, ACR50, and ACR70 response rates.\n\nConclusion\nIn this exploratory trial, atacicept in combination with rituximab showed no new safety issues. Peripheral B cell counts remained too low to determine whether atacicept delayed B cell re‐expansion following rituximab‐mediated depletion. Despite clear biologic effects, adding atacicept to rituximab in patients with active RA was not associated with clinical benefit.\n\nMerck Serono S.A. (Geneva, Switzerland)Merck KGaA (Darmstadt, Germany) source-schema-version-number2.0component-idart39262cover-dateNovember 2015details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:4.9.4 mode:remove_FC converted:12.10.2016\nClinicalTrials.gov identifier: NCT00664521.\n==== Body\nUse of the B cell–depleting agent rituximab results in clinical improvements in disease activity in patients with rheumatoid arthritis (RA) 1, 2, 3, providing proof‐of‐concept for the importance of B cells in the pathogenesis of this chronic inflammatory autoimmune disorder 4. B cells act as antigen‐presenting cells, secrete proinflammatory cytokines, and produce autoantibodies in RA 4. In spite of the efficacy of rituximab in RA, not all patients respond 5, 6. Lack of response is associated with persistence of B‐lineage cells, in particular plasma cells, at the site of inflammation, the synovium 7.\n\nThe persistence of B‐lineage cells in the synovial tissue may be associated with increased levels of the B cell maturation/survival factors B lymphocyte stimulator (BLyS) and APRIL (a proliferation‐inducing ligand) 8, 9, 10. Importantly, serum BLyS levels rise sharply following B cell depletion by rituximab, returning to normal only after B cells recover to baseline levels 11. This supports the hypothesis that the beneficial effects of rituximab may be limited by the survival or re‐expansion of autoreactive B‐lineage cells supported by BLyS. It has previously been suggested that interfering with APRIL and BLyS may help to optimize the clinical response to rituximab treatment in RA 7. This could be achieved by treatment with atacicept, which is a soluble, fully human recombinant fusion protein that neutralizes the activity of BLyS and APRIL 12, 13.\n\nIn clinical trials featuring combinations of other biologic agents, an increased risk of infections has been observed 14, 15. The present study, the Atacicept for Reduction of Signs and Symptoms in Rheumatoid Arthritis Trial III (AUGUST III), was an exploratory study with the primary objective of assessing the safety and tolerability of atacicept in patients with active RA receiving rituximab re‐treatment. Secondary objectives focused on evaluating the effects of combination treatment with atacicept and rituximab on the proportions of peripheral B cell populations, levels of biomarkers reflecting disease activity and drug‐related mechanisms of action, and measures of efficacy.\n\nPATIENTS AND METHODS\nStudy design\nIn this multicenter, phase II, randomized, double‐blind, placebo‐controlled pilot trial (AUGUST III), we assessed the safety and tolerability of atacicept in combination with rituximab re‐treatment in patients with moderate or severe RA. The study comprised a 7‐week rituximab treatment period, a 25‐week atacicept/placebo treatment period, and a 32‐week posttreatment followup period. In the rituximab period, all patients received two 1000‐mg doses of rituximab by intravenous infusion, 2 weeks apart (weeks 1 and 3). At week 7 (after 28 days without treatment), patients were randomized 2:1 to receive subcutaneous atacicept at a dose of 150 mg or placebo, once weekly for 25 weeks. Randomization was stratified by rheumatoid factor (RF) status (positive or negative) and country, and an interactive voice response system was used to allocate treatment kit numbers.\n\nThis study was approved by the Institutional Review Boards and independent Ethics Committees at the participating institutions, and conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonisation guidelines, and any local requirements. All patients provided written informed consent.\n\nStudy population\nThe study population consisted of male and female patients ages ≥18 years who had been diagnosed as having RA according to the American College of Rheumatology (ACR) 1987 revised criteria 16, had a disease duration of ≥12 months, had previously responded to treatment with rituximab, and had residual disease activity. The patients were recruited from multiple European sites and were treated on an outpatient basis. Patients had to have a Disease Activity Score in 28 joints (DAS28) of >3.2 17, with a documented response to, and good tolerance of, previous rituximab treatment. They also were required to have significant residual disease (DAS28 >3.2) or clinical deterioration (an increase of ≥0.6 in the DAS28) after such treatment.\n\nPatients were not eligible for inclusion if they had an inflammatory joint disease other than RA, had displayed any contraindication to rituximab, had received disease‐modifying antirheumatic drug therapy for <3 months or changed their regimen within 28 days of study day 1, had received either methotrexate at a dosage of >25 mg/week, an anti–tumor necrosis factor agent (anakinra or tocilizumab) within 12 weeks of study day 1, or abatacept or another cell‐depleting therapy within 24 weeks of study day 1, or had received prednisone at a dosage of >10 mg/day or changed their steroid dosage within 28 days of day 1. One intraarticular steroid injection during each of the screening and treatment periods was permitted.\n\nStudy end points\nPrimary safety end points included the following: the nature, incidence, and severity of adverse events (AEs), particularly infection‐related AEs; the proportion of patients with an IgG level of <3 gm/liter; changes over time and abnormalities in vital signs and routine safety laboratory parameters; and changes over time in immunization status (titers of antibodies against tetanus toxoid, pneumococcus, and diphtheria toxin).\n\nSecondary end points included the following: changes over time in the proportion of peripheral B cell populations; changes over time in markers of disease activity, consisting of concentrations of C‐reactive protein (CRP), the erythrocyte sedimentation rate (ESR), and RF status, together with other ACR core set measures and the severity of morning stiffness, all comprising variables that enabled calculation of the ACR 20% [ACR20], ACR50, and ACR70 composite scores of improvement response [18]); and changes over time in the levels of IgG, IgM, and IgA. To preserve blinding, all joint evaluations were performed by independent efficacy assessors.\n\nStatistical analysis\nAs this was an exploratory pilot study, sample size was not based on formal calculations of statistical power. Data were summarized using descriptive statistics. The safety analysis was performed in the safety population, which included all patients who had received at least one dose of atacicept or placebo and for whom followup safety data were available. The intent‐to‐treat (ITT) population was identical to the safety population.\n\nRESULTS\nPatient characteristics\nThis study was conducted between March 25, 2008 and January 26, 2011. Twenty‐eight patients were enrolled and treated with rituximab. Of these patients, 27 were randomized to receive atacicept (n = 18) or placebo (n = 9) and were included in the safety and ITT analyses (Figure 1). Patient demographics and disposition were similar between the groups, except that there were more women in the atacicept group (Table 1).\n\nFigure 1 Disposition of the study patients treated with two 1,000‐mg infusions of rituximab given 2 weeks apart, followed by 150 mg atacicept or placebo given once weekly for 25 weeks. AE = adverse event; FU = followup; ITT = intent‐to‐treat.\n\nTable 1 Baseline demographic and clinical characteristics of the study patientsa\n\n\n\tRituximab then atacicept (n = 18)\tRituximab then placebo (n = 9)\tOverall (n = 27)\t\nAge, years\t57.0 ± 11.0\t57.7 ± 11.5\t57.2 ± 11.0\t\nFemale, no. (%)\t12 (66.7)\t8 (88.9)\t20 (74.1)\t\nWeight, kg\t76.5 ± 15.0\t74.9 ± 17.1\t76.0 ± 15.4\t\nDisease duration, years\t12.3 ± 5.6\t13.0 ± 5.8\t12.6 ± 5.5\t\nRF positive, no. (%)\t17 (94.4)\t8 (88.9)\t25 (92.6)\t\nOral corticosteroid use, no. (%)\t13 (72.2)\t6 (66.7)\t19 (70.4)\t\nMethotrexate use, no. (%)\t12 (66.7)\t7 (77.8)\t19 (70.4)\t\nCRP, mg/liter\t28.9 ± 35.2\t36.2 ± 36.8\t31.3 ± 35.2\t\nESR, mm/hour\t34.4 ± 22.8\t42.1 ± 23.1\t37.0 ± 22.8\t\nDAS28‐CRP\t5.5 ± 1.0\t5.8 ± 1.0\t5.6 ± 1.0\t\na Except where indicated otherwise, values are the mean ± SD. RF = rheumatoid factor; ESR = erythrocyte sedimentation rate; DAS28‐CRP = Disease Activity Score in 28 joints based on the C‐reactive protein (CRP) level.\n\nAmong the randomized patients, 4 (22.2%) in the atacicept group and 5 (55.6%) in the placebo group were re‐treated with rituximab during the posttreatment followup period, at the discretion of the treating physician. This imbalanced randomization posed a risk to the trial and to the identification of causality of AEs.\n\nPrimary end points\nSafety\nAtacicept/placebo treatment period\nThe majority of AEs were reported during the 25‐week atacicept/placebo treatment period, during which 295 AEs were reported by 26 (96.3%) of the 27 randomized patients (Table 2). The AEs were mostly mild or moderate in intensity and occurred with similar frequency across both treatment groups (17 patients [94.4%] in the atacicept group and 9 patients [100%] in the placebo group). Three patients experienced a total of 4 serious AEs (SAEs) during the atacicept/placebo treatment period: 2 in the placebo group (transient ischemic attack [TIA], ruptured cerebral aneurysm) and 1 in the atacicept group (drug hypersensitivity and TIA).\n\nTable 2 Incidence of SAEs and AEs during the 25‐week atacicept/placebo treatment period (safety population)a\n\n\nType of event, system\tRituximab then atacicept\tRituximab then placebo\tOverall\t\norgan class preferred term\tPatients\tEvents\tPatients\tEvents\tPatients\tEvents\t\nSAEs\t\t\t\t\t\t\t\nAll\t1/18 (5.6)\t2/2 (100.0)\t2/9 (22.2)\t2/2 (100.0)\t3/27 (11.1)\t4/4 (100.0)\t\nNervous system disorders Transient ischemic attack\t1/18 (5.6)\t1/2 (50.0)\t1/9 (11.1)\t1/2 (50.0)\t2/27 (7.4)\t2/4 (50.0)\t\nRuptured cerebral aneurysm\t\t\t1/9 (11.1)\t1/2 (50.0)\t1/27 (3.7)\t1/4 (25.0)\t\nImmune system disorders, drug hypersensitivity\t1/18 (5.6)\t1/2 (50.0)\t0\t0\t1/27 (3.7)\t1/4 (25.0)\t\nAEs\t\t\t\t\t\t\t\nAll\t17/18 (94.4)\t241/241 (100.0)\t9/9 (100.0)\t54/54 (100.0)\t26/27 (96.3)\t295/295 (100.0)\t\nGeneral disorders and administration site conditions\t13/18 (72.2)\t156/241 (64.7)\t4/9 (44.4)\t20/54 (37.0)\t17/27 (63.0)\t176/295 (59.7)\t\nInfections and infestations\t8/18 (44.4)\t11/241 (4.6)\t6/9 (66.7)\t10/54 (18.5)\t14/27 (51.9)\t21/295 (7.1)\t\nMusculoskeletal and connective tissue disorders\t6/18 (33.3)\t6/241 (2.5)\t5/9 (55.6)\t5/54 (9.3)\t11/27 (40.7)\t11/295 (3.7)\t\nSkin and subcutaneous tissue disorders\t8/18 (44.4)\t16/241 (6.6)\t2/9 (22.2)\t2/54 (3.7)\t10/27 (37.0)\t18/295 (6.1)\t\nGastrointestinal disorders\t5/18 (27.8)\t10/241 (4.1)\t3/9 (33.3)\t3/54 (5.6)\t8/27 (29.6)\t13/295 (4.4)\t\nNervous system disorders\t3/18 (16.7)\t8/241 (3.3)\t4/9 (44.4)\t8/54 (14.8)\t7/27 (25.9)\t16/295 (5.4)\t\nRespiratory, thoracic, and mediastinal disorders\t3/18 (16.7)\t22/241 (9.1)\t3/9 (33.3)\t3/54 (5.6)\t6/27 (22.2)\t25/295 (8.5)\t\nImmune system disorders\t4/18 (22.2)\t4/241 (1.7)\t0\t0\t4/27 (14.8)\t4/295 (1.4)\t\nEye disorders\t3/18 (16.7)\t3/241 (1.2)\t0\t0\t3/27 (11.1)\t3/295 (1.0)\t\nInjury, poisoning, and procedural complications\t2/18 (11.1)\t3/241 (1.2)\t0\t0\t2/27 (7.4)\t3/295 (1.0)\t\nVascular disorders\t1/18 (5.6)\t1/241 (0.4)\t1 (11.1)\t1 (1.9)\t2 (7.4)\t2/295 (0.7)\t\nCardiac disorders\t1/18 (5.6)\t1/241 (0.4)\t\t\t1 (3.7)\t1/295 (0.3)\t\nInvestigationsb\n\t0\t0\t1 (11.1)\t1 (1.9)\t1 (3.7)\t1/295 (0.3)\t\nReproductive system and breast disorders\t0\t0\t1 (11.1)\t1 (1.9)\t1 (3.7)\t1/295 (0.3)\t\na Serious adverse events (SAEs) and AEs were evaluated in the safety population (comprising patients who were randomized and received at least one study treatment dose and for whom safety data were available; n = 27). The atacicept period ranged from the date of the first atacicept/placebo dose to the date of the last atacicept/placebo dose plus 7 days. AEs were coded using MedDRA version 13.0. Values are the number/total number (percentage) of patients or events.\n\nb Defined as laboratory abnormalities.\n\nAEs leading to discontinuation were more frequent in the atacicept group than in the placebo group: 4 patients (22.2%) in the atacicept group (2 patients with a drug/type I hypersensitivity reaction, 1 patient with diarrhea and gastritis, and 1 patient with pruritus), and 1 patient (11.1%) in the placebo group (ruptured cerebral aneurysm).\n\nFewer infections occurred in the atacicept group (8 patients [44.4%] experienced 11 events) compared to the placebo group (6 patients [66.7%] experienced 10 events), and generally these represented commonly encountered infections: upper respiratory tract infection, influenza, nasopharyngitis, conjunctivitis, rhinitis, hordeolum, and urinary tract infection. There were no infection‐related SAEs during the treatment period.\n\nLocal injection‐site reactions were more frequent in atacicept‐treated patients (11 [61.1%]) than in placebo‐treated patients (2 [22.2%]). These reactions were consistent with those observed in previous studies of patients treated with atacicept 19 and comprised mild‐to‐moderate erythema, itching, and swelling.\n\nHypersensitivity reactions were more frequent in atacicept‐treated patients (9 [50.0%]) than in placebo‐treated patients (2 [22.2%]), and led to withdrawal in 2 atacicept‐treated patients. Six of the atacicept‐treated patients with hypersensitivity‐related events had skin and subcutaneous tissue disorders (including pruritus), 4 (22.2%) had immune system disorders (including drug hypersensitivity and type I hypersensitivity), and 2 (11.1%) had respiratory disorders (cough and dyspnea).\n\nFollowup period\nSix patients in the atacicept group experienced a total of 12 SAEs during the nontreatment followup period, distributed as follows: 1 patient with atrial fibrillation, 1 patient with cardiac arrest and ventricular fibrillation, 1 patient with pelvic fracture, joint capsule rupture, and arthropathy, 1 patient with visual impairment and muscular weakness, 1 patient with gastroenteritis, and 1 patient with demyelination, glioma, and nervous system disorder. This latter SAE occurred in a 30‐year‐old female patient who had no history of demyelinating disease. This patient experienced a suspected focal glioma or focal demyelination in the cerebellum, with symptoms beginning ∼3 months after atacicept treatment, which led to hospitalization. Magnetic resonance imaging (MRI) revealed a stable, nonprogressing lesion in the right cerebellum and medically significant multifocal changes of vascular origin in the white matter of both hemispheres. Symptoms did not progress over 6 months of followup. As of January 3, 2014, the investigator confirmed that this patient was still under his supervision, and no new neurologic signs and symptoms were present. The patient was doing well under a treatment regimen of biologic agents. With the exception of this patient, SAEs resolved in all other patients. No trends in the nature of the SAEs reported were observed in patients treated with atacicept.\n\nImmunologic status\nA reduction in IgG levels to <3 gm/liter was not observed in any patients, and there were no notable changes in clinical or laboratory parameters in any patients throughout the study treatment period. The median antibody titers at week 32 were reduced from baseline in the atacicept‐treated patients but not in the placebo‐treated patients, with median changes from baseline in the atacicept group versus the placebo group as follows: for anti–tetanus toxoid, −18.0% (interquartile range [IQR] −34.29, 0.00) versus 0.0% (IQR −7.67, 23.68); for anti–diphtheria toxin, −33.7% (IQR −50.00, 0.00) versus 8.4% (IQR 0.00, 0.00); and for antipneumococcus, −18.5% (IQR −35.18, 0.00) versus 0.0% (IQR 0.39, 33.93). These values returned to close to baseline levels by week 16 of the followup period. There were few shifts to below‐protective antibody titers, and there were no between‐group differences with respect to the frequency of shifts.\n\nSecondary end points\nFigure 2 shows the median percentage change in the levels of total, mature, and memory B cells over time. Following treatment with rituximab, the median levels of total, mature, and memory B cells were reduced to 0 (total B cells, median 0 [range 0–2.0 cells/mm3]; mature B cells, median 0 [range 0–0 cells/mm3]; and memory B cells, median 0 [range 0–1.0 cells/mm3]), and little recovery of B cells was observed in either treatment group. Mature B cell recovery at week 64 was <10% in the placebo group and ∼50% in the atacicept group. There were no notable differences in the proportions of T cells between treatment groups; median total T cell levels at week 32 in the atacicept and placebo treatment groups were 1,051/mm3 and 1,124/mm3, respectively, whereas the median levels of T helper cells were 769.5/mm3 and 744/mm3, respectively.\n\nFigure 2 Change in the levels of total, mature, and memory B cells over time in patients treated with two 1,000‐mg infusions of rituximab given 2 weeks apart, followed by 150 mg atacicept or placebo given once weekly for 25 weeks. Values are the percentage change from baseline, expressed as the median with interquartile range. The horizontal broken line indicates baseline.\n\nCombination treatment with atacicept was not associated with a greater decrease in the CRP level compared to re‐treatment with rituximab alone. Reductions from baseline in the median ESR were numerically greater with atacicept compared to placebo from week 12 onward, with the greatest difference observed at week 32 (see Supplementary Table 1, available on the Arthritis & Rheumatology web site at http://onlinelibrary.wiley.com/doi/10.1002/art.39262/abstract). The greatest reductions in the median levels of IgG‐RF, IgM‐RF and IgA‐RF were observed at week 32, and these reductions were all numerically greater with atacicept (see Supplementary Table 2, available on the Arthritis & Rheumatology web site at http://onlinelibrary.wiley.com/doi/10.1002/art.39262/abstract).\n\nTreatment with atacicept was associated with greater median reductions from baseline to week 32 in the levels of IgG, IgM, and IgA (median change from baseline −31.2% [IQR −49.6, −24.1], −60.9% [IQR −71.88, −54.43]), and −56.4% [IQR −66.84, −45.49], respectively) compared to placebo (median change from baseline −4.4% [IQR −10.17, −1.32], −15.9% [IQR −22.92, −7.82], and −8.2% [IQR −19.69, −2.02], respectively) (Figure 3). Median IgG and IgM levels were below the lower limits of normal in the atacicept group from week 20 to week 32. The median IgG levels recovered after cessation of treatment, to reach levels that were 10.9% lower than those at baseline by followup at week 64. However, the median IgM levels had not recovered in all patients by the end of the followup period.\n\nFigure 3 Change in levels of IgG, IgM, and IgA from baseline to week 32 in patients treated with two 1,000‐mg infusions of rituximab given 2 weeks apart, followed by 150 mg atacicept or placebo given once weekly for 25 weeks. In A, values are the levels of each immunoglobulin (in gm/liter) over time. The horizontal broken line indicates the lower limit of normal. In B, values are the percentage change from baseline. The horizontal broken line indicates baseline. All results are expressed as the median with interquartile range.\n\nClinical efficacy\nThere were no noteworthy between‐group differences in clinical response to treatment over time, as defined by the ACR20, ACR50, and ACR70 improvement response criteria based on the CRP level (Figure 4). The mean DAS28 (based on the CRP level or ESR) remained below the values observed at baseline from week 7 onward in both treatment groups (data not shown).\n\nFigure 4 Proportion of patients responding to combination treatment with atacicept versus those treated with placebo over time. Patients were treated with two 1,000‐mg infusions of rituximab given 2 weeks apart, followed by 150 mg atacicept or placebo given once weekly for 25 weeks. Responses were defined according to the American College of Rheumatology 20% improvement criteria (ACR20), the ACR50, and the ACR70 based on the C‐reative protein (CRP) level.\n\nDISCUSSION\nIn this phase II pilot study of atacicept in combination with rituximab re‐treatment in patients with moderate to severe RA, the safety profile of atacicept was consistent with previous experience, and no new safety trends were observed 15, 20. AEs were common (driven mainly by injection‐site reactions and infections), were mostly mild or moderate, and occurred with a similar frequency in both the active treatment and placebo groups.\n\nSAEs occurred in 8 patients during the study: 2 in the treatment period, 1 during the treatment and followup periods, and 5 during followup. The SAEs that occurred during followup were observed in patients who had received atacicept. There were, however, no notable trends in the types of SAEs that emerged, and all except one (focal demyelination/glioma) resolved. This patient developed a focal demyelination and demonstrated multifocal changes in the white matter on MRI, which did not progress over a 6‐month period, and symptoms did not progress over 4 years of followup.\n\nThe etiology of the white matter lesions identified by MRI in this patient is not clear, although the changes are consistent with a demyelinating process and ischemic changes. It should be noted that demyelination due to progressive multifocal leukoencephalopathy (PML) following rituximab treatment in RA patients, leading to estimates of increased risk in the order of 1 per 25,000 patients treated, has been reported in the literature 21. Rituximab‐induced depletion of B cells has been suggested to permit the reactivation of JC virus (JCV), which is responsible for PML 21. However, the JCV status of the patients in the present study was not investigated. In a clinical trial of patients with multiple sclerosis, atacicept treatment was associated with exacerbation of the disease. However, there have been no new diagnoses of demyelinating processes reported in any other atacicept clinical trial. It is not possible to tell from this small pilot study whether atacicept contributed to the demyelination event in this patient. The investigator, however, considered the focal demyelination, suspected focal glioma, and multifocal changes in the white matter to be either unrelated or unlikely to be related to the study medication. RA itself was reported as an alternative explanation for this SAE.\n\nInfection‐related AEs observed in this study were mostly infections that are commonly encountered, consistent with previous reports 15, 20. The infection rate was slightly higher than that previously reported to be associated with treatment with atacicept (44% in the present study versus 34–35% in prior studies [15,20]), but was still lower than that in patients treated with rituximab alone (66.7%). Rituximab re‐treatment has been associated with a reported rate of infection of 50–60% in clinical trials 22, 23. Thus, re‐treatment with rituximab may be contributing to the higher infection rate seen in patients also treated with atacicept. Importantly, no serious infections were reported among atacicept‐treated patients during the treatment period, despite the clear effect of atacicept on B cell levels established in other clinical trials of atacicept in RA patients; one event of severe gastroenteritis occurred 4 months after treatment in a patient who had recently visited Thailand.\n\nThe percentage of patients who withdrew due to AEs was twice as high with atacicept as with placebo. Injection‐site reactions with atacicept were more frequent than previously reported (72.2% in the present study versus 10–11% in prior studies [19,20]), and the incidence of hypersensitivity reactions was also higher in atacicept‐treated patients (50.0%) than in placebo‐treated patients (22.2%). The reasons for this remain unclear; the small sample size could have led to chance results, or rituximab could have increased hypersensitivity to atacicept.\n\nAs in other phase I and phase II trials 15, 20, atacicept was not associated with an increased rate of total infection, despite its Ig‐lowering effects. A small reduction in antibody titers was observed. The reduction in protective titers was, however, not greater than the reduction in total IgG levels. There was no apparent correlation between patients with infections and those with the lowest mean levels of each Ig subclass (data not shown).\n\nAtacicept demonstrated marked biologic activity, as indicated by the decreases in the ESR, B cell subset counts, and concentrations of Ig subclasses and RF in atacicept‐treated patients compared to placebo‐treated patients. The magnitude and pattern of the decrease in total Ig levels following treatment with rituximab and atacicept were similar to those observed in previous RA trials with atacicept alone 15, 20. Consistent with those earlier studies, atacicept‐associated reductions in the ESR were greater than the reductions in the CRP level, which may be attributed to the reduction in total Ig levels associated with atacicept 15, 20. As expected, B cell subsets in the peripheral blood were completely depleted by rituximab, but there was no indication that atacicept delayed the recovery of B cell populations. In some cases, particularly for mature B cells, recovery was quicker following atacicept treatment compared to placebo treatment. Interpretation of these data is, however, limited by a high degree of interindividual variability, the small study size, very low starting numbers of lymphocyte cell populations (typically <10 cells/mm3, with a resolution of 1 cell/mm3), and a between‐group difference in the proportion of patients who received rituximab re‐treatment during followup, which was numerically higher in the placebo group.\n\nThe mechanisms of action of rituximab and atacicept on B cell populations are understood to be complementary, suggesting a potential for additive or synergistic clinical benefit following their combination 7, 11, 12. However, no treatment benefit, as measured by the ACR response rates and DAS28, was observed following the addition of atacicept to rituximab re‐treatment in this study. Published phase II studies of atacicept in RA have previously demonstrated only modest clinical effects despite considerable biologic activity 15, 20. The reasons for this disparity remain unclear. BLyS and APRIL may regulate both B cell and T cell function, and could have both proinflammatory and antiinflammatory activities in RA 24. The possibility also exists that atacicept did not sufficiently block BLyS and APRIL locally in the synovium, leading to insufficient local reduction of B cells and plasma cells. In addition, it is possible that sequential therapy that starts with atacicept first, in order to mobilize memory B cells from niche compartments, followed by rituximab could have higher therapeutic benefit.\n\nIn this study, the rates of clinical response to rituximab were lower than those previously reported 1, 2. Patients in other studies had not been previously treated with rituximab at baseline, and thus may have had a larger response than those being re‐treated in the present study. Patients in this study may have experienced some residual therapeutic effect, meaning that re‐treatment with rituximab did not lower the CRP level as much as initial treatment.\n\nThe number of patients who were re‐treated with rituximab was lower in the atacicept group compared to the placebo group; thus, there is a possibility that atacicept treatment was associated with a more persistent response. Indeed, this was the original hypothesis that led to this trial. Unfortunately, no other measured outcome provides independent support for this hypothesis, and so it remains an intriguing possibility, at best. The study limitations included the small numbers of patients in each group, and the short duration of this pilot study.\n\nIn conclusion, this pilot study demonstrated that administering atacicept following rituximab re‐treatment presented no new safety concerns and was associated with an AE profile consistent with that reported previously for atacicept in phase II studies. Atacicept exerted clear biologic effects, but no additional clinical benefit was observed. Any evidence of an effect of atacicept on delayed B cell re‐expansion following rituximab‐mediated depletion could not be evaluated, since there was virtually no recovery of B cells in the placebo group during the followup period. These findings, therefore, do not suggest that the combination of atacicept and rituximab should be pursued as a therapeutic option for patients with RA.\n\nAUTHOR CONTRIBUTIONS\nAll authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. van Vollenhoven had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.\n\n\nStudy conception and design. van Vollenhoven, Wax, Li, Tak.\n\n\nAcquisition of data. van Vollenhoven, Wax, Li, Tak.\n\n\nAnalysis and interpretation of data. van Vollenhoven, Wax, Li, Tak.\n\nROLE OF THE STUDY SPONSOR\nMerck Serono was involved in the study design and in the collection, analysis, and interpretation of the data. Authors Wax and Li are employees of EMD Serono and were involved in writing the manuscript. All authors were jointed involved in the decision to submit the manuscript for publication. Publication of the article was not contingent upon approval by Merck Serono.\n\nADDITIONAL DISCLOSURES\nAuthor Tak is an employee of GlaxoSmithKline.\n\nSupporting information\n\nSupplementary Table 1. C‐reactive protein (CRP) levels and erythrocyte sedimentation rate (ESR) in patients treated with 1,000 mg rituximab followed by once‐weekly 150 mg atacicept or placebo\n\n\nSupplementary Table 2. Levels of Ig–rheumatoid factor in patients treated with 1,000 mg rituximab followed by once‐weekly 150 mg atacicept or placebo.\n\nClick here for additional data file.\n\n ACKNOWLEDGMENTS\nWe thank Marieke Herenius, MD and Danielle M. Gerlag, MD, PhD for including patients from the Academic Medical Center/University of Amsterdam. We also thank all patients and their families for their participation in the study. Editorial assistance and medical writing support were provided by Linda Edmondson, Paul FitzGerald, and Jose Heroys of Syntropy Medica Ltd. (Worthing, UK), which was supported by EMD Serono Inc. (Rockland, MA), a subsidiary of Merck KGaA (Darmstadt, Germany), and by Sharon Cato, Yasmeen Arif, and Helen Clarke of Discovery London (London, UK), which was supported by Merck KGaA (Darmstadt, Germany).\n==== Refs\nREFERENCES\n1 \n\nCohen \nSB \n, \n\nEmery \nP \n, \n\nGreenwald \nMW \n, \n\nDougados \nM \n, \n\nFurie \nRA \n, \n\nGenovese \nMC \n, et al, for the REFLEX Trial Group. Rituximab for rheumatoid arthritis refractory to anti–tumor necrosis factor therapy: results of a multicenter, randomized, double‐blind, placebo‐controlled, phase III trial evaluating primary efficacy and safety at twenty‐four weeks . Arthritis Rheum \n2006 ;54 :2793 –806 .\n16947627 \n2 \n\nEmery \nP \n, \n\nFleischmann \nR \n, \n\nFilipowicz‐Sosnowska \nA \n, \n\nSchechtman \nJ \n, \n\nSzczepanski \nL \n, \n\nKavanaugh \nA \n, et al, for the DANCER Study Group \n. 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Arthritis Rheum \n1988 ;31 :315 –24 .\n3358796 \n17 \n\nPrevoo \nML \n, \n\nvan 't Hof \nMA \n, \n\nKuper \nHH \n, \n\nvan Leeuwen \nMA \n, \n\nvan de Putte \nLB \n, \n\nvan Riel \nPL. \n\nModified disease activity scores that include twenty‐eight–joint counts: development and validation in a prospective longitudinal study of patients with rheumatoid arthritis . Arthritis Rheum \n1995 ;38 :44 –8 .\n7818570 \n18 \n\nFelson \nDT \n, \n\nAnderson \nJJ \n, \n\nBoers \nM \n, \n\nBombardier \nC \n, \n\nFurst \nD \n, \n\nGoldsmith \nC \n, et al. American College of Rheumatology preliminary definition of improvement in rheumatoid arthritis . Arthritis Rheum \n1995 ;38 :727 –35 .\n7779114 \n19 \n\nTak \nPP \n, \n\nThurlings \nRM \n, \n\nRossier \nC \n, \n\nNestorov \nI \n, \n\nDimic \nA \n, \n\nMircetic \nV \n, et al. Atacicept in patients with rheumatoid arthritis: results of a multicenter, phase Ib, double‐blind, placebo‐controlled, dose‐escalating, single‐ and repeated‐dose study . 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Rheumatology (Oxford) \n2010 ;49 :1683 –93 .\n20463186 \n23 \n\nEmery \nP \n, \n\nDeodhar \nA \n, \n\nRigby \nWF \n, \n\nIsaacs \nJD \n, \n\nCombe \nB \n, \n\nRacewicz \nAJ \n, et al. Efficacy and safety of different doses and retreatment of rituximab: a randomised, placebo‐controlled trial in patients who are biological naive with active rheumatoid arthritis and an inadequate response to methotrexate (Study Evaluating Rituximab's Efficacy in MTX iNadequate rEsponders (SERENE)) [published erratum appears in Ann Rheum Dis. 2011;70:1519] . Ann Rheum Dis \n2010 ;69 :1629 –35 .\n20488885 \n24 \n\nSeyler \nTM \n, \n\nPark \nYW \n, \n\nTakemura \nS \n, \n\nBram \nRJ \n, \n\nKurtin \nPJ \n, \n\nGoronzy \nJJ \n, et al. BLyS and APRIL in rheumatoid arthritis . J Clin Invest \n2005 ;115 :3083 –92 .\n16239971\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2326-5191", "issue": "67(11)", "journal": "Arthritis & rheumatology (Hoboken, N.J.)", "keywords": null, "medline_ta": "Arthritis Rheumatol", "mesh_terms": "D000368:Aged; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011993:Recombinant Fusion Proteins; D000069283:Rituximab; D016896:Treatment Outcome", "nlm_unique_id": "101623795", "other_id": null, "pages": "2828-36", "pmc": null, "pmid": "26137975", "pubdate": "2015-11", "publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't", "references": "21555606;16508933;17965121;18163485;7818570;22540992;16649186;18050206;16935912;20488885;18035324;21452294;16947627;20097226;16239971;20463186;3358796;7779114;12687540;20131284;21452293;11407690;11520463;22012969", "title": "Safety and efficacy of atacicept in combination with rituximab for reducing the signs and symptoms of rheumatoid arthritis: a phase II, randomized, double-blind, placebo-controlled pilot trial.", "title_normalized": "safety and efficacy of atacicept in combination with rituximab for reducing the signs and symptoms of rheumatoid arthritis a phase ii randomized double blind placebo controlled pilot trial" }	[ { "companynumb": "SE-ROCHE-1076577", "fulfillexpeditecriteria": "1", "occurcountry": "SE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ATACICEPT" }, "drugadditional": null, "drugadministrationroute": "058", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "FOR 25 WEEKS.", "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ATACICEPT" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "103705", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INFUSION", "drugdosagetext": "TWO DOSES AT WEEKS 1 AND 3", "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "2", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Ventricular fibrillation", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Visual impairment", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Transient ischaemic attack", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypersensitivity", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Joint capsule rupture", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Gastritis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Arthropathy", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Ruptured cerebral aneurysm", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Atrial fibrillation", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pelvic fracture", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Muscular weakness", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": ", WAX S, LI Y AND TAK P. SAFETY AND EFFICACY OF ATACICEPT IN COMBINATION WITH RITUXIMAB FOR REDUCING THE SIGNS AND SYMPTOMS OF RHEUMATOID ARTHRITIS: A PHASE II, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED PILOT TRIAL. ARTHRITIS + RHEUMATOLOGY (HOBOKEN, N.J.) 2015 NOV?67 (11):2828-2836.", "literaturereference_normalized": "safety and efficacy of atacicept in combination with rituximab for reducing the signs and symptoms of rheumatoid arthritis a phase ii randomized double blind placebo controlled pilot trial", "qualification": "1", "reportercountry": "SE" }, "primarysourcecountry": "SE", "receiptdate": "20151104", "receivedate": "20120622", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 8630319, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160305" } ]
{ "abstract": "Cervical spondylotic myelopathy is a disease of high variability and its progressive form leads to severe disability. This paper reports on a case of a 31-year-old woman with whiplash neck injury sustained at the age of 11, and subsequent neck pain and numbness of arms. Slow progression of symptoms led to tetraparesis, and C3C4 disc herniation along with cervical myelopathy were revealed at the age of 26. Previously, she started a treatment for hypothyroidism. She underwent anterior cervical discectomy and fusion. Two additional operative treatments were done during the next two years due to lack of clinical improvement. Because of chronic pain the number of medications and the number of symptoms have gradually increased. We emphasize the problem of long-term treatment for chronic non-malignant pain and therapeutic dilemma in situations of inadequate analgesia.", "affiliations": "Special Medical Rehabilitation Hospital, Varaždinske Toplice, Croatia. [email protected]", "authors": "Vrabec-Matković\|Dragica\|D\|;Budisin\|Vesna\|V\|;Pahić\|Renato\|R\|", "chemical_list": null, "country": "Bosnia and Herzegovina", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1840-0132", "issue": "8(2)", "journal": "Medicinski glasnik : official publication of the Medical Association of Zenica-Doboj Canton, Bosnia and Herzegovina", "keywords": null, "medline_ta": "Med Glas (Zenica)", "mesh_terms": "D000328:Adult; D002574:Cervical Vertebrae; D059350:Chronic Pain; D005260:Female; D006801:Humans; D007405:Intervertebral Disc Displacement; D019547:Neck Pain; D059408:Pain Management; D010291:Paresis; D013118:Spinal Cord Diseases; D017211:Treatment Failure; D014911:Whiplash Injuries", "nlm_unique_id": "101250177", "other_id": null, "pages": "309-11", "pmc": null, "pmid": "21849962", "pubdate": "2011-08", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Failure in long-term treatment of chronic pain in cervical spondylotic myelopathy.", "title_normalized": "failure in long term treatment of chronic pain in cervical spondylotic myelopathy" }	[ { "companynumb": "HR-NAPPMUNDI-USA-2011-0075747", "fulfillexpeditecriteria": "1", "occurcountry": "HR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "OXYCODONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "022272", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PAIN", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "200904", "drugstartdateformat": "610", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXYCODONE HYDROCHLORIDE (SIMILAR TO NDA 22-272)" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OXYCODONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "022272", "drugbatchnumb": "UNK", "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "13 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "13", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXYCODONE HYDROCHLORIDE (SIMILAR TO NDA 22-272)" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "BACLOFEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNK", "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DOSE: 3X10 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "PAIN", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "200709", "drugstartdateformat": "610", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BACLOFEN." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "BACLOFEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25 MG, TID", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "201003", "drugstartdateformat": "610", "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BACLOFEN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ALPRAZOLAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DOSAGE FORM: UNSPECIFIED", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALPRAZOLAM." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "GABAPENTIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3X300 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, 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null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DOSE: 3X25 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "200805", "drugstartdateformat": "610", "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BACLOFEN." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "SERTRALINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "COATED TABLET", "drugdosagetext": "50 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "HEADACHE", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "200904", "drugstartdateformat": "610", "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SERTRALINE" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DOSAGE FORM: UNSPECIFIED", "drugenddate": null, "drugenddateformat": null, "drugindication": "PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBUPROFEN." } ], "patientagegroup": null, "patientonsetage": "31", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Depression", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Erythema", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Persistent depressive disorder", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Quadriparesis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Oedema", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Constipation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dizziness", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sedation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pruritus", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Disturbance in attention", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Loss of consciousness", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Feeling abnormal", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Musculoskeletal stiffness", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cognitive disorder", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Syncope", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Confusional state", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Asthenia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pain", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Conversion disorder", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Headache", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anxiety", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Schizophrenia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Euphoric mood", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fatigue", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sensory disturbance", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neurosis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diplopia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrointestinal motility disorder", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Psychomotor skills impaired", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VRABEC-MATKOVIC, DRAGICA? ET AL.. FAILURE IN LONG-TERM TREATMENT OF CHRONIC PAIN IN CERVICAL SPONDYLOTIC MYELOPATHY. MEDICINSKI GLASNIK. 2011?8 (2):309-311", "literaturereference_normalized": "failure in long term treatment of chronic pain in cervical spondylotic myelopathy", "qualification": "1", "reportercountry": "HR" }, "primarysourcecountry": "HR", "receiptdate": "20190214", "receivedate": "20190124", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15864416, "safetyreportversion": 5, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "HR-JNJFOC-20110904470", "fulfillexpeditecriteria": "1", "occurcountry": "HR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "SERTRALINE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "HEADACHE", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "200904", "drugstartdateformat": "610", "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SERTRALINE" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "PIROXICAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PIROXICAM." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "BACLOFEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DOSE: 3X10 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "200709", "drugstartdateformat": "610", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BACLOFEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OXYCODONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, 3X PER DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "201003", "drugstartdateformat": "610", "drugstructuredosagenumb": "30", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXYCODONE HYDROCHLORIDE (SIMILAR TO NDA 22-272)" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "BACLOFEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25 MG, TID", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "200904", "drugstartdateformat": "610", "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BACLOFEN." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "FEXOFENADINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "180 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HEADACHE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "180", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FEXOFENADINE HYDROCHLORIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TRAMADOL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3 X 37.5 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "112.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAMADOL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "GINKGO" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "120 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "RASH", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "120", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GINKO BILOBA" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYANOCOBALAMIN\\PYRIDOXINE\\RIBOFLAVIN\\THIAMINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2X1 TABLET", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "032", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NEUROBION FORTE /06411001/" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "GINKGO" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GINKO BILOBA" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PREGABALIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DOSE: 2X300 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "PAIN", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "201003", "drugstartdateformat": "610", "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREGABALIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUPRENORPHINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPRENORPHINE (SIMILAR TO NDA 21-306)" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SERTRALINE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "200805", "drugstartdateformat": "610", "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SERTRALINE" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "LEVOTHYROXINE SODIUM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOTHYROXINE SODIUM." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "GABAPENTIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3X300 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "900", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GABAPENTIN." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "FENTANYL" }, "drugadditional": null, "drugadministrationroute": "062", "drugauthorizationnumb": null, "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 UG/72 H, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201003", "drugstartdateformat": "610", "drugstructuredosagenumb": "100", "drugstructuredosageunit": "004", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FENTANYL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARBAMAZEPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DOSE: 3X200 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "PAIN", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "200709", "drugstartdateformat": "610", "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBAMAZEPINE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "BACLOFEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25 MG, TID", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "201003", "drugstartdateformat": "610", "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BACLOFEN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DIAZEPAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, 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null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DOSE: 3X 2 (375/325MG)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "200805", "drugstartdateformat": "610", "drugstructuredosagenumb": "975", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PARACETAMOL W/TRAMADOL" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "ACETAMINOPHEN\\TRAMADOL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "37.5 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"drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PANTOPRAZOLE" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "LEVOTHYROXINE SODIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "75 UG", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOTHYROXINE SODIUM." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DIAZEPAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 UG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "200709", "drugstartdateformat": "610", "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIAZEPAM." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ESOMEPRAZOLE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2X20 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "ASTHENIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "201003", "drugstartdateformat": "610", "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESOMEPRAZOL /01479301/" } ], "patientagegroup": null, "patientonsetage": "31", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Euphoric mood", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fatigue", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Persistent depressive disorder", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Schizophrenia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Oedema", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Loss of consciousness", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Headache", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Musculoskeletal stiffness", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sedation", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Erythema", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neurosis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pain", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diplopia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Disturbance in attention", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Asthenia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pruritus", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cognitive disorder", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrointestinal motility disorder", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Confusional state", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Quadriparesis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sensory disturbance", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Feeling abnormal", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Psychomotor skills impaired", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Syncope", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dizziness", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anxiety", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Constipation", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Depression", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VRABEC-MATKOVIC D, BUDISIN V, PAHIC R.. FAILURE IN LONG-TERM TREATMENT OF CHRONIC PAIN IN CERVICAL SPONDYLOTIC MYELOPATHY. MED GLAS LJEK KOMORE ZENICKO-DOBOJ KANTONA. 2011?8(2):309-311", "literaturereference_normalized": "failure in long term treatment of chronic pain in cervical spondylotic myelopathy", "qualification": "3", "reportercountry": "HR" }, "primarysourcecountry": "HR", "receiptdate": "20191008", "receivedate": "20190125", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15867360, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "HR-PFIZER INC-2011204503", "fulfillexpeditecriteria": "1", "occurcountry": "HR", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "RANITIDINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "150 MG, 2X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": "200709", "drugstartdateformat": "610", "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RANITIDINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, 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"drugdosagetext": "300 MG, 3X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": "200904", "drugstartdateformat": "610", "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GABAPENTIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FENTANYL" }, "drugadditional": "3", "drugadministrationroute": "062", "drugauthorizationnumb": "019115", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100UG/72H", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, 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"drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SERTRALINE HCL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN\\TRAMADOL" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3X2 (37.5/325MG)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "200709", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAMADOL/ACETAMINOPHEN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OXYCODONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, 3X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": "200904", "drugstartdateformat": "610", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXYCODONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYANOCOBALAMIN\\PYRIDOXINE HYDROCHLORIDE\\THIAMINE DISULFIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "2X1", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "200805", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NEUROBION FORTE" } ], "patientagegroup": null, "patientonsetage": "31", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Asthenia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pruritus", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fatigue", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Constipation", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rash", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sedation", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Confusional state", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dizziness", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Oedema", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ataxia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VRABEC?MATKOVIC, D.. FAILURE IN LONG?TERM TREATMENT OF CHRONIC PAIN IN CERVICAL SPONDYLOTIC MYELOPATHY. MEDICINSKI GLASNIK. 2011?8(2):309-311", "literaturereference_normalized": "failure in long term treatment of chronic pain in cervical spondylotic myelopathy", "qualification": "3", "reportercountry": "HR" }, "primarysourcecountry": "HR", "receiptdate": "20191017", "receivedate": "20190117", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15838291, "safetyreportversion": 6, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "HR-SANOFI-AVENTIS-2011SA056460", "fulfillexpeditecriteria": "1", "occurcountry": "HR", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "PIROXICAM" }, "drugadditional": null, 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null, "drugstartdateformat": null, "drugstructuredosagenumb": "37.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAMADOL." } ], "patientagegroup": "5", "patientonsetage": "31", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Loss of consciousness", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrointestinal motility disorder", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Constipation", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neurosis", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Disturbance in attention", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Erythema", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Asthenia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rash", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sedation", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Conversion disorder", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pruritus", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Euphoric mood", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Quadriparesis", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Musculoskeletal stiffness", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Psychomotor skills impaired", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Oedema", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diplopia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Persistent depressive disorder", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Syncope", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Schizophrenia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Depression", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dizziness", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ataxia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sensory disturbance", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Feeling abnormal", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pain", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ill-defined disorder", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fatigue", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Headache", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Confusional state", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cognitive disorder", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anxiety", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VRABEC-MATKOVIC D, BUDISIN V, PAHIC R ET AL.. FAILURE IN LONG-TERM TREATMENT OF CHRONIC PAIN IN CERVICAL SPONDYLOTIC MYELOPATHY. MEDICINSKI GLASNIK. 2011?8 (2):309-311", "literaturereference_normalized": "failure in long term treatment of chronic pain in cervical spondylotic myelopathy", "qualification": "1", "reportercountry": "HR" }, "primarysourcecountry": "HR", "receiptdate": "20200520", "receivedate": "20110909", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 8128401, "safetyreportversion": 4, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200714" } ]
{ "abstract": "BACKGROUND\nThis registry evaluated the 24-month safety and efficacy of levodopa-carbidopa intestinal gel (LCIG) treatment in advanced Parkinson's disease (PD) patients under routine clinical care.\n\n\nMETHODS\nMotor fluctuations, dyskinesia, non-motor symptoms, quality of life, and safety were evaluated. Observations were fully prospective for treatment-naïve patients (60% of patients) and partially retrospective for patients with ≤12 months of pre-treatment with LCIG (40% of patients). Hours of \"On\" and \"Off\" time were assessed with a modified version of the Unified Parkinson's Disease Rating Scale part IV items 32 and 39.\n\n\nRESULTS\nOverall, 375 patients were enrolled by 75 movement disorder centers in 18 countries and 258 patients completed the registry. At 24 months LCIG treatment led to significant reductions from baseline in \"Off\" time (hours/day) (mean ± SD = -4.1 ± 3.5, P < 0.001), \"On\" time with dyskinesia (hours/day) (-1.1 ± 4.8, P = 0.006), Non-Motor Symptom Scale total (-16.7 ± 43.2, P < 0.001) and individual domains scores, and Parkinson's Disease Questionnaire-8 item total score (-7.1 ± 21.0, P < 0.001). Adverse events deemed to have a possible/probable causal relationship to treatment drug/device were reported in 194 (54%) patients; the most frequently reported were decreased weight (6.7%), device related infections (5.9%), device dislocations (4.8%), device issues (4.8%), and polyneuropathy (4.5%).\n\n\nCONCLUSIONS\nLCIG treatment led to sustained improvements in motor fluctuations, non-motor symptoms particularly sleep/fatigue, mood/cognition and gastrointestinal domains, as well as quality of life in advanced PD patients over 24 months. Safety events were consistent with the established safety profile of LCIG.", "affiliations": "Department of Neurosciences, University of Padua, Italy. Electronic address: [email protected].;Medical University of Innsbruck, Innsbruck, Austria. Electronic address: [email protected].;King's College and King's College Hospital, London, United Kingdom.;Department of Neurology, Center of Clinical Neurosciences, Charles University in Prague, General University Hospital in Prague, Prague, Czech Republic.;University Hospital Antwerp, Antwerp, Belgium; Michigan State University, Mercy Health Hauenstein Neurosciences, Grand Rapids, MI, USA.;University Medical Center Ljubljana, Ljubljana, Slovenia.;University of Medicine and Pharmacy Tirgu-Mures, Emergency Clinical County Hospital Mures, Tîrgu Mureş, Romania.;Clinical and Provincial Hospital of Barcelona, Barcelona, Spain.;Lindenbrunn Hospital, Coppenbrügge, Germany.;AbbVie Inc., North Chicago, IL, USA.;AbbVie Inc., North Chicago, IL, USA.;AbbVie Inc., North Chicago, IL, USA.;AbbVie Inc., North Chicago, IL, USA.;Lund University, Lund, Sweden.", "authors": "Antonini\|Angelo\|A\|;Poewe\|Werner\|W\|;Chaudhuri\|K Ray\|KR\|;Jech\|Robert\|R\|;Pickut\|Barbara\|B\|;Pirtošek\|Zvezdan\|Z\|;Szasz\|Jozsef\|J\|;Valldeoriola\|Francesc\|F\|;Winkler\|Christian\|C\|;Bergmann\|Lars\|L\|;Yegin\|Ashley\|A\|;Onuk\|Koray\|K\|;Barch\|David\|D\|;Odin\|Per\|P\|;\|\|\|", "chemical_list": "D000978:Antiparkinson Agents; D004338:Drug Combinations; D005782:Gels; C009265:carbidopa, levodopa drug combination; D007980:Levodopa; D002230:Carbidopa", "country": "England", "delete": false, "doi": "10.1016/j.parkreldis.2017.09.018", "fulltext": null, "fulltext_license": null, "issn_linking": "1353-8020", "issue": "45()", "journal": "Parkinsonism & related disorders", "keywords": "Levodopa-carbidopa intestinal gel; Motor symptoms; Non-motor symptoms; Parkinson's disease; Routine patient care", "medline_ta": "Parkinsonism Relat Disord", "mesh_terms": "D000368:Aged; D000978:Antiparkinson Agents; D002230:Carbidopa; D004338:Drug Combinations; D005260:Female; D005782:Gels; D006801:Humans; D007441:Intubation, Gastrointestinal; D007980:Levodopa; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease; D012042:Registries", "nlm_unique_id": "9513583", "other_id": null, "pages": "13-20", "pmc": null, "pmid": "29037498", "pubdate": "2017-12", "publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study", "references": null, "title": "Levodopa-carbidopa intestinal gel in advanced Parkinson's: Final results of the GLORIA registry.", "title_normalized": "levodopa carbidopa intestinal gel in advanced parkinson s final results of the gloria registry" }	[ { "companynumb": "IT-MYLANLABS-2017M1083803", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARBIDOPA\\LEVODOPA" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "075091", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "ADMINISTERED THROUGH A TEMPORARY NASOJEJUNAL TUBE, FOLLOWED BY ADMINISTRATION THROUGH A PEG-J TUBE.", "drugenddate": null, "drugenddateformat": null, "drugindication": "PARKINSON^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBIDOPA/LEVODOPA" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cerebrovascular accident", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Pneumonia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ANTONINI A, POEWE W, CHAUDHURI KR, JECH R, PICKUT B, PIRTOSEK Z, ET AL. LEVODOPA-CARBIDOPA INTESTINAL GEL IN ADVANCED PARKINSON^S: FINAL RESULTS OF THE GLORIA REGISTRY. PARKINSON-RELAT-DIS 2017?45:13-20.", "literaturereference_normalized": "levodopa carbidopa intestinal gel in advanced parkinson s final results of the gloria registry", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20180110", "receivedate": "20180110", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14372787, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" }, { "companynumb": "IT-MYLANLABS-2017M1083868", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARBIDOPA\\LEVODOPA" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "075091", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "ADMINISTERED THROUGH A TEMPORARY NASOJEJUNAL TUBE, FOLLOWED BY ADMINISTRATION THROUGH A PEG-J TUBE.", "drugenddate": null, "drugenddateformat": null, "drugindication": "PARKINSON^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBIDOPA/LEVODOPA" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Small intestinal obstruction", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ANTONINI A, POEWE W, CHAUDHURI KR, JECH R, PICKUT B, PIRTOSEK Z, ET AL. LEVODOPA-CARBIDOPA INTESTINAL GEL IN ADVANCED PARKINSON^S: FINAL RESULTS OF THE GLORIA REGISTRY. PARKINSON-RELAT-DIS 2017?45:13-20.", "literaturereference_normalized": "levodopa carbidopa intestinal gel in advanced parkinson s final results of the gloria registry", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20180110", "receivedate": "20180110", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14372238, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" }, { "companynumb": "IT-MYLANLABS-2017M1083851", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARBIDOPA\\LEVODOPA" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "075091", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "ADMINISTERED THROUGH A TEMPORARY NASOJEJUNAL TUBE, FOLLOWED BY ADMINISTRATION THROUGH A PEG-J TUBE.", "drugenddate": null, "drugenddateformat": null, "drugindication": "PARKINSON^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBIDOPA/LEVODOPA" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ANTONINI A, POEWE W, CHAUDHURI KR, JECH R, PICKUT B, PIRTOSEK Z, ET AL. LEVODOPA-CARBIDOPA INTESTINAL GEL IN ADVANCED PARKINSON^S: FINAL RESULTS OF THE GLORIA REGISTRY. PARKINSON-RELAT-DIS 2017?45:13-20.", "literaturereference_normalized": "levodopa carbidopa intestinal gel in advanced parkinson s final results of the gloria registry", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20180110", "receivedate": "20180110", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14372699, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" }, { "companynumb": "IT-EDENBRIDGE PHARMACEUTICALS, LLC-IT-2018EDE000009", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARBIDOPA" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "205304", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PARKINSON^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBIDOPA." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ANTONINI A, POEWE W, CHAUDHURI KR, JECH R, PICKUT B, PIRTOSEK Z, ET AL.. LEVODOPA-CARBIDOPA INTESTINAL GEL IN ADVANCED PARKINSON^S: FINAL RESULTS OF THE GLORIA REGISTRY. PARKINSON-RELAT-DIS. 2017?4513-20", "literaturereference_normalized": "levodopa carbidopa intestinal gel in advanced parkinson s final results of the gloria registry", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20180129", "receivedate": "20180129", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14452859, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "IT-MYLANLABS-2017M1083827", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARBIDOPA\\LEVODOPA" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "075091", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "ADMINISTERED THROUGH A TEMPORARY NASOJEJUNAL TUBE, FOLLOWED BY ADMINISTRATION THROUGH A PEG-J TUBE.", "drugenddate": null, "drugenddateformat": null, "drugindication": "PARKINSON^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBIDOPA/LEVODOPA" } ], "patientagegroup": "6", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Peritonitis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Small intestinal perforation", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ANTONINI A, POEWE W, CHAUDHURI KR, JECH R, PICKUT B, PIRTOSEK Z, ET AL. LEVODOPA-CARBIDOPA INTESTINAL GEL IN ADVANCED PARKINSON^S: FINAL RESULTS OF THE GLORIA REGISTRY. PARKINSON-RELAT-DIS 2017?45:13-20.", "literaturereference_normalized": "levodopa carbidopa intestinal gel in advanced parkinson s final results of the gloria registry", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20180110", "receivedate": "20180110", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14372182, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" }, { "companynumb": "IT-EDENBRIDGE PHARMACEUTICALS, LLC-IT-2018EDE000011", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARBIDOPA" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "205304", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PARKINSON^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBIDOPA." } ], "patientagegroup": "6", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Intestinal perforation", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Peritonitis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ANTONINI A, POEWE W, CHAUDHURI KR, JECH R, PICKUT B, PIRTOSEK Z, ET AL.. LEVODOPA-CARBIDOPA INTESTINAL GEL IN ADVANCED PARKINSON^S: FINAL RESULTS OF THE GLORIA REGISTRY. 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LEVODOPA-CARBIDOPA INTESTINAL GEL IN ADVANCED PARKINSON^S: FINAL RESULTS OF THE GLORIA REGISTRY. PARKINSON-RELAT-DIS. 2017?4513-20", "literaturereference_normalized": "levodopa carbidopa intestinal gel in advanced parkinson s final results of the gloria registry", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20180129", "receivedate": "20180129", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14453581, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "IT-EDENBRIDGE PHARMACEUTICALS, LLC-IT-2018EDE000010", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARBIDOPA" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "205304", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PARKINSON^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBIDOPA." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Small intestinal obstruction", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ANTONINI A, POEWE W, CHAUDHURI KR, JECH R, PICKUT B, PIRTOSEK Z, ET AL.. LEVODOPA-CARBIDOPA INTESTINAL GEL IN ADVANCED PARKINSON^S: FINAL RESULTS OF THE GLORIA REGISTRY. PARKINSON-RELAT-DIS. 2017?4513-20", "literaturereference_normalized": "levodopa carbidopa intestinal gel in advanced parkinson s final results of the gloria registry", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20180129", "receivedate": "20180129", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14453631, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" } ]
{ "abstract": "A 71-year-old woman on aspirin presented for a distal pancreatectomy, splenectomy, and partial colectomy with a T8/9 epidural catheter placed preoperatively in 3 attempts. Prophylactic 5000 units of subcutaneous heparin were given before the procedure. After catheter removal on postoperative day 2, the patient developed transient bilateral lower extremity paralysis, with near complete recovery within 30 minutes. An urgent MRI revealed a T4-T8 epidural hematoma prompting an emergent T3-T8 laminectomy. This case presentation highlights the need for heightened awareness regarding complications related to neuraxial analgesia in patients receiving unfractionated heparin for thromboembolism prophylaxis with concurrent aspirin use.", "affiliations": "From the Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts.", "authors": "VanderWielen\|Beth\|B\|;Rubenstein\|Lindsay\|L\|;Shnider\|Marc\|M\|;Ku\|Cindy\|C\|;Wakakuwa\|Jason\|J\|", "chemical_list": "D000925:Anticoagulants; D005343:Fibrinolytic Agents; D010975:Platelet Aggregation Inhibitors", "country": "United States", "delete": false, "doi": "10.1213/XAA.0000000000000492", "fulltext": null, "fulltext_license": null, "issn_linking": "2325-7237", "issue": "8(11)", "journal": "A & A case reports", "keywords": null, "medline_ta": "A A Case Rep", "mesh_terms": "D000368:Aged; D000767:Anesthesia, Epidural; D000925:Anticoagulants; D002408:Catheters, Indwelling; D020878:Device Removal; D005260:Female; D005343:Fibrinolytic Agents; D046748:Hematoma, Epidural, Spinal; D006801:Humans; D007796:Laminectomy; D008279:Magnetic Resonance Imaging; D010243:Paralysis; D010975:Platelet Aggregation Inhibitors; D011237:Predictive Value of Tests; D012307:Risk Factors; D013904:Thoracic Vertebrae; D016896:Treatment Outcome", "nlm_unique_id": "101637720", "other_id": null, "pages": "294-296", "pmc": null, "pmid": "28079662", "pubdate": "2017-06-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Recognition of a Thoracic Epidural Hematoma in the Setting of Transient Paralysis: A Case Report.", "title_normalized": "recognition of a thoracic epidural hematoma in the setting of transient paralysis a case report" }	[ { "companynumb": "PHHY2017US112339", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "HYDROMORPHONE" }, "drugadditional": 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RECOGNITION OF A THORACIC EPIDURAL HEMATOMA IN THE SETTING OF TRANSIENT PARALYSIS: A CASE REPORT.. 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RECOGNITION OF A THORACIC EPIDURAL HEMATOMA IN THE SETTING OF TRANSIENT PARALYSIS: A CASE REPORT. 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RECOGNITION OF A THORACIC EPIDURAL HEMATOMA IN THE SETTING OF TRANSIENT PARALYSIS: A CASE REPORT. 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RECOGNITION OF A THORACIC EPIDURAL HEMATOMA IN THE SETTING OF TRANSIENT PARALYSIS: A CASE REPORT. A-A-CASE-REP. 2017;8(11):294-296", "literaturereference_normalized": "recognition of a thoracic epidural hematoma in the setting of transient paralysis a case report", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170926", "receivedate": "20170926", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14013011, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20171128" } ]
{ "abstract": "An 82-year-old bedridden man with sequelae from a cerebral infarction was admitted to a welfare institution for the elderly. He developed a high fever and hematuria and was prescribed levofloxacin for the treatment of a suspected urinary tract infection. Although his condition improved, the symptoms subsequently recurred; therefore, levofloxacin was again administered. He remained febrile and was admitted to a hospital due to recalcitrant urinary tract infection. Immediately after admission, he developed ischuria and pyuria. Urine and blood cultures at admission indicated the presence of levofloxacin-resistant Oligella urethralis (O. urethralis). He recovered with ceftriaxone medication. To our knowledge, this is the first report of bacteremia associated with a urinary tract infection caused by O. urethralis in Japan.", "affiliations": null, "authors": "Murase\|Kyoko\|K\|;Noda\|Kazushige\|K\|;Otaki\|Yoshihiro\|Y\|;Yasuda\|Jun-ichi\|J\|;Oda\|Toshimi\|T\|;Yokozawa\|Takayuki\|T\|;Kikuchi\|Ken\|K\|", "chemical_list": null, "country": "Japan", "delete": false, "doi": "10.11150/kansenshogakuzasshi.89.274", "fulltext": null, "fulltext_license": null, "issn_linking": "0387-5911", "issue": "89(2)", "journal": "Kansenshogaku zasshi. The Journal of the Japanese Association for Infectious Diseases", "keywords": null, "medline_ta": "Kansenshogaku Zasshi", "mesh_terms": "D000369:Aged, 80 and over; D016470:Bacteremia; D016946:Gram-Negative Aerobic Rods and Cocci; D016905:Gram-Negative Bacterial Infections; D006801:Humans; D008297:Male; D014552:Urinary Tract Infections", "nlm_unique_id": "0236671", "other_id": null, "pages": "274-8", "pmc": null, "pmid": "26552126", "pubdate": "2015-03", "publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article", "references": null, "title": "A Case of Bacteremia Which Followed a Urinary Tract Infection by Oligella urethralis.", "title_normalized": "a case of bacteremia which followed a urinary tract infection by oligella urethralis" }	[ { "companynumb": "JP-LUPIN PHARMACEUTICALS INC.-2015-04401", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "LEVOFLOXACIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "078424", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOFLOXACIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEVOFLOXACIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "078424", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "URINARY TRACT INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOFLOXACIN." } ], "patientagegroup": null, "patientonsetage": "82", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug resistance", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MURASE K, NODA K, OTAKI Y, YASUDA J, ODA T, YOKOZAWA T, KIKUCHI K. A CASE OF BACTEREMIA WHICH FOLLOWED A URINARY TRACT INFECTION BY OLIGELLA URETHRALIS. KANSENSHOGAKU ZASSHI. 2015 MAR?89(2):274-278.", "literaturereference_normalized": "a case of bacteremia which followed a urinary tract infection by oligella urethralis", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20151230", "receivedate": "20151230", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 11878009, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160305" } ]
{ "abstract": "We present a case of a 30-year-old woman who suffered a central retinal artery occlusion while taking tranexamic acid. She had no vascular risk factors and was placed on the drug for treatment of menorrhagia. After 1 month of taking the drug, she suffered a central retinal artery occlusion in her left eye. Tranexamic acid was discontinued to prevent vision loss in the following eye. She remains with no perception of light vision in the affected eye.", "affiliations": "Cardiff Eye Unit, Cardiff and Vale University Health Board, Cardiff, UK.;Cardiff Eye Unit, Cardiff and Vale University Health Board, Cardiff, UK.;Ophthalmology Department, Singleton Hospital, Swansea, UK.", "authors": "Wijetilleka\|Sidath\|S\|;Yeo\|Damien Chia Ming\|DCM\|;Sharma\|Bhavana\|B\|", "chemical_list": "D000933:Antifibrinolytic Agents; D014148:Tranexamic Acid", "country": "England", "delete": false, "doi": "10.1136/bcr-2016-218246", "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "2017()", "journal": "BMJ case reports", "keywords": "Retina; Unwanted Effects / Adverse Reactions", "medline_ta": "BMJ Case Rep", "mesh_terms": "D000328:Adult; D000933:Antifibrinolytic Agents; D005260:Female; D005451:Fluorescein Angiography; D006801:Humans; D008595:Menorrhagia; D015356:Retinal Artery Occlusion; D014148:Tranexamic Acid", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "28705840", "pubdate": "2017-07-13", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "3163896;9033905", "title": "Central retinal artery occlusion in a 30-year-old woman taking tranexamic acid.", "title_normalized": "central retinal artery occlusion in a 30 year old woman taking tranexamic acid" }	[ { "companynumb": "GB-MYLANLABS-2017M1052484", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TRANEXAMIC ACID" }, "drugadditional": "2", "drugadministrationroute": "065", "drugauthorizationnumb": "091657", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MENORRHAGIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRANEXAMIC ACID." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Blindness", "reactionmeddraversionpt": "20.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Retinal artery occlusion", "reactionmeddraversionpt": "20.1", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "WIJETILLEKA S, YEO DCM, SHARMA B. CENTRAL RETINAL ARTERY OCCLUSION IN A 30-YEAR-OLD WOMAN TAKING TRANEXAMIC ACID. BMJ-CASE-REP 2017;2017:218246.", "literaturereference_normalized": "central retinal artery occlusion in a 30 year old woman taking tranexamic acid", "qualification": "1", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20170824", "receivedate": "20170824", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13903984, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" } ]
{ "abstract": "Adefovir dipivoxil (ADV) was an important cause of adult-onset hypophosphatemic osteomalacia. However, its clinical characteristics and mechanisms have not been well defined.\n\n\n\nThe objective of the study was to summarize the clinical characteristics of ADV-induced osteomalacia and to explore the association between ADV-associated tubulopathy and polymorphisms in genes encoding drug transporters.\n\n\n\nSeventy-six affected patients were clinically studied. The SLC22A6 and ABCC2 genes were screened and compared with healthy people from the HapMap.\n\n\n\nHypophosphatemia, high serum alkaline phosphatase (ALP) levels, hypouricemia, nondiabetic glycosuria, proteinuria, metabolic acidosis and high bone turnover markers were the main metabolic characteristics. Fractures and pseudofractures occurred in 39 patients. Stopping ADV administration, supplementing calcitriol and calcium was effective during the follow-up period. Single SNP analysis revealed a higher percentage of the G/A genotype at c.2934 in exon 22 of the ABCC2 gene (rs3740070) in patients than in healthy people (12% [7 of 58 patients] vs. 0% [0 of 45 patients]; P=0.017), while there was no subject with homozygosity for the A allele at c.2934.\n\n\n\nADV can be nephrotoxic at a conventional dosage. The G/A genotype at c.2934 of the ABCC2 gene may be a predictor of patients at greater risk for developing ADV-associated tubulopathy. Larger case-control studies are needed to further verify this finding.", "affiliations": "Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.;Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.;Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.;Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China. Electronic address: [email protected].", "authors": "Wei\|Zhe\|Z\|;He\|Jin-Wei\|JW\|;Fu\|Wen-Zhen\|WZ\|;Zhang\|Zhen-Lin\|ZL\|", "chemical_list": "C000715087:ABCC2 protein, human; D000089762:Multidrug Resistance-Associated Protein 2; D027425:Multidrug Resistance-Associated Proteins; D027362:Organic Anion Transport Protein 1; D063065:Organophosphonates; D000225:Adenine; C106812:adefovir dipivoxil", "country": "United States", "delete": false, "doi": "10.1016/j.bone.2016.09.017", "fulltext": null, "fulltext_license": null, "issn_linking": "1873-2763", "issue": "93()", "journal": "Bone", "keywords": "ABCC2; Adefovir dipivoxil; Clinical characteristic; Hypophosphatemic osteomalacia; Risk genotype; SLC22A6", "medline_ta": "Bone", "mesh_terms": "D000225:Adenine; D000595:Amino Acid Sequence; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:Multidrug Resistance-Associated Proteins; D027362:Organic Anion Transport Protein 1; D063065:Organophosphonates; D010018:Osteomalacia; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D017386:Sequence Homology, Amino Acid", "nlm_unique_id": "8504048", "other_id": null, "pages": "97-103", "pmc": null, "pmid": "27664568", "pubdate": "2016-12", "publication_types": "D016428:Journal Article", "references": null, "title": "Osteomalacia induced by long-term low-dose adefovir dipivoxil: Clinical characteristics and genetic predictors.", "title_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors" }	[ { "companynumb": "CN-GILEAD-2016-0247457", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "0 MG, QD", "drugenddate": "201206", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2007", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK UNKNOWN, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "60", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010944, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247455", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "201102", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2007", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK UNKNOWN, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "43", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201008" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161207", "receivedate": "20161207", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13007554, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247610", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "6", "patientonsetage": "76", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201310" } }, "primarysource": { "literaturereference": "WEI Z, HE J-W, FU W-Z, Z Z-L. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010834, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247589", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20121203", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2005", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": "20121203", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2005", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "50", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201202" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13009974, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247582", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": "20140324", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2009", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20140324", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2009", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "51", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201303" } }, "primarysource": { "literaturereference": "WEI, Z. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13011094, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247585", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20130508", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2000", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": "20130508", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2000", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "6", "patientonsetage": "71", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13009874, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247616", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20160628", "drugenddateformat": "102", "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2001", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "48", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201506" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161209", "receivedate": "20161209", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13013797, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247415", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20150205", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2009", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "57", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201402" } }, "primarysource": { "literaturereference": "WEI Z.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010567, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247604", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20151026", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2007", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK UNKNOWN, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "36", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201310" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161209", "receivedate": "20161209", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13013747, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247460", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "201203", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2003", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": "201203", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2003", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201111" } }, "primarysource": { "literaturereference": "WEI Z, ET AL. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010917, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247583", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20130722", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2005", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": "20130722", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2005", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "50", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201107" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13009828, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247299", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20130301", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2006", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "46", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201104" } }, "primarysource": { "literaturereference": "WEI, Z.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161209", "receivedate": "20161209", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13013748, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247459", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "201203", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2007", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": "201203", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2007", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "46", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WEI Z. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010948, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247606", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20150624", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2007", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": "20150624", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2007", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "6", "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201206" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161209", "receivedate": "20161209", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13014528, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247289", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "200806", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2003", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 200706" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010188, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247613", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20140514", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2009", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": "20140514", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2009", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "25", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201205" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010458, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247303", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "201103", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2007", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "47", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 200912" } }, "primarysource": { "literaturereference": "ZHE WEI. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161209", "receivedate": "20161209", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13013628, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247304", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "200910", "drugenddateformat": "610", "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2003", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "58", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 200810" } }, "primarysource": { "literaturereference": "WEI Z, HE J-W, FU W-Z, ZHANG Z-L. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161207", "receivedate": "20161207", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13005966, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247458", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "201209", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2009", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": "201209", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2009", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR /01480802/" } ], "patientagegroup": "5", "patientonsetage": "47", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201109" } }, "primarysource": { "literaturereference": "WEI Z, HE J-W, FU W-Z, ZHANG Z-L. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010946, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0239203", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161207", "receivedate": "20161020", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 12867616, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247300", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "201203", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2007", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "6", "patientonsetage": "65", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201109" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161209", "receivedate": "20161209", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13013696, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247615", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20160718", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2009", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": "20160718", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2009", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "6", "patientonsetage": "68", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201407" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161209", "receivedate": "20161209", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13013786, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247419", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20140708", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2008", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "45", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201304" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010549, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247414", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20150902", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2000", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "58", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201405" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010659, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247297", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20140217", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2010", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "49", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201307" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010279, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247306", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "200809", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2004", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "57", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 200709" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010259, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247301", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "201106", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2006", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "46", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201105" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161209", "receivedate": "20161209", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13013699, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247298", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20130701", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2005", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "61", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201107" } }, "primarysource": { "literaturereference": "WEI., Z.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010339, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247462", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, UNK", "drugenddate": "201111", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2006", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, UNK", "drugenddate": "201111", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2006", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR" } ], "patientagegroup": "5", "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201011" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010929, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247416", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, UNK", "drugenddate": "20150202", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2009", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "53", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201402" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010672, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247456", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": "201211", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2010", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "201211", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2010", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201205" } }, "primarysource": { "literaturereference": "ZHE WEI. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "1", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13011082, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247417", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20141110", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2005", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "58", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201402" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010472, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247302", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "201103", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2005", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "46", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 200803" } }, "primarysource": { "literaturereference": "ZHE WEI. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161209", "receivedate": "20161209", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13013662, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247587", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK UNK, QD", "drugenddate": "201212", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2005", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK UNK, QD", "drugenddate": "201212", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2005", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "28", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201112" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13009952, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247618", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "201512", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2012", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, UNK", "drugenddate": "201512", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2012", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "54", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201404" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "1", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010832, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247617", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20160510", "drugenddateformat": "102", "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2006", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": "20160510", "drugenddateformat": "102", "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2006", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "56", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201305" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161209", "receivedate": "20161209", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13013802, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247586", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": "201304", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2008", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "201304", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2008", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WEI, Z. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13009892, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247464", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "201104", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2004", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": "201104", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2004", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "49", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 200804" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010932, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247411", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20160201", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2007", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "53", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201402" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13011052, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247413", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20141207", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2007", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201412" } }, "primarysource": { "literaturereference": "WEI Z.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010662, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247580", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK UNK, QD", "drugenddate": "20140514", "drugenddateformat": "102", "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2006", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK UNK, QD", "drugenddate": "20140514", "drugenddateformat": "102", "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2006", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "54", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201205" } }, "primarysource": { "literaturereference": "WEI Z. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161209", "receivedate": "20161209", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13013720, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247611", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK", "drugenddate": "20140825", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2009", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "52", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201208" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161209", "receivedate": "20161209", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13013770, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247608", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "6", "patientonsetage": "70", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201401" } }, "primarysource": { "literaturereference": "WEI Z, HE J-W, FU W-Z, Z Z-L. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010830, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247581", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20140512", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201205" } }, "primarysource": { "literaturereference": "WEI Z, HE J-W, FU W-Z, ZHANG Z-L. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13009820, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247461", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "201202", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2009", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": "201202", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2009", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "6", "patientonsetage": "74", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201008" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010925, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247305", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "200812", "drugenddateformat": "610", "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2004", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "34", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 200612" } }, "primarysource": { "literaturereference": "WEI Z, HE J-W, FU W-Z, ZHANG Z-L. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13009875, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247588", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20121224", "drugenddateformat": "102", "drugindication": "CHRONIC HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2008", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": "20121224", "drugenddateformat": "102", "drugindication": "CHRONIC HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2008", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "44", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201203" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13009965, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247418", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, UNK", "drugenddate": "20140928", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2009", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "51", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201309" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010465, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247619", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20160223", "drugenddateformat": "102", "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2008", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": "20160223", "drugenddateformat": "102", "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2008", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "46", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201308" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "1", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161209", "receivedate": "20161209", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13013825, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247612", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK", "drugenddate": "20140714", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2009", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "52", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201401" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161209", "receivedate": "20161209", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13013795, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247609", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201210" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010835, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247584", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": "20130713", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2009", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20130713", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2009", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "40", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201304" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ AND ZHANG ZL. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103.", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13009851, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247607", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": "20150318", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2007", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20150318", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2007", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "49", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201203" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161209", "receivedate": "20161209", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13013751, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247412", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK", "drugenddate": "20151230", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2006", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "6", "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201412" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-1036", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010671, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247403", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20140603", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2006", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "61", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201404" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010661, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247410", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20160827", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2010", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": "20160827", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2010", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201308" } }, "primarysource": { "literaturereference": "WEI Z, ET AL. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010663, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247605", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": "20150810", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2011", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20150810", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2011", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "6", "patientonsetage": "75", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201308" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161209", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13009993, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247463", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "201105", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2005", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": "201105", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2005", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "6", "patientonsetage": "66", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201011" } }, "primarysource": { "literaturereference": "WEI Z. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010943, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" } ]
{ "abstract": "A 64-year-old woman with refractory cellulitis in the lower legs was referred for inadequate glycaemic control. Physical examination revealed cushingoid features including central obesity. CT of the abdomen revealed a right adrenal mass that was positive on 131I-adosterol imaging. Findings on endocrine evaluation confirmed a diagnosis of Cushing's syndrome, which was cured with a right adrenalectomy. Two months after surgery, the patient complained of pain and marked swelling of the hands during hydrocortisone replacement therapy (20 mg per day) given for postoperative adrenal insufficiency. Laboratory examination was unremarkable. However, contrast-enhanced T2-weighted MRI of the hands revealed enhanced signals surrounding the flexor tendons, leading to a diagnosis of remitting seronegative symmetrical synovitis with pitting oedema. Prednisolone (15 mg per day) was then initiated, and the symptoms disappeared within a few days. This case illustrates the possibility that successful treatment of Cushing's syndrome may trigger emergence of a glucocorticoid-responsive disease.", "affiliations": "Department of Internal Medicine, Toshiba Rinkan Hospital, Sagamihara, Kanagawa, Japan [email protected].;Department of Urology, Toshiba Rinkan Hospital, Sagamihara, Kanagawa, Japan.;Department of Pathology, Toshiba Rinkan Hospital, Sagamihara, Kanagawa, Japan.", "authors": "Iwasaki\|Hiroaki\|H\|;Kanno\|Hitomi\|H\|;Jiang\|Shi-Xu\|SX\|", "chemical_list": "D006854:Hydrocortisone", "country": "England", "delete": false, "doi": "10.1136/bcr-2019-232959", "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "13(3)", "journal": "BMJ case reports", "keywords": "adrenal disorders; rheumatoid arthritis", "medline_ta": "BMJ Case Rep", "mesh_terms": "D000306:Adrenal Cortex Neoplasms; D018246:Adrenocortical Adenoma; D003480:Cushing Syndrome; D004487:Edema; D005260:Female; D020249:Hormone Replacement Therapy; D006801:Humans; D006854:Hydrocortisone; D008875:Middle Aged; D013585:Synovitis", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "32234852", "pubdate": "2020-03-31", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Remitting seronegative symmetrical synovitis with pitting oedema after surgical remission of Cushing's syndrome.", "title_normalized": "remitting seronegative symmetrical synovitis with pitting oedema after surgical remission of cushing s syndrome" }	[ { "companynumb": "JP-PFIZER INC-2021003983", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "HYDROCORTISONE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "008697", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG PER DAY TAPERED TO 30 MG PER DAY WITHIN 1 WEEK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCORTISONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "HYDROCORTISONE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "008697", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "15 MG IN THE MORNING ON ARISING AND 5 MG LATE IN THE DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCORTISONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMLODIPINE BESYLATE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CELECOXIB" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ARTHROPATHY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CELECOXIB." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "HYDROCORTISONE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "008697", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "150 MG PER DAY TAPERED TO 75 MG PER DAY WITHIN 3 DAYS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ADRENAL INSUFFICIENCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCORTISONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SITAGLIPTIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SITAGLIPTIN" } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Seronegative arthritis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "IWASAKI, H.. REMITTING SERONEGATIVE SYMMETRICAL SYNOVITIS WITH PITTING OEDEMA AFTER SURGICAL REMISSION OF CUSHING^S SYNDROME. BMJ CASE REPORTS. 2020?13(3):10.1136/BCR?2019?232959", "literaturereference_normalized": "remitting seronegative symmetrical synovitis with pitting oedema after surgical remission of cushing s syndrome", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20210113", "receivedate": "20210113", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18735156, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210419" } ]
{ "abstract": "There are no standardized treatments for giant cell tumors of the bone (GCTB) in rare locations such as the spine and pelvis or for those that are inoperable and recurrent, let alone for multicentric GCTB. This study reports a novel case of multicentric GCTB treated with a promising antiangiogenic drug, apatinib, a small-molecule tyrosine kinase inhibitor. The efficacy of apatinib in the treatment of GCTB has not been reported previously.\nA 27-year-old female presented with two giant cell tumors of the spine and sacrum-ilium diagnosed on December 15, 2016. Surgery and selective arterial embolization (SAE) were not reasonable options for this patient, and denosumab was unavailable; therefore, the antiangiogenic drug apatinib and the osteoclast inhibitor zoledronic acid were administered. Apatinib was initially administered at a dose of 850 mg daily, which was decreased to 425 mg daily after 7 months, and then increased again to 635 mg after 11 months. The patient was prescribed a maintenance dose of 500 mg daily after 16 months. The patient reported side effects of Grades I-III nausea, vomiting, and Grades II-III hand-foot syndrome. The patient underwent SAE at 26 months, and at that time, she was switched to denosumab instead of zoledronic acid.\nThe patient showed noticeable symptomatic improvement and visibly reduced tumor size after the first month of treatment. Computed tomography in the 4th month identified a partial response based on the RECIST criteria. The patient has achieved an objective reduction in tumor size at 32 months.\nComprehensive treatment including apatinib represents a potential new treatment strategy for inoperable GCTB, with tolerable side effects. However, further clinical trials are now necessary to confirm an effective dose and determine the efficacy and safety of apatinib in the treatment of GCTB.", "affiliations": "Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University; Li Chengli Innovation Studio, Jinan, China.;Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.;Department of Chemistry and Biochemistry, University of California, Santa Barbara, California, USA.;Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.;Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.", "authors": "Li\|Jun\|J\|;Zhou\|Jun\|J\|;Liu\|Yuntong\|Y\|;Sun\|Xiaogang\|X\|;Song\|Wei\|W\|", "chemical_list": "D011725:Pyridines; C553458:apatinib; D000077211:Zoledronic Acid", "country": "India", "delete": false, "doi": "10.4103/jcrt.JCRT_892_19", "fulltext": null, "fulltext_license": null, "issn_linking": "1998-4138", "issue": "16(5)", "journal": "Journal of cancer research and therapeutics", "keywords": "Apatinib; denosumab; multicentric giant cell tumor of the bone; selective arterial embolization; zoledronic acid", "medline_ta": "J Cancer Res Ther", "mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001859:Bone Neoplasms; D005260:Female; D018212:Giant Cell Tumor of Bone; D006801:Humans; D010386:Pelvic Neoplasms; D011725:Pyridines; D013125:Spinal Neoplasms; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D000077211:Zoledronic Acid", "nlm_unique_id": "101249598", "other_id": null, "pages": "1020-1026", "pmc": null, "pmid": "33004743", "pubdate": "2020-09", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Comprehensive treatment for multicentric giant cell tumors of the pelvis and spine using apatinib: A case report and literature review.", "title_normalized": "comprehensive treatment for multicentric giant cell tumors of the pelvis and spine using apatinib a case report and literature review" }	[ { "companynumb": "CN-AMGEN-CHNSP2020162991", "fulfillexpeditecriteria": "2", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DENOSUMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "125320", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN FORMULATION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE GIANT CELL TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "XGEVA" } ], "patientagegroup": "5", "patientonsetage": "25", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Bone giant cell tumour", "reactionmeddraversionpt": "23.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Therapy non-responder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "L JUN.? ZHOU J.? L YUNTONG. ET. AL.. COMPREHENSIVE TREATMENT FOR MULTICENTRIC GIANT CELL TUMORS OF THE PELVIS AND SPINE USING APATINIB: A CASE REPORT AND LITERATURE REVIEW. JOURNAL OF CANCER RESEARCH AND THERAPEUTICS. 2020?16 (5):1020-1026", "literaturereference_normalized": "comprehensive treatment for multicentric giant cell tumors of the pelvis and spine using apatinib a case report and literature review", "qualification": "1", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20201014", "receivedate": "20201014", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18380928, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210114" } ]
{ "abstract": "BACKGROUND\nOptimal anti-epileptic drug (AED) treatment maximises therapeutic response and minimises adverse effects (AEs). Key to therapeutic AED treatment is adherence. Non-adherence is often related to severity of AEs. Frequently, patients do not spontaneously report, and clinicians do not specifically query, critical AEs that lead to non-adherence, including sexual dysfunction. Sexual dysfunction prevalence in patients with epilepsy ranges from 40 to 70%, often related to AEDs, epilepsy or mood states. This case reports lamotrigine-induced sexual dysfunction leading to periodic non-adherence.\n\n\nOBJECTIVE\nTo report lamotrigine-induced sexual dysfunction leading to periodic lamotrigine non-adherence in the context of multiple comorbidities and concurrent antidepressant and antihypertensive pharmacotherapy.\n\n\nMETHODS\nCase analysis with PubMed literature review.\n\n\nRESULTS\nA 56-year-old male patient with major depression, panic disorder without agoraphobia and post-traumatic stress disorder was well-controlled with escitalopram 20 mg bid, mirtazapine 22.5 mg qhs and alprazolam 1 mg tid prn. Comorbid conditions included complex partial seizures, psychogenic non-epileptic seizures (PNES), hypertension, gastroesophageal reflux disease and hydrocephalus with patent ventriculoperitoneal shunt that were effectively treated with lamotrigine 100 mg tid, enalapril 20 mg qam and lansoprazole 30 mg qam. He acknowledged non-adherence with lamotrigine secondary to sexual dysfunction. With lamotrigine 300 mg total daily dose, he described no libido with impotence/anejaculation/anorgasmia. When off lamotrigine for 48 h, he described becoming libidinous with decreased erectile dysfunction but persistent anejaculation/anorgasmia. When off lamotrigine for 72 h to maximise sexual functioning, he developed auras. Family confirmed patient's consistent monthly non-adherence for 2-3 days during the past year.\n\n\nCONCLUSIONS\nSexual dysfunction is a key AE leading to AED non-adherence. This case describes dose-dependent lamotrigine-induced sexual dysfunction with episodic non-adherence for 12 months. Patient/clinician education regarding AED-induced sexual dysfunction is warranted as are routine sexual histories to ensure adherence.\n\n\nBACKGROUND\nNo financial interests. K.R.K. is Editor of BJPsych Open; he took no part in the peer-review of this work.\n© The Royal College of Psychiatrists 2017. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) license.", "affiliations": ", MD, FRCPsych, DLFAPA, FAES, Departments of Psychiatry, Neurology and Anesthesiology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.;, BS, Department of Psychiatry, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.;, MD, Department of Neurology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.;, BA, Department of Psychiatry, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.", "authors": "Kaufman\|Kenneth R\|KR\|;Coluccio\|Melissa\|M\|;Sivaraaman\|Kartik\|K\|;Campeas\|Miriam\|M\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1192/bjpo.bp.117.005538", "fulltext": "\n==== Front\nBJPsych OpenBJPsych OpenbjporcpsychbjporcpsychBJPsych Open2056-4724The Royal College of Psychiatrists bjporcpsych00553810.1192/bjpo.bp.117.005538Short ReportLamotrigine-induced sexual dysfunction and non-adherence: case analysis with literature review† Sex, lamotrigine, non-adherenceKaufman et alKaufman Kenneth R. Coluccio Melissa Sivaraaman Kartik Campeas Miriam Kenneth R. Kaufman, MD, FRCPsych, DLFAPA, FAES, Departments of Psychiatry, Neurology and Anesthesiology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USAMelissa Coluccio, BS, Department of Psychiatry, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USAKartik Sivaraaman, MD, Department of Neurology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USAMiriam Campeas, BA, Department of Psychiatry, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USACorrespondence: Kenneth R. Kaufman, Departments of Psychiatry, Neurology and Anesthesiology, Rutgers Robert Wood Johnson Medical School, 125 Paterson Street, Suite #2200, New Brunswick, NJ 08901, USA. E-mail:[email protected]† Presented in part at the 19th Annual Conference of the International Society of Bipolar Disorders, Washington DC, 4–7 May 2017.\n\n4 10 2017 9 2017 3 5 249 253 7 7 2017 7 8 2017 23 8 2017 © 2017 The Royal College of Psychiatrists2017The Royal College of PsychiatristsThis is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Background\nOptimal anti-epileptic drug (AED) treatment maximises therapeutic response and minimises adverse effects (AEs). Key to therapeutic AED treatment is adherence. Non-adherence is often related to severity of AEs. Frequently, patients do not spontaneously report, and clinicians do not specifically query, critical AEs that lead to non-adherence, including sexual dysfunction. Sexual dysfunction prevalence in patients with epilepsy ranges from 40 to 70%, often related to AEDs, epilepsy or mood states. This case reports lamotrigine-induced sexual dysfunction leading to periodic non-adherence.\n\nAims\nTo report lamotrigine-induced sexual dysfunction leading to periodic lamotrigine non-adherence in the context of multiple comorbidities and concurrent antidepressant and antihypertensive pharmacotherapy.\n\nMethod\nCase analysis with PubMed literature review.\n\nResults\nA 56-year-old male patient with major depression, panic disorder without agoraphobia and post-traumatic stress disorder was well-controlled with escitalopram 20 mg bid, mirtazapine 22.5 mg qhs and alprazolam 1 mg tid prn. Comorbid conditions included complex partial seizures, psychogenic non-epileptic seizures (PNES), hypertension, gastroesophageal reflux disease and hydrocephalus with patent ventriculoperitoneal shunt that were effectively treated with lamotrigine 100 mg tid, enalapril 20 mg qam and lansoprazole 30 mg qam. He acknowledged non-adherence with lamotrigine secondary to sexual dysfunction. With lamotrigine 300 mg total daily dose, he described no libido with impotence/anejaculation/anorgasmia. When off lamotrigine for 48 h, he described becoming libidinous with decreased erectile dysfunction but persistent anejaculation/anorgasmia. When off lamotrigine for 72 h to maximise sexual functioning, he developed auras. Family confirmed patient’s consistent monthly non-adherence for 2–3 days during the past year.\n\nConclusions\nSexual dysfunction is a key AE leading to AED non-adherence. This case describes dose-dependent lamotrigine-induced sexual dysfunction with episodic non-adherence for 12 months. Patient/clinician education regarding AED-induced sexual dysfunction is warranted as are routine sexual histories to ensure adherence.\n\nDeclaration of interest\nNo financial interests. K.R.K. is Editor of BJPsych Open; he took no part in the peer-review of this work.\n\nCopyright and usage\n© The Royal College of Psychiatrists 2017. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) license.\n==== Body\nOptimal anti-epileptic drug (AED) treatments for persons with epilepsy (PWE) and psychotropic treatments for persons with mood disorders maximise therapeutic response and minimise adverse effects (AEs).1,2 The key to successful pharmacotherapies, whether AEDs or psychotropics, remains medicine adherence. The degree of non-adherence is often underappreciated both by patients and clinicians.3,4 One review of treatment adherence in bipolar patients extracted from a VA database (N=44,637) noted that only 54.1% of all patients were fully adherent.5 A recent UK primary care study of PWE (n=398) found that 36.7% had low adherence,4 which is consistent with a US study addressing elderly PWE with data extracted from the Integrated Health Care Information Services Managed Care Benchmark Database (N=1278) that reported a 40.7% non-adherence rate.6\n\nIn light of the degree of non-adherence and the associated negative effect on acute and long-term treatment outcomes for PWE and persons with mood disorders, especially when considering the direct and indirect costs of these illnesses to society,6–9 research has focused on potential predictive and risk factors. Specific significant predictive and risk factor associations for medication adherence and non-adherence have been reported with, but not limited to, ethnicity, socioeconomics, education, culture, stigma, age, illness status/duration, comorbid substance use disorders, understanding illness process, perceptions related to medication and AEs.4,5,10–13\n\nAE severity is a critical determinant of non-adherence that can be readily addressed during meaningful clinical interactions wherein dosing, alternative pharmacotherapy or even treatment for a specific AE can be considered. Frequently, PWE and persons with mood disorders do not spontaneously report and clinicians do not specifically query critical AEs that lead to non-adherence, including sexual dysfunction.14–17 Sexual functioning is an important marker of quality of life. Sexual dysfunction prevalence in PWE ranges from 40 to 70%, often related to the AEDs, epilepsy, hormonal status or mood states.18,19 Similarly, sexual dysfunction prevalence in patients with mood disorders ranges from 25 to 80% with attribution to psychotropics, mood state and hormonal status.16,20–22\n\nThis case reports lamotrigine-induced sexual dysfunction leading to periodic lamotrigine non-adherence in the context of multiple comorbidities and concurrent antidepressant and antihypertensive pharmacotherapy.\n\nMethod\nCase analysis with PubMed literature review was employed. Search terms utilised in the PubMed literature review included but were not limited to: (1) sexual dysfunction (expanded to all forms of sexual dysfunction – decreased libido, lack of libido, erectile dysfunction, impotence, ejaculatory inhibition, anejaculation, delayed orgasm, anorgasmia, priapism, premature ejaculation, retrograde ejaculation and hypersexuality); (2) general aetiologies (from general reviews this was expanded to reviews addressing neurologic disorders, hypertension, cardiovascular disease, hormonal disorders, psychiatric and substance use disorders, medication and psychotropics); (3) specific aetiologies by patient’s psychiatric diagnoses (mood disorders, anxiety disorders, major depression, panic disorder and post-traumatic stress disorder (PTSD)); (4) specific aetiologies by the patient’s medical diagnoses (epilepsy, complex partial seizures, psychogenic non-epileptic seizures (PNES), hypertension, gastroesophageal reflux disease (GERD) and hydrocephalus); (5) specific aetiologies by the patient’s psychotropics (antidepressants, selective serotonin reuptake inhibitors (SSRIs), escitalopram, mirtazapine, anxiolytics, benzodiazepines and alprazolam); (6) specific aetiologies by the patient’s pharmacotherapy utilised for medical conditions (anticonvulsants, AEDs, lamotrigine, antihypertensive agents, angiotensin converting enzyme (ACE) inhibitors, enalapril, proton pump inhibitors (PPIs) and lansoprazole); (7) lamotrigine and drug interactions; (8) adherence (therapeutic drug monitoring (TDM), discontinuation syndrome and reporting of AEs) and (9) probability rating scale.\n\nResults\nA 56-year-old male patient with major depression, panic disorder without agoraphobia, and PTSD was well-controlled with escitalopram 20 mg bid, mirtazapine 22.5 mg qhs and alprazolam 1 mg tid prn. Comorbid medical conditions included complex partial seizures, PNES, hypertension, GERD and hydrocephalus with patent ventriculoperitoneal shunt that were effectively treated with lamotrigine 100 mg tid, enalapril 20 mg qam and lansoprazole 30 mg qam.\n\nThe patient did not spontaneously report sexual dysfunction; however, he acknowledged such on direct questioning. He desired to maintain his current rational polypharmacy as opposed to potential alternative psychotropics or dose reductions as he focused on his stable psychiatric status. Further, he emphasised adherence to his entire medication regimen, which had remained unchanged over an extended time period.\n\nWhen an issue arose regarding an inappropriately delayed lamotrigine script refill, the patient was confronted with apparent lamotrigine non-adherence and the potential need to reinitiate lamotrigine titration to avoid Stevens–Johnson syndrome. Only then did he acknowledge non-adherence with lamotrigine secondary to sexual dysfunction. Specifically, with lamotrigine 300 mg total daily dose, he described total sexual dysfunction with lack of libido, impotence, anejaculation and anorgasmia.\n\nWhen off lamotrigine for 48 h, he described becoming libidinous with difficult intercourse secondary to erectile dysfunction and persistent anejaculation/anorgasmia. When off lamotrigine for 72 h to maximise sexual functioning (decreased erectile dysfunction but persistent anejaculation/anorgasmia), he developed auras without sexual content. His family confirmed the patient’s consistent monthly non-adherence for 2–3 days during the past year. Though the treating psychiatrist warned the patient that this non-adherence posed the risk of further seizures and even depressive decompensation, he admitted continuing this periodic non-adherence until instructed to cease by his wife.\n\nDiscussion\nMale sexual dysfunction has multiple presentations (decreased libido, lack of libido, erectile dysfunction, impotence, ejaculatory inhibition, anejaculation, delayed orgasm, anorgasmia, priapism, premature ejaculation and retrograde ejaculation)23,24 with multiple reported aetiologies (medical conditions including, but not limited to, neurologic disorders, hypertension, cardiovascular disease and hormonal disorders; psychiatric disorders including, but not limited to mood, anxiety, trauma-related and substance use disorders; and pharmacotherapies).16,18–30 This unique case permits discussion of these issues in the context of the patient’s comorbid conditions and pharmacotherapies from which a determination of probable aetiology for this patient’s lack of libido can be ascertained.31\n\nFirst, the patient had three psychiatric diagnoses: major depression, panic disorder and PTSD. Depression is clearly associated with sexual dysfunction, and decreased libido is a cardinal symptom during a major depressive episode (MDE).20 Erectile dysfunction is associated with both untreated non-MDE depression32 and untreated MDE depression.33 Further, ejaculatory delay has been reported in untreated MDE depression.33 Though there is literature supporting the interrelationship between anxiety and sexual dysfunction,24,34 there is limited research addressing panic disorder in men with associated sexual dysfunction with findings suggesting that panic disorder has a small effect after controlling for comorbid conditions and pharmacotherapies.35 Male military veterans with PTSD have a marked increased prevalence of sexual dysfunctions (including decreased libido, erectile dysfunction and orgasmic difficulties) with recent research addressing the joint neuroendocrine underpinnings of sexual dysfunctions and PTSD.29,36\n\nSecond, the patient had five comorbid medical diagnoses: complex partial seizures, PNES, hypertension, GERD and hydrocephalus. Significant literature, including animal and pre/post-epilepsy neurosurgery studies, supports increased prevalence of multiple sexual dysfunctions (especially decreased libido, as well as erectile dysfunction and orgasm disturbances) in PWE ranging from 40 to 70% with an emphasis on limbic discharges (complex partial seizures), hormonal status and seizure frequency though these factors are confounded by AED treatment and comorbid mood disorders.18,19,37,38 In addition to decreased sexual functioning in PWE, sexual auras and ictal hypersexuality have been reported.39,40 Though prevalence rates for physical and sexual abuse associated with PNES is well-researched,41,42 there are no prevalence rates reported for sexual dysfunction in patients with PNES. Hypertension has negative effects on vascular function and structure resulting in significant sexual dysfunction (erectile dysfunction and impotence in men) with: (1) approximately two-fold increased prevalence when comparing hypertensive patients with normotensive individuals26,43 and (2) large epidemiologic studies revealing increased relative risk range for developing erectile dysfunction in hypertension of 1.3–6.9.43 Sexual dysfunction has been reported with GERD; specifically, untreated patients with GERD have an increased difficulty in obtaining orgasm when compared with healthy individuals.44 Chronic hydrocephalus may be associated with sexual dysfunction (decreased libido, erectile dysfunction and decreased ejaculation), which in one study markedly improved following shunt placement.45\n\nThird, the patient was treated with three psychotropics (escitalopram, mirtazapine and alprazolam), which all have reported treatment-emergent sexual dysfunction. SSRIs, including escitalopram, negatively impact all spheres of sexual functioning in men (libido, erection, ejaculation and orgasm); SSRIs as a class of antidepressants have a significantly increased prevalence of total sexual dysfunction ranging from 25 to 80% of treated patients (escitalopram 37%).16,46 In a prospective study comparing sexual dysfunction among 10 antidepressants, mirtazapine had a prevalence rate of 24.5% involving all spheres; however, the prevalence rate and severity of symptoms were less when compared to SSRIs.47 Though there are limited studies addressing benzodiazepines and alprazolam in particular, one retrospective audit of male veteran PTSD patients treated with benzodiazepines noted significant sexual dysfunction (erectile dysfunction) only with clonazepam, whereas one report of two patients receiving alprazolam in a double-blind protocol noted dose-dependent decreased libido, erectile dysfunction, anejaculation and anorgasmia.48,49\n\nFourth, the patient was also treated with three additional medical condition pharmacotherapies (lamotrigine, enalapril and lansoprazole) which all may be associated with changes in sexual functioning. Lamotrigine, a sodium channel inhibitor with antiglutamatergic properties, is an AED with FDA approval for monotherapy treatment of partial seizures and is used to treat multiple psychiatric disorders including mood disorders.50 Hepatic cytochrome P450 enzyme inducing AEDs, and even some non-enzyme inducing AEDs, have well-reported multiple sexual dysfunction presentations (decreased libido, erectile dysfunction, impotence, delayed ejaculation, anejaculation and anorgasmia).19,22,23,51 Lamotrigine does not have enzyme inducing properties and monotherapy lamotrigine treatment was noted to have minimal sexual effects in men but improvement in all spheres in women.52,53 This finding was supported by a further study comparing Arizona Sexual Experience Scale (ASEX) scores among different AEDs and healthy controls noting improvement in ASEX scores in women but not men treated with lamotrigine.54 Further, one report of three male patients with epilepsy on AEDs with sexual dysfunction noted improvement in sexual functioning with the addition of lamotrigine;55 however all three case were confounded by the discontinuation of gabapentin which has been reported to cause total loss of libido, impotence, anorgasmia and anejaculation at 300 mg total daily dose.23 Patients receiving antihypertensive agents have an increased prevalence of sexual dysfunction compared with untreated patients with hypertension;43 however, this depends both on the class of antihypertensive agent utilised and the generation within that class.56–58 Enalapril is an ACE inhibitor antihypertensive agent; ACE inhibitors are noted to have minimally negative or neutral effect on sexual functioning.56,57,59 Lansoprazole is a PPI without published reports of sexual dysfunction; however, its potential for causing sexual dysfunction must be considered for it induces testosterone metabolism60 and omeprazole, another PPI, is associated with decreased libido, erectile dysfunction and impotence.61,62\n\nFifth, key to determining the aetiology of an AE is a time-line incorporating all diagnostic conditions and pharmacotherapies. In this case, all medical and psychiatric conditions had prolonged stability suggesting that these were not immediate factors in the patient’s decreased libido. With regard to pharmacotherapies, only lamotrigine was changed with an on/off/on/off protocol determined by the patient’s monthly non-adherence. When off lamotrigine for 48 h, he went from no libido to being libidinous. The degree to which the patient’s being off lamotrigine for an additional day improved his erectile dysfunction, he describes improved though still difficult sexual performance (decreased erectile dysfunction but persistent anejaculation/anorgasmia), is unclear. Since multiple medical conditions and pharmacotherapies could cause erectile dysfunction, anejaculation and anorgasmia individually or in combination as described above, the determination of probability by the Naranjo Scale will be limited to lamotrigine and lack of libido. By the Naranjo Scale (a 10-item weighted adverse drug effect scale which is used to determine the probability of such AE being definite, probable, possible or doubtful),31 the decreased libido adverse drug effect is scored as probable.\n\nThis report presents lamotrigine-induced decreased libido as a probable treatment-emergent adverse drug effect. The mechanism for such is unknown. Potentially, there may exist pharmacokinetic or pharmacodynamic interactions;63 however, such interactions impacting sexual functioning and lamotrigine have not been reported. Nonetheless, to better address potential mechanisms, time-sensitive TDM of all pharmacotherapies with sexual hormones would be of benefit.\n\nThis case has multiple limitations. (1) As a case report (N=1), the findings cannot be generalised. (2) No sexual psychometric scale was used to judge degree of sexual dysfunction on lamotrigine and during the periods of lamotrigine non-adherence. (3) No hormone levels were obtained to verify whether concomitant monthly hormonal variations occurred with lamotrigine non-adherence and increased libido. (4) No electroencephalograms (EEGs) were performed during the periods of lamotrigine non-adherence though the patient denied any sexual content to his auras. (5) Lamotrigine concentration-dependent decreased libido could not be determined in the absence of routine lamotrigine TDM. The patient acknowledged that he was non-adherent with ordered lamotrigine TDM, to a large extent because the insurance mandated laboratory was inconvenient. (6) TDM monitoring and daily pill counts were not obtained to ensure that the patient was adherent with all other medications negatively impacting sexual functioning as such additional non-adherence would have confounded the purported impact of lamotrigine non-adherence. Though possible, this was unlikely for 48–72 h psychotropic non-adherence (escitalopram and/or mirtazapine) would have resulted in discontinuation syndrome symptoms (rebound depression, anxiety, confusion, etc.), which the patient denied. This patient had been advised regarding the significance of non-adherence – for his AED, potential recurrent seizures; and for his psychotropics, potential discontinuation syndrome requiring psychiatric hospitalisation. When queried regarding this point, the patient emphasised his desire to avoid any psychiatric decompensation, but did acknowledge his willingness to even develop auras with lamotrigine non-adherence to permit increased sexual functioning. (7) Though an on/off/on/off case design based on patient’s recurrent non-adherence, for ethical reasons the patient could not be requested to redo such non-adherence with additional testing.\n\nSexual dysfunction is a key AE leading to AED non-adherence which is often not volunteered by the patient. This case describes dose-dependent lamotrigine-induced sexual dysfunction with episodic non-adherence for 12 months. Patient/clinician education regarding AED-induced sexual dysfunction is warranted, as are routine sexual histories to ensure adherence, and optimal treatment.\n==== Refs\nReferences\n1 Boon \nP , Engelborghs \nS , Hauman \nH , Jansen \nA , Lagae \nL , Legros \nB , et al\nRecommendations for the treatment of epilepsy in adult patients in general practice in Belgium: an update . Acta Neurol Belg \n2012 ; 112 : 119 –31 .22544726 \n2 Ketter \nTA , Miller \nS , Dell’Osso \nB , Calabrese \nJR , Frye \nMA , Citrome \nL . Balancing benefits and harms of treatments for acute bipolar depression . J Affect Disord \n2014 ; 169 (suppl 1 ): S24 –33 .25533911 \n3 Buelow \nJM , Smith \nMC . Medication management by the person with epilepsy: perception versus reality . Epilepsy Behav \n2004 ; 5 : 401 –6 .15145311 \n4 Chapman \nSC , Horne \nR , Chater \nA , Hukins \nD , Smithson \nWH . Patients’ perspectives on antiepileptic medication: relationships between beliefs about medicines and adherence among patients with epilepsy in UK primary care . Epilepsy Behav \n2014 ; 31 : 312 –20 .24290250 \n5 Sajatovic \nM , Valenstein \nM , Blow \nF , Ganoczy \nD , Ignacio \nR . Treatment adherence with lithium and anticonvulsant medications among patients with bipolar disorder . Psychiatr Serv \n2007 ; 58 : 855 –63 .17535948 \n6 Ettinger \nAB , Manjunath \nR , Candrilli \nSD , Davis \nKL . Prevalence and cost of nonadherence to antiepileptic drugs in elderly patients with epilepsy . Epilepsy Behav \n2009 ; 14 : 324 –9 .19028602 \n7 Olesen \nJ , Gustavsson \nA , Svensson \nM , Wittchen \nHU , Jönsson \nB , CDBE2010 Study Group \net al\nThe economic cost of brain disorders in Europe . Eur J Neurol \n2012 ; 19 : 155 –62 .22175760 \n8 Whiteford \nHA , Ferrari \nAJ , Degenhardt \nL , Feigin \nV , Vos \nT . The global burden of mental, neurological and substance use disorders: an analysis from the Global Burden of Disease Study 2010 . PLoS One \n2015 ; 10 : e0116820 .25658103 \n9 Kessler \nRC , Akiskal \nHS , Ames \nM , Birnbaum \nH , Greenberg \nP , Hirschfeld \nRM , et al\nPrevalence and effects of mood disorders on work performance in a nationally representative sample of U.S. workers . Am J Psychiatry \n2006 ; 163 : 1561 –8 .16946181 \n10 Getnet \nA , Woldeyohannes \nSM , Bekana \nL , Mekonen \nT , Fekadu \nW , Menberu \nM , et al\nAntiepileptic drug nonadherence and its predictors among people with epilepsy . Behav Neurol \n2016 ; 2016 : 3189108 .28053370 \n11 Nakhutina \nL , Gonzalez \nJS , Margolis \nSA , Spada \nA , Grant \nA . Adherence to antiepileptic drugs and beliefs about medication among predominantly ethnic minority patients with epilepsy . Epilepsy Behav \n2011 ; 22 : 584 –6 .21907627 \n12 Baldessarini \nRJ , Perry \nR , Pike \nJ . 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Heterogeneity in psychogenic nonepileptic seizures: understanding the role of psychiatric and neurological factors . Epilepsy Behav \n2010 ; 17 : 236 –41 .20089460 \n43 Doumas \nM , Douma \nS . Sexual dysfunction in essential hypertension: myth or reality? \nJ Clin Hypertens (Greenwich) \n2006 ; 8 : 269 –74 .16596030 \n44 Iovino \nP , Pascariello \nA , Limongelli \nP , Tremolaterra \nF , Consalvo \nD , Sabbatini \nF , et al\nThe prevalence of sexual behavior disorders in patients with treated and untreated gastroesophageal reflux disease . Surg Endosc \n2007 ; 21 : 1104 –10 .17353980 \n45 Missori \nP , Scollato \nA , Formisano \nR , Currà \nA , Mina \nC , Marianetti \nM , et al\nRestoration of sexual activity in patients with chronic hydrocephalus after shunt placement . Acta Neurochir (Wien) \n2009 ; 151 : 1241 –4 .19823916 \n46 La Torre \nA , Giupponi \nG , Duffy \nD , Conca \nA . Sexual dysfunction related to psychotropic drugs: a critical review – part I: antidepressants . 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Epilepsy Behav \n2012 ; 24 : 283 –4 .22560189 \n52 Herzog \nAG , Drislane \nFW , Schomer \nDL , Pennell \nPB , Bromfield \nEB , Dworetzky \nBA , et al\nDifferential effects of antiepileptic drugs on sexual function and hormones in men with epilepsy . Neurology \n2005 ; 65 : 1016 –20 .16217052 \n53 Gil-Nagel \nA , López-Muñoz \nF , Serratosa \nJM , Moncada \nI , García-García \nP , Alamo \nC . Effect of lamotrigine on sexual function in patients with epilepsy . Seizure \n2006 ; 15 : 142 –9 .16434217 \n54 Svalheim \nS , Taubøll \nE , Luef \nG , Lossius \nA , Rauchenzauner \nM , Sandvand \nF , et al\nDifferential effects of levetiracetam, carbamazepine, and lamotrigine on reproductive endocrine function in adults . Epilepsy Behav \n2009 ; 16 : 281 –7 .19716343 \n55 Husain \nAM , Carwile \nST , Miller \nPP , Radtke \nRA . Improved sexual function in three men taking lamotrigine for epilepsy . South Med J . 2000 ; 93 : 335 –6 .10728528 \n56 Grimm \nRH \nJr, Grandits \nGA , Prineas \nRJ , McDonald \nRH , Lewis \nCE , Flack \nJM , et al\nLong-term effects on sexual function of five antihypertensive drugs and nutritional hygienic treatment in hypertensive men and women. Treatment of Mild Hypertension Study (TOMHS ). Hypertension \n1997 ; 29 (Pt 1 ): 8 –14 .9039073 \n57 La Torre \nA , Giupponi \nG , Duffy \nD , Conca \nA , Catanzariti \nD . Sexual dysfunction related to drugs: a critical review. Part IV: cardiovascular drugs . Pharmacopsychiatry \n2015 ; 48 : 1 –6 .25405774 \n58 Brixius \nK , Middeke \nM , Lichtenthal \nA , Jahn \nE , Schwinger \nRH . Nitric oxide, erectile dysfunction and beta-blocker treatment (MR NOED study): benefit of nebivolol versus metoprolol in hypertensive men . Clin Exp Pharmacol Physiol \n2007 ; 34 : 327 –31 .17324145 \n59 Fogari \nR , Zoppi \nA . Effects of antihypertensive therapy on sexual activity in hypertensive men . Curr Hypertens Rep \n2002 ; 4 : 202 –10 .12003702 \n60 Coulson \nM , Gibson \nGG , Plant \nN , Hammond \nT , Graham \nM . Lansoprazole increases testosterone metabolism and clearance in male Sprague-Dawley rats: implications for Leydig cell carcinogenesis . Toxicol Appl Pharmacol \n2003 ; 192 : 154 –63 .14550749 \n61 Lindquist \nM , Edwards \nIR . Endocrine adverse effects of omeprazole . BMJ \n1992 ; 305 : 451 –2 .1392958 \n62 Lareb . Omeprazole and Erectile Dysfunction (http://databankws.lareb.nl/Downloads/kwb_2006_4_omep.pdf).\n63 Cascorbi \nI . Drug interactions – principles, examples and clinical consequences . Dtsch Arztebl Int \n2012 ; 109 : 546 –56 .23152742\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2056-4724", "issue": "3(5)", "journal": "BJPsych open", "keywords": null, "medline_ta": "BJPsych Open", "mesh_terms": null, "nlm_unique_id": "101667931", "other_id": null, "pages": "249-253", "pmc": null, "pmid": "29034101", "pubdate": "2017-09", "publication_types": "D016428:Journal Article", "references": "21478749;16434217;3348461;15145311;14550749;11229449;24781439;24222012;17353980;15184917;18162417;21471773;28053370;16596030;21178782;15582828;23152742;10728528;27371882;26469800;15324820;11399748;19716343;17324145;23489403;25658103;17535948;19823916;1392958;12404311;9160580;26940022;12003702;17962080;17570434;16953246;22544726;16946181;9039073;26953830;21482195;21498130;26529050;12764707;25596624;25818906;1447396;27989023;19440080;19028602;18058849;21612983;24290250;25405774;16217052;22560189;23737245;25533911;22175760;20089460;21907627", "title": "Lamotrigine-induced 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"reactionoutcome": "6" }, { "reactionmeddrapt": "Sexual dysfunction", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KAUFMAN KR, COLUCCIO M, SIVARAAMAN K, CAMPEAS M. 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LAMOTRIGINE-INDUCED SEXUAL DYSFUNCTION AND NON-ADHERENCE: CASE ANALYSIS WITH LITERATURE REVIEW. DOI: 10.1192/BJPO.BP.117.005538. BJPSYCH OPEN. 2017?3:249-253", "literaturereference_normalized": "lamotrigine induced sexual dysfunction and non adherence case analysis with literature review", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190306", "receivedate": "20190306", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16038965, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190418" }, { "companynumb": "US-009507513-1810USA011791", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "MIRTAZAPINE" }, "drugadditional": null, 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"drugstructuredosagenumb": "30", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LANSOPRAZOLE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "ESCITALOPRAM OXALATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MILLIGRAM, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESCITALOPRAM" }, { 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"reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anorgasmia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Erectile dysfunction", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Loss of libido", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ejaculation failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KAUFMAN KR, COLUCCIO M, SIVARAAMAN K, CAMPEAS M. 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MIRTAZAPINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALPRAZOLAM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "074342", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "POST-TRAUMATIC STRESS DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALPRAZOLAM." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LAMOTRIGINE" }, "drugadditional": "2", "drugadministrationroute": null, "drugauthorizationnumb": "76420", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "1", "drugrecurrence": [ { "drugrecuraction": "Loss of libido" } ], "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMOTRIGINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ENALAPRIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "75479", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MILLIGRAM DAILY; EVERY MORNING", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ENALAPRIL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MIRTAZAPINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "76119", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "22.5 MILLIGRAM DAILY; EVERY BEDTIME", "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "22.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MIRTAZAPINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LAMOTRIGINE" }, "drugadditional": "2", "drugadministrationroute": "065", "drugauthorizationnumb": "76420", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "TID", "drugenddate": null, "drugenddateformat": null, "drugindication": "FOCAL DYSCOGNITIVE SEIZURES", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "1", "drugrecurrence": [ { "drugrecuraction": "Loss of libido" } ], "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMOTRIGINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ESCITALOPRAM OXALATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "076765", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PANIC DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESCITALOPRAM" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALPRAZOLAM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "074342", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "TID WHEN NECESSARY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALPRAZOLAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALPRAZOLAM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "074342", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PANIC DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALPRAZOLAM." } ], "patientagegroup": null, "patientonsetage": "6", "patientonsetageunit": "800", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Anorgasmia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Loss of libido", "reactionmeddraversionpt": "21.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Ejaculation failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Erectile dysfunction", "reactionmeddraversionpt": "21.1", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "KAUFMAN KR, COLUCCIO M, SIVARAAMAN K, CAMPEAS M. LAMOTRIGINE-INDUCED SEXUAL DYSFUNCTION AND NON-ADHERENCE: CASE ANALYSIS WITH LITERATURE REVIEW. BJPSYCH-OPEN 2017?3(5):249-253.", "literaturereference_normalized": "lamotrigine induced sexual dysfunction and non adherence case analysis with literature review", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20181108", "receivedate": "20181108", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15597623, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" } ]
{ "abstract": "This case report describes an intentional intoxication with 18 g of hydroxychloroquine (HCQ) presenting with unconsciousness, ventricular dysrhythmias, cardiogenic shock and pulmonary oedema. Initial treatment consisted of sodium bicarbonate, lipid emulsion, diazepam and norepinephrine. Because of persistent cardiogenic shock veno-arterial extracorporeal membrane oxygenation (V-A ECMO) was successfully used as a bridge to recovery. This case underscores the possible side effects of HCQ and the importance of considering ECMO in cardiogenic shock caused by HCQ intoxication which may occur also in patients with coronavirus disease 2019 (COVID-19) based on the currently frequent use of such a compound.", "affiliations": "Department of Cardiology, Ziekenhuis Oost-Limburg, Genk, Belgium.;Department of Clinical Pharmacy, Maastricht University Medical Center, Maastricht, The Netherlands.;Department of Clinical Pharmacy, Maastricht University Medical Center, Maastricht, The Netherlands.;Department of Cardio-thoracic Surgery, Maastricht University Medical Center, Maastricht, The Netherlands.;Department of Intensive Care, Maastricht University Medical Center, Maastricht, The Netherlands.;Department of Intensive Care and Cardiology, Maastricht University Medical Center, Maastricht, The Netherlands.", "authors": "Holvoet\|Wouter\|W\|https://orcid.org/0000-0002-7951-5239;van Soest\|Kaja\|K\|;Havenith\|Thomas\|T\|;Lorusso\|Roberto\|R\|;van Mook\|Walther N K A\|WNKA\|;Delnoij\|Thijs\|T\|", "chemical_list": "D018501:Antirheumatic Agents; D006886:Hydroxychloroquine", "country": "England", "delete": false, "doi": "10.1080/00015385.2020.1802903", "fulltext": null, "fulltext_license": null, "issn_linking": "0001-5385", "issue": "76(2)", "journal": "Acta cardiologica", "keywords": "COVID-19; Hydroxychloroquine; cardiogenic shock; extracorporeal membrane oxygenation; intoxication", "medline_ta": "Acta Cardiol", "mesh_terms": "D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D000086382:COVID-19; D017028:Caregivers; D015897:Comorbidity; D015199:Extracorporeal Membrane Oxygenation; D005260:Female; D006801:Humans; D006886:Hydroxychloroquine; D008875:Middle Aged", "nlm_unique_id": "0370570", "other_id": null, "pages": "200-203", "pmc": null, "pmid": "33308005", "pubdate": "2021-04", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Bail-out extracorporeal membrane oxygenation for hydroxychloroquine intoxication: a warning for COVID-19 health-care givers.", "title_normalized": "bail out extracorporeal membrane oxygenation for hydroxychloroquine intoxication a warning for covid 19 health care givers" }	[ { "companynumb": "BE-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-304624", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "201691", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "18 GRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "18", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROXYCHLOROQUINE" } ], "patientagegroup": null, "patientonsetage": "54", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Coma scale abnormal", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Electrocardiogram ST segment depression", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Atrial fibrillation", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Suicide attempt", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Coma", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Electrocardiogram QT prolonged", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "HOLVOET W, VAN SOEST K, HAVENITH T, LORUSSO R, VAN MOOK WNKA DELNOIJ T.. BAIL?OUT EXTRACORPOREAL MEMBRANE OXYGENATION FOR HYDROXYCHLOROQUINE INTOXICATION: A WARNING FOR COVID?19 HEALTH?CARE GIVERS. ACTA CARDIOL. 2021?76(2):200?03", "literaturereference_normalized": "bail out extracorporeal membrane oxygenation for hydroxychloroquine intoxication a warning for covid 19 health care givers", "qualification": "3", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20210720", "receivedate": "20210720", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19582148, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20211014" } ]
{ "abstract": "Pneumonia caused by methicillin-resistant Staphylococcus aureus (MRSA) is associated with poor clinical outcomes. We surveyed clinical outcomes of MRSA pneumonia in daily practice to identify risk factors for the clinical failure and mortality in patients with MRSA pneumonia. This multicenter prospective observational study was performed across 48 Japanese medical institutions. Adult patients with culture-positive MRSA pneumonia were recruited and treated with anti-MRSA antibiotics. The relationships between clinical and microbiological characteristics and clinical outcomes at test of cure (TOC) or 30-day all-cause mortality were analyzed. In total, 199 eligible patients, including nursing and healthcare-associated pneumonia (n = 95), hospital-acquired pneumonia (n = 76), and community-acquired pneumonia (n = 25), received initial treatment with anti-MRSA agents such as vancomycin (n = 135), linezolid (n = 36), or teicoplanin (n = 22). Overall clinical failure rate at TOC and the 30-day mortality rate were 51.1% (48/94 patients) and 33.7% (66/196 patients), respectively. Multivariable logistic regression analyses for vancomycin-treated populations revealed that abnormal white blood cell count (odds ratio [OR] 4.34, 95% confidence interval [CI] 1.31-14.39) was a risk factor for clinical failure and that no therapeutic drug monitoring (OR 3.10, 95% CI 1.35-7.12) and abnormally high C-reactive protein level (OR 3.54, 95% CI 1.26-9.92) were risk factors for mortality. In conclusion, this study provides evidence that majority of MRSA pneumonia patients are initially treated with vancomycin in Japan, and the absence of therapeutic drug monitoring for vancomycin is significantly associated with the mortality in patients with MRSA pneumonia.", "affiliations": "Department of Respiratory Medicine, Nagasaki University Hospital, Nagasaki, Japan; Department of Infectious Diseases, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. Electronic address: [email protected].;Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.;Department of Infection Control Science, Graduate School of Medicine, Osaka City University, Osaka, Japan.;Department of Infectious Diseases, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.;Department of Respiratory Medicine, Nagasaki University Hospital, Nagasaki, Japan.;Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Aichi, Japan.;Department of Clinical Infectious Diseases, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Toyama, Japan.;Department of Microbiology and Infectious Diseases, Toho University School of Medicine, Tokyo, Japan.;Division of Infection Control and Prevention, Osaka University Hospital, Osaka, Japan.;Department of Respiratory Medicine, Kurashiki Central Hospital, Okayama, Japan.;Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Aichi, Japan.;Division of Clinical Infectious Diseases, Department of Medicine, School of Medicine, Showa University, Tokyo, Japan.;Research Division for Development of Anti-Infective Agents, Institute of Development, Aging and Cancer, Tohoku University, Miyagi, Japan.;Emergency Medical Center, Kitasato University Hospital, Kanagawa, Japan.;Department of Respiratory Medicine, Nagasaki University Hospital, Nagasaki, Japan.", "authors": "Miyazaki\|Taiga\|T\|;Yanagihara\|Katsunori\|K\|;Kakeya\|Hiroshi\|H\|;Izumikawa\|Koichi\|K\|;Mukae\|Hiroshi\|H\|;Shindo\|Yuichiro\|Y\|;Yamamoto\|Yoshihiro\|Y\|;Tateda\|Kazuhiro\|K\|;Tomono\|Kazunori\|K\|;Ishida\|Tadashi\|T\|;Hasegawa\|Yoshinori\|Y\|;Niki\|Yoshihito\|Y\|;Watanabe\|Akira\|A\|;Soma\|Kazui\|K\|;Kohno\|Shigeru\|S\|", "chemical_list": "D000900:Anti-Bacterial Agents; D017334:Teicoplanin; D014640:Vancomycin; D000069349:Linezolid", "country": "Netherlands", "delete": false, "doi": "10.1016/j.jiac.2019.08.018", "fulltext": null, "fulltext_license": null, "issn_linking": "1341-321X", "issue": "26(2)", "journal": "Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy", "keywords": "Linezolid; MRSA; Prospective study; Therapeutic drug monitoring; Vancomycin", "medline_ta": "J Infect Chemother", "mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D015331:Cohort Studies; D003428:Cross Infection; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D007564:Japan; D000069349:Linezolid; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus; D008875:Middle Aged; D011023:Pneumonia, Staphylococcal; D011379:Prognosis; D011446:Prospective Studies; D012307:Risk Factors; D017334:Teicoplanin; D016896:Treatment Outcome; D014640:Vancomycin", "nlm_unique_id": "9608375", "other_id": null, "pages": "242-251", "pmc": null, "pmid": "31575499", "pubdate": "2020-02", "publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study", "references": null, "title": "Daily practice and prognostic factors for pneumonia caused by methicillin-resistant Staphylococcus aureus in Japan: A multicenter prospective observational cohort study.", "title_normalized": "daily practice and prognostic factors for pneumonia caused by methicillin resistant staphylococcus aureus in japan a multicenter prospective observational cohort study" }	[ { "companynumb": "JP-TEVA-2020-JP-1203640", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "PIPERACILLIN SODIUM\\TAZOBACTAM SODIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMONIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PIPERACILLIN/TAZOBACTAM" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VANCOMYCIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "065510", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMONIA STAPHYLOCOCCAL", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VANCOMYCIN" } ], "patientagegroup": "6", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "MIYAZAKI T, YANAGIHARA K, KAKEYA H, IZUMIKAWA K, MUKAE H, SHINDO Y, ET AL. DAILY PRACTICE AND PROGNOSTIC FACTORS FOR PNEUMONIA CAUSED BY METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS IN JAPAN: A MULTICENTER PROSPECTIVE OBSERVATIONAL COHORT STUDY. J-INFECT-CHEMOTHER 2020?26(2):242-251.", "literaturereference_normalized": "daily practice and prognostic factors for pneumonia caused by methicillin resistant staphylococcus aureus in japan a multicenter prospective observational cohort study", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20200317", "receivedate": "20200317", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17548714, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200409" }, { "companynumb": "JP-TEVA-2020-JP-1203635", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CLARITHROMYCIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "065145", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMONIA PSEUDOMONAL", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLARITHROMYCIN." } ], "patientagegroup": "6", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "MIYAZAKI T, YANAGIHARA K, KAKEYA H, IZUMIKAWA K, MUKAE H, SHINDO Y, ET AL. DAILY PRACTICE AND PROGNOSTIC FACTORS FOR PNEUMONIA CAUSED BY METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS IN JAPAN: A MULTICENTER PROSPECTIVE OBSERVATIONAL COHORT STUDY. 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DAILY PRACTICE AND PROGNOSTIC FACTORS FOR PNEUMONIA CAUSED BY METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS IN JAPAN: A MULTICENTER PROSPECTIVE OBSERVATIONAL COHORT STUDY. 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DAILY PRACTICE AND PROGNOSTIC FACTORS FOR PNEUMONIA CAUSED BY METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS IN JAPAN: A MULTICENTER PROSPECTIVE OBSERVATIONAL COHORT STUDY. 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DAILY PRACTICE AND PROGNOSTIC FACTORS FOR PNEUMONIA CAUSED BY METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS IN JAPAN: A MULTICENTER PROSPECTIVE OBSERVATIONAL COHORT STUDY. J-INFECT-CHEMOTHER 2020?26(2):242-251.. 2020?26(2):242-251", "literaturereference_normalized": "daily practice and prognostic factors for pneumonia caused by methicillin resistant staphylococcus aureus in japan a multicenter prospective observational cohort study", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20200312", "receivedate": "20200312", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17532956, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200409" }, { "companynumb": "NVSC2020JP070302", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "VANCOMYCIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "90250", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMONIA STAPHYLOCOCCAL", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VANCOMYCIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pulmonary haemorrhage", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MIYAZAKI T, YANAGIHARA K, KAKEYA H, IZUMIKAWA K, MUKAE H, SHINDO Y ET AL.. DAILY PRACTICE AND PROGNOSTIC FACTORS FOR PNEUMONIA CAUSED BY METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS IN JAPAN: A MULTICENTER PROSPECTIVE OBSERVATIONAL COHORT STUDY. 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DAILY PRACTICE AND PROGNOSTIC FACTORS FOR PNEUMONIA CAUSED BY METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS IN JAPAN: A MULTICENTER PROSPECTIVE OBSERVATIONAL COHORT STUDY. 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DAILY PRACTICE AND PROGNOSTIC FACTORS FOR PNEUMONIA CAUSED BY METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS IN JAPAN: A MULTICENTER PROSPECTIVE OBSERVATIONAL COHORT STUDY. 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DAILY PRACTICE AND PROGNOSTIC FACTORS FOR PNEUMONIA CAUSED BY METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS IN JAPAN: A MULTICENTER PROSPECTIVE OBSERVATIONAL COHORT STUDY. 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DAILY PRACTICE AND PROGNOSTIC FACTORS FOR PNEUMONIA CAUSED BY METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS IN JAPAN: A MULTICENTER PROSPECTIVE OBSERVATIONAL COHORT STUDY. 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DAILY PRACTICE AND PROGNOSTIC FACTORS FOR PNEUMONIA CAUSED BY METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS IN JAPAN: A MULTICENTER PROSPECTIVE OBSERVATIONAL COHORT STUDY. 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DAILY PRACTICE AND PROGNOSTIC FACTORS FOR PNEUMONIA CAUSED BY METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS IN JAPAN: A MULTICENTER PROSPECTIVE OBSERVATIONAL COHORT STUDY. 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DAILY PRACTICE AND PROGNOSTIC FACTORS FOR PNEUMONIA CAUSED BY METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS IN JAPAN: A MULTICENTER PROSPECTIVE OBSERVATIONAL COHORT STUDY. 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DAILY PRACTICE AND PROGNOSTIC FACTORS FOR PNEUMONIA CAUSED BY METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS IN JAPAN: A MULTICENTER PROSPECTIVE OBSERVATIONAL COHORT STUDY.. 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DAILY PRACTICE AND PROGNOSTIC FACTORS FOR PNEUMONIA CAUSED BY METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS IN JAPAN: A MULTICENTER PROSPECTIVE OBSERVATIONAL COHORT STUDY. 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DAILY PRACTICE AND PROGNOSTIC FACTORS FOR PNEUMONIA CAUSED BY METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS IN JAPAN: A MULTICENTER PROSPECTIVE OBSERVATIONAL COHORT STUDY. 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DAILY PRACTICE AND PROGNOSTIC FACTORS FOR PNEUMONIA CAUSED BY METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS IN JAPAN: A MULTICENTER PROSPECTIVE OBSERVATIONAL COHORT STUDY. 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{ "abstract": "The increasing incidence of diffuse large B-cell lymphoma (DLBCL) in ageing populations places a significant burden on healthcare systems. Co-morbidity, frailty, and reduced organ and physiological reserve contribute to treatment-related complications. The optimal dose intensity of R-CHOP to optimize outcome across different ages with variable frailty and comorbidity burden is unclear.\n\n\n\nWe examined the influence of intended (IDI) and relative (RDI) dose intensity of the combination of cyclophosphamide and doxorubicin, age and comorbidity on outcomes for DLBCL patients ≥70 years in a representative, consecutive cohort across eight UK centres (2009-2018). We determined predictors of survival using multivariable Cox regression, and predictors of recurrence before death using competing risks regression.\n\n\n\nPorgression-free survival (PFS) and overall survival (OS) were significantly inferior in patients ≥80 vs. 70-79 years (P < 0.001). In contrast, 2-year cumulative relapse incidence, when accounting for non-relapse mortality as a competing risk, was no different between 70-79 vs. ≥80 years (P = 0.27) or comorbidity status (CIRS-G: 0-6 vs. >6) (P = 0.27). In 70-79 years, patients with an IDI ≥80% had a significantly improved PFS and OS (P < 0.001) compared to IDI < 80%. Conversely, in patients ≥80 years, there was no difference in PFS (P = 0.88) or OS (P = 0.75) according to IDI <80% vs. ≥80%. On multivariable analysis, when comparing by age, there was a significantly higher cumulative relapse rate for patients aged 70-79 years with an IDI <80% (vs. >80%) (P = 0.04) but not for patients ≥80 years comparing IDI (P = 0.32).\n\n\n\n'R-mini-CHOP' provides adequate lymphoma-specific disease control and represents a reasonable treatment option in elderly patients ≥80 years aiming for cure.", "affiliations": "Department of Haematology, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.;Department of Clinical Haematology, Nottingham University Hospitals NHS Trust, Nottingham, UK.;Department of Haematology, Milton Keynes Hospital, Milton Keynes, UK.;Nuffield Department of Medicine, University of Oxford, Oxford, UK.;Oxford University Medical School, Oxford, UK.;Department of Haematology, Great Western Hospital, Swindon, UK.;Department of Haematology, Great Western Hospital, Swindon, UK.;Department of Haematology, Guys and St Thomas' Hospitals NHS Foundation Trust, London, UK.;Department of Haematology, Guys and St Thomas' Hospitals NHS Foundation Trust, London, UK.;Department of Haematology, University Hospitals Bristol NHS Foundation Trust, Bristol, UK.;Department of Cancer Pharmacy, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.;Department of Haematology, Royal Berkshire Hospital NHS Foundation Trust, Reading, UK.;Department of Clinical Haematology, Nottingham University Hospitals NHS Trust, Nottingham, UK.;Department of Clinical Haematology, Nottingham University Hospitals NHS Trust, Nottingham, UK.;Department of Clinical Haematology, Nottingham University Hospitals NHS Trust, Nottingham, UK.;Department of Haematology, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.;Department of Haematology, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.", "authors": "Eyre\|T A\|TA\|0000-0002-6631-9749;Martinez-Calle\|N\|N\|;Hildyard\|C\|C\|;Eyre\|D W\|DW\|;Plaschkes\|H\|H\|;Griffith\|J\|J\|;Wolf\|J\|J\|;Fields\|P\|P\|;Gunawan\|A\|A\|;Oliver\|R\|R\|;Djebbari\|F\|F\|0000-0001-9578-7632;Booth\|S\|S\|;McMillan\|A\|A\|;Fox\|C P\|CP\|;Bishton\|M J\|MJ\|;Collins\|G P\|GP\|;Hatton\|C S R\|CSR\|", "chemical_list": "C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone", "country": "England", "delete": false, "doi": "10.1111/joim.12889", "fulltext": null, "fulltext_license": null, "issn_linking": "0954-6820", "issue": "285(6)", "journal": "Journal of internal medicine", "keywords": "R-CHOP; diffuse large B-cell lymphoma; dose intensity; elderly", "medline_ta": "J Intern Med", "mesh_terms": "D017677:Age Distribution; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D015331:Cohort Studies; D015897:Comorbidity; D003520:Cyclophosphamide; D004317:Doxorubicin; D005260:Female; D006801:Humans; D015994:Incidence; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D011241:Prednisone; D012008:Recurrence; D012189:Retrospective Studies; D000069283:Rituximab; D016896:Treatment Outcome; D014750:Vincristine", "nlm_unique_id": "8904841", "other_id": null, "pages": "681-692", "pmc": null, "pmid": "30811713", "pubdate": "2019-06", "publication_types": "D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Impact of intended and relative dose intensity of R-CHOP in a large, consecutive cohort of elderly diffuse large B-cell lymphoma patients treated with curative intent: no difference in cumulative incidence of relapse comparing patients by age.", "title_normalized": "impact of intended and relative dose intensity of r chop in a large consecutive cohort of elderly diffuse large b cell lymphoma patients treated with curative intent no 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IMPACT OF INTENDED AND RELATIVE DOSE INTENSITY OF R-CHOP IN A LARGE, CONSECUTIVE COHORT OF ELDERLY DIFFUSE LARGE B-CELL LYMPHOMA PATIENTS TREATED WITH CURATIVE INTENT: NO DIFFERENCE IN CUMULATIVE INCIDENCE OF RELAPSE COMPARING PATIENTS BY AGE. 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IMPACT OF INTENDED AND RELATIVE DOSE INTENSITY OF R-CHOP IN A LARGE, CONSECUTIVE COHORT OF ELDERLY DIFFUSE LARGE B-CELL LYMPHOMA PATIENTS TREATED WITH CURATIVE INTENT: NO DIFFERENCE IN CUMULATIVE INCIDENCE OF RELAPSE COMPARING PATIENTS BY AGE. 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IMPACT OF INTENDED AND RELATIVE DOSE INTENSITY OF R-CHOP IN A LARGE, CONSECUTIVE COHORT OF ELDERLY DIFFUSE LARGE B-CELL LYMPHOMA PATIENTS TREATED WITH CURATIVE INTENT: NO DIFFERENCE IN CUMULATIVE INCIDENCE OF RELAPSE COMPARING PATIENTS BY AGE. 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IMPACT OF INTENDED AND RELATIVE DOSE INTENSITY OF R-CHOP IN A LARGE, CONSECUTIVE COHORT OF ELDERLY DIFFUSE LARGE B-CELL LYMPHOMA PATIENTS TREATED WITH CURATIVE INTENT: NO DIFFERENCE IN CUMULATIVE INCIDENCE OF RELAPSE COMPARING PATIENTS BY AGE. 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IMPACT OF INTENDED AND RELATIVE DOSE INTENSITY OF R-CHOP IN A LARGE, CONSECUTIVE COHORT OF ELDERLY DIFFUSE LARGE B-CELL LYMPHOMA PATIENTS TREATED WITH CURATIVE INTENT: NO DIFFERENCE IN CUMULATIVE INCIDENCE OF RELAPSE COMPARING PATIENTS BY AGE. 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IMPACT OF INTENDED AND RELATIVE DOSE INTENSITY OF R-CHOP IN A LARGE, CONSECUTIVE COHORT OF ELDERLY DIFFUSE LARGE B-CELL LYMPHOMA PATIENTS TREATED WITH CURATIVE INTENT: NO DIFFERENCE IN CUMULATIVE INCIDENCE OF RELAPSE COMPARING PATIENTS BY AGE. 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IMPACT OF INTENDED AND RELATIVE DOSE INTENSITY OF R-CHOP IN A LARGE, CONSECUTIVE COHORT OF ELDERLY DIFFUSE LARGE B-CELL LYMPHOMA PATIENTS TREATED WITH CURATIVE INTENT: NO DIFFERENCE IN CUMULATIVE INCIDENCE OF RELAPSE COMPARING PATIENTS BY AGE. JOURNAL OF INTERNAL MEDICINE. 2019?1-12", "literaturereference_normalized": "impact of intended and relative dose intensity of r chop in a large consecutive cohort of elderly diffuse large b cell lymphoma patients treated with curative intent no difference in cumulative incidence of relapse comparing patients by age", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20190413", "receivedate": "20190413", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16193973, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190711" } ]
{ "abstract": "Five patients developed symmetrical paraparesis due to a combination of: compartment syndrome, rhabdomyolysis, renal failure, and demyelinative sensory-motor polyneuropathy, after prolonged sleep in a sitting position. The long deep sleep was induced by consumption of alcohol or drugs. Long-term follow-up showed that these patients remained paraparetic. No damage to the autonomic nervous system was found. Although some suspected that these patients developed \"intensive care neuropathy\", we suggest that this syndrome is different, and should be regarded as a \"new syndrome\".", "affiliations": "Department of Rehabilitation Medicine, Reuth Medical Center, Tel Aviv.;Department of Rehabilitation Medicine, Reuth Medical Center, Tel Aviv.;Department of Rehabilitation Medicine, Reuth Medical Center, Tel Aviv.;Department of Rehabilitation Medicine, Reuth Medical Center, Tel Aviv.;Department of Rehabilitation Medicine, Reuth Medical Center, Tel Aviv.", "authors": "Ohry\|Avi\|A\|;Shemesh\|Frida\|F\|;Haddad\|Najib\|N\|;Lifshitz\|Anatoly\|A\|;Goldin\|Diana\|D\|", "chemical_list": null, "country": "Israel", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0017-7768", "issue": "157(9)", "journal": "Harefuah", "keywords": null, "medline_ta": "Harefuah", "mesh_terms": "D003161:Compartment Syndromes; D006801:Humans; D020335:Paraparesis; D012206:Rhabdomyolysis; D000077708:Sitting Position", "nlm_unique_id": "0034351", "other_id": null, "pages": "582-584", "pmc": null, "pmid": "30221858", "pubdate": "2018-09", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "PARAPARESIS DUE TO RHABDOMYOLYSIS AND A COMPARTMENT SYNDROME IN FIVE PATIENTS WHO HAD BEEN IN A PROLONGED SLEEP IN A SITTING POSITION.", "title_normalized": "paraparesis due to rhabdomyolysis and a compartment syndrome in five patients who had been in a prolonged sleep in a sitting position" }	[ { "companynumb": "IL-TEVA-2019-IL-1070642", "fulfillexpeditecriteria": "1", "occurcountry": "IL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "74569", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "TOOK TWO TABLETS", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "032", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." } ], "patientagegroup": null, "patientonsetage": "22", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Compartment syndrome", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Confusional state", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Paraparesis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Demyelinating polyneuropathy", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Anuria", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Blood lactate dehydrogenase increased", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Depression", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Rhabdomyolysis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Aspartate aminotransferase increased", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Platelet count increased", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hypersomnia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "OHRY A, SHEMESH F, HADDAD N, LIFSHITZ A, GOLDIN D. PARAPARESIS DUE TO RHABDOMYOLYSIS AND A COMPARTMENT SYNDROME IN FIVE PATIENTS WHO HAD BEEN IN A PROLONGED SLEEP IN A SITTING POSITION. HAREFUAH 2018?157(9):582-584.", "literaturereference_normalized": "paraparesis due to rhabdomyolysis and a compartment syndrome in five patients who had been in a prolonged sleep in a sitting position", "qualification": "3", "reportercountry": "IL" }, "primarysourcecountry": "IL", "receiptdate": "20190704", "receivedate": "20190704", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16530046, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": 1, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20191004" } ]
{ "abstract": "BACKGROUND\nPsoriasis is an emerging paradoxical side effect in patients with inflammatory bowel disease (IBD) when treated with anti-TNF alpha. Patients with severe skin lesions unresponsive to topical therapy need to withdraw from treatment.\n\n\nOBJECTIVE\nTo estimate the incidence of paradoxical psoriasis in a large cohort of IBD patients treated with anti-TNF alpha and to analyse its clinical correlates.\n\n\nMETHODS\nA retrospective cohort study on all IBD patients who started anti-TNF alpha at our IBD Centre from January 2008 to December 2013 was performed. Proportional hazards regression models were used to estimate the association between each predictor and time to the development of psoriasis. Time-dependent predictors were updated at each available time point.\n\n\nRESULTS\nFour hundred and two patients were included. Participants contributed a total of 839 person-years of follow-up, during which 42 incident cases of psoriasis were recorded, with an incidence rate of five per 100 person-years. Cox-regression survival analysis revealed smoking as independent predictor of psoriasis (HR: 2.37, 95% CI: 1.36-4.48; P = 0.008). Conversely, concomitant immunosuppressive therapy was inversely related to psoriasis (HR: 0.33, 95% CI: 0.12-0.92; P = 0.03).\n\n\nCONCLUSIONS\nParadoxical psoriasis is a relevant side effect of anti-TNF alpha therapy, with an incidence rate of five per 100 person-years. Smoking is confirmed as the main risk factor for developing lesions. The combination therapy with anti-TNF alpha plus immunosuppressants is associated with a reduced risk of paradoxical psoriasis.", "affiliations": "IBD Unit, Internal Medicine and Gastroenterology, Complesso Integrato Columbus, Catholic University, Rome, Italy.;IBD Unit, Internal Medicine and Gastroenterology, Complesso Integrato Columbus, Catholic University, Rome, Italy.;Nephrology, Complesso Integrato Columbus, Catholic University, Rome, Italy.;IBD Unit, Internal Medicine and Gastroenterology, Complesso Integrato Columbus, Catholic University, Rome, Italy.;IBD Unit, Internal Medicine and Gastroenterology, Complesso Integrato Columbus, Catholic University, Rome, Italy.;Dermatology, Complesso Integrato Columbus, Catholic University, Rome, Italy.;IBD Unit, Internal Medicine and Gastroenterology, Complesso Integrato Columbus, Catholic University, Rome, Italy.;IBD Unit, Internal Medicine and Gastroenterology, Complesso Integrato Columbus, Catholic University, Rome, Italy.;IBD Unit, Internal Medicine and Gastroenterology, Complesso Integrato Columbus, Catholic University, Rome, Italy.;IBD Unit, Internal Medicine and Gastroenterology, Complesso Integrato Columbus, Catholic University, Rome, Italy.;IBD Unit, Internal Medicine and Gastroenterology, Complesso Integrato Columbus, Catholic University, Rome, Italy.;IBD Unit, Internal Medicine and Gastroenterology, Complesso Integrato Columbus, Catholic University, Rome, Italy.;IBD Unit, Internal Medicine and Gastroenterology, Complesso Integrato Columbus, Catholic University, Rome, Italy.", "authors": "Pugliese\|D\|D\|;Guidi\|L\|L\|;Ferraro\|P M\|PM\|;Marzo\|M\|M\|;Felice\|C\|C\|;Celleno\|L\|L\|;Landi\|R\|R\|;Andrisani\|G\|G\|;Pizzolante\|F\|F\|;De Vitis\|I\|I\|;Papa\|A\|A\|;Rapaccini\|G L\|GL\|;Armuzzi\|A\|A\|", "chemical_list": "D007166:Immunosuppressive Agents; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000068879:Adalimumab", "country": "England", "delete": false, "doi": "10.1111/apt.13352", "fulltext": null, "fulltext_license": null, "issn_linking": "0269-2813", "issue": "42(7)", "journal": "Alimentary pharmacology & therapeutics", "keywords": null, "medline_ta": "Aliment Pharmacol Ther", "mesh_terms": "D000068879:Adalimumab; D000328:Adult; D000368:Aged; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007166:Immunosuppressive Agents; D015994:Incidence; D015212:Inflammatory Bowel Diseases; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D011565:Psoriasis; D012189:Retrospective Studies; D012307:Risk Factors; D014409:Tumor Necrosis Factor-alpha", "nlm_unique_id": "8707234", "other_id": null, "pages": "880-8", "pmc": null, "pmid": "26235565", "pubdate": "2015-10", "publication_types": "D016428:Journal Article", "references": null, "title": "Paradoxical psoriasis in a large cohort of patients with inflammatory bowel disease receiving treatment with anti-TNF alpha: 5-year follow-up study.", "title_normalized": "paradoxical psoriasis in a large cohort of patients with inflammatory bowel disease receiving treatment with anti tnf alpha 5 year follow up study" }	[ { "companynumb": "IT-JNJFOC-20150912554", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "INFLIXIMAB" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "103772", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "LYOPHILIZED POWDER", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "INFLAMMATORY BOWEL DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INFLIXIMAB, RECOMBINANT" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Alopecia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Psoriasis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Eczema", "reactionmeddraversionpt": "18.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "ARMUZZI A, GUIDI L, FERRARO PM, MARZO M, FELICE C, CELLENO L, ET AL. PARADOXICAL PSORIASIS IN A LARGE COHORT OF PATIENTS WITH INFLAMMATORY BOWEL DISEASE RECEIVING TREATMENT WITH ANTI-TNF ALPHA: 5-YEAR FOLLOW-UP STUDY. ALIMENTARY PHARMACOLOGY AND THERAPEUTICS 01-OCT-2015;42(7):880-888.", "literaturereference_normalized": "paradoxical psoriasis in a large cohort of patients with inflammatory bowel disease receiving treatment with anti tnf alpha 5 year follow up study", "qualification": "1", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20150924", "receivedate": "20150924", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11546126, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20151125" } ]
{ "abstract": "Multiple myeloma (MM) is characterized by the neoplastic proliferation of monoclonal plasma cells in the bone marrow and results in complications. In Taiwan, melphalan and several novel agents are used to treat myeloma patients who are not candidate for hematopoietic stem cell transplant (HSCT). This retrospective study aimed to evaluate the characteristics, treatment outcome, and prognostic factors of MM patients who were ineligible for HSCT at our institution from October 2000 until November 2012. A total of 101 MM patients were reviewed. The median age was 71.0 years, and median overall survival (OS) was 22.0 months. Most of patients were diagnosed as IgG-type myeloma (55.4 %). The initial presentations included anemia (89.1 %), skeletal events (49.5 %), severe renal insufficiency (30.7 %), and hypercalcemia (28.7 %). With regard to the frontline therapy, thalidomide/steroid was the most common. Infection was the leading cause of death and adverse effects. Treatment with bortezomib, almost in the second- or third-line setting, was associated with longer median OS (35.5 months) and the median time to progression (TTP) (6.0 months). Bortezomib treatment, chemotherapy, International Staging System (ISS) stage I, and better performance status significantly correlated with survival benefit. In the bortezomib-treated subgroup, better treatment response caused excellent median OS (67.7 months) and also significantly delayed TTP. Therefore, this current analysis concluded a median OS of 22 months in myeloma patients ineligible for HSCT at our institution during the past 10 years. The use of bortezomib with better treatment response also achieved significantly better median OS and TTP.", "affiliations": "Division of Hematology/Oncology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, No. 325, Cheng-Kung Road, Sec. 2, Neihu 114, Taipei, Taiwan.", "authors": "Huang\|Tzu-Chuan\|TC\|;Chen\|Jia-Hong\|JH\|;Wu\|Yi-Ying\|YY\|;Chang\|Ping-Ying\|PY\|;Dai\|Ming-Shen\|MS\|;Chao\|Tsu-Yi\|TY\|;Kao\|Woei-Yau\|WY\|;Chen\|Yeu-Chin\|YC\|;Ho\|Ching-Liang\|CL\|", "chemical_list": "D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib", "country": "Germany", "delete": false, "doi": "10.1007/s00277-014-2165-2", "fulltext": null, "fulltext_license": null, "issn_linking": "0939-5555", "issue": "94(1)", "journal": "Annals of hematology", "keywords": null, "medline_ta": "Ann Hematol", "mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D001897:Boronic Acids; D000069286:Bortezomib; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D011719:Pyrazines; D012189:Retrospective Studies; D013624:Taiwan; D016896:Treatment Outcome", "nlm_unique_id": "9107334", "other_id": null, "pages": "107-15", "pmc": null, "pmid": "25047657", "pubdate": "2015-01", "publication_types": "D016428:Journal Article", "references": null, "title": "The treatment outcome of multiple myeloma patients ineligible for hematopoietic transplantation--a single institutional experience in Taiwan.", "title_normalized": "the treatment outcome of multiple myeloma patients ineligible for hematopoietic transplantation a single institutional experience in taiwan" }	[ { "companynumb": "TW-CELGENEUS-153-20785-14080020", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DOXORUBICIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "THALIDOMIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "020785", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Capsules", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "THALIDOMIDE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BORTEZOMIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BORTEZOMIB" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LENALIDOMIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "021880", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Capsules", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "REVLIMID" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cytomegalovirus infection", "reactionmeddraversionpt": "17.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Sedation", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Somnolence", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urinary tract infection", "reactionmeddraversionpt": "17.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Osteonecrosis of jaw", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrointestinal disorder", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venous thrombosis", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pancytopenia", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Plasma cell myeloma", "reactionmeddraversionpt": "17.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Tuberculosis", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Renal failure acute", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumocystis jirovecii infection", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neuropathy peripheral", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bacteraemia", "reactionmeddraversionpt": "17.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Pneumonia bacterial", "reactionmeddraversionpt": "17.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Candida infection", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fatigue", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rash", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HO C,HUANG T,CHEN J,WU Y,CHANG P,DAI M. THE TREATMENT OUTCOME OF MULTIPLE MYELOMA PATIENTS INELIGIBLE FOR HEMATOPOIETIC TRANSPLANTATION-A SINGLE INSTITUTIONAL EXPERIENCE IN TAIWAN.. ANN HEMATOL 2014;.", "literaturereference_normalized": "the treatment outcome of multiple myeloma patients ineligible for hematopoietic transplantation a single institutional experience in taiwan", "qualification": "1", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20140813", "receivedate": "20140806", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10364681, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150326" } ]
{ "abstract": "Lung cancer is diagnosed at a late stage although we have novel diagnostic tools. The association of smoking and other environmental factors are well known. However; there are cases where a malignancy is associated with previous radiation treatment. There is an association between radiotherapy treatment and cancer incidence. We present a case where lung cancer and laryngeal cancer was induced 20 years after radiation therapy of a hogkin lymphoma.", "affiliations": "3rd Department of Surgery, \"AHEPA\" University Hospital, Aristotle University of Thessaloniki, Medical School, Thessaloniki, Greece.;3rd Department of Surgery, \"AHEPA\" University Hospital, Aristotle University of Thessaloniki, Medical School, Thessaloniki, Greece.;Anesthesiology Department, \"AHEPA\" University General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.;3rd Department of Surgery, \"AHEPA\" University Hospital, Aristotle University of Thessaloniki, Medical School, Thessaloniki, Greece.;3rd Department of Surgery, \"AHEPA\" University Hospital, Aristotle University of Thessaloniki, Medical School, Thessaloniki, Greece.;3rd Department of Surgery, \"AHEPA\" University Hospital, Aristotle University of Thessaloniki, Medical School, Thessaloniki, Greece.;Ear, Nose and Throat Department, \"Saint Luke\" Private Hospital, Thessaloniki, Panorama, Greece.;Ear, Nose and Throat Department, \"Saint Luke\" Private Hospital, Thessaloniki, Panorama, Greece.;Radiotherapy Department-Oncology Unit, \"Theageneio\" Cancer Hospital, Thessaloniki, Greece.;Pulmonary Department-Oncology Unit, \"Theageneio\" Cancer Hospital, Thessaloniki, Greece.;Thoracic Surgery Department, University General Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece.;Surgery Department (NHS), University General Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece.;Surgery Department (NHS), University General Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece.;Department of Pharmacology & Clinical Pharmacology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece.;Thoracic Surgery Department (NHS), \"Theageneio\" Cancer Hospital, Thessaloniki, Greece.;Thoracic Surgery Department (NHS), \"Theageneio\" Cancer Hospital, Thessaloniki, Greece.;Hellenic Open University, Cyprus.;Pulmonary Department-Oncology Unit, \"Theageneio\" Cancer Hospital, Thessaloniki, Greece.;3rd Department of Surgery, \"AHEPA\" University Hospital, Aristotle University of Thessaloniki, Medical School, Thessaloniki, Greece.", "authors": "Sapalidis\|Konstantinos\|K\|;Laskou\|Stella\|S\|;Amaniti\|Aikaterini\|A\|;Mantalovas\|Stylianos\|S\|;Giannakidis\|Dimitris\|D\|;Koulouris\|Charilaos\|C\|;Karapantzos\|Ilias\|I\|;Karapantzou\|Chrysa\|C\|;Mponiou\|Konstantina\|K\|;Tsiouda\|Theodora\|T\|;Konstantinou\|Fotis\|F\|;Kougioumtzi\|Ioanna\|I\|;Katsikogiannis\|Nikos\|N\|;Sardeli\|Chrysa\|C\|;Gogakos\|Apostolos\|A\|;Schizas\|Nikos\|N\|;Domeyer\|Philip\|P\|;Zarogoulidis\|Paul\|P\|;Kesisoglou\|Isaak\|I\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1016/j.rmcr.2018.03.013", "fulltext": "\n==== Front\nRespir Med Case RepRespir Med Case RepRespiratory Medicine Case Reports2213-0071Elsevier S2213-0071(18)30073-X10.1016/j.rmcr.2018.03.013Case ReportLung cancer induced from chemotherapy a 20 years old case Sapalidis Konstantinos aLaskou Stella aAmaniti Aikaterini bMantalovas Stylianos aGiannakidis Dimitris aKoulouris Charilaos aKarapantzos Ilias cKarapantzou Chrysa cMponiou Konstantina dTsiouda Theodora eKonstantinou Fotis fKougioumtzi Ioanna gKatsikogiannis Nikos gSardeli Chrysa hGogakos Apostolos iSchizas Nikos iDomeyer Philip jZarogoulidis Paul [email protected]∗Kesisoglou Isaak aa 3rd Department of Surgery, “AHEPA” University Hospital, Aristotle University of Thessaloniki, Medical School, Thessaloniki, Greeceb Anesthesiology Department, “AHEPA” University General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greecec Ear, Nose and Throat Department, “Saint Luke” Private Hospital, Thessaloniki, Panorama, Greeced Radiotherapy Department-Oncology Unit, “Theageneio” Cancer Hospital, Thessaloniki, Greecee Pulmonary Department-Oncology Unit, “Theageneio” Cancer Hospital, Thessaloniki, Greecef Thoracic Surgery Department, University General Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greeceg Surgery Department (NHS), University General Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greeceh Department of Pharmacology & Clinical Pharmacology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greecei Thoracic Surgery Department (NHS), “Theageneio” Cancer Hospital, Thessaloniki, Greecej Hellenic Open University, Cyprus∗ Corresponding author. [email protected] 3 2018 2018 27 3 2018 24 32 34 19 3 2018 21 3 2018 25 3 2018 © 2018 The Authors2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Lung cancer is diagnosed at a late stage although we have novel diagnostic tools. The association of smoking and other environmental factors are well known. However; there are cases where a malignancy is associated with previous radiation treatment. There is an association between radiotherapy treatment and cancer incidence. We present a case where lung cancer and laryngeal cancer was induced 20 years after radiation therapy of a hogkin lymphoma.\n\nKeywords\nHodgkin lymphomaLaryngeal cancerLung cancerRadiationEBUS\n==== Body\n1 Introduction\nWe have recent advances in the diagnosis and treatment of lung cancer with novel instruments and therapies. The convex-probe endobronchial ultrasound and the radial endobronchial ultrasound (EBUS) brought a revolution to the diagnosis of lung cancer, however; they are not tools that can be used in every pulmonary department [[1], [2], [3]]. On the other hand we have novel therapies for non-small cell lung cancer (NSCLC) such as; immunotherapy (nivolumab and pembrolizumab) and targeted therapies with tyrosine kinase inhibitors (TKIs) for epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), murine sarcoma viral oncogene homolog B (BRAF) and proto-oncogene tyrosine-protein kinase (ROS-1) [4]. Radiotherapy can be used either as a primary therapy for NSCLC or palliative care [5]. In any case the medical history of the patient might reveal co-occurrence of multiple primary cancers. There is also the case where radiotherapy or chemotherapy pretreatment induced another type of cancer [6]. In the current case we will present a patient diagnosed with Hodgkin lymphoma in 1997 and presented in situ laryngeal cancer after 15 years and lung cancer after 20 years. Occurrence of a cancer after radiotherapy treatment has been previously reported and the association of radiotherapy treatment and cancer has been established [7].\n\n2 Case presentation\nA 57 year old patient (age today) was diagnosed with Hodgkin lymphoma in 1997 from a tracheal lymph-node. Smoking history when diagnosed with Hodgkin lymphoma with 15 p/y. He received in total 3000 rad of radiotherapy as primary therapy. The disease was stable until 2010 were the patient presented in the outpatient cabinet with enlarged lymph-nodes in the whole body. Again a biopsy from a tracheal lymph node revealed Hodgkin disease relapse. He received 6 cycles of Andriamycin 45mg Bleomycin 670mg Viblastine 10mg Detisene 680mg for 6 months. A positron emission tomography 3 months after the last chemotherapy was negative for active disease. The patient remained under observation as an outpatient for 4 years without disease relapse. However; early in 2016 he presented in the outpatient cabinet with hemoptysis and a in situ laryngeal cancer was diagnosed (Fig. 1). He received 6000 rad as radiotherapy treatment and platinum analog for six cycles carboplatin AUC 600mg. The patient remained under observation. In 2017 a CT thorax revealed a mass in the right lower lobe and enlarged mesothorax lymph-nodes positive with PET-CT (Fig. 2). Biopsy of the lymph-nodes with a convex probe endobronchial ultrasound revealed adenocarcinoma with EGFR and ALK negative expression(Fig. 3). He received 6 cycles of carboplatin AUC 600 and pemetrexed 1000mg. He was disease free for 4 months until a new staging with PET-CT revealed disease relapse and 4 cycles of carboplatin AUC 600 and taxane 370 derivative was administered. A further investigation in the first biopsy for BRAF, ROS-1 and PD-L1 expression revealed negative expression.Fig. 1 Figure from microlaryngoscopy.\n\nFig. 1Fig. 2 CT of the thorax.\n\nFig. 2Fig. 3 Endoscopy with convex probe endobronchial ultrasound (EBUS) blue arrow indicating the block of lymph-nodes.\n\nFig. 3\n\n3 Discussion\nIt is known from the epidemiological study of survivors of atomic bomb irradiation [8,9] and it has been suggested and observed in clinical practice that irradiation of surrounding tissues can cause second cancers [10,11]. The benefits of radiotherapy outweigh the risks of developing subsequent cancers, therefore methods of minimizing the radiation dose delivered to surrounding tissues or the volume should be further investigated. However; there also other factors contributing to carcinogenesis like; environmental exposure to carcinogens, genetic predisposition, misdiagnosis of metastases as primary cancers, reproductive factors. Therefore increased medical surveillance should follow the first cancer for treatment-related effects. It has been observed that genetic and environmental predisposition may increase the incidence of a second cancer, while treatment related tumors are expected to develop some time after an iatrogenic effect. Previous clinical observations indicate that second cancers after an exposure to radiation would develop within a time window of 5 years for leukemia and 10 years for solid tumors [[12], [13], [14], [15], [16], [17]]. Previously it has been suggested that a certain latency period passes before a new tumor appears. There is a clear association between latency time and cancer type. Moreover; chemotherapy can induce second cancer development [18]. An excess incidence of acute myeloid leukemia and myelodysplastic syndrome has been associated with therapy in those patients who received doxorubicin when compared with those who received doxorubicin combined with cyclophosphamide therapy [16]. The incidence was higher in those patients that received intensified cyclophosphamide doses (requiring granulocyte colony-stimulating factor support). An excess incidence of lung cancer has been observed at 10 years or more after radiotherapy, in several studies [17,19]. In our case we have an association of radiotherapy, chemotherapy and secondary factors which we believe were smoking history and genetic predisposition. The patient is under close follow-up to date.\n\nDisclosure\nThe authors declare no conflict of interest.\n==== Refs\nReferences\n1 Zarogoulidis P. Huang H. Bai C. Kosmidis C. Trakada G. Veletza L. Tsiouda T. Barbetakis N. Paliouras D. Athanasiou E. Hatzibougias D. Kallianos A. Panagiotopoulos N. Papaemmanouil L. Hohenforst-Schmidt W. Endobronchial ultrasound convex probe for lymphoma, sarcoidosis, lung cancer and other thoracic entities. A case series Res. Med. Case Rep. 22 2017 187 196 \n2 Haidong H. Yunye N. Wei Z. Zarogoulidis P. Hohenforst-Schmidt W. Man Y.G. Yuguang Y. Yuchao D. Chong B. Multiple guided technologies based on radial probe endobronchial ultrasound for the diagnosis of solitary peripheral pulmonary lesions: a single-center study J. Cancer 8 17 2017 3514 3521 29151936 \n3 Hohenforst-Schmidt W. Zarogoulidis P. Pitsiou G. Linsmeier B. Tsavlis D. Kioumis I. Papadaki E. Freitag L. Tsiouda T. Turner J.F. Browning R. Simoff M. Sachpekidis N. Tsakiridis K. Zaric B. Yarmus L. Baka S. Stratakos G. Rittger H. Drug eluting stents for malignant airway obstruction: a critical review of the literature J. Cancer 7 4 2016 377 390 26918052 \n4 Moya-Horno I. Viteri S. Karachaliou N. Rosell R. 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Res. 160 6 2003 707 717 14640793 \n9 Preston D.L. Shimizu Y. Pierce D.A. Suyama A. Mabuchi K. Studies of mortality of atomic bomb survivors Report 13: Solid cancer and noncancer disease mortality: 1950-1997 Radiat. Res. 160 4 2003 381 407 12968934 \n10 Neugut A.I. Weinberg M.D. Ahsan H. Rescigno J. Carcinogenic effects of radiotherapy for breast cancer Oncology 13 9 1999 1245 1256 discussion 1257, 1261-5 10509322 \n11 Harvey E.B. Brinton L.A. Second cancer following cancer of the breast in Connecticut, 1935-82 Natl. Canc. Inst. Monogr. 68 1985 99 112 \n12 Boice J.D. Jr. Day N.E. Andersen A. Brinton L.A. Brown R. Choi N.W. Clarke E.A. Coleman M.P. Curtis R.E. Flannery J.T. Second cancers following radiation treatment for cervical cancer. An international collaboration among cancer registries J Nat. Cancer Ins. 74 5 1985 955 975 \n13 Land C.E. Boice J.D. Jr. Shore R.E. Norman J.E. Tokunaga M. Breast cancer risk from low-dose exposures to ionizing radiation: results of parallel analysis of three exposed populations of women J Nat. Cancer Ins. 65 2 1980 353 376 \n14 Neugut A.I. Robinson E. Lee W.C. Murray T. Karwoski K. Kutcher G.J. Lung cancer after radiation therapy for breast cancer Cancer 71 10 1993 3054 3057 8490833 \n15 Rubino C. de Vathaire F. Shamsaldin A. Labbe M. Le M.G. Radiation dose, chemotherapy, hormonal treatment and risk of second cancer after breast cancer treatment Br. J. Cancer 89 5 2003 840 846 12942115 \n16 Smith R.E. Bryant J. DeCillis A. Anderson S. National Surgical Adjuvant B. Bowel Project E. Acute myeloid leukemia and myelodysplastic syndrome after doxorubicin-cyclophosphamide adjuvant therapy for operable breast cancer: the National Surgical Adjuvant Breast and Bowel Project Experience J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 21 7 2003 1195 1204 \n17 Zablotska L.B. Neugut A.I. 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"actiondrug": "5", "activesubstance": { "activesubstancename": "DACARBAZINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HODGKIN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "680", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DETICENE" } ], "patientagegroup": null, "patientonsetage": "6", "patientonsetageunit": "800", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lung adenocarcinoma", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Laryngeal cancer", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2016" } }, "primarysource": { "literaturereference": "SAPALIDIS K, LASKOU S, AMANITI A, MANTALOVAS S, GIANNAKIDIS D, KOULOURIS C, ET AL. LUNG CANCER INDUCED FROM CHEMOTHERAPY A 20 YEARS OLD CASE. 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"drugauthorizationnumb": "076517", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "4 CYCLES OF CARBOPLATIN AUC 600 (UNIT NOT STATED)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VINBLASTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, 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"DOXORUBICIN HCL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076517", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6 CYCLES OF CARBOPLATIN AUC 600 (UNIT NOT STATED)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "BLEOMYCIN SULFATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "670 MG, 6 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "HODGKIN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "670", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BLEOMYCIN" } ], "patientagegroup": null, "patientonsetage": "57", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Second primary malignancy", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lung adenocarcinoma", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2017" } }, "primarysource": { "literaturereference": "SAPALIDIS, K.. LUNG CANCER INDUCED FROM CHEMOTHERAPY A 20 YEARS OLD CASE. RESPIRATORY MEDICINE CASE REPORTS. 2018?24:32?34", "literaturereference_normalized": "lung cancer induced from chemotherapy a 20 years old case", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20180706", "receivedate": "20180606", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14979521, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" }, { "companynumb": "GR-MYLANLABS-2018M1027806", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VINBLASTINE" }, "drugadditional": null, "drugadministrationroute": "065", 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"patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Laryngeal cancer", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lung adenocarcinoma", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2016" } }, "primarysource": { "literaturereference": "SAPALIDIS K, LASKOU S, AMANITI A, MANTALOVAS S, GIANNAKIDIS D, KOULOURIS C, ET AL. LUNG CANCER INDUCED FROM CHEMOTHERAPY A 20 YEARS OLD CASE. RESPIRAT-MED-CASE-REPORT 2018?24:32-34.", "literaturereference_normalized": "lung cancer induced from chemotherapy a 20 years old case", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20180503", "receivedate": "20180503", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14843371, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180711" } ]
{ "abstract": "Malignant hyperthermia (MH), an inherited myopathia varying in severity and course, is induced by halogenated anesthetic agents and depolarizing muscle relaxants. First recognized as a distinct disease entity in 1960, MH is defined as an anesthesia-related disease due to the agents by which it is triggered. Given the wide use of these preparations in prehospital emergency medicine and intensive care treatment, physicians in other disciplines may also encounter MH.", "affiliations": "Klinik für Anästhesie, operative Intensivmedizin und Schmerztherapie, Helios St. Johannes Klinik Duisburg, An der Abtei 7-11, 47166, Duisburg, Deutschland.", "authors": "Wendlandt\|B\|B\|;Turinsky\|S\|S\|;Schmitz\|M\|M\|", "chemical_list": "D007530:Isoflurane", "country": "Germany", "delete": false, "doi": "10.1007/s00063-014-0450-4", "fulltext": null, "fulltext_license": null, "issn_linking": "2193-6218", "issue": "110(2)", "journal": "Medizinische Klinik, Intensivmedizin und Notfallmedizin", "keywords": null, "medline_ta": "Med Klin Intensivmed Notfmed", "mesh_terms": "D000280:Administration, Inhalation; D016887:Cardiopulmonary Resuscitation; D003131:Combined Modality Therapy; D016292:Conscious Sedation; D004554:Electric Countershock; D006336:Heart Massage; D006801:Humans; D007036:Hypothermia, Induced; D007362:Intensive Care Units; D007530:Isoflurane; D008297:Male; D008305:Malignant Hyperthermia; D008875:Middle Aged; D009203:Myocardial Infarction; D015912:Thrombolytic Therapy", "nlm_unique_id": "101575086", "other_id": null, "pages": "155-8", "pmc": null, "pmid": "25585653", "pubdate": "2015-04", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "1536407;20081135;20837722;8383206", "title": "Isoflurane-induced malignant hyperthermia during intensive-care treatment.", "title_normalized": "isoflurane induced malignant hyperthermia during intensive care treatment" }	[ { "companynumb": "DE-BAXTER-2019BAX005433", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "MIDAZOLAM HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, 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"drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SEDATIVE THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ISOFLURAN BAXTER" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ETOMIDATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INTUBATION ON SITE TOOK PLACE", "drugenddate": null, "drugenddateformat": null, "drugindication": "GENERAL ANAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOMIDATE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "EPINEPHRINE" }, "drugadditional": null, "drugadministrationroute": "041", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HAEMODYNAMIC INSTABILITY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ISOFLURAN BAXTER" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SUFENTANIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANALGESIC THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SUFENTANIL" } ], "patientagegroup": null, "patientonsetage": "53", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hyperthermia malignant", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "WENDLANDT B, TURINSKY S, SCHMITZ M. ISOFLURANE-INDUCED MALIGNANT HYPERTHERMIA DURING INTENSIVE-CARE TREATMENT. MEDIZINISCHE KLINIK - INTENSIVMEDIZIN UND NOTFALLMEDIZIN. 2015 APR?110(2):155-158.", "literaturereference_normalized": "isoflurane induced malignant hyperthermia during intensive care treatment", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20190322", "receivedate": "20190322", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16108308, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190418" } ]
{ "abstract": "The possible onset of cardiotoxic manifestations during chemotherapy with 5-fluorouracil (5-FU) was evaluated in 1083 patients treated with the drug for various kinds of neoplasm. We recognized 17 cases of 5-FU cardiopathy (usually anginous crises but also myocardial infarction). The comprehensive incidence was 1.6%, with a significantly greater risk (4.5% vs 1.1%) for patients with a positive anamnesis of previous cardiopathy. On the contrary, age and combination with other antiblastic drugs had no affect on the appearance of cardiopathy. We conclude that 5-FU cardiopathy, although rare, has to be taken into account in oncologic practice, chiefly in those patients already affected with cardiac diseases.", "affiliations": null, "authors": "Labianca\|R\|R\|;Beretta\|G\|G\|;Clerici\|M\|M\|;Fraschini\|P\|P\|;Luporini\|G\|G\|", "chemical_list": "D005472:Fluorouracil", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0300-8916", "issue": "68(6)", "journal": "Tumori", "keywords": null, "medline_ta": "Tumori", "mesh_terms": "D000368:Aged; D000787:Angina Pectoris; D004359:Drug Therapy, Combination; D005260:Female; D005472:Fluorouracil; D006321:Heart; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction; D009369:Neoplasms; D012306:Risk", "nlm_unique_id": "0111356", "other_id": null, "pages": "505-10", "pmc": null, "pmid": "7168016", "pubdate": "1982-12-31", "publication_types": "D016428:Journal Article", "references": null, "title": "Cardiac toxicity of 5-fluorouracil: a study on 1083 patients.", "title_normalized": "cardiac toxicity of 5 fluorouracil a study on 1083 patients" }	[ { "companynumb": "IT-PFIZER INC-2013297329", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "202668", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK (7 DAYS AFTER THE 3RD DOSE OF 5?FU IN THE 3RD CYCLE PREVIOUSLY: REPEATED ANGINOUS CRISES IN CONC", "drugenddate": null, "drugenddateformat": null, "drugindication": "NEOPLASM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUOROURACIL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK UNK, CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "NEOPLASM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "202668", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUOROURACIL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTOXAN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK UNK, CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "NEOPLASM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTOXAN" } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Angina pectoris", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Myocardial infarction", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LABIANCA, R.. CARDIAC TOXICITY OF 5?FLUOROURACIL: A STUDY ON 1083 PATIENTS. TUMORI. 1982?68 (6):505?510", "literaturereference_normalized": "cardiac toxicity of 5 fluorouracil a study on 1083 patients", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20210125", "receivedate": "20131018", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 9632122, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210420" } ]
{ "abstract": "Gene transfer targeting hematopoietic stem cells (HSC) in children has shown sustained therapeutic benefit in the treatment of genetic diseases affecting the immune system, most notably in severe combined immunodeficiencies affecting T-cell function. The HSC compartment has also been successfully targeted using gene transfer in children with genetic diseases affecting the central nervous system, such as metachromatic leukodystrophy and adrenoleukodystrophy. HSCs are also a target for genetic modification in strategies aiming to confer drug resistance to chemotherapy agents so as to reduce off-target toxicity, and to allow for chemotherapy dose escalation with the possibility of enhanced therapeutic benefit. In a trial of this strategy in adult glioma patients, significant engraftment of gene-modified HSCs expressing a mutant of the DNA repair protein O6-methyl-guanine-methyl-transferase (MGMT(P140K)) showed potential in conferring drug resistance against the combined effect of O6-benzylguanine (O6BG)/temozolomide (TMZ) chemotherapy. The aim was to test the safety and feasibility of this approach in children with poor prognosis brain tumors. In this Phase I trial, seven patients received gene-modified HSC following myelo-suppressive conditioning, but with only transient low-level engraftment of MGMT(P140K) gene-modified cells detectable in four patients. All patients received O6BG/TMZ chemotherapy following infusion of gene-modified cells, with five patients eligible for chemotherapy dose escalation, though in the absence of demonstrable transgene-mediated chemoprotection. Since all gene-modified cell products met the criteria for release and assays for engraftment potential met expected outcome measures, inadequate cell dose, conditioning chemotherapy, and/or underlying bone-marrow function may have contributed to the lack of sustained engraftment of gene-modified cells. We were able to demonstrate safe conduct of a technically complex Phase I study encompassing manufacture of the gene therapy vector, genetically modified cells, and a drug product specifically for the trial in compliance with both local and national regulatory requirements.", "affiliations": "1 Children's Cancer Research Unit, The Children's Hospital at Westmead, Westmead, Australia.;1 Children's Cancer Research Unit, The Children's Hospital at Westmead, Westmead, Australia.;1 Children's Cancer Research Unit, The Children's Hospital at Westmead, Westmead, Australia.;1 Children's Cancer Research Unit, The Children's Hospital at Westmead, Westmead, Australia.;1 Children's Cancer Research Unit, The Children's Hospital at Westmead, Westmead, Australia.;1 Children's Cancer Research Unit, The Children's Hospital at Westmead, Westmead, Australia.;1 Children's Cancer Research Unit, The Children's Hospital at Westmead, Westmead, Australia.;2 Gene Therapy Research Unit, Children's Medical Research Institute, Westmead, Australia and the Children's Hospital at Westmead, Westmead, Australia.;4 Children's Cancer Centre, The Children's Hospital at Westmead, Westmead, Australia.", "authors": "Kramer\|Belinda\|B\|;Singh\|Radhika\|R\|;Wischusen\|Jessica\|J\|;Dent\|Rebecca\|R\|;Rush\|Amanda\|A\|;Middlemiss\|Shiloh\|S\|;Ching\|Yu Wooi\|YW\|;Alexander\|Ian E\|IE\|;McCowage\|Geoffrey\|G\|", "chemical_list": "D025521:Tumor Suppressor Proteins; C064976:O(6)-benzylguanine; D006147:Guanine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide", "country": "United States", "delete": false, "doi": "10.1089/hum.2017.235", "fulltext": null, "fulltext_license": null, "issn_linking": "1043-0342", "issue": "29(8)", "journal": "Human gene therapy", "keywords": "cancer; clinical trial; gene therapy; pediatric brain tumors", "medline_ta": "Hum Gene Ther", "mesh_terms": "D001932:Brain Neoplasms; D002648:Child; D015254:DNA Modification Methylases; D045643:DNA Repair Enzymes; D019008:Drug Resistance, Neoplasm; D005260:Female; D015316:Genetic Therapy; D006147:Guanine; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells; D006801:Humans; D008297:Male; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins", "nlm_unique_id": "9008950", "other_id": null, "pages": "874-885", "pmc": null, "pmid": "29385852", "pubdate": "2018-08", "publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Clinical Trial of MGMT(P140K) Gene Therapy in the Treatment of Pediatric Patients with Brain Tumors.", "title_normalized": "clinical trial of mgmt p140k gene therapy in the treatment of pediatric patients with brain tumors" }	[ { "companynumb": "AU-MYLANLABS-2018M1067961", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TEMOZOLOMIDE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "205227", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "LEVEL 1 (CYCLE 3 AND 4)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TEMOZOLOMIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "6-O-BENZYLGUANINE" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MG/M2/HOUR INFUSION FOR 48 HRS", "drugenddate": null, "drugenddateformat": null, "drugindication": "BRAIN STEM GLIOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "O6?BENZYLGUANINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TEMOZOLOMIDE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "205227", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "LEVEL 2; 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CLINICAL TRIAL OF MGMT(P140K) GENE THERAPY IN THE TREATMENT OF PEDIATRIC PATIENTS WITH BRAIN TUMORS. 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CLINICAL TRIAL OF MGMT(P140K) GENE THERAPY IN THE TREATMENT OF PEDIATRIC PATIENTS WITH BRAIN TUMORS. HUM?GENE?THER 2018?29(8):874?885.", "literaturereference_normalized": "clinical trial of mgmt p140k gene therapy in the treatment of pediatric patients with brain tumors", "qualification": "1", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20180919", "receivedate": "20180919", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15403823, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" } ]
{ "abstract": "Objective To illustrate an unusual case of Listeria cerebral abscess. Material and methods A 32-year-old pregnant woman with thrombotic antiphospholipid syndrome (APS) received corticotherapy for two weeks due to hemolysis, elevated liver enzymes, low platelet (HELLP) syndrome. After delivery she presented with neurological symptoms and fever. Results The MRI scan confirmed the presence of a brain abscess, and Listeria monocytogenes was isolated in blood cultures. After eight weeks of antibiotic treatment, the patient presented no sequelae. Conclusion L. monocytogenes should be included in the differential diagnosis of patients with fever and neurological dysfunction, especially in those with a recent history of corticotherapy.", "affiliations": "1 Maternal Fetal Medicine Department, Hospital Clinic, Barcelona, Catalonia, Spain.;2 Infectious Diseases Department, Hospital Clinic, Barcelona, Catalonia, Spain.;3 Medical Intensive Care Unit, Hospital Clinic, Barcelona, Catalonia, Spain.;1 Maternal Fetal Medicine Department, Hospital Clinic, Barcelona, Catalonia, Spain.;1 Maternal Fetal Medicine Department, Hospital Clinic, Barcelona, Catalonia, Spain.;4 Autoimmune Diseases Department, Hospital Clinic, Barcelona, Catalonia, Spain.;4 Autoimmune Diseases Department, Hospital Clinic, Barcelona, Catalonia, Spain.", "authors": "Fervienza\|A\|A\|;Bodro\|M\|M\|;Castro\|P\|P\|;Hernández\|S\|S\|;Teixidó\|I\|I\|;Espinosa\|G\|G\|;Cervera\|R\|R\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1177/0961203316682856", "fulltext": null, "fulltext_license": null, "issn_linking": "0961-2033", "issue": "26(9)", "journal": "Lupus", "keywords": "Antiphospholipid syndrome; Listeria monocytogenes; pregnancy", "medline_ta": "Lupus", "mesh_terms": "D000328:Adult; D016736:Antiphospholipid Syndrome; D001922:Brain Abscess; D003937:Diagnosis, Differential; D005260:Female; D005334:Fever; D017359:HELLP Syndrome; D006801:Humans; D008089:Listeria monocytogenes; D008088:Listeriosis; D008279:Magnetic Resonance Imaging; D009422:Nervous System Diseases; D011247:Pregnancy; D011248:Pregnancy Complications; D016896:Treatment Outcome", "nlm_unique_id": "9204265", "other_id": null, "pages": "1002-1004", "pmc": null, "pmid": "27927881", "pubdate": "2017-08", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Brain abscess due to Listeria monocytogenes after HELLP syndrome in a patient with antiphospholipid syndrome.", "title_normalized": "brain abscess due to listeria monocytogenes after hellp syndrome in a patient with antiphospholipid syndrome" }	[ { "companynumb": "ES-FRESENIUS KABI-FK201707749", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HELLP SYNDROME", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "12", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, 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BRAIN ABSCESS DUE TO LISTERIA MONOCYTOGENES AFTER HELLP SYNDROME IN A PATIENT WITH ANTIPHOSPHOLIPID SYNDROME. 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BRAIN ABSCESS DUE TO LISTERIA MONOCYTOGENES AFTER HELLP SYNDROME IN A PATIENT WITH ANTIPHOSPHOLIPID SYNDROME. 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"drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "LISTERIOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LINEZOLID." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HEPARIN SODIUM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "ANTICOAGULATION DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HEPARIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG/24HR ((10MG/12HR)), UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HELLP SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": "5", "patientonsetage": "32", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug administration error", "reactionmeddraversionpt": "20.1", "reactionoutcome": null }, { "reactionmeddrapt": "Cerebral haemorrhage", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "HELLP syndrome", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Premature delivery", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Listeriosis", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "20.1", "reactionoutcome": null }, { "reactionmeddrapt": "Brain abscess", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Maternal exposure during pregnancy", "reactionmeddraversionpt": "20.1", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "FERVIENZA A; BODRO M; CASTRO P; HERNANDEZ S; TEIXIDO I; ESPINOSA G; CERVERA R. BRAIN ABSCESS DUE TO LISTERIA MONOCYTOGENES AFTER HELLP SYNDROME IN A PATIENT WITH ANTIPHOSPHOLIPID SYNDROME. LUPUS. 2017;26:9:1002-1004", "literaturereference_normalized": "brain abscess due to listeria monocytogenes after hellp syndrome in a patient with antiphospholipid syndrome", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20170807", "receivedate": "20170807", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13841316, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" }, { "companynumb": "PHHY2017ES131434", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "FOETAL EXPOSURE DURING PREGNANCY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "HEPARIN SODIUM" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "FOETAL EXPOSURE DURING PREGNANCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HEPARIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "FOETAL EXPOSURE DURING PREGNANCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MAGNESIUM SULFATE" }, "drugadditional": "3", "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "FOETAL EXPOSURE DURING PREGNANCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MAGNESIUM SULPHATE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Premature baby", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary haemorrhage", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "FERVIENZA A, BODRO M, CASTRO P, HERNANDEZ S, TEIXIDO I, ESPINOSA G, ET AL.. BRAIN ABSCESS DUE TO LISTERIA MONOCYTOGENES AFTER HELLP SYNDROME IN A PATIENT WITH ANTIPHOSPHOLIPID SYNDROME. LUPUS. 2017;26(9):1002-4", "literaturereference_normalized": "brain abscess due to listeria monocytogenes after hellp syndrome in a patient with antiphospholipid syndrome", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20170908", "receivedate": "20170908", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13948956, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171128" }, { "companynumb": "ES-SUN PHARMACEUTICAL INDUSTRIES LTD-2017R1-154990", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "UNSPECIFIED INGREDIENT" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOW MOLECULAR WEIGHT HEPARIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "084764", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "4 MG, TID", "drugenddate": null, "drugenddateformat": null, "drugindication": "HELLP SYNDROME", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "8", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MAGNESIUM SULFATE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HELLP SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MAGNESIUM SULPHATE" } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pulmonary haemorrhage", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Premature baby", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "FERVIENZA A, BODRO M, CASTRO P, HERNANDEZ S, TEIXIDO I, ESPINOSA G ET AL. BRAIN ABSCESS DUE TO LISTERIA MONOCYTOGENES AFTER HELLP SYNDROME IN A PATIENT WITH ANTIPHOSPHOLIPID SYNDROME. LUPUS. 2017;26(9):1002-4", "literaturereference_normalized": "brain abscess due to listeria monocytogenes after hellp syndrome in a patient with antiphospholipid syndrome", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20171124", "receivedate": "20171124", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14222019, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180321" }, { "companynumb": "ES-SUN PHARMACEUTICAL INDUSTRIES LTD-2017R1-149987", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MAGNESIUM SULFATE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HELLP SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MAGNESIUM SULPHATE" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "UNSPECIFIED INGREDIENT" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOW MOLECULAR WEIGHT HEPARIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "084764", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "4 MG, TID", "drugenddate": null, "drugenddateformat": null, "drugindication": "HELLP SYNDROME", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "8", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": null, "patientonsetage": "32", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Brain abscess", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Premature delivery", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Listeriosis", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Nervous system disorder", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Foetal growth restriction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Infarction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Platelet count decreased", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "FERVIENZA A, BODRO M, CASTRO P, HERNANDEZ S, TEIXIDO I, ESPINOSA G ET AL. BRAIN ABSCESS DUE TO LISTERIA MONOCYTOGENES AFTER HELLP SYNDROME IN A PATIENT WITH ANTIPHOSPHOLIPID SYNDROME. LUPUS. 2017;26(9):1002-4", "literaturereference_normalized": "brain abscess due to listeria monocytogenes after hellp syndrome in a patient with antiphospholipid syndrome", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20171124", "receivedate": "20170918", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13981210, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180321" }, { "companynumb": "PHHY2017ES132029", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MAGNESIUM SULFATE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HELLP SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MAGNESIUM SULFATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPHOSPHOLIPID SYNDROME", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETYLSALICYLIC ACID" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "HEPARIN SODIUM" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "91659", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPHOSPHOLIPID SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HEPARIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "4 MG, Q8H", "drugenddate": null, "drugenddateformat": null, "drugindication": "HELLP SYNDROME", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "8", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, Q12H", "drugenddate": null, "drugenddateformat": null, "drugindication": "PLATELET COUNT DECREASED", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "12", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "32", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Abdominal pain upper", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "HELLP syndrome", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Premature delivery", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Maternal exposure during pregnancy", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "FERVIENZA A, BODRO M, CASTRO P, HERNANDEZ S, TEIXIDO I, ESPINOSA G, ET AL.. BRAIN ABSCESS DUE TO LISTERIA MONOCYTOGENES AFTER HELLP SYNDROME IN A PATIENT WITH ANTIPHOSPHOLIPID SYNDROME. LUPUS. 2017;26(9):1002-4", "literaturereference_normalized": "brain abscess due to listeria monocytogenes after hellp syndrome in a patient with antiphospholipid syndrome", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20170927", "receivedate": "20170913", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13966135, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171128" }, { "companynumb": "ES-BAYER-2017-146351", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "021317", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETYLSALICYLIC ACID({=100 MG)" } ], "patientagegroup": "1", "patientonsetage": "3", "patientonsetageunit": "804", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "20.1", "reactionoutcome": null }, { "reactionmeddrapt": "Premature baby", "reactionmeddraversionpt": "20.1", "reactionoutcome": null }, { "reactionmeddrapt": "Pulmonary haemorrhage", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Foetal growth restriction", "reactionmeddraversionpt": "20.1", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "FERVIENZA A; BODRO M; CASTRO P; HERNANDEZ S; TEIXIDO I; ESPINOSA G; CERVERA R. BRAIN ABSCESS DUE TO LISTERIA MONOCYTOGENES AFTER HELLP SYNDROME IN A PATIENT WITH ANTIPHOSPHOLIPID SYNDROME. LUPUS. 2017;26:9:1002-1004", "literaturereference_normalized": "brain abscess due to listeria monocytogenes after hellp syndrome in a patient with antiphospholipid syndrome", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20170807", "receivedate": "20170807", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13840325, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" }, { "companynumb": "ES-MYLANLABS-2017M1057440", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "MAGNESIUM SULFATE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HELLP SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MAGNESIUM SULFATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "080292", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HELLP SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN /00002701/" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "LATER DOSE WAS REDUCED TO 2 MG/12 HOURS", "drugenddate": null, "drugenddateformat": null, "drugindication": "HELLP SYNDROME", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "8", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." } ], "patientagegroup": null, "patientonsetage": "32", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Brain abscess", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cerebral haemorrhage", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cerebral infarction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Maternal exposure during pregnancy", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Listeriosis", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "FERVIENZA A, BODRO M, CASTRO P, HERNANDEZ S, TEIXIDO I, ESPINOSA G, ET AL. BRAIN ABSCESS DUE TO LISTERIA MONOCYTOGENES AFTER HELLP SYNDROME IN A PATIENT WITH ANTIPHOSPHOLIPID SYNDROME. LUPUS 2017;26(9):1002-1004.", "literaturereference_normalized": "brain abscess due to listeria monocytogenes after hellp syndrome in a patient with antiphospholipid syndrome", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20170918", "receivedate": "20170918", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13984213, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20171128" } ]
{ "abstract": "This study assessed trends in transesophageal echocardiography (TEE) use, rate of left atrial appendage (LAA) thrombus detection, and incidence of periprocedural cerebrovascular accident (CVA) since transitioning to a strategy of uninterrupted warfarin or briefly interrupted novel oral anticoagulant therapy in 2010.\n\n\n\nTEE is routinely performed before ablation for atrial fibrillation (AF) to ensure absence of LAA thrombus.\n\n\n\nPatients with AF ablation presenting between January 2010 and September 2015 at Johns Hopkins Hospital were enrolled in an AF ablation registry; TEE and ablation outcomes were retrospectively analyzed. Presence of LAA thrombus, dense spontaneous echo contrast (SEC), or patent foramen ovale (PFO) were recorded. CVA incidence from procedure onset to 30 days post-procedure was evaluated using electronic medical record review.\n\n\n\nPre-procedure TEE was performed in 646 of 1,224 AF ablation cases (52.8%). There was a decline in pre-procedure TEE use from 86% in 2010 to 42% in 2015 (p < 0.001). CVA incidence was 4/1,224 (0.33%) cases, and did not change during the study period. TEE findings included LAA thrombus (n = 6; 0.93%), PFO (n = 23; 3.6%), and dense spontaneous echo contrast (n = 99; 15.3%). Both SEC and LAA thrombus were associated with persistent AF, higher CHA2DS2VASC score, increased LA size, reduced LAA flow velocity, and decreased left ventricular ejection fraction. PFO was not associated with prior AF ablation, and SEC was not associated with increased CVA incidence.\n\n\n\nCVA is a rare complication of AF ablation in patients with minimally interrupted anticoagulation. Pre-ablation TEE may be reasonably avoided in patients without high-risk features.", "affiliations": "Johns Hopkins Hospital Heart and Vascular Institute, Baltimore, Maryland.;Johns Hopkins Hospital Heart and Vascular Institute, Baltimore, Maryland.;Johns Hopkins Hospital Heart and Vascular Institute, Baltimore, Maryland.;Johns Hopkins Hospital Heart and Vascular Institute, Baltimore, Maryland.;Johns Hopkins Hospital Heart and Vascular Institute, Baltimore, Maryland.;Johns Hopkins Hospital Heart and Vascular Institute, Baltimore, Maryland.;Johns Hopkins Hospital Heart and Vascular Institute, Baltimore, Maryland.;Johns Hopkins Hospital Heart and Vascular Institute, Baltimore, Maryland.;Johns Hopkins Hospital Heart and Vascular Institute, Baltimore, Maryland.;Johns Hopkins Hospital Heart and Vascular Institute, Baltimore, Maryland.;Johns Hopkins Hospital Heart and Vascular Institute, Baltimore, Maryland. Electronic address: [email protected].", "authors": "Balouch\|Muhammad\|M\|;Gucuk Ipek\|Esra\|E\|;Chrispin\|Jonathan\|J\|;Bajwa\|Rizma J\|RJ\|;Zghaib\|Tarek\|T\|;Berger\|Ronald D\|RD\|;Ashikaga\|Hiroshi\|H\|;Calkins\|Hugh\|H\|;Nazarian\|Saman\|S\|;Marine\|Joseph E\|JE\|;Spragg\|David D\|DD\|", "chemical_list": "D000925:Anticoagulants", "country": "United States", "delete": false, "doi": "10.1016/j.jacep.2016.09.011", "fulltext": null, "fulltext_license": null, "issn_linking": "2405-500X", "issue": "3(4)", "journal": "JACC. Clinical electrophysiology", "keywords": "ablation; atrial fibrillation; transesophageal echocardiography", "medline_ta": "JACC Clin Electrophysiol", "mesh_terms": "D000368:Aged; D000925:Anticoagulants; D001281:Atrial Fibrillation; D017115:Catheter Ablation; D017548:Echocardiography, Transesophageal; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012042:Registries; D012189:Retrospective Studies; D020521:Stroke; D013927:Thrombosis; D016896:Treatment Outcome", "nlm_unique_id": "101656995", "other_id": null, "pages": "329-336", "pmc": null, "pmid": "29759444", "pubdate": "2017-04", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Trends in Transesophageal Echocardiography Use, Findings, and Clinical Outcomes in the Era of Minimally Interrupted Anticoagulation for Atrial Fibrillation Ablation.", "title_normalized": "trends in transesophageal echocardiography use findings and clinical outcomes in the era of minimally interrupted anticoagulation for atrial fibrillation ablation" }	[ { "companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2017-BI-029724", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DABIGATRAN ETEXILATE MESYLATE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "022512", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ATRIAL FIBRILLATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PRADAXA" } ], "patientagegroup": null, "patientonsetage": "47", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Transient ischaemic attack", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SPRAGG D, BALOUCH M, IPEK E, CHRISPIN J, CHRISPIN J, BAJWA R, ET AL. TRENDS IN TRANSESOPHAGEAL ECHOCARDIOGRAPHY USE, FINDINGS, AND CLINICAL OUTCOMES IN THE ERA OF MINIMALLY INTERRUPTED ANTICOAGULATION FOR ATRIAL FIBRILLATION ABLATION. JACC. CLINICAL ELECTROPHYSIOLOGY. 2017;3:4:329-336.", "literaturereference_normalized": "trends in transesophageal echocardiography use findings and clinical outcomes in the era of minimally interrupted anticoagulation for atrial fibrillation ablation", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170529", "receivedate": "20170529", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13590959, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" } ]
{ "abstract": "Progressive multifocal leukoencephalopathy (PML) is a severe opportunistic infection of the central nervous system. A 52-year-old man with HIV infection, recently started on antiretroviral therapy, presented with symptoms of mental cloudiness, blurry vision and ataxia. MRI of the brain showed nodular perivascular space enhancement with surrounding vasogenic oedema and midline shift. A lumbar puncture revealed non-inflammatory cerebrospinal fluid and was positive for JC virus. As the patient developed worsening symptoms in the setting of initiation of antiretroviral therapy with immune recovery, a diagnosis of JC virus-associated immune reconstitution inflammatory syndrome (IRIS) was made. With recent literature on the use of CCR5 antagonist maraviroc in PML, our patient was started on maraviroc and noted to have improvement in PML IRIS. This is the first case of an HIV-positive patient successfully treated for PML IRIS with maraviroc, as verified by our literature review; also, our case has clinical implications in improving outcome in PML IRIS.", "affiliations": "Department of Internal Medicine, Baylor College of Medicine, Houston, Texas, USA.;Department of Internal Medicine, Baylor College of Medicine, Houston, Texas, USA.;Department of Internal Medicine, Baylor College of Medicine, Houston, Texas, USA Department of Medicine, Michael E DeBakey Veterans Affairs Medical Center, Houston, Texas, USA.", "authors": "Shahani\|Lokesh\|L\|;Shah\|Minal\|M\|;Tavakoli-Tabasi\|Shahriar\|S\|", "chemical_list": "D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes; D014230:Triazoles; D000077592:Maraviroc", "country": "England", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "2015()", "journal": "BMJ case reports", "keywords": null, "medline_ta": "BMJ Case Rep", "mesh_terms": "D065100:CCR5 Receptor Antagonists; D018414:CD8-Positive T-Lymphocytes; D003510:Cyclohexanes; D018450:Disease Progression; D015658:HIV Infections; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome; D007577:JC Virus; D007968:Leukoencephalopathy, Progressive Multifocal; D008297:Male; D000077592:Maraviroc; D008875:Middle Aged; D016896:Treatment Outcome; D014230:Triazoles", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "26063110", "pubdate": "2015-06-10", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": "11517410;12086750;20298966;12218391;8451420;15750393;24476450;22687798;19901246;19129505;23733308;21908480;9571254;10194089;18753934;22382480;21840066", "title": "Immune reconstitution inflammatory syndrome in a patient with progressive multifocal leukoencephalopathy.", "title_normalized": "immune reconstitution inflammatory syndrome in a patient with progressive multifocal leukoencephalopathy" }	[ { "companynumb": "US-GILEAD-2015-0165720", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "EMTRICITABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HIV INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EMTRICITABINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DARUNAVIR\\RITONAVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HIV INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DARUNAVIR W/RITONAVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TENOFOVIR DISOPROXIL FUMARATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021356", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HIV INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TENOFOVIR DISOPROXIL FUMARATE." } ], "patientagegroup": "5", "patientonsetage": "52", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "JC virus infection", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Immune reconstitution inflammatory syndrome", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SHAHANI L., SHAH M., AND TAVAKOLI-TABASI S.. IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME IN A PATIENT WITH PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY. BMJ CASE REPORTS. 2015;ARTICLE NO A904:1-3", "literaturereference_normalized": "immune reconstitution inflammatory syndrome in a patient with progressive multifocal leukoencephalopathy", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150803", "receivedate": "20150803", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11334257, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20151125" }, { "companynumb": "US-JNJFOC-20150721565", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DARUNAVIR" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "021976", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLETS", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HIV INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DARUNAVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TENOFOVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HIV INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TENOFOVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITONAVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HIV INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITONAVIR." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "EMTRICITABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HIV INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EMTRICITABINE" } ], "patientagegroup": "5", "patientonsetage": "52", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Immune reconstitution inflammatory syndrome", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Progressive multifocal leukoencephalopathy", "reactionmeddraversionpt": "18.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SHAHANI L, SHAH M, TAVAKOLI-TABASI S. IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME IN A PATIENT WITH PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY. BMJ CASE REPORTS 2015:1-3.", "literaturereference_normalized": "immune reconstitution inflammatory syndrome in a patient with progressive multifocal leukoencephalopathy", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150902", "receivedate": "20150902", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11447626, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20151125" } ]
{ "abstract": "We report the case of a 40-year-old patient followed for post-traumatic stress disorder. A re-evaluation of its pharmacological treatment with the introduction of mirtazapine (30 mg/day) was associated with a rhabdomyolysis (CK> 20,000 IU/L at day 3). The diagnosis of mirtazapine induced rhabdomyolysis was made. After withdrawal of this drug combined with a symptomatic treatment (hydratation), the patient recovered well and was discharged without any nephrological sequelae. This article is intended to underline the diagnostic approach to elevated CK activity and the potential role of the \"medical biologist\" as a consultant for the relevant use of biological examinations. A physiopathological mechanism of this rhabdomyolysis is also proposed.", "affiliations": "Département des laboratoires, Hôpital d'instruction des armées Bégin, Saint Mandé, France.;Service de psychiatrie, Hôpital d'instruction des armées Bégin, Saint Mandé, France.;Service de psychiatrie, Hôpital d'instruction des armées Bégin, Saint Mandé, France.;Département des laboratoires, Hôpital d'instruction des armées Bégin, Saint Mandé, France.;Service de psychiatrie, Hôpital d'instruction des armées Bégin, Saint Mandé, France.;Service de psychiatrie, Hôpital d'instruction des armées Bégin, Saint Mandé, France, Ecole du Val-de-Grâce, Paris, France.;Département des laboratoires, Hôpital d'instruction des armées Bégin, Saint Mandé, France, Ecole du Val-de-Grâce, Paris, France.", "authors": "Ratnam\|Caroline\|C\|;Saguin\|Emeric\|E\|;Keou\|Symphonie\|S\|;Plantamura\|Julie\|J\|;Mennessier\|Coralie\|C\|;Lahutte\|Bertrand\|B\|;Delacour\|Hervé\|H\|", "chemical_list": "D014150:Antipsychotic Agents; D008803:Mianserin; D000078785:Mirtazapine", "country": "France", "delete": false, "doi": "10.1684/abc.2018.1351", "fulltext": null, "fulltext_license": null, "issn_linking": "0003-3898", "issue": "76(3)", "journal": "Annales de biologie clinique", "keywords": "advisory service; antipsychotic agents; creatine kinase; interpretative comments; mirtazapine; rhabdomyolysis", "medline_ta": "Ann Biol Clin (Paris)", "mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D006801:Humans; D008297:Male; D008803:Mianserin; D000078785:Mirtazapine; D012206:Rhabdomyolysis; D013313:Stress Disorders, Post-Traumatic", "nlm_unique_id": "2984690R", "other_id": null, "pages": "329-335", "pmc": null, "pmid": "29862972", "pubdate": "2018-06-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Antipsychotic induced rhabdomyolysis.", "title_normalized": "antipsychotic induced rhabdomyolysis" }	[ { "companynumb": "FR-MYLANLABS-2019M1052652", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "PAROXETINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "POST-TRAUMATIC STRESS DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PAROXETINE." }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090323", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "600 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "PAROXETINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PAROXETINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PERICIAZINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "POST-TRAUMATIC STRESS DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPERICIAZINE" }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090323", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "POST-TRAUMATIC STRESS DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PRAZOSIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "POST-TRAUMATIC STRESS DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PRAZOSIN." } ], "patientagegroup": null, "patientonsetage": "40", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug resistance", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "RATNAM C, SAGUIN E, KEOU S, PANTAMURA J, MENNESSIER C, LAHUTTE B ET AL.. ANTIPSYCHOTIC-INDUCED RHABDOMYOLYSIS. ANNALS OF CLINICAL BIOLOGY. 2018?76 (3):329-35", "literaturereference_normalized": "antipsychotic induced rhabdomyolysis", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20190607", "receivedate": "20190607", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16406516, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190711" }, { "companynumb": "FR-AUROBINDO-AUR-APL-2018-060123", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "MIRTAZAPINE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "76921", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MILLIGRAM, ONCE A DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Post-traumatic stress disorder", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MIRTAZAPINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PAROXETINE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PAROXETINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PAROXETINE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PAROXETINE" }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "600 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE" }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PRAZOSIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "Post-traumatic stress disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PRAZOSIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PERICIAZINE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "Post-traumatic stress disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PERICIAZINE" } ], "patientagegroup": null, "patientonsetage": "40", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Rhabdomyolysis", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Blood creatine phosphokinase increased", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug resistance", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Ratnam C, Saguin E, Keou S, Pantamura J, Mennessier C, Lahutte B et al. Antipsychotic-induced rhabdomyolysis. Annals of Clinical Biology. 2018;76(3):329-35", "literaturereference_normalized": "antipsychotic induced rhabdomyolysis", "qualification": "1", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20220316", "receivedate": "20181215", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15725446, "safetyreportversion": 4, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "PHHY2018FR067836", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "PAROXETINE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK (THE INITIAL DOSE FOR 2 DAYS)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PAROXETINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PRAZOSIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "POST-TRAUMATIC STRESS DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PRAZOSIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MIRTAZAPINE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "76189", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "45 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "DEPRESSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "45", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MIRTAZAPINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PAROXETINE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "POST-TRAUMATIC STRESS DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PAROXETINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PERICIAZINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "POST-TRAUMATIC STRESS DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PERICIAZINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PAROXETINE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PAROXETINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PERICIAZINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "POST-TRAUMATIC STRESS DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPERICIAZINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "78679", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "600 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MIRTAZAPINE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "76189", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "15 MG/KG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MIRTAZAPINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "78679", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG, UNK (INCREASED)", "drugenddate": null, "drugenddateformat": null, "drugindication": "POST-TRAUMATIC STRESS DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MIRTAZAPINE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "76189", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "30 MG, QD (DAY 2)", "drugenddate": null, "drugenddateformat": null, "drugindication": "POST-TRAUMATIC STRESS DISORDER", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MIRTAZAPINE." } ], "patientagegroup": null, "patientonsetage": "40", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rhabdomyolysis", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "RATNAM C, SAGUIN E, KEOU S, PLANTAMURA J, MENNESSIER C, LAHUTTE B, ET AL. ANTIPSYCHOTIC INDUCED RHABDOMYOLYSIS. ANNALES DE BIOLOGIE CLINIQUE. 2018?76(3):329-35", "literaturereference_normalized": "antipsychotic induced rhabdomyolysis", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20200616", "receivedate": "20180814", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15278369, "safetyreportversion": 5, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20200713" } ]
{ "abstract": "OBJECTIVE\nWe present a case report of a patient who developed an epidural hematoma following an interlaminar epidural steroid injection with no risk factors aside from old age and aspirin use for secondary prevention.\n\n\nMETHODS\nA 79-year-old man developed an epidural hematoma requiring surgical treatment following an uncomplicated interlaminar epidural steroid injection performed for neurogenic claudication. In the periprocedural period, he continued aspirin for secondary prophylaxis following a myocardial infarction.\n\n\nCONCLUSIONS\nFor patients taking aspirin for primary or secondary prophylaxis, the American Society of Regional Anesthesia and Pain Medicine antiplatelet and anticoagulation guidelines for spine and pain procedures recommend a shared assessment and risk stratification when deciding to hold the medication for intermediate-risk neuraxial procedures. Cases such as this serve to highlight the importance of giving careful consideration to medical optimization of a patient even when a low- or intermediate-risk procedure is planned.", "affiliations": "From the Pain Division, Mayo Clinic Department of Anesthesiology and Perioperative Medicine, Rochester, MN.", "authors": "Sanders\|Rebecca A\|RA\|;Bendel\|Markus A\|MA\|;Moeschler\|Susan M\|SM\|;Mauck\|William D\|WD\|", "chemical_list": "D010975:Platelet Aggregation Inhibitors; D013256:Steroids; D001241:Aspirin", "country": "England", "delete": false, "doi": "10.1097/AAP.0000000000000730", "fulltext": null, "fulltext_license": null, "issn_linking": "1098-7339", "issue": "43(3)", "journal": "Regional anesthesia and pain medicine", "keywords": null, "medline_ta": "Reg Anesth Pain Med", "mesh_terms": "D000368:Aged; D001241:Aspirin; D046748:Hematoma, Epidural, Spinal; D006801:Humans; D007268:Injections, Epidural; D017116:Low Back Pain; D008279:Magnetic Resonance Imaging; D008297:Male; D010975:Platelet Aggregation Inhibitors; D012307:Risk Factors; D055502:Secondary Prevention; D013256:Steroids; D016896:Treatment Outcome", "nlm_unique_id": "9804508", "other_id": null, "pages": "310-312", "pmc": null, "pmid": "29319605", "pubdate": "2018-04", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Epidural Hematoma Following Interlaminar Epidural Injection in Patient Taking Aspirin.", "title_normalized": "epidural hematoma following interlaminar epidural injection in patient taking aspirin" }	[ { "companynumb": "US-NOVAST LABORATORIES, LTD-US-2018NOV000241", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "ASPIRIN\\CARISOPRODOL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "040832", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "81 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "81", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARISOPRODOL\\ASPIRIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "NIFEDIPINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NIFEDIPINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ROSUVASTATIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ROSUVASTATIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ZINC" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ZINC." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ATENOLOL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ATENOLOL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "NITROGLYCERIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NITROGLYCERIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "TAMSULOSIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TAMSULOSIN" } ], "patientagegroup": null, "patientonsetage": "79", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Extradural haematoma", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SANDERS RA, BENDEL MA, MOESCHLER SM, MAUCK WD. EPIDURAL HEMATOMA FOLLOWING INTERLAMINAR EPIDURAL INJECTION IN PATIENT TAKING ASPIRIN. REGION-ANESTH-PAIN-MED. 2018?43(3):310-312", "literaturereference_normalized": "epidural hematoma following interlaminar epidural injection in patient taking aspirin", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180625", "receivedate": "20180625", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15059095, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180711" } ]
{ "abstract": "The objective of this study was to compare short-term outcomes of neonatal opioid withdrawal syndrome (NOWS) treatment in infants exposed in-utero to opioids and selective serotonin reuptake inhibitors (SSRIs) or opioids alone.\n\n\n\nThis was a retrospective cohort study of mother-infant dyads, 34 weeks or greater gestation, receiving opioids and/or SSRIs during pregnancy. Intravenous or oral methadone was administered according to a pre-existing protocol for NOWS treatment guided by withdrawal scores. Primary outcome was length of treatment (LOT). Secondary outcomes included length of stay (LOS), total methadone exposure, time to symptom control, need for a second agent, and NOWS medications at discharge.\n\n\n\nFifty-five mother-infant dyads were included in the study. LOT was longer in the infants in the SSRI plus opioid group but not significantly different [24 ± 23 days (SSRI plus opioid) vs 20 ± 14 days (opioid alone); P = 0.78]. There was a trend towards shorter LOS (30 ± 22 day vs 27 ± 15 days; P = 0.86), lower total methadone exposure (3.2 ± 4.3 mg/kg vs 2.7 ± 5.1 mg/kg; P = 0.66), less time to control symptoms (1 ± 1.7 days vs 0.5 ± 0.36 days; P = 0.31) and less need for a second agent (OR 2.65, 95% CI 0.69-10.5) in the opioid only group, although these observations also did not reach statistical significance.\n\n\n\nThis study could not demonstrate a statistically significant difference in short-term NOWS outcome of LOT between the 2 groups. However, there was a trend towards longer LOT and LOS in the SSRI plus opioid group which could be clinically significant. A larger cohort may detect a true significant difference in these short-term outcomes.", "affiliations": "Department of Clinical Pharmacy, College of Pharmacy (VB-M); Department of Pediatrics, Michigan Medicine, University of Michigan (VB-M, JS, RES); Department of Pharmacy, Ascension St. John Hospital, Ann Arbor, MI (JR).", "authors": "Bhatt-Mehta\|Varsha\|V\|;Richards\|Jessika\|J\|;Sturza\|Julie\|J\|;Schumacher\|Robert E\|RE\|", "chemical_list": "D000701:Analgesics, Opioid; D017367:Serotonin Uptake Inhibitors", "country": "United States", "delete": false, "doi": "10.1097/ADM.0000000000000484", "fulltext": null, "fulltext_license": null, "issn_linking": "1932-0620", "issue": "13(3)", "journal": "Journal of addiction medicine", "keywords": null, "medline_ta": "J Addict Med", "mesh_terms": "D000328:Adult; D000701:Analgesics, Opioid; D003863:Depression; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007902:Length of Stay; D008297:Male; D008824:Michigan; D009357:Neonatal Abstinence Syndrome; D009293:Opioid-Related Disorders; D011247:Pregnancy; D011248:Pregnancy Complications; D011297:Prenatal Exposure Delayed Effects; D012189:Retrospective Studies; D017367:Serotonin Uptake Inhibitors; D062606:Tertiary Care Centers; D055815:Young Adult", "nlm_unique_id": "101306759", "other_id": null, "pages": "227-234", "pmc": null, "pmid": "30489344", "pubdate": "2019", "publication_types": "D016428:Journal Article", "references": null, "title": "Impact of In-utero Exposure to Selective Serotonin Reuptake Inhibitors and Opioids on Neonatal Opioid Withdrawal Syndrome.", "title_normalized": "impact of in utero exposure to selective serotonin reuptake inhibitors and opioids on neonatal opioid withdrawal syndrome" }	[ { "companynumb": "US-ALLERGAN-1938628US", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "FLUOXETINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "021860", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "EXPOSURE DURING PREGNANCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUOXETINE HCL UNK" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "UNSPECIFIED INGREDIENT" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "EXPOSURE DURING PREGNANCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OPIOIDS" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pregnancy", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug withdrawal syndrome neonatal", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "BHATT-MEHTA V, RICHARDS J, STURZA J, SCHUMACHER RE. IMPACT OF IN-UTERO EXPOSURE TO SELECTIVE SEROTONIN REUPTAKE INHIBITORS AND OPIOIDS ON NEONATAL OPIOID WITHDRAWAL SYNDROME. 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IMPACT OF IN-UTERO EXPOSURE TO SELECTIVE SEROTONIN REUPTAKE INHIBITORS AND OPIOIDS ON NEONATAL OPIOID WITHDRAWAL SYNDROME. 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IMPACT OF IN-UTERO EXPOSURE TO SELECTIVE SEROTONIN REUPTAKE INHIBITORS AND OPIOIDS ON NEONATAL OPIOID WITHDRAWAL SYNDROME. JOURNAL OF ADDICTION MEDICINE. 2019?13(3):227-234", "literaturereference_normalized": "impact of in utero exposure to selective serotonin reuptake inhibitors and opioids on neonatal opioid withdrawal syndrome", "qualification": "2", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190924", "receivedate": "20190924", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16847223, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20191005" } ]
{ "abstract": "This paper reports the first case of a patient with hepatocellular carcinoma with lymph node metastasis treated by sorafenib combined with gemcitabine plus oxaliplatin, with a partial response and normalization of α fetoprotein, which allowed curative surgery. The potential synergy between these three drugs needs to be confirmed, and is currently being investigated in a randomized phase II trial.", "affiliations": "Department of Gastroenterology, Europeen Georges Pompidou Hospital, Medical University, 75908 Paris, France. [email protected]", "authors": "Williet\|Nicolas\|N\|;Dubreuil\|Olivier\|O\|;Boussaha\|Tarek\|T\|;Trouilloud\|Isabelle\|I\|;Landi\|Bruno\|B\|;Housset\|Martin\|M\|;Botti\|Muriel\|M\|;Rougier\|Philippe\|P\|;Belghiti\|Jacques\|J\|;Taieb\|Julien\|J\|", "chemical_list": "D001557:Benzenesulfonates; D009944:Organoplatinum Compounds; D010671:Phenylurea Compounds; D011725:Pyridines; D000077150:Oxaliplatin; D003841:Deoxycytidine; D009536:Niacinamide; D000077157:Sorafenib; C056507:gemcitabine", "country": "United States", "delete": false, "doi": "10.3748/wjg.v17.i17.2255", "fulltext": null, "fulltext_license": null, "issn_linking": "1007-9327", "issue": "17(17)", "journal": "World journal of gastroenterology", "keywords": "Gemcitabine; Hepatocellular carcinoma; Neoadjuvant therapy; Oxaliplatin; Sorafenib", "medline_ta": "World J Gastroenterol", "mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001557:Benzenesulfonates; D006528:Carcinoma, Hepatocellular; D003841:Deoxycytidine; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009536:Niacinamide; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D010671:Phenylurea Compounds; D011725:Pyridines; D000077157:Sorafenib", "nlm_unique_id": "100883448", "other_id": null, "pages": "2255-8", "pmc": null, "pmid": "21633538", "pubdate": "2011-05-07", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "19106535;15231247;10412945;17376045;16622265;10951336;15913915;15864213;16728631;18172362;20075738;16798837;14669287;17160521;18650514;15637262;18412149;21351269;19160192;12181257;20207091;19581537;17330837", "title": "Neoadjuvant sorafenib combined with gemcitabine plus oxaliplatin in advanced hepatocellular carcinoma.", "title_normalized": "neoadjuvant sorafenib combined with gemcitabine plus oxaliplatin in advanced hepatocellular carcinoma" }	[ { "companynumb": "FR-PFIZER INC-2020068217", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "GEMCITABINE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Concentrate for solution for infusion", "drugdosagetext": "DOSE: 1 G/M2 ON DAY 1; CYCLICAL THERAPY (GEMOX REGIMEN)", "drugenddate": null, "drugenddateformat": null, "drugindication": "Hepatocellular carcinoma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2010", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "GEMCITABINE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Concentrate for solution for infusion", "drugdosagetext": "1000 MILLIGRAM/SQ. METER, ADMINISTERED ON DAY 1 OF THE CYCLE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2010", "drugstartdateformat": "602", "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": "205529", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "ADMINISTERED ON DAY 2; CYCLICAL THERAPY (GEMOX REGIMEN)", "drugenddate": "2010", "drugenddateformat": "602", "drugindication": "Hepatocellular carcinoma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2010", "drugstartdateformat": "602", "drugstructuredosagenumb": "100", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "SORAFENIB" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "800 MILLIGRAM, ONCE A DAY (ADMINISTERED ALONGSIDE THE GEMOX REGIMEN)", "drugenddate": "2010", "drugenddateformat": "602", "drugindication": "Hepatocellular carcinoma", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2010", "drugstartdateformat": "602", "drugstructuredosagenumb": "800", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SORAFENIB" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "SORAFENIB" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MILLIGRAM, ONCE A DAY", "drugenddate": "2010", "drugenddateformat": "602", "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2010", "drugstartdateformat": "602", "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SORAFENIB" } ], "patientagegroup": null, "patientonsetage": "61", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "94", "reaction": [ { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "24.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Asthenia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20100101" } }, "primarysource": { "literaturereference": "Williet N.Dubreuil O, Boussaha T, Trouilloud I, Landi B, Housset M.. Neoadjuvant sorafenib combined with gemcitabine plus oxaliplatin in advanced hepatocellular carcinoma.. World Journal of Gastroenterology. 2011;17(17):2255-2258", "literaturereference_normalized": "neoadjuvant sorafenib combined with gemcitabine plus oxaliplatin in advanced hepatocellular carcinoma", "qualification": "1", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20220201", "receivedate": "20200306", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17507556, "safetyreportversion": 8, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "FR-PFIZER INC-2020068217", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "SORAFENIB" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG, 2X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATOCELLULAR CARCINOMA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SORAFENIB" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "078813", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG/M2, CYCLIC, (FOUR CYCLES,ON DAY 2, REPEATED EVERY 2 WK )", "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATOCELLULAR CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "GEMCITABINE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "200795", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "UNK, CYCLIC (1 G/M2 ON DAY 1, FOUR CYCLES, REPEATED EVERY 2 WK)", "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATOCELLULAR CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": "61", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "94", "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Asthenia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILLIET, N.. NEOADJUVANT SORAFENIB COMBINED WITH GEMCITABINE PLUS OXALIPLATIN IN ADVANCED HEPATOCELLULAR CARCINOMA. WORLD JOURNAL OF GASTROENTEROLOGY. 2011?17 (17):10.3748/WJG.V17.I17.2255", "literaturereference_normalized": "neoadjuvant sorafenib combined with gemcitabine plus oxaliplatin in advanced hepatocellular carcinoma", "qualification": "1", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20210407", "receivedate": "20200221", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17445749, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210716" }, { "companynumb": "FR-BAYER-2011-048711", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "SORAFENIB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021923", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Film-coated tablet", "drugdosagetext": "400 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Hepatocellular carcinoma", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NEXAVAR" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SORAFENIB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021923", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Film-coated tablet", "drugdosagetext": "400 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "Hepatocellular carcinoma", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2010", "drugstartdateformat": "602", "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NEXAVAR" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "GEMCITABINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 UNK, 1 UNK G/M2 DAY 1 EVERY 2 WK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Hepatocellular carcinoma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE HYDROCHLORIDE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "GEMCITABINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Hepatocellular carcinoma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2010", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE HYDROCHLORIDE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG/M2, ON DAY 2 EVERY 2 WK", "drugenddate": "2010", "drugenddateformat": "602", "drugindication": "Hepatocellular carcinoma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2010", "drugstartdateformat": "602", "drugstructuredosagenumb": "100", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN" } ], "patientagegroup": "5", "patientonsetage": "61", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "94", "reaction": [ { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "24.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Asthenia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20100101" } }, "primarysource": { "literaturereference": "Williet N, Dubreuil O, Boussaha T, Trouilloud I, Landi B, Rougier P, Taieb J, Housset M, Botti M, Belghiti J. Neoadjuvant sorafenib combined with gemcitabine plus oxaliplatin in advanced hepatocellular carcinoma. World Journal of Gastroenterology. 2011;17 (17):2255-2258", "literaturereference_normalized": "neoadjuvant sorafenib combined with gemcitabine plus oxaliplatin in advanced hepatocellular carcinoma", "qualification": "1", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20220120", "receivedate": "20110614", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 7989225, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "FR-PFIZER INC-2020068217", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "GEMCITABINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "200145", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Solution for injection", "drugdosagetext": "UNK UNK, CYCLE, 1 G/M2 ON DAY 1, FOUR CYCLES, REPEATED EVERY 2 WK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Hepatocellular carcinoma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "GEMCITABINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "200145", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Solution for injection", "drugdosagetext": "ADMINISTERED ON DAY 1 OF THE CYCLE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2010", "drugstartdateformat": "602", "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": "2", "drugadministrationroute": null, "drugauthorizationnumb": "091358", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG/M2, CYCLIC, (FOUR CYCLES,ON DAY 2, REPEATED EVERY 2 WK )", "drugenddate": "2010", "drugenddateformat": "602", "drugindication": "Hepatocellular carcinoma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2010", "drugstartdateformat": "602", "drugstructuredosagenumb": "100", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "SORAFENIB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG, 2X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Hepatocellular carcinoma", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "800", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SORAFENIB" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "SORAFENIB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2010", "drugstartdateformat": "602", "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SORAFENIB" } ], "patientagegroup": null, "patientonsetage": "61", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "94", "reaction": [ { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "24.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Asthenia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20100101" } }, "primarysource": { "literaturereference": "Williet N, Dubreuil O, Boussaha T, Trouilloud I, Landi B, Housset M, et al.. Neoadjuvant sorafenib combined with gemcitabine plus oxaliplatin in advanced hepatocellular carcinoma.. World Journal of Gastroenterology.. 2011;17 (17):2255-2258", "literaturereference_normalized": "neoadjuvant sorafenib combined with gemcitabine plus oxaliplatin in advanced hepatocellular carcinoma", "qualification": "1", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20220303", "receivedate": "20200319", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17562655, "safetyreportversion": 8, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220424" }, { "companynumb": "FR-FRESENIUS KABI-FK202104321", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "GEMCITABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090242", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "1 G/M2, EVERY 2 WK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATOCELLULAR CARCINOMA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "2", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "078811", "drugbatchnumb": "UNKNOWN,UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "DOSE:100 MG/M2, EVERY 2 WK?FOUR CYCLES OF THE GEMOX REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATOCELLULAR CARCINOMA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "2", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN (MANUFACTURER UNKNOWN)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SORAFENIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "400 MG, TWICE, EVERY DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATOCELLULAR CARCINOMA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SORAFENIB" } ], "patientagegroup": null, "patientonsetage": "61", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "94", "reaction": [ { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Asthenia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILLIET N, DUBREUIL O, BOUSSAHA T, TROUILLOUD I, LANDI B, HOUSSET M. NEOADJUVANT SORAFENIB COMBINED WITH GEMCITABINE PLUS OXALIPLATIN IN ADVANCED HEPATOCELLULAR CARCINOMA.. WORLD JOURNAL OF GASTROENTEROLOGY. 2011 MAY 07?17(17):2255?2258.", "literaturereference_normalized": "neoadjuvant sorafenib combined with gemcitabine plus oxaliplatin in advanced hepatocellular carcinoma", "qualification": "1", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20210429", "receivedate": "20210429", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19195483, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" } ]
{ "abstract": "OBJECTIVE\nDiffuse high-grade gliomas are known to develop in children after cranial irradiation for other malignancies. Here, clinicopathological characteristics are outlined.\n\n\nMETHODS\nNine children received cranial irradiation and chemotherapy for medulloblastoma (n=2) or acute lymphoblastic leukemia (n=7). They developed a high-grade glioma 7-14 years thereafter. Clinical charts, radiologic findings, and pathologic specimens were reviewed. Archival material was stained immunohistochemically.\n\n\nCONCLUSIONS\nGliomas evolving as second malignant neoplasms show peculiarities and differ in some aspects from their \"spontaneous\" counterparts. Most are supratentorial, contrast-enhancing, space-occupying lesions. They are composed mainly of small undifferentiated cells, which are mainly negative for glial fibrillary acidic protein and positive for microtubule associated proteins 2 (MAP2). Epidermal growth factor receptor labeling could not be detected in any of them. Ki67-labeling was usually high, whereas p53- and h-ras p21-staining was variable. The median survival was only 12 months despite intensive treatment.", "affiliations": "Institut für Neuropathologie, Universitätsklinikum des Saarlandes, 66421, Homburg/Saar, Germany. [email protected]", "authors": "Romeike\|Bernd F M\|BF\|;Kim\|Yoo-Jin\|YJ\|;Steudel\|Wolf-Ingo\|WI\|;Graf\|Norbert\|N\|", "chemical_list": "D005904:Glial Fibrillary Acidic Protein; D019394:Ki-67 Antigen; C489788:MAP2 protein, human; D008869:Microtubule-Associated Proteins", "country": "Germany", "delete": false, "doi": "10.1007/s00381-006-0199-z", "fulltext": null, "fulltext_license": null, "issn_linking": "0256-7040", "issue": "23(2)", "journal": "Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery", "keywords": null, "medline_ta": "Childs Nerv Syst", "mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001932:Brain Neoplasms; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005904:Glial Fibrillary Acidic Protein; D005910:Glioma; D006801:Humans; D019394:Ki-67 Antigen; D008279:Magnetic Resonance Imaging; D008297:Male; D008869:Microtubule-Associated Proteins; D016609:Neoplasms, Second Primary; D010372:Pediatrics; D012189:Retrospective Studies", "nlm_unique_id": "8503227", "other_id": null, "pages": "185-93", "pmc": null, "pmid": "17021727", "pubdate": "2007-02", "publication_types": "D016430:Clinical Trial; D016428:Journal Article", "references": "14714135;176331;2536806;10406363;10329596;8468607;14704813;8374881;15146346;1845944;12865017;12651207;1905840;9228960;6326557;3072075;9007876;3173432;16550739;9810442;10779419;6251397;12917300;11058888;15926395;1922234;11878577", "title": "Diffuse high-grade gliomas as second malignant neoplasms after radio-chemotherapy for pediatric malignancies.", "title_normalized": "diffuse high grade gliomas as second malignant neoplasms after radio chemotherapy for pediatric malignancies" }	[ { "companynumb": "DE-JNJFOC-20190409151", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { 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"drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE SULFATE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MERCAPTOPURINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", 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"drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ASPARAGINASE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" } ], "patientagegroup": "3", "patientonsetage": "12", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Glioblastoma multiforme", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intracranial pressure increased", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neurological examination abnormal", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Glioma", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ROMEIKE B, KIM YJ, STEUDEL WI, GRAF N. DIFFUSE HIGH-GRADE GLIOMAS AS SECOND MALIGNANT NEOPLASMS AFTER RADIO-CHEMOTHERAPY FOR PEDIATRIC MALIGNANCIES. CHILDS NERV SYST 2007?23:185-93.", "literaturereference_normalized": "diffuse high grade gliomas as second malignant neoplasms after radio chemotherapy for pediatric malignancies", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20190417", "receivedate": "20190410", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16180274, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "DE-JNJFOC-20190415624", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "THIOGUANINE ANHYDROUS" }, "drugadditional": null, 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"medicinalproduct": "CYTARABINE." } ], "patientagegroup": "3", "patientonsetage": "11", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Glioblastoma multiforme", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Nervous system disorder", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Intracranial pressure increased", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Glioma", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ROMEIKE BF, KIM YJ, STEUDEL WI, GRAF N. DIFFUSE HIGH-GRADE GLIOMAS AS SECOND MALIGNANT NEOPLASMS AFTER RADIO-CHEMOTHERAPY FOR PEDIATRIC MALIGNANCIES. 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"medicinalproduct": "CYCLOPHOSPHAMIDE" } ], "patientagegroup": null, "patientonsetage": "11", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Glioblastoma multiforme", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "Romeike BFM, Kim Y-J, Steudel W-I, Graf N... Diffuse high-grade gliomas as second malignant neoplasms after radio-chemotherapy for pediatric malignancies. 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DIFFUSE HIGH-GRADE GLIOMAS AS SECOND MALIGNANT NEOPLASMS AFTER RADIO-CHEMOTHERAPY FOR PEDIATRIC MALIGNANCIES. CHILDS NERV SYST. 2007?23/2:185 - 193", "literaturereference_normalized": "diffuse high grade gliomas as second malignant neoplasms after radio chemotherapy for pediatric malignancies", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20190423", "receivedate": "20070331", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 6276657, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190711" }, { "companynumb": "DE-JNJFOC-20190409361", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CORTISONE\\HYDROCORTISONE" }, 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null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": "START PERIOD 10 YEARS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MERCAPTOPURINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, 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"drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE SULFATE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOXORUBICIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "050718", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "LIPOSOME INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ASPARAGINASE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" } ], "patientagegroup": "4", "patientonsetage": "15", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Nervous system disorder", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Intracranial pressure increased", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Glioma", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Astrocytoma", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Glioblastoma multiforme", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ROMEIKE B, KIM YJ, STEUDEL WI, GRAF N. DIFFUSE HIGH GRADE GLIOMAS AS SECOND MALIGNANT NEOPLASMS AFTER RADIO-CHEMOTHERAPY FOR PEDIATRIC MALIGNANCIES. CHILDS NERVOUS SYSTEM 2007?23 (2):185-193.", "literaturereference_normalized": "diffuse high grade gliomas as second malignant neoplasms after radio chemotherapy for pediatric malignancies", "qualification": "5", "reportercountry": "FR" }, "primarysourcecountry": "DE", "receiptdate": "20190430", "receivedate": "20190416", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16202958, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "DE-SA-200712047GDDC", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "4", "drugadministrationroute": null, "drugauthorizationnumb": "081235", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Acute lymphocytic leukaemia", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOXORUBICIN" }, "drugadditional": "4", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Acute lymphocytic leukaemia", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": "4", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Acute lymphocytic leukaemia", 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"drugtreatmentdurationunit": null, "medicinalproduct": "MERCAPTOPURINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ASPARAGINASE" }, "drugadditional": "4", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Acute lymphocytic leukaemia", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "4", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Acute lymphocytic leukaemia", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VINCRISTINE SULFATE" }, "drugadditional": "4", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Acute lymphocytic leukaemia", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE SULFATE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "THIOGUANINE" }, "drugadditional": "4", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Acute lymphocytic leukaemia", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "THIOGUANINE" } ], "patientagegroup": null, "patientonsetage": "13", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Glioblastoma multiforme", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "Romeike BFM, Kim Y-J, Steudel W-I, Graf N.. Diffuse high-grade gliomas as second malignant neoplasms after radio-chemotherapy for pediatric malignancies.. Childs Nerv Syst.. 2007;23:185-93", "literaturereference_normalized": "diffuse high grade gliomas as second malignant neoplasms after radio chemotherapy for pediatric malignancies", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20211018", "receivedate": "20190829", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16756558, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 1, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220304" }, { "companynumb": "DE-SA-200712041GDDC", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "4", "drugadministrationroute": 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"patientweight": null, "reaction": [ { "reactionmeddrapt": "Glioblastoma multiforme", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Nervous system disorder", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Intracranial pressure increased", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Glioma", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ROMEIKE BFM, KIM YJ, STEUDEL WI, GRAF N. DIFFUSE HIGH GRADE GLIOMAS AS SECOND MALIGNANT NEOPLASMS AFTER RADIO-CHEMOTHERAPY FOR PEDIATRIC MALIGNANCIES. Childs Nerv Syst. 2007;23 (02):185-93", "literaturereference_normalized": "diffuse high grade gliomas as second malignant neoplasms after radio chemotherapy for pediatric malignancies", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20211022", "receivedate": "20190830", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16760476, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 1, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220303" }, { "companynumb": "DE-SA-200712053GDDC", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "4", "drugadministrationroute": "037", "drugauthorizationnumb": "201529", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Injection", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Acute lymphocytic leukaemia", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOXORUBICIN" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, 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"summary": null }, "primarysource": { "literaturereference": "Romeike BFM, Kim Y-J, Steudel W-I, Graf N.. Diffuse high grade gliomas as second malignant neoplasms after radio-chemotherapy for pediatric malignancies.. 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"ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE SULFATE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "071868", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "POWDER FOR SOLUTION FOR INJECTION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DAUNORUBICIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DAUNORUBICIN" } ], "patientagegroup": null, "patientonsetage": "15", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Glioma", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Second primary malignancy", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ROMEIKE, B.. DIFFUSE HIGH-GRADE GLIOMAS AS SECOND MALIGNANT NEOPLASMS AFTER RADIO-CHEMOTHERAPY FOR PEDIATRIC MALIGNANCIES. CHILD^S NERVOUS SYSTEM. 2007?23 (2):185 - 193", "literaturereference_normalized": "diffuse high grade gliomas as second malignant neoplasms after radio chemotherapy for pediatric malignancies", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20190418", "receivedate": "20070331", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 6276659, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190711" }, { "companynumb": "DE-PFIZER INC-15852", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": "3", 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{ "actiondrug": "1", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "FREQ: FREQ UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Brain cancer metastatic", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE" } ], "patientagegroup": null, "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Glioma", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "Romeike, B.. Diffuse high-grade gliomas as second malignant neoplasms after radio-chemotherapy for pediatric malignancies. Childs Nervous System. 2007;185-193", "literaturereference_normalized": "diffuse high grade gliomas as second malignant neoplasms after radio chemotherapy for pediatric malignancies", "qualification": "5", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20220315", "receivedate": "20190417", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16207362, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 1, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220424" }, { "companynumb": "DE-JNJFOC-20190409379", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VINCRISTINE SULFATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": 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"drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MERCAPTOPURINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "6-MERCAPTOPURINE MONOHYDRATE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DAUNORUBICIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DAUNORUBICIN" } ], "patientagegroup": "5", "patientonsetage": "19", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Glioblastoma multiforme", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ROMEIKE B, KIM YJ, STEUDEL WI, GRAF N. DIFFUSE HIGH GRADE GLIOMAS AS SECOND MALIGNANT NEOPLASMS AFTER RADIO-CHEMOTHERAPY FOR PEDIATRIC MALIGNANCIES. . CHILDS NERV SYST 2007?23:185-93.", "literaturereference_normalized": "diffuse high grade gliomas as second malignant neoplasms after radio chemotherapy for pediatric malignancies", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20190411", "receivedate": "20190411", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16185992, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "DE-ASPEN-GLO2007DE007020", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VINCRISTINE SULFATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE SULFATE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MERCAPTOPURINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MERCAPTOPURINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, 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LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOXORUBICIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." } ], "patientagegroup": null, "patientonsetage": "12", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Intracranial pressure increased", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Glioblastoma multiforme", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Glioma", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Neurological examination abnormal", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ROMEIKE BFM, KIM Y-J, STEUDEL W-I, GRAF N... DIFFUSE HIGH-GRADE GLIOMAS AS SECOND MALIGNANT NEOPLASMS AFTER RADIO-CHEMOTHERAPY FOR PEDIATRIC MALIGNANCIES.. CHILDS NERV SYST... 2007?23(2):185-93", "literaturereference_normalized": "diffuse high grade gliomas as second malignant neoplasms after radio chemotherapy for pediatric malignancies", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20190417", "receivedate": "20190410", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 16178850, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "DE-PFIZER INC-2007024620", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", 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"actiondrug": "5", "activesubstance": { "activesubstancename": "DOXORUBICIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "050467", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN" } ], "patientagegroup": null, "patientonsetage": "19", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Glioma", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Second primary malignancy", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ROMEIKE, B.. DIFFUSE HIGH-GRADE GLIOMAS AS SECOND MALIGNANT NEOPLASMS AFTER RADIO-CHEMOTHERAPY FOR PEDIATRIC MALIGNANCIES. CHILD^S NERVOUS SYSTEM. 2007?23 (2):DOI 10.1007/S00381-006-0199-Z", "literaturereference_normalized": "diffuse high grade gliomas as second malignant neoplasms after radio chemotherapy for pediatric malignancies", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20190418", "receivedate": "20070331", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 6276660, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190711" }, { "companynumb": "DE-SA-200712049GDDC", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, 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null, "medicinalproduct": "MERCAPTOPURINE" } ], "patientagegroup": null, "patientonsetage": "12", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Glioblastoma multiforme", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "Romeike BFM, Kim Y-J, Steudel W-I, Graf N.. 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"patientagegroup": null, "patientonsetage": "15", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Glioblastoma multiforme", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Astrocytoma", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ROMEIKE BFM, KIM YJ, STEUDEL WI, GRAF N. DIFFUSE HIGH GRADE GLIOMAS AS SECOND MALIGNANT NEOPLASMS AFTER RADIO-CHEMOTHERAPY FOR PEDIATRIC MALIGNANCIES.. CHILDS NERVOUS SYSTEM. 2007;23:185-93", "literaturereference_normalized": "diffuse high grade gliomas as second malignant neoplasms after radio chemotherapy for pediatric malignancies", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20211021", "receivedate": "20190830", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16760475, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 1, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220303" }, { "companynumb": "DE-JNJFOC-20190414326", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ASPARAGINASE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOXORUBICIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "050718", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "LIPOSOME INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN HYDROCHLORIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VINCRISTINE SULFATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE SULFATE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MERCAPTOPURINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, 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"activesubstance": { "activesubstancename": "THIOGUANINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "THIOGUANINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DAUNORUBICIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DAUNORUBICIN" } ], "patientagegroup": "3", "patientonsetage": "13", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Glioblastoma multiforme", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ROMEIKE B, KIM YJ, STEUDEL WI, GRAF N. DIFFUSE HIGH-GRADE GLIOMAS AS SECOND MALIGNANT NEOPLASMS AFTER RADIO-CHEMOTHERAPY FOR PEDIATRIC MALIGNANCIES. CHILDS NERV SYST 2007?23:185-93.", "literaturereference_normalized": "diffuse high grade gliomas as second malignant neoplasms after radio chemotherapy for pediatric malignancies", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20190411", "receivedate": "20190411", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16185993, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "DE-PFIZER INC-2007024606", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DAUNORUBICIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DAUNORUBICIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "THIOGUANINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "THIOGUANINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "071484", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", 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"drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CORTISONE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOXORUBICIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "050467", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "POWDER FOR SOLUTION FOR INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHOTREXATE" }, 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"ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MERCAPTOPURINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MERCAPTOPURINE." } ], "patientagegroup": null, "patientonsetage": "15", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Second primary malignancy", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Glioma", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ROMEIKE B. DIFFUSE HIGH-GRADE GLIOMAS AS SECOND MALIGNANT NEOPLASMS AFTER RADIO-CHEMOTHERAPY FOR PEDIATRIC MALIGNANCIES. CHILDS NERV SYST. 2007?23/2:185 - 193", "literaturereference_normalized": "diffuse high grade gliomas as second malignant neoplasms after radio chemotherapy for pediatric malignancies", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20190423", "receivedate": "20070331", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 6276653, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190711" }, { "companynumb": "DE-PFIZER INC-2007024628", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MERCAPTOPURINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MERCAPTOPURINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "POWDER FOR SOLUTION FOR INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "071484", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" } ], "patientagegroup": null, "patientonsetage": "11", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Glioma", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Second primary malignancy", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ROMEIKE, B.. DIFFUSE HIGH-GRADE GLIOMAS AS SECOND MALIGNANT NEOPLASMS AFTER RADIO-CHEMOTHERAPY FOR PEDIATRIC MALIGNANCIES. CHILD^S NERVOUS SYSTEM. 2007?23 (2):185 - 193", "literaturereference_normalized": "diffuse high grade gliomas as second malignant neoplasms after radio chemotherapy for pediatric malignancies", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20190418", "receivedate": "20190418", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16214733, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190711" } ]
{ "abstract": "Cytomegalovirus encephalitis is a rare but life-threatening infection in non-AIDS patients. To our knowledge, no case that followed conventional treatment for Hodgkin's lymphoma has been reported. We present a patient with Hodgkin's disease in complete remission after combined modality treatment who was succesfully treated with a combination of ganciclovir and foscarnet.", "affiliations": "Antwerp University Hospital, Division of Hematology, Edegem, Belgium. [email protected]", "authors": "Van Droogenbroeck\|J\|J\|;De Ceuninck\|M\|M\|;Snoeck\|H W\|HW\|;Schroyens\|W\|W\|;Berneman\|Z\|Z\|", "chemical_list": "D000998:Antiviral Agents; D017245:Foscarnet; D015774:Ganciclovir", "country": "Germany", "delete": false, "doi": "10.1007/s002770050384", "fulltext": null, "fulltext_license": null, "issn_linking": "0939-5555", "issue": "76(3-4)", "journal": "Annals of hematology", "keywords": null, "medline_ta": "Ann Hematol", "mesh_terms": "D000998:Antiviral Agents; D003131:Combined Modality Therapy; D003586:Cytomegalovirus Infections; D018792:Encephalitis, Viral; D005260:Female; D017245:Foscarnet; D015774:Ganciclovir; D006689:Hodgkin Disease; D006801:Humans; D008875:Middle Aged; D012074:Remission Induction", "nlm_unique_id": "9107334", "other_id": null, "pages": "179-81", "pmc": null, "pmid": "9619737", "pubdate": "1998", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Successful treatment of cytomegalovirus encephalitis in a patient with Hodgkin's disease in remission.", "title_normalized": "successful treatment of cytomegalovirus encephalitis in a patient with hodgkin s disease in remission" }	[ { "companynumb": "BE-PFIZER INC-2018413071", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PROCARBAZINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "HODGKIN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROCARBAZINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "HODGKIN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MECHLORETHAMINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "HODGKIN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MECHLORETHAMINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BLEOMYCIN SULFATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "HODGKIN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BLEOMYCIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINBLASTINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "HODGKIN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINBLASTINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOXORUBICIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "050467", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "HODGKIN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN HCL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "HODGKIN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" } ], "patientagegroup": null, "patientonsetage": "50", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Encephalitis cytomegalovirus", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Retinitis viral", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VAN, D.. SUCCESSFUL TREATMENT OF CYTOMEGALOVIRUS ENCEPHALITIS IN A PATIENT WITH HODGKIN^S DISEASE IN REMISSION. ANN HEMATOL. 1998?76:179-181", "literaturereference_normalized": "successful treatment of cytomegalovirus encephalitis in a patient with hodgkin s disease in remission", "qualification": "3", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20181015", "receivedate": "20181015", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15500468, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "BE-BAUSCH-BL-2018-028978", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FOSCARNET" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ENCEPHALITIS CYTOMEGALOVIRUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FOSCARNET" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "GANCICLOVIR" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "022211", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RETINITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GANCICLOVIR." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FOSCARNET" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RETINITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FOSCARNET" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "GANCICLOVIR" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "022211", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ENCEPHALITIS CYTOMEGALOVIRUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GANCICLOVIR." } ], "patientagegroup": null, "patientonsetage": "50", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "VAN D, DE CEUNINCK M, SNOECK H, SCHROYENS W, BERNEMAN Z. SUCCESSFUL TREATMENT OF CYTOMEGALOVIRUS ENCEPHALITIS IN A PATIENT WITH HODGKIN^S DISEASE IN REMISSION. ANNALS OF HEMATOLOGY. 1998?76:179-181.", "literaturereference_normalized": "successful treatment of cytomegalovirus encephalitis in a patient with hodgkin s disease in remission", "qualification": "3", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20181231", "receivedate": "20181024", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15545702, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" } ]
{ "abstract": "Cutaneous eruptions and hypersensitivity represent frequently reported side effects of anti-seizure medications. However, these side-effects have rarely been previously reported for lacosamide, a newer-generation anti-seizure medication with a novel mechanism of action. Here, we report a case of diffuse skin eruption in a patient with history of epilepsy soon after initiation of lacosamide. The rash resolved after discontinuation of lacosamide and use of antihistamines and steroids. We also review the information on drug hypersensitivity syndrome.", "affiliations": "Department of Neurology.;Department of Neurology.;Department of Dermatology, George Washington University, Washington DC, USA.", "authors": "Koubeissi\|Mohamad Z\|MZ\|;Vismer\|Marta\|M\|;Ehrlich\|Alison\|A\|", "chemical_list": "D000081:Acetamides; D000927:Anticonvulsants; D000078334:Lacosamide", "country": "France", "delete": false, "doi": "10.1684/epd.2014.0667", "fulltext": null, "fulltext_license": null, "issn_linking": "1294-9361", "issue": "16(3)", "journal": "Epileptic disorders : international epilepsy journal with videotape", "keywords": "allergic; lacosamide; rash", "medline_ta": "Epileptic Disord", "mesh_terms": "D000081:Acetamides; D000328:Adult; D000927:Anticonvulsants; D004827:Epilepsy; D005076:Exanthema; D005260:Female; D006801:Humans; D000078334:Lacosamide", "nlm_unique_id": "100891853", "other_id": null, "pages": "380-3", "pmc": null, "pmid": "25035958", "pubdate": "2014-09", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Lacosamide-induced rash.", "title_normalized": "lacosamide induced rash" }	[ { "companynumb": "US-CIPLA LTD.-2015US08018", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LAMOTRIGINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "077783", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "EPILEPSY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMOTRIGINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ZONISAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "EPILEPSY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ZONISAMIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEVETIRACETAM" }, 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LACOSAMIDE-INDUCED RASH. 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LACOSAMIDE-INDUCED RASH. EPILEPTIC DISORDERS 2014;16(3):380-3.", "literaturereference_normalized": "lacosamide induced rash", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150525", "receivedate": "20150321", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10938959, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150821" } ]
{ "abstract": "We report a 61-year-old man with intracranial multiple myeloma (MM) presenting as a posttransplant lymphoproliferative disorder (PTLD) following a kidney transplant. Two months after his transplant, the man developed acute rejection with Epstein-Barr virus (EBV) viremia, requiring aggressive immunosuppression. Twenty months following transplantation, the patient presented with multiple neurologic deficits. Imaging revealed numerous lytic lesions in the skull, most conspicuously a 4.1cm right frontal skull mass with prominent intracranial extension. Histologic sections of the frontal bone lesion showed sheets of atypical plasma cells that were positive for CD138 and kappa immunoglobulin light chains. Chromogenic in situ hybridization for EBV-encoded small RNA was also positive. Plasma cell neoplasms, either as MM or a plasmacytoma, are one of the least common forms of PTLD, and their rarity limits the possibility of major studies to detail their behavior. Most often seen after renal transplantation, the majority are EBV-driven, similarly to other PTLD. While studies have demonstrated several risk factors, behavior and optimal management of PTLD plasma cell neoplasms are unknown. Plasma cell neoplasms affect the nervous system in a variety of ways but rarely via intracranial disease. MM usually presents initially with several classic signs and symptoms, but our patient's presentation was typical of a localized brain tumor with generalized and focal gross neurologic defects.", "affiliations": "Department of Pathology, Cleveland Clinic, Level 25, 9500 Euclid Avenue, Cleveland, OH 44195, USA; Department of Pathology, University of Colorado School of Medicine, Aurora, CO, USA.;Department of Pathology, Cleveland Clinic, Level 25, 9500 Euclid Avenue, Cleveland, OH 44195, USA. Electronic address: [email protected].", "authors": "Wilberger\|Adam C\|AC\|;Prayson\|Richard A\|RA\|", "chemical_list": null, "country": "Scotland", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0967-5868", "issue": "22(11)", "journal": "Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia", "keywords": "Brain; Epstein–Barr virus; Multiple myeloma; Posttransplant lymphoproliferative disorder", "medline_ta": "J Clin Neurosci", "mesh_terms": "D001932:Brain Neoplasms; D020031:Epstein-Barr Virus Infections; D004854:Herpesvirus 4, Human; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D012307:Risk Factors", "nlm_unique_id": "9433352", "other_id": null, "pages": "1850-1", "pmc": null, "pmid": "26375326", "pubdate": "2015-11", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Intracranial involvement of posttransplant lymphoproliferative disorder multiple myeloma.", "title_normalized": "intracranial involvement of posttransplant lymphoproliferative disorder multiple myeloma" }	[ { "companynumb": "US-DRREDDYS-USA/USA/16/0081776", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090509", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." } ], "patientagegroup": null, "patientonsetage": "61", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Post transplant lymphoproliferative disorder", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Staphylococcal bacteraemia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "WILBERGER A, PRAYSON R. INTRACRANIAL INVOLVEMENT OF POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDER MULTIPLE MYELOMA. 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INTRACRANIAL INVOLVEMENT OF POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDER MULTIPLE MYELOMA. 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INTRACRANIAL INVOLVEMENT OF POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDER MULTIPLE MYELOMA. J CLIN NEUROSCI. 2015;22(11):1850-1", "literaturereference_normalized": "intracranial involvement of posttransplant lymphoproliferative disorder multiple myeloma", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170719", "receivedate": "20170719", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13767449, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" }, { "companynumb": "US-TEVA-678747USA", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "KIDNEY TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "4 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "KIDNEY TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "65457", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "KIDNEY TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." } ], "patientagegroup": null, "patientonsetage": "61", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Post transplant lymphoproliferative disorder", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Plasma cell myeloma", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILBERGER AC, PRAYSON RA. INTRACRANIAL INVOLVEMENT OF POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDER MULTIPLE MYELOMA. J-CLIN-NEUROSCI 2015;22(11):1850-1.", "literaturereference_normalized": "intracranial involvement of posttransplant lymphoproliferative disorder multiple myeloma", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160722", "receivedate": "20160722", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12582505, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" } ]
{ "abstract": "OBJECTIVE\nThe pathogenesis, viral localization and histopathological features of Middle East respiratory syndrome - coronavirus (MERS-CoV) in humans are not described sufficiently. The aims of this study were to explore and define the spectrum of histological and ultrastructural pathological changes affecting various organs in a patient with MERS-CoV infection and represent a base of MERS-CoV histopathology.\n\n\nRESULTS\nWe analysed the post-mortem histopathological findings and investigated localisation of viral particles in the pulmonary and extrapulmonary tissue by transmission electron microscopic examination in a 33-year-old male patient of T cell lymphoma, who acquired MERS-CoV infection. Tissue needle biopsies were obtained from brain, heart, lung, liver, kidney and skeletal muscle. All samples were collected within 45 min from death to reduce tissue decomposition and artefact. Histopathological examination showed necrotising pneumonia, pulmonary diffuse alveolar damage, acute kidney injury, portal and lobular hepatitis and myositis with muscle atrophic changes. The brain and heart were histologically unremarkable. Ultrastructurally, viral particles were localised in the pneumocytes, pulmonary macrophages, renal proximal tubular epithelial cells and macrophages infiltrating the skeletal muscles.\n\n\nCONCLUSIONS\nThe results highlight the pulmonary and extrapulmonary pathological changes of MERS-CoV infection and provide the first evidence of the viral presence in human renal tissue, which suggests tissue trophism for MERS-CoV in kidney.", "affiliations": "Division of Anatomical Pathology, Department of Pathology and Laboratory Medicine, King Abdulaziz Medical City, Riyadh, Saudi Arabia.;King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.;King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.;King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.;Division of Anatomical Pathology, Department of Pathology and Laboratory Medicine, King Abdulaziz Medical City, Riyadh, Saudi Arabia.;Division of Anatomical Pathology, Department of Pathology and Laboratory Medicine, King Abdulaziz Medical City, Riyadh, Saudi Arabia.;King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.;King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.;King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.;King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.;King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.;King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.;King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.", "authors": "Alsaad\|Khaled O\|KO\|http://orcid.org/0000-0003-3389-9035;Hajeer\|Ali H\|AH\|;Al Balwi\|Mohammed\|M\|;Al Moaiqel\|Mohammed\|M\|;Al Oudah\|Nourah\|N\|;Al Ajlan\|Abdulaziz\|A\|;AlJohani\|Sameera\|S\|;Alsolamy\|Sami\|S\|;Gmati\|Giamal E\|GE\|;Balkhy\|Hanan\|H\|;Al-Jahdali\|Hamdan H\|HH\|;Baharoon\|Salim A\|SA\|;Arabi\|Yaseen M\|YM\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1111/his.13379", "fulltext": null, "fulltext_license": null, "issn_linking": "0309-0167", "issue": "72(3)", "journal": "Histopathology", "keywords": "MERS-CoV; Middle East respiratory syndrome coronavirus; electron microscopy; extra pulmonary; histopathology; pulmonary; renal", "medline_ta": "Histopathology", "mesh_terms": "D000328:Adult; D018352:Coronavirus Infections; D006801:Humans; D008297:Male; D046529:Microscopy, Electron, Transmission; D065207:Middle East Respiratory Syndrome Coronavirus", "nlm_unique_id": "7704136", "other_id": null, "pages": "516-524", "pmc": null, "pmid": "28858401", "pubdate": "2018-02", "publication_types": "D002363:Case Reports", "references": "27426423;23075143;26486634;23486063;16009768;27572168;24474051;24364985;27051251;15609228;24062443;26857507;23727167;28858401;14767982;26713056;17392154", "title": "Histopathology of Middle East respiratory syndrome coronovirus (MERS-CoV) infection - clinicopathological and ultrastructural study.", "title_normalized": "histopathology of middle east respiratory syndrome coronovirus mers cov infection clinicopathological and ultrastructural study" }	[ { "companynumb": "SA-EDENBRIDGE PHARMACEUTICALS, LLC-SA-2018EDE000035", "fulfillexpeditecriteria": "1", "occurcountry": "SA", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "PREDNISOLONE SODIUM PHOSPHATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "203559", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYCOSIS FUNGOIDES", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, 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null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYCOSIS FUNGOIDES", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "IFOSFAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYCOSIS FUNGOIDES", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IFOSFAMIDE." } ], "patientagegroup": null, "patientonsetage": "33", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Middle East respiratory syndrome", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Shock", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Hypoxia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ALSAAD KO, HAJEER AH, AL BALWI M, AL MOAIQEL M, AL OUDAH N, AL AJLAN A, ET AL.. HISTOPATHOLOGY OF MIDDLE EAST RESPIRATORY SYNDROME CORONOVIRUS (MERS-COV) INFECTION - CLINICOPATHOLOGICAL AND ULTRASTRUCTURAL STUDY.. 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FUNGOIDES", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201507", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ASPARAGINASE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "CYCLICAL", "drugenddate": "2015", "drugenddateformat": "602", "drugindication": "MYCOSIS FUNGOIDES", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201507", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "L-ASPARGINASE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "IFOSFAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "CYCLICAL", "drugenddate": "2015", "drugenddateformat": "602", "drugindication": "MYCOSIS FUNGOIDES", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201507", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IFOSFAMIDE." } ], "patientagegroup": null, "patientonsetage": "33", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2015" } }, "primarysource": { "literaturereference": "ALSAAD K, HAJEER A, AL BALWI M, AL MOAIQEL M, AL OUDAH N, AL AJLAN A. HISTOPATHOLOGY OF MIDDLE EAST RESPIRATORY SYNDROME CORONOVIRUS (MERS-COV) INFECTION - CLINICOPATHOLOGICAL AND ULTRASTRUCTURAL STUDY. HISTOPATHOLOGY. 2018?72(3):516-524.", "literaturereference_normalized": "histopathology of middle east respiratory syndrome coronovirus mers cov infection clinicopathological and ultrastructural study", "qualification": "1", "reportercountry": "SA" }, "primarysourcecountry": "SA", "receiptdate": "20180216", "receivedate": "20180216", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14542901, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" } ]
{ "abstract": "Kidney transplantation is the treatment of choice in pediatric patients with end-stage renal disease. This population presents technical challenges particularly in those less than 20 kg due to anomalous anatomy, vascular access issues prior to transplantation, and a generally small size for age. Standard allograft outflow is usually achieved utilizing the iliac veins or IVC. When use of the iliocaval system is not feasible, alternative anastomosis must be considered. Herein, we report a case of a pediatric kidney transplantation where successful allograft outflow was achieved using the SMV when he was found to have an atretic IVC intraoperatively. In this setting, use of the portal system was required to achieve adequate allograft outflow. We created a donor iliac graft for added length to anastomose the renal vein with the SMV. In the setting of IVC occlusion with poor drainage, we utilized a patent vessel with larger caliber for outflow to reduce the risk of high venous pressures, allograft failure, venous rotation, and thrombosis. We conclude that the SMV may serve as an alternative outflow tract in the small pediatric patient and provides the vessel caliber needed to reduce the risks of complications.", "affiliations": "Division of Abdominal Transplantation, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas.;Division of Abdominal Transplantation, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas.;Division of Abdominal Transplantation, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas.;Division of Abdominal Transplantation, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas.;Division of Abdominal Transplantation, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas.;Division of Abdominal Transplantation, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas.;Division of Abdominal Transplantation, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas.;Division of Abdominal Transplantation, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas.;Renal Section, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.;Division of Abdominal Transplantation, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas.;Renal Section, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.;Division of Abdominal Transplantation, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas.", "authors": "Geha\|John A\|JA\|0000-0003-0916-3589;Geha\|Joseph D\|JD\|;Goss\|Matthew\|M\|;Kueht\|Michael L\|ML\|;Cotton\|Ronald T\|RT\|;Rana\|Abbas\|A\|0000-0003-2979-0598;Goss\|John A\|JA\|;Bhakta\|Kirti\|K\|;Swartz\|Sarah J\|SJ\|;O'Mahony\|Christine A\|CA\|;Brewer\|Eileen D\|ED\|;Galvan\|Nhu T N\|NTN\|0000-0002-1289-4692", "chemical_list": "D057911:Angiotensin Receptor Antagonists; D007093:Imidazoles; D013777:Tetrazoles; C437965:olmesartan", "country": "Denmark", "delete": false, "doi": "10.1111/petr.13497", "fulltext": null, "fulltext_license": null, "issn_linking": "1397-3142", "issue": "23(6)", "journal": "Pediatric transplantation", "keywords": "inferior vena cava; kidney transplantation; pediatric; superior mesenteric vein; surgical technique; thrombosis", "medline_ta": "Pediatr Transplant", "mesh_terms": "D064591:Allografts; D000714:Anastomosis, Surgical; D057911:Angiotensin Receptor Antagonists; D001011:Aorta; D002675:Child, Preschool; D006801:Humans; D007084:Iliac Vein; D007093:Imidazoles; D007668:Kidney; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008297:Male; D010372:Pediatrics; D011184:Postoperative Period; D012082:Renal Veins; D013777:Tetrazoles; D013927:Thrombosis; D058017:Vascular Grafting; D014682:Vena Cava, Inferior; D020246:Venous Thrombosis", "nlm_unique_id": "9802574", "other_id": null, "pages": "e13497", "pmc": null, "pmid": "31210008", "pubdate": "2019-09", "publication_types": "D002363:Case Reports", "references": null, "title": "Successful kidney transplantation in a small child with end-stage renal disease due to angiotensin receptor blocker fetopathy and atretic inferior vena cava.", "title_normalized": "successful kidney transplantation in a small child with end stage renal disease due to angiotensin receptor blocker fetopathy and atretic inferior vena cava" }	[ { "companynumb": "US-TEVA-2020-US-1812724", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "OLMESARTAN" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "091079", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLMESARTAN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Angiopathy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vena cava thrombosis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Premature baby", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Chronic kidney disease", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "End stage renal disease", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Pelvic venous thrombosis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Foetal disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Congenital anomaly", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GEHA JA, GEHA JD, GOSS M, KUEHT ML, COTTON RT, RANA A, ET AL. SUCCESSFUL KIDNEY TRANSPLANTATION IN A SMALL CHILD WITH END?STAGE RENAL DISEASE DUE TO ANGIOTENSIN RECEPTOR BLOCKER FETOPATHY AND ATRETIC INFERIOR VENA CAVA. PEDIATR?TRANSPLANT 2019?23(6):E13497.", "literaturereference_normalized": "successful kidney transplantation in a small child with end stage renal disease due to angiotensin receptor blocker fetopathy and atretic inferior vena cava", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200827", "receivedate": "20200813", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18146618, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 1, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "US-DSJP-DSU-2020-122874", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "OLMESARTAN MEDOXOMIL" }, "drugadditional": "3", "drugadministrationroute": "064", "drugauthorizationnumb": "021286", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLMESARTAN AG" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chronic kidney disease", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hepatoblastoma", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "End stage renal disease", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "JOHN A.GEHA ELT. SUCCESSFUL KIDNEY TRANSPLANTATION IN A SMALL CHILD WITH END?STAGE RENAL DISEASE DUE TO ANGIOTENSIN RECEPTOR BLOCKER FETOPATHY AND ATRETIC INFERIOR VENA CAVA. PEDIATRIC TRANSPLANTATION. 2019?1?4", "literaturereference_normalized": "successful kidney transplantation in a small child with end stage renal disease due to angiotensin receptor blocker fetopathy and atretic inferior vena cava", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200811", "receivedate": "20200811", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18136203, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" } ]
{ "abstract": "Differentiation and fate of virus-specific CD8+ T cells after cessation of chronic antigen stimulation is unclear. Here we show that a TCF1+CD127+PD1+ hepatitis C virus (HCV)-specific CD8+ T-cell subset exists in chronically infected patients with phenotypic features of T-cell exhaustion and memory, both before and after treatment with direct acting antiviral (DAA) agents. This subset is maintained during, and for a long duration after, HCV elimination. After antigen re-challenge the less differentiated TCF1+CD127+PD1+ population expands, which is accompanied by emergence of terminally exhausted TCF1-CD127-PD1hi HCV-specific CD8+ T cells. These results suggest the TCF1+CD127+PD1+ HCV-specific CD8+ T-cell subset has memory-like characteristics, including antigen-independent survival and recall proliferation. We thus provide evidence for the establishment of memory-like virus-specific CD8+ T cells in a clinically relevant setting of chronic viral infection and we uncover their fate after cessation of chronic antigen stimulation, implicating a potential strategy for antiviral immunotherapy.", "affiliations": "Department of Medicine II, University Hospital Freiburg - Faculty of Medicine, University of Freiburg, Hugstetter Straße 55, Freiburg 79106, Germany.;Department of Medicine II, University Hospital Freiburg - Faculty of Medicine, University of Freiburg, Hugstetter Straße 55, Freiburg 79106, Germany.;Department of Medicine II, University Hospital Freiburg - Faculty of Medicine, University of Freiburg, Hugstetter Straße 55, Freiburg 79106, Germany.;Institute for Cell and Gene Therapy, University Hospital Freiburg, Hugstetter Straße 55, 79106 Freiburg, Germany.;Institute of Molecular Immunology and Experimental Oncology, Technische Universität München, Klinikum rechts der Isar, Ismaningerstr. 22, München 81675, Germany.;Department of Medicine II, University Hospital Freiburg - Faculty of Medicine, University of Freiburg, Hugstetter Straße 55, Freiburg 79106, Germany.;Ludwig Center for Cancer Research, Department of Fundamental Oncology, University of Lausanne, 155, Ch. Des Boveresses, Epalinges 1066, Switzerland.;Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University Munich, Freising, Weihenstephaner Berg 3, Freising 85354, Germany.;Department of Medicine II, University Hospital Freiburg - Faculty of Medicine, University of Freiburg, Hugstetter Straße 55, Freiburg 79106, Germany.;Department of Medicine II, University Hospital Freiburg - Faculty of Medicine, University of Freiburg, Hugstetter Straße 55, Freiburg 79106, Germany.", "authors": "Wieland\|Dominik\|D\|;Kemming\|Janine\|J\|;Schuch\|Anita\|A\|;Emmerich\|Florian\|F\|;Knolle\|Percy\|P\|;Neumann-Haefelin\|Christoph\|C\|;Held\|Werner\|W\|0000-0003-3292-1536;Zehn\|Dietmar\|D\|;Hofmann\|Maike\|M\|;Thimme\|Robert\|R\|", "chemical_list": "D000998:Antiviral Agents; C496487:HNF1A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha", "country": "England", "delete": false, "doi": "10.1038/ncomms15050", "fulltext": "\n==== Front\nNat CommunNat CommunNature Communications2041-1723Nature Publishing Group ncomms1505010.1038/ncomms1505028466857ArticleTCF1+ hepatitis C virus-specific CD8+ T cells are maintained after cessation of chronic antigen stimulation Wieland Dominik 123Kemming Janine 13Schuch Anita 13Emmerich Florian 4Knolle Percy 5Neumann-Haefelin Christoph 1Held Werner 6http://orcid.org/0000-0003-3292-1536Zehn Dietmar 7Hofmann Maike 1Thimme Robert a11 Department of Medicine II, University Hospital Freiburg — Faculty of Medicine, University of Freiburg, Hugstetter Straße 55, Freiburg 79106, Germany2 Spemann Graduate School of Biology and Medicine, University of Freiburg, Freiburg 79104, Germany3 Faculty of Biology, University of Freiburg, Freiburg 79104, Germany4 Institute for Cell and Gene Therapy, University Hospital Freiburg, Hugstetter Straße 55, 79106 Freiburg, Germany5 Institute of Molecular Immunology and Experimental Oncology, Technische Universität München, Klinikum rechts der Isar, Ismaningerstr. 22, München 81675, Germany6 Ludwig Center for Cancer Research, Department of Fundamental Oncology, University of Lausanne, 155, Ch. Des Boveresses, Epalinges 1066, Switzerland7 Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University Munich, Freising, Weihenstephaner Berg 3, Freising 85354, Germanya [email protected]* These authors jointly supervised this work.\n\n03 05 2017 2017 8 1505003 09 2016 23 02 2017 Copyright © 2017, The Author(s)2017The Author(s)This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/Differentiation and fate of virus-specific CD8+ T cells after cessation of chronic antigen stimulation is unclear. Here we show that a TCF1+CD127+PD1+ hepatitis C virus (HCV)-specific CD8+ T-cell subset exists in chronically infected patients with phenotypic features of T-cell exhaustion and memory, both before and after treatment with direct acting antiviral (DAA) agents. This subset is maintained during, and for a long duration after, HCV elimination. After antigen re-challenge the less differentiated TCF1+CD127+PD1+ population expands, which is accompanied by emergence of terminally exhausted TCF1-CD127-PD1hi HCV-specific CD8+ T cells. These results suggest the TCF1+CD127+PD1+ HCV-specific CD8+ T-cell subset has memory-like characteristics, including antigen-independent survival and recall proliferation. We thus provide evidence for the establishment of memory-like virus-specific CD8+ T cells in a clinically relevant setting of chronic viral infection and we uncover their fate after cessation of chronic antigen stimulation, implicating a potential strategy for antiviral immunotherapy.\n\nVirus-specific CD8+ T cells lose effector function over the course of chronic infection, a process called ‘exhaustion', but the fate of these cells after treatment-induced antigen elimination is unknown. Here the authors show that exhausted cells persist in patients even after direct-acting antiviral therapy removes antigen exposure, and that these cells are responsive on re-exposure to antigen.\n==== Body\nHuman chronic viral infections with hepatitis C virus (HCV), hepatitis B virus (HBV) and human immunodeficiency virus (HIV) are a major global health problem. A rheostat that determines control versus active persistence of these viral infections is the virus-specific CD8+ T-cell response12. Virus-specific CD8+ T cells are polyfunctional in controlled infection, whereas virus-specific CD8+ T-cell function is compromised in actively persisting infection. One important mechanism underlying impaired virus-specific CD8+ T-cell responses in human chronic viral infection is the progressive loss of effector functions, a phenomenon called T-cell exhaustion345. Thus, immunotherapeutic strategies that interfere with virus-specific CD8+ T-cell exhaustion and consequently boost polyfunctional CD8+ T-cell responses are considered to be promising approaches to combat or prevent chronic viral infections in humans.\n\nMajor advances in the understanding of CD8+ T-cell exhaustion during chronic viral infection in general have been made using the lymphocytic choriomeningitis virus (LCMV) mouse model. In particular, exhausted CD8+ T cells can be defined by a reduced cytokine production, an impaired proliferative capacity, the expression of multiple co-inhibitory molecules, the up-regulation of ectonucleotidase CD39 and an altered global transcriptional program and epigenetic profile6789. Several of these characteristics have also been reported for exhausted virus-specific CD8+ T cells in human chronic infections including functional impairment, co-expression of inhibitory receptors and the increased expression of CD39 and the transcription factor Eomes1011121314. Importantly, in chronic LCMV infection, exhausted virus epitope-specific CD8+ T-cell populations are not homogeneous. Two subsets of exhausted LCMV epitope-specific CD8+ T cells are defined by differential levels of the inhibitory receptor PD1 and the two transcription factors Tbet and Eomes15. TbethiEomesdimPD1int LCMV-specific CD8+ T cells are progenitor cells that can give rise to terminally exhausted TbetdimEomeshiPD1hi cells. Both progenitor and terminal subsets of exhausted LCMV epitope-specific CD8+ T cells are required to sustain viral control during viral persistence15. With respect to chronic infections in humans, however, our knowledge about subsets, differentiation and maintenance of virus-specific CD8+ T cells is limited and efficient immunotherapeutic approaches are required.\n\nAlthough, the mechanisms responsible for CD8+ T-cell exhaustion are not completely understood, an important feature seems to be prolonged and continuous exposure to antigen and, consequently, progressive terminal differentiation161718. Additional factors, including lack of CD4+ T-cell help, immunosuppressive cytokines and instructive signals directly from inhibitory receptors also contribute to T-cell exhaustion61920. Remarkably, blockade of the PD1/PDL1 inhibitory pathway leads to functional restoration of exhausted virus-specific CD8+ T cells212223. Therefore, despite ongoing antigen recognition and consequently progressive terminal differentiation, functional T-cell exhaustion, in principle, is reversible. Importantly, only a distinct sub-population of less differentiated PD1+ virus-specific CD8+ T cells is rescued by blockade of the PD1/PDL1 pathway in chronic LCMV infection, whereas terminally exhausted subsets do not respond well24. PD1+ LCMV-specific CD8+ T cells that provide the proliferative burst after PD1/PDL1 pathway blockade are characterized by CXCR5 and TCF1 expression and by a unique gene signature25262728. Interestingly, this LCMV-specific CD8+ T-cell population possesses self-renewal capacity, gives rise to terminally exhausted effector subsets and therefore sustains the virus-specific CD8+ T-cell pool during antigen persistence. Furthermore, the LCMV-specific TCF1+CD8+ T-cell subset readily expands after transfer into naive mice and upon re-challenge with LCMV, suggesting memory-like characteristics27.\n\nThe fate of exhausted virus-specific CD8+ T cells after cessation of chronic antigen stimulation in a previously persistently infected organism has not been defined - neither in mice nor in humans. In the LCMV mouse model, drugs that efficiently eliminate the virus are not available. The same holds true for human persistent infections with the exception of IFNα-based therapies for chronic viral hepatitis. IFNα has a known immunomodulatory effect during therapy, rendering studies of immune function difficult to interpret2930. The fate of exhausted virus-specific CD8+ T cells after removal of persistent antigen, however, is of central clinical relevance since it has implications for protection from re-infection after antigen elimination. By approval of direct acting antiviral (DAA) agents for HCV therapy that are highly efficient at viral elimination this important question can now be addressed for the first time. Here we take advantage of a well-defined cohort of chronically HCV-infected patients who have been treated successfully with DAAs. We comprehensively study virus-specific CD8+ T-cell responses during and after chronic antigen exposure at a single-cell level. Importantly, we identify a CD127+PD1+ population of exhausted HCV epitope-specific CD8+ T cells during antigen persistence that is maintained long-term after cessation of chronic antigen stimulation. This CD127+PD1+ subset is further characterized by the expression of TCF1 and BCL2 and thus shows phenotypic features of both T-cell memory and exhaustion. When re-stimulated in vitro the TCF1+CD127+PD1+ subset contains the proliferative capacity of the HCV-specific CD8+ T-cell population both during and after antigen persistence. Moreover, this subset expands in response to viral relapse in vivo. In sum, TCF1 defines a CD127+PD1+ subset of HCV-specific CD8+ T cells that exhibits memory-like characteristics and therefore appear to be a promising target to boost HCV-specific CD8+ T cell responses for immunotherapeutic interventions and protection from re-infection.\n\nResults\nT-cell heterogeneity during persistent antigen recognition\nIn chronic HCV infection, the expression levels of the inhibitory receptor PD1 and the IL7R α-chain, CD127, have been proposed to discriminate between virus-specific CD8+ T cells that are exhausted due to persistent recognition of autologous viral epitopes and virus-specific CD8+ T cells that do not recognize autologous viral epitopes due to the emergence of viral escape mutations1031. Indeed, HCV-specific CD8+ T-cell populations that predominantly express CD127 indicate the presence of viral sequence variations in the corresponding viral epitope. In contrast, in the absence of viral sequence variations and thus ongoing antigen triggering, HCV-specific CD8+ T cells exhibit high expression of PD1, co-expression of additional inhibitory receptors and low proliferative capacity, suggesting exhaustion of this T-cell population. However, whether an exhausted HCV-specific CD8+ T-cell population targeting a single epitope is a homogeneous population has not been analysed previously. To address this question we performed co-expression analyses of PD1 and CD127 on single HCV epitope-specific CD8+ T cells and applied the peptide/MHCI tetramer-associated magnetic bead enrichment technique to allow high sensitivity HCV epitope-specific CD8+ T-cell characterization (Supplementary Fig. 1). Peptide/MHCI tetramers specific for three well-described HLA-A02-restricted epitopes (NS31073; NS31406; NS52594) were utilized and naive HCV epitope-specific CD8+ T cells were excluded from the analyses (Supplementary Fig. 2). CD127/PD1 co-expression of 24 HCV epitope-specific CD8+ T-cell populations derived from 19 chronically HCV-infected patients that target autologous viral epitopes (Table 1) is depicted in Fig. 1a with a representative dot plot shown on the left. Interestingly, most HCV epitope-specific CD8+ T-cell populations did not display a homogenous but rather a heterogeneous phenotype that included CD127+PD1+ (Mdn: 45.7%; IQR: 22.0-65.7%), CD127-PD1lo (Mdn: 17.7; IQR: 6.6-25.7%) and CD127-PD1hi (Mdn: 17.1; IQR: 11.0-51.1%) subsets, rendering a subset of the HCV epitope-specific CD8+ T cells responsive to the T-cell maintenance factor IL-7.\n\nTo determine whether this heterogeneous phenotype of HCV epitope-specific CD8+ T cells is linked to persistent antigen recognition, we next analysed CD127 and PD1 co-expression on 5 HCV epitope-specific CD8+ T-cell populations derived from 5 chronically HCV-infected patients that did not recognize the autologous viral epitope due to the presence of viral escape mutations (Table 1). As shown in Fig. 1b, HCV epitope-specific CD8+ T cells that target variant epitopes and are thus not triggered by ongoing antigen recognition do not show strong heterogeneity but rather consist of a predominantly CD127+PD1+ population (Mdn: 82.7%; IQR: 73.8-93.1%). These results clearly demonstrate that persistent antigen recognition induces heterogeneity of a single HCV epitope-specific CD8+ T-cell population and more specifically the occurrence of a CD127-PD1hi HCV epitope-specific CD8+ T-cell subset.\n\nTCF1 defines a memory-like HCV-specific CD8+ T-cell subset\nNext we set out to define the molecular signatures of the different CD127/PD1 subsets of HCV epitope-specific CD8+ T cells. CD127-PD1hi HCV epitope-specific CD8+ T cells exhibited increased levels of the inhibitory receptors 2B4 and TIGIT (Fig. 2a), expressed the ectonucleotidase CD39 (Fig. 2b) and displayed high levels of the transcription factor Eomes (Fig. 2c). Thus, this subset displayed typical features of terminal T-cell exhaustion. In contrast, CD127+PD1+ HCV epitope-specific CD8+ T cells expressed low levels of inhibitory receptors, CD39 and Eomes (Fig. 2a–c). Of note, all HCV-specific CD8+ T cells are T-betdim (Supplementary Fig. 3). To further address the differentiation stage of the particular CD127/PD1 subsets, we stained for the effector cell molecule perforin and the transcription factor TCF1 that is required for the differentiation and persistence of memory CD8+ T cells323334. While 14.9% (IQR: 5.6–47.4%) of CD127-PD1hi HCV epitope-specific CD8+ T cells expressed perforin, CD127+PD1+ subsets almost completely lacked perforin expression (Fig. 2d). On the other hand, CD127+PD1+ HCV epitope-specific CD8+ T cells harboured the highest proportion of TCF1 expressing cells (Mdn: 80.0%; IQR: 66.5–91.0%) compared to CD127-PD1lo (Mdn: 38.3%; IQR: 19.7–60.8%) and CD127-PD1hi (Mdn: 26.2%; IQR: 16.3–33.7%) subsets (Fig. 2e). Of note, we did not observe expression of CXCR5 on TCF1+ HCV epitope-specific CD8+ T cells (Supplementary Fig. 4). Altogether, these data suggest that CD127+PD1+ HCV epitope-specific CD8+ T cells represent less differentiated memory-like cells while CD127-PD1hi cells define terminally exhausted effector subsets of HCV epitope-specific CD8+ T cells. As shown in Fig. 2f, this hypothesis was further supported by the finding, that similar to memory CD8+ T cells CD127+PD1+ HCV epitope-specific CD8+ T cells expressed the anti-apoptotic molecule BCL2 to a great extent (Mdn: 78.8%; IQR: 60.7–91.1%) whereas CD127-PD1hi subsets showed minor expression of BCL2 (Mdn: 20.2%; IQR: 6.8-33.2%). The low expression of BCL2 in this terminal differentiated sub-population was accompanied by high caspase-8 activity (Fig. 2g) suggesting depletion of the CD127-PD1hi sub-population by apoptosis. Interestingly, CD127-PD1hi HCV epitope-specific CD8+ T cells are positive for CD122 (Mdn: 84.6%; IQR: 69.1-90.3%; Supplementary Fig. 5) rendering these cells susceptible for IL-15-mediated bystander proliferation as has been reported for effector and effector-memory CD8+ T cells.\n\nMemory-like T cells are maintained antigen-independently\nAntigen-independent survival is a hallmark of memory CD8+ T cells in resolved infections. In the LCMV mouse model of chronic infection, antigen-independent maintenance and consequently memory potential of exhausted virus-specific CD8+ T cells has also been demonstrated after transfer in naive mice1835. However, in humans, very little is known about memory potential including survival characteristics of exhausted virus-specific CD8+ T-cell subsets. To assess whether CD127/PD1 subsets reveal differences in survival depending on the presence of antigen we longitudinally analysed HCV epitope-specific CD8+ T cells of 22 chronically HCV-infected patients after initiation of DAA therapy (Table 1 and Supplementary Fig. 6). As shown in Fig. 3a and Table 1, DAA therapy led to a rapid decline of viremia early after therapy initiation and to a sustained virological response (SVR), defined as undetectable HCV RNA 12 weeks post treatment in all but one treated patients. The single patient with viral relapse was excluded from the SVR cohort (n=21) and analysed separately. Inhibition of viral replication and most likely removal of viral antigen led to significant dynamic changes in the CD127/PD1 subset distribution within single HCV epitope-specific CD8+ T-cell populations (Fig. 3b). As shown in Fig. 3c–e and Supplementary Fig. 7b, we found a dramatic decrease in the frequency of CD127-PD1hi HCV epitope-specific CD8+ T cells (Fig. 3c) with a concomitant increase in the frequency of the CD127+PD1+ subset (Fig. 3d and Supplementary Fig. 8) while the CD127-PD1lo T-cell population remained rather unchanged (Fig. 3e). Of note, we did not observe changes in the overall frequency of HCV epitope-specific CD8+ T cells (Supplementary Fig. 7a). In agreement with our finding that the CD127-PD1hi subset represents terminally exhausted T cells, we also observed a significant decrease in the frequencies of HCV epitope-specific CD8+ T cells that highly express CD39 (Fig. 3f) and Eomes (Fig. 3g) after initiation of DAA therapy and consequent cessation of chronic antigen stimulation. In addition, initiation of DAA therapy led to a significant relative increase of TCF1+ HCV epitope-specific CD8+ T cells (Fig. 3h,i) that can be ascribed to the increased frequency of CD127+PD1+ HCV epitope-specific CD8+ T cells since TCF1 expression remained stable within the CD127+PD1+ subset (Fig. 3h,j and Supplementary Fig. 9). To confirm that the dynamic changes of HCV epitope-specific CD8+ T cells induced by DAA therapy are indeed due to the cessation of chronic antigen stimulation we additionally analysed HLA-A0201-restricted Flu M158 - and CMV pp65495-specific CD8+ T cells derived from DAA-treated HCV-infected patients (Supplementary Table 1). Importantly, these virus-specific CD8+ T cells remained phenotypically stable (Supplementary Fig. 10a–e) clearly indicating that the observed changes in HCV epitope-specific CD8+ T cells are linked to cessation of chronic antigen stimulation rather than abrogation of the inflammatory milieu. To further confirm antigen-dependency and to exclude DAA-specific effects, we analysed HCV epitope-specific CD8+ T-cell responses of patients successfully treated with IFNα-based therapy. Due to the immunomodulatory effects of IFNα-based therapy, we comapred patient samples acquired before therapy and at a late time point following IFNα administration. The observed changes in CD127/PD1, CD39, Eomes and TCF1 expression of HCV epitope-specific CD8+ T cells based on IFNα therapy (Supplementary Table 2 and Supplementary Fig. 10f–k) were similar to the ones observed with IFNα-free DAA therapy. These results confirm the impact of persistent antigen on virus-specific CD8+ T cells and the presence of memory-like HCV epitope-specific CD8+ T cells that are maintained after antigen elimination.\n\nMemory-like and conventional memory T cells differ\nNext, we asked whether the HCV epitope-specific CD8+ T-cell populations that are maintained after spontaneous or DAA-mediated viral clearance show a similar phenotype (Table 1). As shown in Fig. 4a-d, the CD127/PD1 subset distribution of HCV epitope-specific CD8+ T cells differed between the two cohorts. Specifically, HCV epitope-specific CD8+ T cells derived from donors with spontaneous HCV elimination contained a CD127+PD1- subset (Mdn: 33.1%; IQR: 19.8-43.9%) that was almost completely absent in HCV epitope-specific CD8+ T cells from DAA-treated donors (Fig. 4c). This difference in CD127/PD1 subset distribution was accompanied on a transcriptional level by a lower expression of Eomes (Fig. 4e) and a higher expression of TCF1 (Fig. 4f). Taken together, these results clearly show phenotypical differences between memory-like HCV epitope-specific CD8+ T cells that are maintained after DAA-mediated viral clearance and conventional memory HCV epitope-specific CD8+ T cells that persist after spontaneous viral clearance. Hence, HCV-specific CD8+ T-cell differentiation varies in chronic and acute resolved infection, although persisting memory and short-lived effector subsets are established in both differentiation programs.\n\nImpaired T-cell effector function after antigen elimination\nIn chronic infection, HCV-specific CD8+ T cells display impaired cytokine secretion and consequently diminished antiviral efficacy due to their functional exhaustion13637. This is in contrast to memory HCV-specific CD8+ T cells after spontaneous virus elimination that exhibit potent antiviral efficacy136. To assess the capability of memory-like HCV epitope-specific CD8+ T cells that are maintained after DAA-mediated HCV elimination to produce cytokines, we performed a combined peptide/MHCI tetramer and intracellular cytokine-staining assay. As shown in Fig. 5a,b, peptide stimulation did not induce ex vivo production of IFNγ or TNF by HCV epitope-specific CD8+ T cells that persisted following DAA therapy.\n\nIn contrast, FLU epitope-specific CD8+ T cells were able to produce IFNγ and TNF after FLU M158 peptide stimulation (Fig. 5b and Supplementary Fig. 11). Of note, we also could not detect ex vivo cytokine production after peptide stimulation of HCV epitope-specific CD8+ T cells derived from donors that spontaneously eliminated HCV possibly reflecting reduced assay sensitivity due to the combination of peptide/MHCI tetramer staining and peptide stimulation (Fig. 5b and Supplementary Fig. 12).\n\nNext, we determined the capability of HCV epitope-specific CD8+ T cells to produce cytokines after HCV peptide-specific expansion of CD8+ T cells. Importantly, we could detect cytokine production by HCV epitope-specific CD8+ T cells after a 14-day expansion (Fig. 5c,d). Interestingly, peptide-expanded HCV-specific CD8+ T cells derived from donors at the end of DAA therapy exhibited increased IFNγ production (Mdn: 1.13%; IQR: 0.23–1.86%) compared to therapy baseline (Mdn: 0.14%; IQR: 0–0.53%) (Fig. 5d). To dissect cytokine production from proliferation, we analysed TNF production by IFNγ+ expanded HCV epitope-specific CD8+ T cells (Fig. 5e). Strikingly, TNF production was elevated among IFNγ+ HCV epitope-specific CD8+ T cells after DAA therapy (Baseline: Mdn: 2.88%; IQR: 0.39–8.52%; end of therapy (EOT): Mdn: 6.39%; IQR: 4.05–23.22%). However, TNF production was still decreased compared to IFNγ+ HCV epitope-specific CD8+ T cells present after spontaneous viral elimination (Mdn: 32.10%; IQR: 16.15–54.32%) suggesting reduced poly-functionality of HCV epitope-specific CD8+ T cells present after DAA-mediated viral elimination as compared to spontaneous HCV resolution.\n\nTCF1 expression correlates with proliferative capacity\nA further aspect of T-cell functionality is the proliferative capacity upon antigen encounter. Therefore, we tested HCV epitope-specific CD8+ T-cell proliferation before and after DAA-mediated HCV elimination. For this, we determined the fold expansion of HCV epitope-specific CD8+ T cells after 14-day HCV peptide-specific expansion assays. As previously shown38, the majority of analysed patients showed a significant increase in the expansion of HCV epitope-specific CD8+ T cells after antigen removal (Fig. 6a). However, the proliferative capacity of HCV epitope-specific CD8+ T cells obtained at the end of DAA treatment (expansion factor: Mdn: 0.63; IQR: 0.13–1.16) was reduced compared to HCV epitope-specific CD8+ T cells obtained from patients with spontaneous viral clearance (expansion factor: Mdn: 2.32; IQR: 1.63–2.87). We next addressed the question whether the abundance of CD127+PD1+ HCV epitope-specific CD8+ T cells accounts for the proliferative potential of the HCV epitope-specific CD8+ T-cell population. Indeed, the proliferative capacity of HCV epitope-specific CD8+ T-cell populations correlated with the abundance of CD127+PD1+ and particularly with that of TCF1+ HCV epitope-specific CD8+ T cells (Fig. 6b,c). These results suggest that TCF1 defines the proliferative capacity of CD127+PD1+ virus-specific CD8+ T cells during and after chronic antigen stimulation.\n\nMemory-like T cells provide recall response\nWe had the single opportunity to analyse the re-expansion capacity of memory-like TCF1+CD127+PD1+ HCV epitope-specific CD8+ T cells in vivo, since one DAA-treated patient presented with viral relapse at the 12-week follow-up (FU12) visit (Table 1 and Fig. 7a). Importantly, as shown in Fig. 7b, viral relapse and thus antigen re-exposure led to a vigorous expansion of HCV NS31073-specific CD8+ T cells that was accompanied with CD127/PD1 subset re-distribution (Fig. 7c and Supplementary Fig. 13) and concomitant phenotypic changes (Fig. 7d–f). More specifically, viral relapse led to a 2.9-fold increase of CD127-PD1hi HCV NS31073-specific T cells that were roughly maintained at a 1-year follow-up visit (2.4-fold increase relative to EOT). In concert with this, expression of CD39 and Eomes increased (Fig. 7d,e) while expression of TCF1 decreased (Fig. 7f) indicative of the re-generation of terminally exhausted effector subsets. These results, therefore, clearly suggest that memory-like TCF1+CD127+PD1+ HCV epitope-specific CD8+ T cells are able to re-expand efficiently in response to antigen re-exposure and can give rise to terminally exhausted effector subsets characterized by TCF1-CD127-PD1hi expression in the context of viral relapse.\n\nDiscussion\nIn this study, we analysed circulating HCV epitope-specific CD8+ T cells in a clinically relevant model. We could define key characteristics of distinct heterogeneous HCV epitope-specific CD8+ T-cell subsets during antigen persistence and elimination in the peripheral blood. Based on CD127/PD1 co-expression analyses, we found that CD127+PD1+, CD127-PD1lo and CD127-PD1hi subsets contribute to the HCV epitope-specific CD8+ T-cell pool during antigen persistence. Intriguingly, however, only the CD127+PD1+ HCV epitope-specific CD8+ T-cell subset is maintained after DAA-mediated HCV clearance indicating memory-like survival characteristics. The CD127+PD1+ HCV-specific CD8+ T-cell subset is characterized by a high expression of the transcription factor TCF1 that has been shown to be essential for the establishment and persistence of CD8+ T-cell responses2527323339. More specifically, it has been reported that TCF1 defines the proliferative capacity of virus-specific CD8+ T cells in the LCMV mouse model of acute and chronic infection252740. In line with this, we could correlate the in vitro proliferative capacity of HCV epitope-specific CD8+ T cells with TCF1 expression clearly suggesting that the TCF1 expressing subset contains the proliferative capacity within the HCV epitope-specific CD8+ T-cell pool. This was further supported by two in vivo observations. First, an increased proliferative capacity of HCV epitope-specific CD8+ T cells after cessation of chronic antigen stimulation occurred in parallel with the increase of the TCF1+CD127+PD1+ HCV epitope-specific T-cell subset. Second, TCF1+CD127+PD1+ HCV epitope-specific CD8+ T cells robustly expanded in a patient with viral relapse. This capacity of robust secondary expansion represents a hallmark of CD8+ T-cell memory clearly supporting the memory-like character of this HCV-specific CD8+ T-cell subset. Consistently, a recent study in the mouse model of chronic LCMV infection has shown that TCF1+ virus-specific CD8+ T cells contain recall proliferative capacity after transfer in acutely infected mice27. Hence, in humans and mice, antigen persistence does not completely abrogate memory potential regarding survival and proliferation characteristics of virus-specific CD8+ T-cell pools. Of note, in human HCV infection, this holds true after years of persistent antigen exposure at least in the peripheral blood broadening the prospects for therapeutic interventions.\n\nRemarkably, memory-like TCF1+CD127+PD1+ HCV epitope-specific CD8+ T cells present after DAA-mediated HCV elimination do not fully resemble memory CD8+ T cells present after spontaneous viral clearance. Although they share phenotypic and molecular memory properties, like CD127, BCL2 and TCF1 expression, memory-like HCV-specific CD8+ T cells display a higher expression of PD1 and Eomes indicative of T-cell exhaustion. This fits to the unique transcriptome of TCF1+ LCMV-specific CD8+ T cells in chronically infected mice that includes key factors of both signatures, T-cell memory and exhaustion2527. Furthermore, TCF1+ virus-specific CD8+ T cells from chronic LCMV infection also maintained an exhausted cytokine profile after re-expansion in vivo27. Similarly, memory-like HCV-specific CD8+ T cells also revealed impaired cytokine production after DAA-mediated compared to spontaneous antigen elimination. These cells therefore exhibit phenotypic and functional characteristics of T-cell memory and exhaustion. Hence, memory-like HCV-specific CD8+ T cells and TCF1+ LCMV-specific CD8+ T cells, both induced during chronic infections, are clearly distinct from memory CD8+ T cells generated in self-limiting infections suggesting a divergent T-cell differentiation program. While conventional memory T cells are equipped with extensive polyfunctionality to rapidly clear re-infection, memory-like T cells established during chronic infection might acquire a differentiation program that is adjusted to the setting of persistent antigen allowing pathogen control without immunopathology. This might have important implications for vaccination strategies aiming to boost virus-specific CD8+ T-cell responses during and after chronic antigen stimulation.\n\nNoteworthy, memory-like TCF1+ LCMV-specific CD8+ T cells from chronically infected mice were able to control LCMV infection after transfer in acutely infected mice27. In humans, however, it is unclear whether memory-like TCF1+CD127+PD1+ HCV-specific CD8+ T cells that persist after DAA-mediated HCV clearance will be able to provide protection against re-infection. In the chimpanzee model of chronic HCV infection, a recent study has suggested that exhausted HCV-specific CD8+ T-cell populations do not functionally recover after DAA-mediated cure and are unable to prevent virus persistence after re-infection4142. In line with this, multiple re-infections of DAA-treated patients have been reported also questioning the presence of protective immune memory after DAA clearance although the role of genotypes and viral escape has not been addressed. Clearly, additional studies are needed to address the protective potential of memory-like HCV-specific CD8+ T cells. Our finding, however, of a significant re-expansion of this HCV-specific CD8+ T-cell subset combined with a decent production of cytokines indicates that protective immunity may be possible at least in a subset of subjects.\n\nImportantly, recall expansion of memory-like TCF1+CD127+PD1+ HCV-specific CD8+ T cells was accompanied by re-occurrence of the TCF1-CD127-PD1hi subset after re-exposure to persisting antigen suggesting a progenitor-progeny relationship of these two subsets during chronic antigen recognition. The CD127-PD1hi subset of HCV epitope-specific CD8+ T cells highly expressed inhibitory receptors and CD39 and exhibited the transcriptional TbetdimEomeshi signature that is characteristic for terminal exhaustion61215. Of note, it has previously been shown that intrahepatic HCV-specific CD8+ T cells obtained from chronically HCV-infected patients exclusively displayed a TbetdimEomeshigh profile15 raising the question of the CD127/PD1 subset distribution at the site of HCV persistence. Furthermore, CD127-PD1hi HCV epitope-specific CD8+ T cells also expressed perforin, at least to some extent, and increased levels of CD122 indicative of effector cell differentiation34434445. Thus, the TCF1-CD127-PD1hi subset of HCV-specific CD8+ T cells contains terminally exhausted effector cells. Importantly, this terminally exhausted TCF1-CD127-PD1hi effector subset was absent or disappeared from the HCV epitope-specific CD8+ T-cell population when the corresponding viral epitope was removed either naturally in the context of viral escape mutations or therapeutically by DAA therapy. In sum, these results clearly indicate that terminal exhaustion of HCV epitope-specific CD8+ T cells is linked to ongoing antigen recognition and support previous findings from the LCMV model showing antigen dependence of terminal exhausted virus-specific CD8+ T cells464748. The mechanism responsible for the disappearance of the TCF1-CD127-PD1hi HCV epitope-specific CD8+ T cells after antigen elimination is not entirely clear but may be linked to a reduced lifespan of these cells due to terminal differentiation. In agreement with this hypothesis, we found low expression of the pro-survival molecule BCL-2 that has been associated with a higher apoptosis rate of virus-specific CD8+ T cells49. Furthermore, the lack of CD127 expression on the TCF1-CD127-PD1hi subset of HCV epitope-specific CD8+ T cells abrogates sensing of IL-7 that is required for antigen-independent survival of CD8+ T cells50. Persisting antigen is therefore required to drive the generation of terminal exhausted HCV-specific CD8+ T cells possibly arising from less differentiated memory-like subsets similar to progenitor and terminal subsets of virus-specific CD8+ T cells found in the mouse model of chronic LCMV infection15252627. Since both subsets are required to sustain the virus-specific CD8+ T-cell response during antigen persistence in mice it is tempting to speculate that a similar mechanism also exists in chronic human infection.\n\nIn conclusion, we demonstrate for the first time the emergence of a less differentiated circulating memory-like subset of virus-specific CD8+ T cells during antigen persistence in a relevant chronic human infection that is maintained after cessation of chronic antigen stimulation. Thus, our results give clinical significant insights into virus-specific CD8+ T-cell immunity after elimination of chronic viral infection and have implications for re-infection and therapeutic vaccination. In particular, memory-like HCV epitope-specific CD8+ T cells contain the proliferative potential and provide recall responses including re-expansion of HCV epitope-specific CD8+ T cells and re-occurrence of terminally exhausted subsets. Thus, this memory-like subset appears to be central to maintain virus-specific CD8+ T-cell responses during chronic infection and after consequent DAA-mediated viral clearance rendering this subset of virus-specific CD8+ T cells a promising target to boost CD8+ T-cell responses in immune therapeutic interventions.\n\nMethods\nStudy cohort\nPatients were recruited at the Department of Medicine II of the University Hospital Freiburg, Germany. 35 HLA-A02 positive patients with chronic HCV infection were included in this study. Twenty nine of these patients could be followed through IFNα-free DAA therapy and five patients were treated with IFNα-based regiments. All patients included in the study were infected with HCV genotype 1a or 1b. Viral loads were determined as part of the clinical diagnostics at the University Hospital Freiburg. In addition, 15 HLA-A02 positive patients who spontaneously resolved HCV infection (anti-HCV positive, HCV-RNA negative) were included. Confirmation of HLA-A02 was performed by antibody staining and four-digit HLA-typing by next generation sequencing. Characteristics of the patient cohort can be found in Table 1.\n\nWritten informed consent was obtained in all cases and the study was conducted according to federal guidelines, local ethics committee regulations (Albert-Ludwigs-Universität, Freiburg, Germany) and the Declaration of Helsinki (1975).\n\nPBMC isolation\nPBMCs were isolated from EDTA anticoagulated blood patient samples through Pancoll (Pan-Biotech) density gradient centrfugation. For best data comparability, all PBMC samples from one patient during therapy were frozen and thawed simultaneously at the day of experiment. PBMCs were thawed in complete medium (RPMI 1640 with 10% fetal bovine serum, 1% penicillin-streptomycin and 1.5% 1 M HEPES (all Thermo Fisher, Germany)) and incubated for 15–30 min at 37 °C in complete medium containing 50 U ml−1 benzonase (Sigma, Germany) before processing.\n\nPeptides and tetramers\nPeptides of HLA-A02-restricted HCV-derived epitopes ((I) genotype 1a: NS31073, CINGVCWTV; NS31406, KLVALGINAV; NS52594, ALYDVVTKL; (II) genotype 1b: NS31073, CVNGVCWTV; NS31406, KLSGLGLNAV; NS52594, ALYDVVSTL), variant epitopes matching patient viral sequences (Table 1), cytomegalovirus (CMV)-derived epitope pp65495, NLVPMVATV, influenza virus (FLU)-derived epitope M158, GILGFVFTL, and Epstein—Barr Virus (EBV)-derived epitope BMFL1280, GLCTLVAML, were obtained from Genaxxon, Germany. Peptides were dissolved in dimethyl sulfoxide (Sigma, Germany) at 20 mg ml−1 and diluted in complete medium to 1 mg ml−1 before usage. Major histocompatibility complex (MHC) class I epitope-specific tetramers were generated by conjugation of biotinylated peptide-MHC class I monomers (kind gift from David Price, Cardiff University) with PE- or APC-conjugated streptavidin at a MHCI:Strepatividin molar ratio of 5:1.\n\nTetramer enrichment\nTetramer enrichment was performed as previously described51. Briefly, PBMCs were labelled with peptide/HLA-A02 tetramers coupled to either phycoerythrin (PE) or allophycocyanin (APC). Subsequent enrichment was performed with anti-PE/APC beads applying MACS technology (Miltenyi Biotec, Germany) according to the manufacturer's protocol. Enriched virus-specific CD8+ T cells were used for flow cytometry or ex vivo stimulation assays. To restrict analysis only to those cells that actually encountered antigen before, CD45RA+CCR7+ or CD45RA+CD27+ naive virus-specific CD8+ T cells were excluded (Supplementary Fig. 2). Samples were excluded when <5 cells could be detected after peptide/HLA-A02 tetramer-based enrichment. Frequencies of virus-specific CD8+ T cells were calculated as described by Alanio et al.51.\n\nMultiparametric flow cytometry\nThe following reagents were used for multi-parametric flow cytometry: anti-HLA-A02 (BB7.2, 1:100), anti-HLA-B27 (FD705-9E1E10, 1:100), anti-CD8 (SK1, 1:50), anti-Eomes (WD1928, 1:30), anti-T-bet (4B10, 1:30), anti-CD14 (61D3, 1:100), anti-CD19 (HIB19, 1:100), anti-TIGIT (MBSA43, 1:30) (eBioscience, Germany). Anti-CCR7 (G043H7, 1:30), anti-CCR7 (G043H7, 1:30), anti-CD127 (A019D5, 1:30), anti-CD45RA (HI100, 1:200), anti-PD1 (EH12.2H7, 1:30), anti-TCF1 (C63D9, 1:30), anti-CD8 (HIT8a, 1:50), anti-2B4 (C1.7, 1:100), anti-CCR7 (150503, 1:30), anti-Rabbit IgG (Poly4064, 1:200), anti-CD45RA (HI100, 1:200), anti-Perforin (dG9, 1:50), anti-CD122 (TU27, 1:30), anti-IFN-γ (4S.B3, 1:50) (BioLegend, UK). Anti-IFN-γ (25723.11, 1:30), anti-Bcl-2 (Bcl-2/100, 1:100), anti-TNF (MAb11, 1:50), anti-CD39 (TU66, 1:30), anti-CD8 (RPA-T8, 1:100), anti-CD14 (MϕP9, 1:100), anti-CD19 (SJ25C1, 1:100) (BD Biosciences, Germany). Anti-TCF1 (C63D9, 1:100) (Cell signaling, Germany). Fixable Viability Dyes (eFluor506 (1:100) or eFluor780 (1:5000), eBioscience, Germany) and 7-AAD (1:30) (BD Biosciences, Germany) were used for live/dead discrimination. FoxP3/Transcription Factor Staining Buffer Set (eBioscience, Germany) was applied according to the manufacturer's instructions to stain for cytoplasmic and nuclear molecules. Cells were fixed with paraformaldehyde (2% PFA) before sample acquisition on a FACSCanto II or an LSRFortessa (BD Biosciences, Germany).\n\nT-cell expansion and calculation of expansion factor\nAround 1–2 × 106 PBMCs were stimulated with epitope-specific peptides (10 μg ml−1) and anti-CD28 (clone CD28.2, 0.5 μg ml−1, BD Biosciences, Germany) in 1 ml complete medium and incubated at 37 °C for 14 days. At day 3, 7 and 10, culture was supplemented with 0.5 ml of fresh medium including 20 IU ml−1 rIL-2 (Miltenyi Biotec, Germany). Tetramer and intracellular cytokine staining were performed at day 14. The expansion index was calculated as follows: [A] The absolute number of virus-specific CD8+ T cells added at day 0 of in vitro expansion was calculated based on peptide/MHCI tetramer enrichments (see above). [B] At day 14 of in vitro expansion, the absolute number of expanded virus-specific CD8+ T cells was determined based on direct FACS analyses. The expansion index was then calculated as (([B]/[A])+1), allowing subsequent logarithmic calculation despite zero values, resulting in the expansion factor=log(expansion index).\n\nCytokine production\nCytokine production of virus-specific CD8+ T cells after 14 days of in vitro expansion or directly ex vivo after peptide/MHCI tetramer enrichment of virus-specific CD8+ T cells was induced by re-stimulating cells with epitope-specific peptides (10 μg ml−1) in the presence of brefeldin A (GolgiPlug; 0.5 μl ml−1) and monensin (GolgiStop; 0.325 μl ml−1) (BD Biosciences, Germany) for 5 h at 37 °C. Stimulation with phorbol 12-myristate 13-acetate (PMA; 50 ng ml−1, Sigma, Germany) and Ionomycin (1 μg ml−1, Sigma, Germany) was performed as positive control. Subsequently, cells were stained as described above.\n\nViral sequencing\nRNA was extracted from sera using the QIAmp viral RNA minikit (Qiagen, Germany) followed by reverse transcription (RT; SuperScript III First-Strand Kit, Invitrogen, Germany) and DNA amplification by nested PCR (both PCRs via GoTaq G2 Flexi DNA Polymerase Kit, Promega, Germany) according to manufacturers' protocols. Specific primers for HCV genotype 1a and 1b can be found in Supplementary Table 3.\n\nT-cell cross-reactivity with viral sequence variations\nEpitope-specific T-cell lines were generated from PBMCs by stimulation with viral peptides (wildtype sequences) and expansion for 14 days as described above. On day 14, T-cell lines were tested for IFNγ production upon peptide-specific stimulation as described above. For stimulation, HLA-A02:01 positive EBV-transformed B-LCLs were loaded with peptides ((a) wildtype peptide; (b) viral sequence variation peptide; (10 μg ml−1)) overnight, then washed extensively and finally co-cultured with T-cell lines at an E:T ratio of 1:1. For production of EBV-transformed B-LCLs from HLA-A02 positive subjects, supernatant from the EBV-producing B95-8 marmoset lymphoblastoid cell line was incubated with donor PBMCs of patients with known HLA-A02 genotype followed by cyclosporine treatment52.\n\nCross-recognition definitions were based on Cox et al.53. Briefly, loss of recognition was defined as at least 20-fold reduction in IFNγ production upon variant peptide stimulation compared to wildtype peptide stimulation; 2-fold and less reduction in IFNγ production was defined as cross-recognition.\n\nStatistics\nFlow cytometry data were analysed using FlowJo software version 9 and 10 (Treestar, USA). During data analysis by FlowJo, no further sub-gate analysis was performed when <5 cells were detected. Statistical analysis was performed with GraphPad 6 software (GraphPad Prism Software Inc., USA). Bar charts show median values with interquartile range. Two-tailed tests were applied to a significance level of 95%. Statistical tests used are indicated in the figure legends. When patients did not appear to one single study time point for unknown reasons, missing at random (MAR) was assumed for statistical analysis. Paired analysis of these data sets was then performed by applying the lastly collected value to the missing time point. (P<0.05; P<0.01; P<0.001; **P<0.0001.)\n\nData availability\nThe data that support the findings of this study are available from the corresponding author on request.\n\nAdditional information\nHow to cite this article: Wieland, D. et al. TCF1+ hepatitis C virus-specific CD8+ T cells are maintained after cessation of chronic antigen stimulation. Nat. Commun.\n8, 15050 doi: 10.1038/ncomms15050 (2017).\n\nPublisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nSupplementary Material\nSupplementary Information\nSupplementary Figures and Supplementary Tables\n\n Peer Review File\n First, we thank all patients for participating in the current study. We also thank Marie Follow and the Core Facility of the University Medical Center Freiburg for expert advice in design of flow cytometry experiments, and David Price, Cardiff University, for peptide/MHCI momomer supply. Work presented was supported by the SFB/TRR 179 (Project 01) of the German Research Foundation (DFG).\n\nThe authors declare no competing financial interests.\n\nAuthor contributions D.W. designed, performed and analysed experiments, interpreted data and wrote the manuscript. J.K. performed viral sequencing. A.S. participated in developing experimental procedures. F.E. performed four-digit HLA-typing by next generation sequencing. P.K., C.N.-H., W.H. and D.Z. contributed to data interpretation. M.H. and R.T. designed the study, contributed to experimental design and planning, interpreted data and wrote the manuscript.\n\nFigure 1 Persistent antigen recognition drives heterogeneity of HCV-specific CD8+ T cells.\n(a) CD127/PD1 co-expression analysis of 24 HCV epitope-specific CD8+ T-cell populations derived from 19 chronically HCV-infected patients targeting autologous viral epitopes. Subset definition, specifically CD127+PD1+, CD127-PD1lo and CD127-PD1hi cells, is depicted in the representative flow cytometry dot plot on the left (red: HCV epitope-specific CD8+ T cells; grey: corresponding bulk CD8+ T cells of the appropriate patient). (b) Analysis of CD127/PD1 co-expression of five HCV epitope-specific CD8+ T-cell populations from five chronically HCV-infected patients that do not recognize viral antigen due to viral escape mutations. Representative dot plot on the left shows HCV epitope-specific (red) and bulk (grey) CD8+ T cells. Bar charts show the median value with interquartile range. Friedman and Dunn's multiple comparison tests were applied for paired statistical analyses. (P<0.05)\n\nFigure 2 TCF1 defines CD127+PD1+ HCV-specific CD8+ T cells that are less differentiated.\nHCV epitope-specific CD8+ T cells were analysed for expression levels (MFI=median fluorescence intensity) of the inhibitory receptors PD1, 2B4, TIGIT (a) and the relative expression of CD39 (b), Eomes (c), Perforin (d), TCF1 (e), BCL2 (f) and active caspase-8 (g) with respect to the CD127/PD1 subsets (n=7–19). Representative flow cytometric histogram plots including gating of the individual markers are depicted (red: HCV epitope-specific CD8+ T cells; grey: corresponding bulk CD8+ T cells). Bar charts show the median value with interquartile range. Statistical significance was assessed by Kruskal-Wallis with Dunn's multiple comparison test. (P<0.05; P<0.01; P<0.001; *P<0.0001.)\n\nFigure 3 TCF1+CD127+PD1+ HCV-specific CD8+ T cells are maintained after cessation of antigen stimulation.\nCD127/PD1 subset distribution of HCV epitope-specific CD8+ T cells after cessation of antigen stimulation by direct acting antiviral (DAA) therapy (n=9–16). (a) Viral loads (HCV RNA) in the sera of DAA-treated HCV patients (n=20) were determined at the indicated time-points. Lower detection limit is indicated by dashed line. (b) Representative dot plots showing CD127/PD1 subset distribution of HCV epitope-specific CD8+ T cells (red) at baseline (left) and at the end of DAA therapy (EOT; right) (grey: corresponding bulk CD8+ T cells). (c–e) Statistical graphs depicting frequencies of the indicated CD127/PD1 subset among HCV epitope-specific CD8+ T cells during DAA-mediated cessation of antigen stimulation. (f,g) Frequencies of CD39+ and Eomeshi HCV epitope-specific CD8+ T cells during DAA-mediated cessation of antigen stimulation. (h) Representative flow cytometric dot plots depict CD127/PD1 co-expression of TCF1+ HCV epitope-specific CD8+ T cells (green; grey: corresponding bulk HCV epitope-specific CD8+ T cells) at baseline (left) and at the end of DAA therapy (EOT, right). Frequencies of TCF1-expressing HCV epitope-specific CD8+ T cells (i) and TCF1-expressing CD127+PD1+ HCV epitope-specific CD8+ T cells (j) during DAA-mediated HCV elimination. Statistical significance was assessed by Friedman and Dunn's multiple comparison tests. (P<0.05; P<0.01; P<0.001; **P<0.0001.)\n\nFigure 4 Memory-like and conventional memory HCV-specific CD8+ T cells differ.\nHCV epitope-specific CD8+ T cells from patients (n=9–10) 12 weeks after the end of DAA therapy (cHCV FU12) were compared to HCV epitope-specific CD8+ T cells from patients who spontaneously resolved HCV infection (SpR; n=6). Representative flow cytometric dot plots depict CD127/PD1 co-expression of HCV epitope-specific CD8+ T cells derived from cHCV FU12 (a) and SpR (b) (red: HCV epitope-specific CD8+ T cells, grey: corresponding bulk CD8+ T cell). Frequencies of the indicated CD127/PD1 subset (c,d), Eomeshi (e) and TCF1+ cells (f) among HCV epitope-specific CD8+ T cells present in cHCV FU12 and SpR. Bar charts show the median value with interquartile range. Statistical significance was assessed by Mann—Whitney test. (P<0.05; **P<0.001.)\n\nFigure 5 Low cytokine production by memory-like HCV-specific CD8+ T cells.\nVirus-specific CD8+ T cells were stimulated with epitope-specific peptides (10 μg ml−1) for 5 h at 37 °C and analysed for cytokine production (a,b). (a) Flow cytometric dot plots demonstrate stability of peptide/MHCI tetramer staining (upper row) and IFNγ and TNF production (lower row) of HCV epitope-specific CD8+ T cells (red gate). (b) Cytokine production by HCV epitope-specific CD8+ T cells of five patients with HCV infection (HCV; six HCV epitope-specific CD8+ T-cell responses), seven spontaneous resolvers (SpR; ten HCV-epitope-specific CD8+ T-cell responses) and five FLU epitope-specific CD8+ T-cell responses (FLU, n=5). (c–e) In vitro peptide-expanded HCV epitope-specific CD8+ T cells from HCV-infected patients (n=9; 12 HCV epitope-specific CD8+ T-cell responses) or spontaneous resolvers (n=8; 13 HCV epitope-specific CD8+ T-cell responses) were analysed for cytokine production after 5 h of peptide-specific re-stimulation. (c) Representative dot plots showing cytokine production by in vitro HCV peptide-expanded CD8+ T cells after HCV peptide-specific re-stimulation (gated on bulk CD8+ T cells). Percentages of the respective quadrant are depicted. (d) Frequencies of IFNγ- (left) and TNF-producing (right) in vitro peptide-expanded HCV epitope-specific CD8+ T cells are shown in the statistical graphs. (e) TNF production by IFNγ+\nin vitro peptide-expanded CD8+ T cells in per cent. Bar charts show the median value with interquartile range. Statistical significance was assessed by Friedman test (HCV/DAA) and by unpaired Kruskal−Wallis (HCV, SpR, FLU). Multiple comparisons were performed with Dunn's test. (P<0.05.)\n\nFigure 6 Proliferative capacity of HCV-specific CD8+ T cells correlates with TCF1 expression.\nHCV epitope-specific CD8+ T cells of eight HCV-infected patients (eleven HCV epitope-specific CD8+ T-cell responses) and four spontaneous resolvers (SpR; five HCV epitope-specific CD8+ T-cell responses) were expanded at baseline and at end of therapy (EOT) for 14 days by HCV epitope-specific peptides and proliferative capacity was determined by the expansion factor. The expansion factor is the logarithmic fold-increase in absolute numbers of HCV epitope-specific CD8+ T cells from day 0 to day 14 of in vitro culture. (a) Representative dot plots of HCV epitope-specific CD8+ T cells determined by peptide/MHCI and CD8 staining at day 14 of expansion at baseline (left plot) or at end of therapy (EOT; right plot), respectively. Quantification of proliferative capacity of HCV epitope-specific CD8+ T cells derived from donors at baseline, at EOT and of SpR is depicted on the right. (b,c) Correlation analyses of the expansion factor with the abundance of memory-like CD127+PD1+ (b) or TCF1+ (c) HCV epitope-specific CD8+ T cells at day 0 of the assay, respectively (grey: baseline; black: EOT; open circles: SpR). Bar chart shows the median value with interquartile range. Statistical significance was assessed with Wilcoxon test (HCV/DAA Baseline to EOT), multiple comparisons with Kruskal–Wallis and Dunn's test (SpR to cHCV Baseline/EOT). Pearson correlation in (b,c) was performed. (P<0.05; P<0.01; ***P<0.0001.)\n\nFigure 7 Memory-like HCV-specific CD8+ T cells provide recall response after viral relapse.\nLongitudinal analyses of HCV epitope-specific CD8+ T cells of one patient with HCV relapse after DAA-mediated antigen elimination. (a) Viral loads (HCV RNA) in serum samples at the indicated time-points were determined. Lower detection limit is indicated by blue dashed line. (b) Frequencies of NS31073-specific CD8+ T-cell populations at end of therapy (EOT) and after viral relapse at FU12 and FU58 are shown. (c) CD127/PD1 subset distribution and relative expression of CD39 (d), Eomeshi (e) and TCF1 (f) of NS31073-specific CD8+ T cells were assessed at the indicated time-points (red: HCV epitope-specific CD8+ T cells; grey: corresponding CD8+ T cells).\n\nTable 1 Patient characteristics.\nPt\tD\tCohort\tTreatment\tOutcome\tgt\tNS31073\tNS31406\tNS52594\tVL\tAge\tSex\tCIR\t\n1\tcHCV\tDAA\tLedipasvir/Sofosbuvir 8 wk\tSVR\t1a\t \t------V---\t \t0.15\t47\tf\tno\t\n2\tcHCV\tDAA\tLedipasvir/Sofosbuvir 12 wk\tSVR\t1a\t---------\t \t \t0.26\t60\tm\tno\t\n3\tcHCV\tDAA\tLedipasvir/Sofosbuvir 12 wk\tSVR\t1a\t---------\t----------\t \t1.06\t52\tm\tno\t\n4\tcHCV\tDAA\tLedipasvir/Sofosbuvir 12 wk\tSVR\t1a\t \t------V---\t \t3.20\t66\tf\tno\t\n5\tcHCV\tDAA\tLedipasvir/Sofosbuvir 12 wk\tSVR\t1a\t---------\t \t----------\t0.63\t59\tf\tno\t\n6\tcHCV\tDAA\tLedipasvir/Sofosbuvir 12 wk\tSVR\t1a\t \t----------\t----------\t0.68\t64\tf\tno\t\n7\tcHCV\tDAA\tLedipasvir/Sofosbuvir 12 wk\tSVR\t1a\t---------\t \t----------\t2.96\t50\tm\tno\t\n8\tcHCV\tDAA\tLedipasvir/Sofosbuvir 12 wk\tSVR\t1a\t---------\t \t \tND\t49\tm\tno\t\n9\tcHCV\tDAA\tLedipasvir/Sofosbuvir 12 wk\tSVR\t1a\t---------\t \t----------\t15.0\t58\tm\tno\t\n10\tcHCV\tDAA\tLedipasvir/Sofosbuvir 12 wk\tSVR\t1a\t---------\t \t \t0.29\t59\tm\tno\t\n11\tcHCV\tDAA\tLedipasvir/Sofosbuvir 12 wk\tSVR\t1a\t---------\t \t \t1.03\t47\tm\tno\t\n12\tcHCV\tDAA\tLedipasvir/Sofosbuvir/Ribavirin 12 wk\tSVR\t1a\t \t------V---\t \t0.04\t73\tf\tno\t\n13\tcHCV\tDAA\tLedipasvir/Sofosbuvir/Ribavirin 12 wk; untreated after relapse\tRELAPSE\t1a\t---------\t \t \tND\t62\tm\tyes\t\n14\tcHCV\tDAA\tLedipasvir/Sofosbuvir 8 wk\tSVR\t1b\t-I-------\t \t \t0.70\t49\tm\tno\t\n15\tcHCV\tDAA\tLedipasvir/Sofosbuvir 8 wk\tSVR\t1b\t---------\t \t \t0.30\t60\tf\tno\t\n16\tcHCV\tDAA\tLedipasvir/Sofosbuvir 12 wk\tSVR\t1b\t---------\t \t \t5.30\t78\tf\tno\t\n17\tcHCV\tDAA\tLedipasvir/Sofosbuvir 12 wk\tSVR\t1b\t---------\t \t \t1.00\t63\tf\tno\t\n18\tcHCV\tDAA\tOmbitasvir/Paritaprevir/Ritonavir/Dasabuvir 12 wk\tSVR\t1b\t-I-------\t \t \t1.23\t29\tm\tno\t\n19\tcHCV\tDAA\tOmbitasvir/Paritaprevir/Ritonavir/Dasabuvir/Ribavirin 12 wk\tSVR\t1b\t---------\t \t \t0.04\t66\tf\tno\t\n20\tcHCV\tDAA\tLedipasvir/Sofosbuvir/Ribavirin 12 wk\tSVR\t1b\t-I-------\t \t \t0.61\t58\tf\tno\t\n21\tcHCV\tuntreated\t-\t-\t1a\t---------\t \t \t1.36\t41\tm\tno\t\n22\tcHCV\tuntreated\t-\t-\t1a\t---------\t \t \t4.59\t51\tm\tno\t\n23\tcHCV\tuntreated\t-\t-\t1a\t \t----------\t \t0.41\t55\tf\tno\t\n1\tcHCV\tESC\tLedipasvir/Sofosbuvir 8 wk\tSVR\t1a\t--------A\t \t \t0.15\t47\tf\tno\t\n4\tcHCV\tESC\tLedipasvir/Sofosbuvir 12 wk\tSVR\t1a\t--------A\t \t \t3.2\t66\tf\tno\t\n12\tcHCV\tESC\tLedipasvir/Sofosbuvir/Ribavirin12 wk\tSVR\t1a\t--------A\t \t \t0.04\t73\tf\tno\t\n24\tcHCV\tESC\tLedipasvir/Sofosbuvir 12 wk\tSVR\t1b\t--S------\t \t \t2.46\t56\tf\tno\t\n25\tcHCV\tESC\t-\tSVR\t1b\t-------SA\t \t \t0.04\t57\tm\tno\t\nPt\tD\tCohort\tApprox. time after primary HCV infection\tAge\tSex\tCIR\t\n26\tSpR\tSpR\t22 years\t43\tm\tno\t\n27\tSpR\tSpR\tunknown\t39\tf\tno\t\n28\tSpR\tSpR\tunknown\t25\tm\tno\t\n29\tSpR\tSpR\tunknown\t67\tf\tno\t\n30\tSpR\tSpR\tunknown\t38\tf\tno\t\n31\tSpR\tSpR\tunknown\t23\tm\tno\t\n32\tSpR\tSpR\tunknown\t54\tm\tno\t\n33\tSpR\tSpR\tunknown\t57\tf\tno\t\n34\tSpR\tSpR\tunknown\t42\tm\tno\t\n35\tSpR\tSpR\t12 years\t39\tf\tno\t\n36\tSpR\tSpR\t19 years\t37\tm\tno\t\n37\tSpR\tSpR\tunknown\t38\tm\tno\t\n38\tSpR\tSpR\tunknown\t60\tf\tno\t\n39\tSpR\tSpR\tunknown\t54\tf\tno\t\n40\tSpR\tSpR\t13 years\t33\tm\tno\t\nCIR, cirrhosis; D, diagnosis; f, female; gt, HCV genotype; m, male; ND, not defined; Pt, patient; SVR, sustained virological response; VL, baseline viral load (IU ml−1 × 106); wk, week.\n\nPatient characteristics are depicted. 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Med. \n201 , 1741 –1752 (2005 ).15939790\n\n", "fulltext_license": "CC BY", "issn_linking": "2041-1723", "issue": "8()", "journal": "Nature communications", "keywords": null, "medline_ta": "Nat Commun", "mesh_terms": "D000328:Adult; D000368:Aged; D000998:Antiviral Agents; D018414:CD8-Positive T-Lymphocytes; D005260:Female; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D051538:Hepatocyte Nuclear Factor 1-alpha; D006801:Humans; D007156:Immunologic Memory; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D016176:T-Lymphocyte Subsets; D055815:Young Adult", "nlm_unique_id": "101528555", "other_id": null, "pages": "15050", "pmc": null, "pmid": "28466857", "pubdate": "2017-05-03", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": "20644163;23197535;10790425;21943489;21867926;12070280;22623779;26485519;1313893;20483725;25127860;17591857;27487330;11356962;23580520;19043418;27455951;20457902;9858507;25032686;24148617;23142136;20727791;18549878;20200354;15939790;24975498;16382236;23644506;15505208;20548953;21398582;7911534;12370255;25004816;24905492;17420267;12663797;24412289;22875805;17950003;9565631;27533016;19906915;27501245;17000870;22337949;23836236;26513111;27501248;19434929;18809920;17287266", "title": "TCF1+ hepatitis C virus-specific CD8+ T cells are maintained after cessation of chronic antigen stimulation.", "title_normalized": "tcf1 hepatitis c virus specific cd8 t cells are maintained after cessation of chronic antigen stimulation" }	[ { "companynumb": "DE-AUROBINDO-AUR-APL-2018-003455", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "RIBAVIRIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "79111", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "FILM-COATED TABLET", "drugdosagetext": "()", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC HEPATITIS C", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBAVIRIN FILM COATED TABLETS" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LEDIPASVIR\\SOFOSBUVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK ()", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC HEPATITIS C", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEDIPASVIR W/SOFOSBUVIR" } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hepatitis C", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WIELAND D. ET AL. TCF1+ HEPATITIS C VIRUS-SPECIFIC CD8+ T CELLS ARE MAINTAINED AFTER CESSATION OF CHRONIC ANTIGEN STIMULATION. NATURE COMMUNICATIONS. 2017", "literaturereference_normalized": "tcf1 hepatitis c virus specific cd8 t cells are maintained after cessation of chronic antigen stimulation", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20180130", "receivedate": "20180130", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14456915, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" } ]
{ "abstract": "There are no clinical trials involving patients with diffuse large B-cell lymphoma (DLBCL) in sub-Saharan Africa since antiretroviral therapy (ART) for HIV became widely available in this region. We aimed to establish the safety and efficacy of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with DLBCL in Malawi.\n\n\n\nThis prospective, single-arm, non-randomised phase 1/2 clinical trial was done at Kamuzu Central Hospital Cancer Clinic (Lilongwe, Malawi). Eligible patients were adults (aged 18-60 years) with newly diagnosed DLBCL, an Eastern Cooperative Oncology Group performance status of 0-2, a CD4 count of 100 cells per μL or higher (if HIV-positive), measurable disease by physical examination, an absolute neutrophil count of 1000 × 109 cells per L or higher, a platelet count of 100 × 109 platelets per L or higher, a serum creatinine concentration of 132·60 μmol/L or less, a total bilirubin concentration of 34·21 μmol/L or less, a negative urine pregnancy test in women of childbearing potential, and no previous cytotoxic therapy. Pregnant or breastfeeding women, and individuals with CNS involvement from DLBCL, chronic hepatitis B infection (unless they were receiving tenofovir plus lamivudine), or any other comorbidities that would compromise the protocol objectives were excluded. Eligible patients received intravenous rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 (maximum 2 mg/m2), and oral prednisone 100 mg or an equivalent drug every 21 days for up to six cycles. HIV-positive patients received concurrent ART. The primary outcome was the proportion of patients with National Cancer Institute Common Terminology Criteria for Adverse Events grade 3 or 4 non-haematological toxic effects or treatment-related deaths after six cycles of treatment. Secondary efficacy outcomes included the proportion of patients with a complete response after six cycles of treatment, and progression-free survival and overall survival at 12 months and 24 months. This trial is registered with ClinicalTrials.gov, NCT02660710.\n\n\n\nBetween Aug 1, 2016, and July 31, 2019, 76 patients were screened, of whom 37 were eligible for the study and received R-CHOP. The median age of patients was 44 years (IQR 39-49) and 16 (43%) were women. Of all 37 patients, 20 (54%) had stage III or IV DLBCL, and the age-adjusted international prognostic index was 2 or higher in 25 (68%) patients. 27 (73%) patients were HIV-positive, with a median CD4 count of 208 cells per μL (IQR 144-422), and 21 (78%) patients were receiving ART at enrolment. Patients completed a median of six cycles (IQR 4-6). Grade 3 or 4 non-haematological toxic effects were reported in 12 (32% [95% CI 19-49]) patients, the most common of which was infection (nine [24%] patients). Of 16 (43%) deaths, ten were due to progression of DLBCL, four were due to treatment-related complications, and two were due to other causes, yielding a treatment-related mortality of 11% (95% CI 4-26%). Grade 3 or 4 neutropenia was observed in 26 (70%) patients, and grade 3 or 4 anaemia was observed in 11 (29%) patients. A total of 22 (59%) patients had a complete response. Overall survival was 68% (95% CI 50-80) at 12 months and 55% (37-70) at 24 months, and progression-free survival was 59% (42-73) at 12 months and 53% (35-68) at 24 months.\n\n\n\nR-CHOP could be feasible, safe, and efficacious in patients with DLBCL in Malawi. This is the first completed clinical trial on DLBCL focused on sub-Saharan African populations. Given the paucity of data on treatment of DLBCL from this region, these results could inform emerging cancer treatment programmes in sub-Saharan Africa.\n\n\n\nThe University of North Carolina Lineberger Comprehensive Cancer Center.", "affiliations": "Department of Medicine, Division of Hematology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; University of North Carolina Project-Malawi, Lilongwe, Malawi.;Department of Medicine, Division of Hematology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; University of North Carolina Project-Malawi, Lilongwe, Malawi.;University of North Carolina Project-Malawi, Lilongwe, Malawi; University of Malawi, College of Medicine, Lilongwe Campus, Lilongwe, Malawi.;University of North Carolina Project-Malawi, Lilongwe, Malawi.;University of North Carolina Project-Malawi, Lilongwe, Malawi.;Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; University of North Carolina Project-Malawi, Lilongwe, Malawi; University of Malawi, College of Medicine, Lilongwe Campus, Lilongwe, Malawi.;Kamuzu Central Hospital, Malawi Ministry of Health, Lilongwe, Malawi.;Kamuzu Central Hospital, Malawi Ministry of Health, Lilongwe, Malawi.;University of North Carolina Project-Malawi, Lilongwe, Malawi.;University of North Carolina Project-Malawi, Lilongwe, Malawi.;University of North Carolina Project-Malawi, Lilongwe, Malawi.;University of North Carolina Project-Malawi, Lilongwe, Malawi.;University of North Carolina Project-Malawi, Lilongwe, Malawi.;University of North Carolina Project-Malawi, Lilongwe, Malawi.;University of North Carolina Project-Malawi, Lilongwe, Malawi.;University of North Carolina Project-Malawi, Lilongwe, Malawi.;Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.;Department of Pathology, Anatomy and Laboratory Medicine, West Virginia University, Morgantown, WV, USA.;University of North Carolina Project-Malawi, Lilongwe, Malawi.;Department of Medicine, Division of Hematology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; University of North Carolina Project-Malawi, Lilongwe, Malawi.;Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; University of North Carolina Project-Malawi, Lilongwe, Malawi.;Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; University of North Carolina Project-Malawi, Lilongwe, Malawi.;Center for Global Health, National Cancer Institute, Rockville, MD, USA. Electronic address: [email protected].", "authors": "Kimani\|Stephen\|S\|;Painschab\|Matthew S\|MS\|;Kaimila\|Bongani\|B\|;Kasonkanji\|Edwards\|E\|;Zuze\|Takondwa\|T\|;Tomoka\|Tamiwe\|T\|;Mulenga\|Maurice\|M\|;Nyasosela\|Richard\|R\|;Chikasema\|Maria\|M\|;Mtangwanika\|Asekanadziwa\|A\|;Chawinga\|Mena\|M\|;Mhango\|Wilberforce\|W\|;Nicholas\|Simon\|S\|;Chimzimu\|Fred\|F\|;Kampani\|Coxcilly\|C\|;Krysiak\|Robert\|R\|;Lilly\|Amy\|A\|;Randall\|Cara\|C\|;Seguin\|Ryan\|R\|;Westmoreland\|Katherine D\|KD\|;Montgomery\|Nathan D\|ND\|;Fedoriw\|Yuri\|Y\|;Gopal\|Satish\|S\|", "chemical_list": "C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone", "country": "England", "delete": false, "doi": "10.1016/S2214-109X(21)00181-9", "fulltext": "\n==== Front\n101613665\n42402\nLancet Glob Health\nLancet Glob Health\nThe Lancet. Global health\n2214-109X\n\n34022150\n10.1016/S2214-109X(21)00181-9\nnihpa1821306\nArticle\nSafety and efficacy of rituximab in patients with diffuse large B-cell lymphoma in Malawi: a prospective, single-arm, non-randomised phase 1/2 clinical trial\nKimani Stephen Department of Medicine, Division of Hematology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA\nLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA\nUniversity of North Carolina Project-Malawi, Lilongwe, Malawi\n\nPainschab Matthew S Department of Medicine, Division of Hematology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA\nLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA\nUniversity of North Carolina Project-Malawi, Lilongwe, Malawi\n\nKaimila Bongani University of North Carolina Project-Malawi, Lilongwe, Malawi\nUniversity of Malawi, College of Medicine, Lilongwe Campus, Lilongwe, Malawi\n\nKasonkanji Edwards University of North Carolina Project-Malawi, Lilongwe, Malawi\n\nZuze Takondwa University of North Carolina Project-Malawi, Lilongwe, Malawi\n\nTomoka Tamiwe Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA\nUniversity of North Carolina Project-Malawi, Lilongwe, Malawi\nUniversity of Malawi, College of Medicine, Lilongwe Campus, Lilongwe, Malawi\n\nMulenga Maurice Kamuzu Central Hospital, Malawi Ministry of Health, Lilongwe, Malawi\n\nNyasosela Richard Kamuzu Central Hospital, Malawi Ministry of Health, Lilongwe, Malawi\n\nChikasema Maria University of North Carolina Project-Malawi, Lilongwe, Malawi\n\nMtangwanika Asekanadziwa University of North Carolina Project-Malawi, Lilongwe, Malawi\n\nChawinga Mena University of North Carolina Project-Malawi, Lilongwe, Malawi\n\nMhango Wilberforce University of North Carolina Project-Malawi, Lilongwe, Malawi\n\nNicholas Simon University of North Carolina Project-Malawi, Lilongwe, Malawi\n\nChimzimu Fred University of North Carolina Project-Malawi, Lilongwe, Malawi\n\nKampani Coxcilly University of North Carolina Project-Malawi, Lilongwe, Malawi\n\nKrysiak Robert University of North Carolina Project-Malawi, Lilongwe, Malawi\n\nLilly Amy Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA\n\nRandall Cara Department of Pathology, Anatomy and Laboratory Medicine, West Virginia University, Morgantown, WV, USA\n\nSeguin Ryan University of North Carolina Project-Malawi, Lilongwe, Malawi\n\nWestmoreland Katherine D Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA\nUniversity of North Carolina Project-Malawi, Lilongwe, Malawi\n\nMontgomery Nathan D Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA\nUniversity of North Carolina Project-Malawi, Lilongwe, Malawi\n\nFedoriw Yuri Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA\nUniversity of North Carolina Project-Malawi, Lilongwe, Malawi\n\nGopal Satish Center for Global Health, National Cancer Institute, Rockville, MD, USA\n\n* Contributed equally\n\nContributors\n\nSG conceptualised the study and supervised the project as the principal investigator. SK, MSP, and SG statistically analysed the data and prepared the first draft of the manuscript. SK, MSP, SG, KDW, and YF reviewed and edited draft versions of the manuscript. SK, MSP, BK, EK, TZ, RN, MaC, AM, MeC, WM, SN, KDW, and SG evaluated and provided treatment to study participants. TT, MM, FC, CK, RK, AL, CR, NDM, and YF processed and analysed laboratory samples. RS provided research support and coordinated the study. All authors reviewed the final draft of the manuscript. SK, MSP, and SG accessed and verified all the data in the study. SG had full access to all of the data in the study and had final responsibility to submit for publication. All authors vouch for the completeness and accuracy of the data and analyses reported, and for the fidelity of the study to the protocol.\n\nCorrespondence to: Dr Satish Gopal, Center for Global Health, National Cancer Institute, Rockville, MD 20892-9760, USA [email protected]\n20 7 2022\n7 2021\n19 5 2021\n30 7 2022\n9 7 e1008e1016\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article under the CC BY 4.0 license.\nSummary\n\nBackground\n\nThere are no clinical trials involving patients with diffuse large B-cell lymphoma (DLBCL) in sub-Saharan Africa since antiretroviral therapy (ART) for HIV became widely available in this region. We aimed to establish the safety and efficacy of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with DLBCL in Malawi.\n\nMethods\n\nThis prospective, single-arm, non-randomised phase 1/2 clinical trial was done at Kamuzu Central Hospital Cancer Clinic (Lilongwe, Malawi). Eligible patients were adults (aged 18–60 years) with newly diagnosed DLBCL, an Eastern Cooperative Oncology Group performance status of 0–2, a CD4 count of 100 cells per μL or higher (if HIV-positive), measurable disease by physical examination, an absolute neutrophil count of 1000×109 cells per L or higher, a platelet count of 100×109 platelets per L or higher, a serum creatinine concentration of 132·60 μmol/L or less, a total bilirubin concentration of 34·21 μmol/L or less, a negative urine pregnancy test in women of childbearing potential, and no previous cytotoxic therapy. Pregnant or breastfeeding women, and individuals with CNS involvement from DLBCL, chronic hepatitis B infection (unless they were receiving tenofovir plus lamivudine), or any other comorbidities that would compromise the protocol objectives were excluded. Eligible patients received intravenous rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 (maximum 2 mg/m2), and oral prednisone 100 mg or an equivalent drug every 21 days for up to six cycles. HIV-positive patients received concurrent ART. The primary outcome was the proportion of patients with National Cancer Institute Common Terminology Criteria for Adverse Events grade 3 or 4 non-haematological toxic effects or treatment-related deaths after six cycles of treatment. Secondary efficacy outcomes included the proportion of patients with a complete response after six cycles of treatment, and progression-free survival and overall survival at 12 months and 24 months. This trial is registered with ClinicalTrials.gov, NCT02660710.\n\nFindings\n\nBetween Aug 1, 2016, and July 31, 2019, 76 patients were screened, of whom 37 were eligible for the study and received R-CHOP. The median age of patients was 44 years (IQR 39–49) and 16 (43%) were women. Of all 37 patients, 20 (54%) had stage III or IV DLBCL, and the age-adjusted international prognostic index was 2 or higher in 25 (68%) patients. 27 (73%) patients were HIV-positive, with a median CD4 count of 208 cells per μL (IQR 144–422), and 21 (78%) patients were receiving ART at enrolment. Patients completed a median of six cycles (IQR 4–6). Grade 3 or 4 non-haematological toxic effects were reported in 12 (32% [95% CI 19–49]) patients, the most common of which was infection (nine [24%] patients). Of 16 (43%) deaths, ten were due to progression of DLBCL, four were due to treatment-related complications, and two were due to other causes, yielding a treatment-related mortality of 11% (95% CI 4–26%). Grade 3 or 4 neutropenia was observed in 26 (70%) patients, and grade 3 or 4 anaemia was observed in 11 (29%) patients. A total of 22 (59%) patients had a complete response. Overall survival was 68% (95% CI 50–80) at 12 months and 55% (37–70) at 24 months, and progression-free survival was 59% (42–73) at 12 months and 53% (35–68) at 24 months.\n\nInterpretation\n\nR-CHOP could be feasible, safe, and efficacious in patients with DLBCL in Malawi. This is the first completed clinical trial on DLBCL focused on sub-Saharan African populations. Given the paucity of data on treatment of DLBCL from this region, these results could inform emerging cancer treatment programmes in sub-Saharan Africa.\n\nFunding\n\nThe University of North Carolina Lineberger Comprehensive Cancer Center.\n==== Body\npmcIntroduction\n\nThe incidence of non-Hodgkin lymphoma is increasing in sub-Saharan Africa, where approximately 50000 new cases were diagnosed in 2019.1 The prevalence of HIV infection in patients with non-Hodgkin lymphoma in this region ranges from 30% to 60%.2,3 Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma worldwide.4 Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the international first-line standard-of-care that cures most patients.4 DLBCL is highly associated with HIV infection,5,6 and is a common, curable lymphoma throughout sub-Saharan Africa, where the global HIV epidemic is concentrated.7,8\n\nAdding rituximab to CHOP has been the primary therapeutic advance for DLBCL in the past two decades, yielding absolute increases in long-term overall survival of 10–20% compared with CHOP alone,4,9,10 and rituximab was approved by the US Food and Drug Administration in 1997. Rituximab also improves outcomes in patients with HIV-associated DLBCL, although this benefit in resource-rich settings is less clear in patients with CD4 cell counts of less than 50 per μL (ie, those with severe immunosuppression) compared with patients who have higher CD4 cell counts due to the increased risk of treatment-related infectious complications.11\n\nRituximab is currently included in the WHO Model List of Essential Medicines, and several biosimilar drugs, with equivalent pharmacokinetic, safety, and efficacy data to the proprietary drug, are commercially available worldwide.12,13 Despite the importance and availability of biosimilar drugs, rituximab remains unavailable in most public sector settings in sub-Saharan Africa because of cost. Additionally, there are no prospective data for rituximab focused on populations in sub-Saharan Africa, where HIV is prevalent, the supportive care infrastructure is weak, haematopoietic growth factors are often unavailable, and the burden of opportunistic infections is high.14 Robust safety, efficacy, and cost-effectiveness data from this region are essential to inform the programmatic implementation of rituximab, and to convince policy makers facing many competing priorities that newer anti-cancer drugs, such as rituximab, can be prudent public health investments.\n\nTo address these gaps, we did a clinical trial of the Indian rituximab biosimilar Reditux (Dr Reddy’s Laboratories, Hyderabad, Telangana, India) plus CHOP in Malawi, a low-income country in sub-Saharan Africa with a gross domestic product of US$411 per person, an annual health expenditure of $38 per person, a human development index rank of 172 of 189 countries, and where the prevalence of HIV is 9%.15–17 We aimed to investigate the safety and efficacy of R-CHOP in HIV-infected and HIV-uninfected patients with DLBCL. We hypothesised that rituximab would be safe and effective for patients with DLBCL, even under routine programmatic conditions.\n\nMethods\n\nStudy design and patients\n\nThis prospective, single-arm, non-randomised phase 1/2 clinical trial was done at the Kamuzu Central Hospital Cancer Clinic in Lilongwe, Malawi.\n\nEligible patients were adults (aged 18–60 years) with newly diagnosed DLBCL, an Eastern Cooperative Oncology Group performance status of 0–2, a CD4 count of 100 cells per μL or higher (if HIV-positive), measurable disease by physical examination, an absolute neutrophil count of 1000×109 cells per L or higher, a platelet count of 100×109 per L or higher, a serum creatinine concentration of 132·60 μmol/L or less, a total bilirubin concentration of 34·21 μmol/L or less, a negative urine pregnancy test in women of childbearing potential, and no previous cytotoxic therapy. Pregnant or breastfeeding women, and individuals with CNS involvement from DLBCL on clinical assessment or by cerebrospinal fluid cytology, chronic hepatitis B infection (unless they were receiving tenofovir plus lamivudine), or any other comorbidities (including cardiac disease) that would compromise the protocol objectives were excluded. For diagnosis of DLBCL, biopsy specimens were evaluated on-site in Lilongwe in real-time by immunohistochemistry and telepathology, with consensus review by 2–4 pathologists in the USA (NDM and YF) and in Malawi (TT and MM). Biopsy tissue specimens from all patients were then transported to the University of North Carolina (Chapel Hill, NC, USA) for delayed repeat immunohistochemical staining and review (by AL and CR).18,19 Baseline staging evaluations were done as described in the appendix (pp 32–33).\n\nAll patients provided written informed consent. The study was approved by the institutional review board at the University of North Carolina at Chapel Hill (Chapel Hill, NC, USA), and the National Health Sciences Research Committee and Pharmacy, Medicines, and Poisons Board (Lilongwe, Malawi).\n\nProcedures\n\nEligible patients received intravenous rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 (maximum 2 mg/m2), and oral prednisone 100 mg or an equivalent drug every 21 days for up to six cycles. Dosing was modelled on the R-CHOP group of the phase 3 Intergroup Trial Alliance/CALGB 50303 study.20 Treatment was administered at the Kamuzu Central Hospital Cancer Clinic and as described in the appendix (pp 9–12). Allopurinol 300 mg twice daily was administered on days 1–5 of cycle one. Haematopoietic growth factors were not routinely available in Malawi during the study period. Between the screening visit and R-CHOP initiation, patients could receive up to 10 days of pre-phase corticosteroids but no cytotoxic treatment. Patients were assessed before treatment; at each treatment visit (ie, every 21 days); and then every 3 months until 24 months after treatment. Assessments by clinicians included clinical history, details of treatment and adverse effects, performance status, and results of blood counts and other relevant tests. Imaging with chest x-ray and abdominal ultrasound were done at baseline and at the end of treatment. A bone marrow biopsy was done at baseline for all patients, but was only repeated at the end of treatment if lymphomatous involvement was present at baseline. Lumbar puncture at baseline was done only in high-risk patients (ie, those with lymphoma, with involvement of two or more extranodal sites and elevated lactate dehydrogenase concentrations, or bone marrow, testicular, epidural, ocular, breast, or paranasal sinus involvement). Lumbar puncture was repeated as clinically indicated (see appendix p 10). In the event of clinical suspicion of relapse, additional evaluation was done as clinically indicated.\n\nProtocol-defined dose adjustments and delays for non-haematological and haematological toxicities are described in the appendix (pp 13–16).\n\nHIV-infected patients received oral co-trimoxazole 960 mg once daily, consistent with Malawi guidelines, plus oral ciprofloxacin 500 mg twice daily during days 8–15 of each chemotherapy cycle, and oral fluconazole 100 mg once daily continuously throughout chemotherapy until recovery of absolute neutrophil counts of 500×109 cells per L or higher after treatment completion. HIV-uninfected patients received oral ciprofloxacin 500 mg twice daily during days 8–15 of each chemotherapy cycle if febrile neutropenia (ie, a neutrophil count of <1×109 cells per L) developed after a previous chemotherapy cycle. For HIV-infected patients, concurrent antiretroviral therapy (ART) was administered to all patients consistent with Malawi guidelines. These guidelines evolved over the study period in accordance with WHO recommendations, with tenofovir, lamivudine, and efavirenz changed to tenofovir, lamivudine, and dolutegravir as the recommended first-line ART for most patients. For patients receiving ritonavir, the dose of vincristine was reduced by 50% with each cycle. Consolidative radiotherapy after R-CHOP was not available in Malawi during the study period for persistent or bulky disease. Patients received transportation reimbursement for all visits, as per Malawi National Health Sciences Research Committee guidelines.\n\nOutcomes\n\nThe primary outcome was the proportion of patients with National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 grade 3 or 4 non-haematological toxic effects or treatment-related deaths after six cycles of treatment. Assigning cause of death in Malawi is often difficult given limited diagnostic capabilities, and some deaths could have occurred outside of health facilities. Therefore, two senior non-study Malawian clinicians were enlisted to review all study data for deceased patients and assign cause of death as probably treatment-related, lymphoma-related, related to another cause, or indeterminable. In the event of discordant conclusions, a third senior clinician made the final decision. Deaths occurring outside Kamuzu Central Hospital Cancer Clinic were adjudicated as related or unrelated to treatment on the basis of known clinical information, including DLBCL status at the time of death, proximity to treatment, a family interview, and review of the most recent cancer clinic records, laboratory data, imaging data, and medical records from peripheral health centres.\n\nThe secondary outcomes were the proportion of patients with grade 3 or 4 non-haematological toxic effects after six cycles of treatment according to HIV status; the dose intensity of R-CHOP in patients with and without HIV infection; treatment efficacy, as assessed by progression-free survival and overall survival at 12 months and 24 months after treatment, and the proportion of patients with a complete response after six cycles, overall and according to HIV status; health-related quality of life, as assessed by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30, overall and according to HIV status; and the cost-effectiveness of R-CHOP administered for six cycles, modelled by use of locally derived clinical trial and cost data. Response was assessed by investigators according to standard international criteria by physical examination, chest radiography, abdominal sonography, and in rare instances CT scan. PET was not available in Malawi during the study period. Progression-free survival was defined as the time from treatment initiation until disease progression or death. Overall survival was defined as the time from treatment initiation until death. A complete response was defined as the disappearance of all evident disease (additional details about treatment response assessments are described in the appendix [pp 32–34]).\n\nPost-hoc exploratory endpoints included the frequency of treatment delays (defined as an interval of 7 days or more between cycles) and the proportion of patients with grade 3 or 4 haematological toxic effects after six cycles of treatment, according to HIV status.\n\nStatistical analysis\n\nGiven the single-arm design of this phase 1/2 study, a sample size of at least 36 patients was calculated on the basis of desired precision of the safety estimates for grade 3 or 4 non-haematological toxicity (maximum allowable 95% CI width of 34%) and treatment-related deaths (maximum allowable 95% CI width of 30%). Primary and safety analyses were done in all patients with measurable disease who had received at least one cycle of R-CHOP.\n\nIn prespecified exploratory post-hoc analyses, differences between HIV-infected and HIV-uninfected patients were assessed with an exact Wilcoxon rank sum test for continuous variables and Fisher’s exact test for categorical variables. All reported p values are two-sided and presented without adjustment for multiple comparisons. Progression-free survival and overall survival were estimated by use of Kaplan-Meier methods, and the log-rank test was used to assess differences between HIV-infected and HIV-uninfected individuals.\n\nStudy data were monitored by the University of North Carolina Lineberger Comprehensive Cancer Center Data and Safety Monitoring Committee. Statistical analyses were done with Stata, version 6.1.\n\nThis trial is registered with ClinicalTrials.gov, NCT02660710.\n\nRole of the funding source\n\nThe funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.\n\nResults\n\nBetween Aug 1, 2016, and July 31, 2019, 76 patients were screened for eligibility (figure 1). The primary reasons for exclusion were non-DLBCL diagnosis (n=17) and having a CD4 count of less than 100 cells per μL (n=11). Of 59 patients with confirmed DLBCL who had completed screening, 39 (66%) were enrolled and received R-CHOP. Of these patients, one (3%) was subsequently diagnosed with Burkitt lymphoma and one (3%) was subsequently diagnosed with follicular lymphoma after pathological review of biopsy specimens in the USA. As such, 37 patients were included in the final analyses. No patients had transformed DLBCL. The median time from screening to initiation of R-CHOP was 10 days (range 2–30).\n\nCharacteristics of the 37 patients with DLBCL who received R-CHOP are shown in table 1. The median age of patients was 44 years (IQR 39–49), and 16 (43%) were women. 20 (54%) patients had stage III or IV disease, 15 (41%) had palpable masses of 10 cm or more in diameter, the median lactate dehydrogenase concentration was 515 IU/L (IQR 373–692; the laboratory upper limit of normal was defined as 250 IU/L), and 25 (68%) patients had an age-adjusted absolute International Prognostic Index of 2 or higher. The median tumour Ki-67 expression score was 80% (IQR 60–90). Epstein-Barr virus (EBV) status, as assessed by EBV-encoded RNA in-situ hybridisation and immunophenotype classification by immunohistochemistry with the Hans classifier,21 was known for 28 (76%) patients. Of these patients, two (7%) were EBV-positive and 16 (57%) had a germinal centre B-cell phenotype. Of all 37 patients, 27 (73%) were HIV-positive, 21 (78%) of whom were receiving ART for 3 months or more before they were diagnosed with DLBCL. Among the 27 HIV-positive patients, the median duration of ART was 36 months (IQR 5–86), the median CD4 count was 208 cells per μL (144–422), and 20 (74%) patients had viral suppression (defined as HIV RNA concentrations of <1000 copies per mL). Baseline characteristics did not differ substantially between HIV-positive and HIV-negative patients.\n\nThe treatment course and proportion of patients with grade 3 or 4 toxic effects are shown in table 2. As of Aug 14, 2020, all patients had completed a median of 6 cycles (IQR 4–6) of R-CHOP. A total of 12 (32% [95% CI 19–49]) patients had grade 3 or 4 non-haematological toxic effects (table 2). The most frequent grade 3 or 4 non-haematological toxic effects were infections (nine [24%] patients), including Escherichia coli bacteraemia (n=2), skin and soft tissue infections (n=2), malaria (n=1), Proteus mirabilis osteomyelitis (n=1), Streptococcus pneumoniae septic arthritis (n=1), Staphylococcus aureus empyema (n=1), and progressive multifocal leukoencephalopathy (n=1). Progressive multifocal leukoencephalopathy associated with John Cunningham virus reactivation occurred in the context of patient nonadherence to ART, and a decline in the CD4 cell count from 145 cells per μL at enrolment to 69 cells per μL at 6 months. After ART was resumed, this patient improved despite persistent neurological impairment. During the initial rituximab infusion, one patient had grade 3 hypersensitivity that resolved with standard measures and did not recur with subsequent R-CHOP cycles. Of note, grade 3 or 4 non-haematological toxic effects in five (42%) of 12 patients were partly attributable to anatomical complications caused by specific sites of bulky disease. These anatomical complications of DLBCL included gram-negative bacteraemia, which was likely to have occurred due to an anal mass with a suspected fistula, intestinal obstruction due to primary intestinal involvement, soft-tissue superinfection of an ulcerated axillary mass, osteomyelitis in a primary bone DLBCL resulting in a non-healing sinus tract, and empyema due to pathologically confirmed pleural involvement of DLBCL.\n\nDisease and vital status were known for all patients, with a median follow-up of 27 months (IQR 19–34). Of 16 total deaths in the study population, ten were due to DLBCL progression, four were due to treatment-related complications, and two were due to other causes, yielding a treatment-related mortality of 11% (95% CI 4–26). Two deaths from treatment-related complications were due to chronic osteomyelitis leading to progressive renal failure and S aureus empyema. Two deaths attributed to treatment-related complications were temporally associated with receipt of treatment, but confirmation of these deaths as treatment-related was not possible, as they occurred at rural health facilities with an inadequate diagnostic infrastructure, such as specialised clinicians, laboratory tests, or imaging. Two deaths from other causes were due to complications of uncontrolled diabetes in patients who responded to R-CHOP, without an alternative infectious or other cause of death identified.\n\nHIV-positive patients had a lower treatment intensity than HIV-negative patients, as reflected by the lower number of treatment cycles, higher frequency of treatment delays, and higher frequency of dose reductions due to the greater severity and duration of neutropenia (table 2). Irrespective of differences in treatment intensity, no significant difference was observed in the overall frequency of grade 3 or 4 neutropenia between HIV-positive and HIV-negative patients. Grade 3 or 4 neutropenia occurred in 26 (70%) of 37 patients overall, and 11 (29%) patients had grade 3 or 4 anaemia. No patients had grade 3 or 4 thrombocytopenia.\n\nOf all 37 patients, 22 (59%) had a protocol-defined complete response. Three additional patients had a protocol-defined partial response with small residual masses, and these patients survived without disease progression for 34 months, 36 months, and 40 months from R-CHOP initiation, suggesting a functional complete response in 25 (68%) patients overall; however, a metabolic complete response could not be confirmed by PET scan in these three patients. Progression-free survival and overall survival in the total cohort are shown in figure 2. Progression-free survival was 59% (95% CI 42–73) at 12 months and 53% (35–68) at 24 months. Overall survival was 68% (50–80) at 12 months and 55% (37–70) at 24 months. No significant differences in progression-free survival (log-rank p=0·43) and overall survival (log-rank p=0·27) according to HIV status were observed.\n\nDiscussion\n\nTo our knowledge, this is the first clinical trial of rituximab for DLBCL focused on sub-Saharan African populations, and the first clinical trial of the treatment of adults with lymphoma in this region in the current era of widespread access to HIV treatment.22 We enrolled patients with DLBCL who had adverse disease characteristics that typically confer poor outcomes (27 [73%] of 37 patients were HIV-positive, 20 [54%] had stage III or IV disease, 15 [41%] had a bulky palpable mass, 25 [68%] had an age-adjusted absolute International Prognostic Index of ≥2, and median lactate dehydrogenase concentrations were more than two times the upper limit of normal). However, relative to cohorts in high-income countries, patients were likely to have been understaged due to absent PET and restricted CT availability in Malawi. No patients were lost to follow-up, and overall survival at 24 months was 55% (95% CI 37–70) under routine programmatic conditions, which is among the best reported outcomes to date in a sub-Saharan African population. We enrolled 39 (66%) of 59 screened patients who presented to the cancer clinic at the national teaching hospital, and who were confirmed to have DLBCL on-site during the study period. We acknowledge that some referral and selection bias might have occurred, given the extreme centralisation of cancer services and multiple barriers patients face in accessing care in Malawi. R-CHOP was initiated a median of 10 days after the initial screening visit. As a reference, 2-year overall survival in patients with HIV-associated DLBCL receiving R-CHOP or infusions of rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin have typically been 60–70%, according to clinical trials done in the USA and Europe.11,23 Additionally, in the USA, long diagnosis-to-treatment intervals of more than 14 days have been independently associated with improved outcomes in patients with DLBCL compared with shorter intervals (ie, ≤14 days).24 These long intervals have been proposed as a reason for better than anticipated outcomes in the control groups of contemporary DLBCL clinical trials, particularly when treatment assignment has required molecular characterisation of tumours.25\n\nA 2020 review by the AIDS Malignancy Consortium, which includes leaders of African clinical trial sites involved in the consortium, found no clinical trials actively enrolling patients with HIV-associated lymphoma in sub-Saharan Africa.26 Additionally, a randomised clinical trial by the same consortium initiated in November, 2016, which aimed to compare an investigational oral regimen with CHOP in patients with HIV-associated DLBCL, was stopped after only seven patients in four sub-Saharan African countries (including Malawi) were enrolled over 2 years.26,27 Before this trial, the only completed clinical trial focused on adults with lymphoma in sub-Saharan Africa evaluated an investigational oral regimen (lomustine, etoposide, cyclophosphamide, and procarbazine) in HIV-infected patients in Kenya and Uganda in 2001–05, before public sector ART was widely available.22 Of 149 screened patients with HIV and lymphoma, 49 (33%) were ultimately given the investigational regimen, among whom median overall survival was 12·3 months. In this previous trial, patients with diverse non-Hodgkin lymphoma histologies were included, with only seven patients having confirmed DLBCL. Therefore, given the extreme paucity of high-grade contemporary clinical trial data from the assessment of a contemporary international standard of care regimen in sub-Saharan Africa, together with the increasing incidence of HIV-associated non-Hodgkin lymphoma throughout the region,6,28,29 our findings can inform emerging efforts to address gaps in cancer treatment. Despite the limitations of our study, including the small sample size, the absence of a control group, and the single-centre design, our data could be informative. For comparison, in a recent report published in 2019, 2-year overall survival was 42% (95% CI 30–53) in an unselected historical cohort of patients (outside a clinical trial) with DLBCL in Malawi who received CHOP without rituximab under similar programmatic conditions to this trial in 2013–17.7 An additional limitation of this study was that quality-of-life data were not collected with sufficient rigour nor completeness. Efforts are underway to translate and validate patient-reported outcome instruments to better capture quality- of-life data in Malawi for future studies.\n\nWe also note the occurrence of frequent grade 3 or 4 toxic effects among patients in our study, including neutropenia (26 [70%] of 37 patients), anaemia (11 [30%]), and infection (nine [24%]). Neutropenia was generally manageable with protocol-specified dose reduction and treatment delay, even in the absence of available routine haematopoietic growth factor during the study period. Recent increases in the availability of haematopoietic growth factor in many sub-Saharan African settings in the past 12 months could help mitigate risk of neutropenia and increase the achievable cumulative dose and dose intensity of R-CHOP in patients with DLBCL. Most treatment-related infectious complications were successfully identified and managed in our study; however, this detection required adverse event monitoring and laboratory diagnostic capacity, which might not be present in many routine programmatic settings across the region. Although increasing haematopoietic growth factor availability in sub-Saharan Africa can help mitigate the risk of infection in future studies, we also excluded patients with a CD4 count of less than 100 cells per μL because of safety concerns for severely immunosuppressed patients, and we mandated concurrent ART in all HIV-infected patients. Therefore, our findings should not be generalised to HIV-positive patients with DLBCL who do not receive concurrent ART or who have low CD4 counts. Treatment-related mortality in our study was 11% (95% CI 4–26), compared with 18% in the unselected historical cohort of patients with DLBCL in Malawi who received CHOP without rituximab in 2013–17 under similar programmatic conditions.7 Of note, two deaths in our study occurred due to uncontrolled diabetes in patients who had a complete response to R-CHOP, without an alternative infectious or other cause of death identified. These outcomes highlight the major challenges we encountered in treating cancer patients with comorbidities other than HIV in Malawi. Robust programmes in sub-Saharan Africa for chronic diseases other than HIV are generally scarce. We diagnosed two patients with new uncontrolled diabetes, one during enrolment and one at R-CHOP initiation, but we did not have the specialised capacity to provide intensive inpatient blood glucose management, as these services were not routinely available in the Malawi public sector.\n\nIn conclusion, R-CHOP could be a feasible treatment option for patients with DLBCL under routine programmatic conditions in Malawi, with a favourable safety and efficacy profile relative to scant existing regional literature. Given the paucity of similar data from this region, our results could inform emerging cancer treatment programmes and priorities in sub-Saharan Africa. Opportunities to participate in oncology clinical trials are scarce throughout the region, which is rightly viewed as an issue of cancer health equity, even if high quality observational data can also inform cancer care policies and practice.30 Large randomised multicentre studies to rigorously test treatments for DLBCL in sub-Saharan Africa are needed, and should include studies evaluating subcutaneous rituximab administration with various chemotherapy platforms and individualised risk-adapted and response-guided strategies to better guide treatment intensification or de-intensification. Finally, in addition to rigorous safety and efficacy evaluation, formal cost-effectiveness analyses of rituximab and other novel drugs in sub-Saharan Africa will be important to provide a strong case for investment to governments and policy makers when they allocate limited resources and consider providing new cancer treatments to the populations they serve.\n\nSupplementary Material\n\n1\n\nAcknowledgments\n\nThis study was funded by a University of North Carolina Lineberger Developmental Research Award awarded to SG. No commercial support was provided for this study. We are exceedingly grateful to the study participants and their families, and for the leadership from Kamuzu Central Hospital, the Malawi Ministry of Health (Lilongwe, Malawi), and the University of North Carolina Project-Malawi (Lilongwe, Malawi) for their support in conducting this study. This Article reflects work done while SG was employed at the University of North Carolina at Chapel Hill (Chapel Hill, NC, USA). The opinions expressed in this Article are the authors own and do not reflect the view of the US National Institutes of Health, the US Department of Health and Human Services, or the US Government.\n\nData sharing\n\nDeidentified individual participant data underlying the reported results will be available with publication of this study. Only approved study proposals with a signed data access agreement will be granted access to these data. A copy of the study protocol is available in the appendix. For all requests, please contact [email protected].\n\nFigure 1: Trial profile\n\nDLBCL=diffuse large B-cell lymphoma. ECOG=Eastern Cooperative Oncology Group. R-CHOP=rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. Seven patients had plasmablastic lymphoma, six had Burkitt lymphoma, three had T-cell lymphoma, and one had primary effusion lymphoma.\n\nFigure 2: Progression-free (A) and overall (B) survival of patients with DLBCL in Malawi receiving R-CHOP\n\nIn A and B, the blue shaded region shows the 95% CIs. DLBCL=diffuse large B-cell lymphoma. R-CHOP=rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone.\n\nTable 1: Baseline characteristics of patients with diffuse large B-cell lymphoma receiving R-CHOP\n\n\tAll patients (n=37)\tHIV-positive patients (n=27)\tHIV-negative patients (n=10)\tp value\t\n\t\nSex\t..\t..\t..\t0·61\t\n Female\t16 (43%)\t11 (41%)\t5 (50%)\t..\t\n Male\t21 (57%)\t16 (59%)\t5 (50%)\t..\t\nAge, years\t44 (39–49)\t46 (39–50)\t40 (35–49)\t0·37\t\nECOG performance status\t..\t..\t..\t0·055\t\n 0\t13 (35%)\t10 (37%)\t3 (30%)\t..\t\n 1\t13 (35%)\t12 (44%)\t1 (10%)\t..\t\n 2\t11 (30%)\t5 (19%)\t6 (60%)\t..\t\nStage III or IV disease\t20 (54%)\t16 (59%)\t4 (40%)\t0·30\t\nPalpable mass of ≥10 cm\t15 (41%)\t12 (44%)\t3 (30%)\t0·43\t\nLactate dehydrogenase, IU/L\t515 (373–692)\t504 (309–692)\t577 (432–740)\t0·34\t\nAge-adjusted absolute International Prognostic Index\t..\t..\t..\t0·91\t\n 0\t1 (3%)\t1 (4%)\t0\t..\t\n 1\t11 (30%)\t8 (30%)\t3 (30%)\t..\t\n 2\t20 (54%)\t15 (56%)\t5 (50%)\t..\t\n 3\t5 (14%)\t3 (11%)\t2 (20%)\t..\t\nOn ART for ≥3 months at diagnosis\t..\t21 (78%)\tNA\t..\t\nDuration of ART, months\t..\t36 (5–86)\tNA\t..\t\nCD4 count, cells per μL\t..\t208 (144–422)\tNA\t..\t\nHIV RNA <1000 copies per mL\t..\t20 (74%)\tNA\t..\t\nEBV-positive tumour†\t2/28 (7%)\t1/22 (5%)\t1/6 (17%)\t0·31\t\nTumour with GCB immunophenotype‡\t16/28 (57%)\t13/22 (59%)\t3/6 (50%)\t0·69\t\nKi67 expression score\t80% (60–90)\t83% (60–95)\t75% (55–80)\t0·11\t\nSelf-reported symptom duration of ≤6 months\t25 (68%)\t20 (74%)\t5 (50%)\t0·24\t\nAny history of tuberculosis treatment\t11 (30%)\t11 (41%)\t0\t0·016\t\nTuberculosis treatment prescribed for lymphadenopathy\t5/11 (45%)\t5/11 (45%)\t0\t..\t\nData are n (%), median (IQR), or n/N (%). R-CHOP=rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. ECOG=Eastern Cooperative Oncology Group. ART=antiretroviral therapy. NA=not applicable. EBV=Epstein-Barr virus. GCB=germinal centre B-cell.\n\n* Laboratory upper limit of normal was 250 IU/L.\n\n† Assessed by EBV-encoded RNA in-situ hybridisation.\n\n‡ Assessed by immunohistochemistry with the Hans classifier.\n\nTable 2: Treatment course and toxic effects in patients with diffuse large B-cell lymphoma who received R-CHOP\n\n\tAll patients (n=37)\tHIV-positive patients (n=27)\tHIV-negative patients (n=10)\tp value\t\n\t\nTreatment course\t\t\t\t\t\n Number of R-CHOP cycles, median (IQR)\t6 (4–6)\t5 (4–6)\t6 (6–6)\t0·041\t\n Completed six R-CHOP cycles\t22 (59%)\t13 (48%)\t9 (90%)\t0·021\t\n Any treatment delay of ≥7 days\t21 (57%)\t18 (67%)\t3 (30%)\t0·046\t\n Any dose reduction\t21 (57%)\t19 (70%)\t2 (20%)\t0·0060\t\n Total number of dose-reduced cycles\t1(0–2)\t1 (0–3)\t0 (0–0)\t0·013\t\n Concentration of cyclophosphamide per cycle, mg/m2\t750 (657–750)\t750 (563–750)\t750 (750–750)\t0·058\t\n Concentration of doxorubicin per cycle, mg/m2\t50 (44–50)\t50 (38–50)\t50 (50–50)\t0·061\t\n Interval between cycles, days\t21 (21–25)\t22 (21–28)\t21 (21–21)\t0·0037\t\nToxic effects\t\t\t\t\t\n Haematological toxicity†‡\t32 (86%)\t23 (85%)\t9 (90%)\t0·70\t\n Neutropenia†\t26 (70%)\t21 (78%)\t5 (50%)\t0·10\t\n Anaemia†\t11 (30%)\t6 (22%)\t5 (50%)\t..\t\n Thrombocytopenia†\t0\t0\t0\t..\t\nNon-haematological toxicity†\t12 (32%)\t10 (37%)\t2 (20%)\t0·33\t\n Infections\t9 (24%)§\t7 (26%)\t2 (20%)\t..\t\n Febrile neutropenia\t4 (11%)\t4 (15%)\t0\t..\t\n Hypersensitivity\t1 (3%)\t1 (4%)\t0\t..\t\n Diarrhoea\t1 (3%)\t1 (4%)\t0\t..\t\n Constipation\t1 (3%)\t1 (4%)\t0\t..\t\n Bowel obstruction\t1 (3%)\t1 (4%)\t0\t..\t\n Anorexia\t1 (3%)\t0\t1 (4%)\t..\t\nData are median (IQR) or n (%). R-CHOP=rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone.\n\n Treatment was considered as delayed if the interval between cycles was 7 days or more.\n\n† Grade 3 or 4 in severity.\n\n‡ The total number of individual grade 3 or 4 toxicities was greater than the total number of patients, as patients could have more than one event.\n\n§ Included Gram-negative bacteraemia (n=2), malaria (n=1), osteomyelitis (n=1), septic arthritis (n=1), cellulitis (n=2), empyema (n=1), and progressive multifocal leukoencephalopathy (n=1).\n\nResearch in context\n\nEvidence before this study\n\nWe searched PubMed, Embase, and Global Health biomedical research databases on Dec 1, 2020, using the search terms “lymphoma”, “non-hodgkin lymphoma”, “diffuse large B-cell lymphoma”, “outcomes”, “survival”, “treatment”, “HIV”, “chemotherapy”, “rituximab plus chemotherapy”, “CHOP”, and “R-CHOP”. We searched for prospective treatment trials for diffuse large B-cell lymphoma (DLBCL) published in English between Jan 1, 1990, and Nov 30, 2020. Non-English articles were included when an English translation of the abstract was available. We also reviewed references from relevant articles to identify studies that might have been missed by the aforementioned search terms. We found that the integration of rituximab (R) to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) has been the primary therapeutic advance for DLBCL in high-income countries in the past two decades, yielding absolute increases in long-term overall survival of 10–20% compared with CHOP alone. Rituximab also improves outcomes in patients with HIV-associated DLBCL, although this benefit in resource-rich settings is less clear in patients with CD4 cell counts of less than 50 cells per μL (ie, those with severe immunosuppression) due to the increased risk of treatment-related infectious complications. We found no prospective data for R-CHOP in patients with DLBCL in sub-Saharan Africa.\n\nAdded value of this study\n\nTo our knowledge, this is the first clinical trial of rituximab for DLBCL focused on sub-Saharan African populations, and the first clinical trial of the treatment of adults with lymphoma in this region in the current era of widespread access to HIV treatment. We enrolled patients with DLBCL who had adverse disease characteristics (ie, those that typically confer poor outcomes). No patients were lost to follow-up, and overall survival at 24 months was 55% under routine programmatic conditions, which is among the best reported outcomes to date for this population in sub-Saharan Africa.\n\nImplications of all the available evidence\n\nR-CHOP could be feasible, safe, and efficacious for patients with DLBCL under routine programmatic conditions in Malawi and in similar settings.\n\nDeclaration of interests\n\nWe declare no competing interests.\n==== Refs\nReferences\n\n1 International Agency for Research on Cancer.Global Cancer Observatory. 2020. https://gco.iarc.fr/today/online-analysis-table?v=2020&mode=population&mode_population=continents&population=900&populations=903_900_991&key=asr&sex=0&cancer=34&type=0&statistic=5&prevalence=0&population_group=0&ages_group%5B%5D=0&ages_group%5B%5D=17&group_cancer=1&include_nmsc=1&include_nmsc_other=1#collapse-group-1-0-3 (accessed Oct 5, 2020).\n2 Wiggill TM , Mantina H , Willem P , Perner Y , Stevens WS . 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J Clin Oncol 2019; 37 : 1790–99.30939090\n21 Hans CP , Weisenburger DD , Greiner TC , Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood 2004; 103 : 275–82.14504078\n22 Mwanda WO , Orem J , Fu P , Dose-modified oral chemotherapy in the treatment of AIDS-related non-Hodgkin’s lymphoma in East Africa. J Clin Oncol 2009; 27 : 3480–88.19470940\n23 Sparano JA , Lee JY , Kaplan LD , Rituximab plus concurrent infusional EPOCH chemotherapy is highly effective in HIV-associated B-cell non-Hodgkin lymphoma. Blood 2010; 115 : 3008–16.20023215\n24 Maurer MJ , Ghesquieres H , Link BK , Diagnosis-to-treatment interval is an important clinical factor in newly diagnosed diffuse large B-cell lymphoma and has implication for bias in clinical trials. J Clin Oncol 2018; 36 : 1603–10.29672223\n25 Crombie JL , Armand P . Diffuse large B-Cell lymphoma’s new genomics: the bridge and the chasm. J Clin Oncol 2020; 38 : 3565–74.32813609\n26 Lin LL , Lakomy DS , Chiao EY , Clinical trials for treatment and prevention of HIV-associated malignancies in sub-Saharan Africa: building capacity and overcoming barriers. JCO Glob Oncol 2020; 6 : 1134–46.32697667\n27 Strother RM , Gopal S , Wirth M , Challenges of HIV lymphoma clinical trials in Africa: lessons from the AIDS Malignancy Consortium 068 Study. JCO Glob Oncol 2020; 6 : 1034–40.32634068\n28 Dryden-Peterson S , Medhin H , Kebabonye-Pusoentsi M , cancer incidence following expansion of HIV treatment in Botswana. PLoS One 2015; 10 : e0135602.26267867\n29 Abayomi EA , Somers A , Grewal R , Impact of the HIV epidemic and anti-retroviral treatment policy on lymphoma incidence and subtypes seen in the Western Cape of South Africa, 2002–2009: preliminary findings of the Tygerberg Lymphoma Study Group. Transfus Apher Sci 2011; 44 : 161–66.21402310\n30 Wells JC , Sharma S , Del Paggio JC , An analysis of contemporary oncology randomized clinical trials from low/middle-income vs high-income countries. JAMA Oncol 2021; 7 : 379–85.33507236\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2214-109X", "issue": "9(7)", "journal": "The Lancet. Global health", "keywords": null, "medline_ta": "Lancet Glob Health", "mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D004317:Doxorubicin; D005260:Female; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008295:Malawi; D008297:Male; D008875:Middle Aged; D011241:Prednisone; D011446:Prospective Studies; D000069283:Rituximab; D016896:Treatment Outcome; D014750:Vincristine", "nlm_unique_id": "101613665", "other_id": null, "pages": "e1008-e1016", "pmc": null, "pmid": "34022150", "pubdate": "2021-07", "publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Safety and efficacy of rituximab in patients with diffuse large B-cell lymphoma in Malawi: a prospective, single-arm, non-randomised phase 1/2 clinical trial.", "title_normalized": "safety and efficacy of rituximab in patients with diffuse large b cell lymphoma in malawi a prospective single arm non randomised phase 1 2 clinical trial" }	[ { "companynumb": "US-PFIZER INC-202101288110", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VINCRISTINE SULFATE" }, "drugadditional": "4", "drugadministrationroute": "042", "drugauthorizationnumb": "071484", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.4 MG/M2 (MAXIMUM 2 MG/M2)", "drugenddate": null, "drugenddateformat": null, "drugindication": "Diffuse large B-cell lymphoma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.4", "drugstructuredosageunit": "009", 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"primarysource": { "literaturereference": "Kimani, S.. Safety and efficacy of rituximab in patients with diffuse large B-cell lymphoma in Malawi: a prospective, single-arm, non-randomised phase 1/2 clinical trial. 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Safety and efficacy of rituximab in patients with diffuse large B-cell lymphoma in Malawi: a prospective, single-arm, non-randomised phase 1/2 clinical trial. The Lancet Global Health. 2021;9 (7):e1008-e1016", "literaturereference_normalized": "safety and efficacy of rituximab in patients with diffuse large b cell lymphoma in malawi a prospective single arm non randomised phase 1 2 clinical trial", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20211001", "receivedate": "20211001", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19905132, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 1, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220303" } ]
{ "abstract": "OBJECTIVE\nDespite successful primary treatment of nasopharyngeal carcinoma (NPC), the incidence of distant metastasis remains 25-34 %. Treatment options are limited, and survival is poor. Intratumoural Epstein-Barr virus (EBV) was used as treatment target. In NPC, EBV is present in a latent state, expressing only few non-immunogenic viral products. Gemcitabine and valproic acid can trigger EBV to the lytic state, wherein viral kinases are expressed, making EBV-positive tumour cells susceptible for antiviral therapy with, i.e. valganciclovir, and inducing an EBV-specific immune response.\n\n\nMETHODS\nThis drug combination was applied in eight patients with EBV-positive NPC, refractory to conventional treatment. The primary endpoints were safety, tolerability and clinical response. Secondary endpoint was to get proof of concept based on biomarkers, i.e. pharmacokinetics, EBV-DNA load in whole blood and nasopharyngeal brushes, EBV-RNA profiling for proof of lytic induction, EBV-IgG and EBV-IgA levels and diversity and EBV-specific T cell response.\n\n\nRESULTS\nThe best observed clinical response was partial in two patients (25 %) and stable disease in three patients (37.5 %). The median survival was 9 months (95 % confidence interval 7-17 months). Effective dose levels were reached. Peaking of EBV-DNA loads in blood and brush proved the biological effect on EBV during most treatment cycles. In one patient, RNA profiling confirmed lytic EBV induction. EBV-IgG and EBV-IgA antibody levels were already high before treatment and did not change during treatment. No changes in EBV-specific T cell response were detected.\n\n\nCONCLUSIONS\nThe treatment was safe with manageable side effects, clinical response was observed, and viral activation corroborated.", "affiliations": "Department of Head and Neck Surgery and Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands, [email protected].", "authors": "Stoker\|Sharon D\|SD\|;Novalić\|Zlata\|Z\|;Wildeman\|Maarten A\|MA\|;Huitema\|Alwin D R\|AD\|;Verkuijlen\|Sandra A W M\|SA\|;Juwana\|Hedy\|H\|;Greijer\|Astrid E\|AE\|;Tan\|I Bing\|IB\|;Middeldorp\|Jaap M\|JM\|;de Boer\|Jan Paul\|JP\|", "chemical_list": "D000914:Antibodies, Viral; D004279:DNA, Viral; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D003841:Deoxycytidine; D014635:Valproic Acid; C056507:gemcitabine", "country": "Germany", "delete": false, "doi": "10.1007/s00432-015-1969-3", "fulltext": null, "fulltext_license": null, "issn_linking": "0171-5216", "issue": "141(10)", "journal": "Journal of cancer research and clinical oncology", "keywords": null, "medline_ta": "J Cancer Res Clin Oncol", "mesh_terms": "D000328:Adult; D000914:Antibodies, Viral; D000971:Antineoplastic Combined Chemotherapy Protocols; D002277:Carcinoma; D004279:DNA, Viral; D003841:Deoxycytidine; D005260:Female; D004854:Herpesvirus 4, Human; D006801:Humans; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D008297:Male; D008875:Middle Aged; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms; D013601:T-Lymphocytes; D014635:Valproic Acid; D017735:Virus Latency", "nlm_unique_id": "7902060", "other_id": null, "pages": "1845-57", "pmc": null, "pmid": "25920375", "pubdate": "2015-10", "publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": "20948438;11408227;21177151;25019625;17117372;12450734;17156439;24213277;23675501;22160379;18087217;17378764;23346186;24638904;23459720;19220831;25228810;14747554;17577879;16145162;21336546;25232180;23089459;16002393;17119113;24297049;16597877;20657553;15507698;15950718;24206918;21586688;25687508;17987110;12482570;16951192;19013244;18256216;22687948;12036863;24351754;11555713;22498709;22761471;16933315;20103659;10203511;10918205;25024604;22500168;2846609;23493345;16572427;21540588;17135642", "title": "Epstein-Barr virus-targeted therapy in nasopharyngeal carcinoma.", "title_normalized": "epstein barr virus targeted therapy in nasopharyngeal carcinoma" }	[ { "companynumb": "NL-CIPLA LTD.-2015NL07914", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "VALPROIC ACID" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "12.5 MG/KG, DAILY, DAY 1 TILL DAY 14", "drugenddate": null, "drugenddateformat": null, "drugindication": "NASOPHARYNGEAL CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "12.5", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALPROIC ACID." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "GANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "450 MG, TID FROM DAY 8 TILL 21", "drugenddate": null, "drugenddateformat": null, "drugindication": "NASOPHARYNGEAL CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "450", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GANCICLOVIR." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "078759", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "1250 MG/KG2 AT DAY 1 AND 8", "drugenddate": null, "drugenddateformat": null, "drugindication": "NASOPHARYNGEAL CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Disease progression", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "STOKER S, BOER J, NOVALIC Z, WILDEMAN M, HUITEMA A, VERKUIJLEN S, JUWANA H, GREIJER A ET AL... EPSTEIN-BARR VIRUS-TARGETED THERAPY IN NASOPHARYNGEAL CARCINOMA. J CANCER RES CLIN ONCOL. 2015?141:1845-1857", "literaturereference_normalized": "epstein barr virus targeted therapy in nasopharyngeal carcinoma", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20151016", "receivedate": "20151016", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11635384, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" }, { "companynumb": "NL-ABBVIE-15P-114-1421472-00", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "GANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": "048", 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EPSTEIN-BARR VIRUS-TARGETED THERAPY IN NASOPHARYNGEAL CARCINOMA. 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EPSTEIN-BARR VIRUS-TARGETED THERAPY IN NASOPHARYNGEAL CARCINOMA. 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EPSTEIN-BARR VIRUS-TARGETED THERAPY IN NASOPHARYNGEAL CARCINOMA. 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EPSTEIN-BARR VIRUS-TARGETED THERAPY IN NASOPHARYNGEAL CARCINOMA. 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EPSTEIN-BARR VIRUS-TARGETED THERAPY IN NASOPHARYNGEAL CARCINOMA. J CANCER RES CLIN ONCOL. 2015?141:1845-1857", "literaturereference_normalized": "epstein barr virus targeted therapy in nasopharyngeal carcinoma", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20151016", "receivedate": "20151016", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11635385, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" }, { "companynumb": "NL-CIPLA LTD.-2015NL07910", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "GANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTASIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GANCICLOVIR." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "078759", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "1250 MG/KG2 AT DAY 1 AND 8 EACH CYCLE FOR 2 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "NASOPHARYNGEAL CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "GANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "450 MG TID FROM DAY 8 TILL 21 EACH CYCLE FOR 2 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "NASOPHARYNGEAL CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "450", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GANCICLOVIR." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VALPROIC ACID" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTASIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALPROIC ACID." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VALPROIC ACID" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "12.5 MG/KG FROM DAY 1 TILL DAY 14 EACH CYCLE FOR 2 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "NASOPHARYNGEAL CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "12.5", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALPROIC ACID." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "078759", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTASIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pneumonia", "reactionmeddraversionpt": "18.1", "reactionoutcome": null }, { "reactionmeddrapt": "Disease progression", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "18.1", "reactionoutcome": null }, { "reactionmeddrapt": "Pulmonary oedema", "reactionmeddraversionpt": "18.1", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "STOKER S, BOER J, NOVALIC Z, WILDEMAN M, HUITEMA A, VERKUIJLEN S, JUWANA H, GREIJER A ET AL... EPSTEIN-BARR VIRUS-TARGETED THERAPY IN NASOPHARYNGEAL CARCINOMA. J CANCER RES CLIN ONCOL. 2015?141:1845-1857", "literaturereference_normalized": "epstein barr virus targeted therapy in nasopharyngeal carcinoma", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20151016", "receivedate": "20151016", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11635381, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160304" }, { "companynumb": "NL-CIPLA LTD.-2015NL07911", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "VALPROIC ACID" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "12.5 MG/KG, QD, DAY 1 TILL DAY 14", "drugenddate": null, "drugenddateformat": null, "drugindication": "NASOPHARYNGEAL CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "12.5", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALPROIC ACID." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "GANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "450 MG, TID FROM DAY 8 TILL 21", "drugenddate": null, "drugenddateformat": null, "drugindication": "NASOPHARYNGEAL CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "450", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GANCICLOVIR." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "078759", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "1250 MG/KG2 AT DAY 1 AND 8", "drugenddate": null, "drugenddateformat": null, "drugindication": "NASOPHARYNGEAL CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatic enzyme increased", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Disease progression", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "STOKER S, BOER J, NOVALIC Z, WILDEMAN M, HUITEMA A, VERKUIJLEN S, JUWANA H, GREIJER A ET AL... EPSTEIN-BARR VIRUS-TARGETED THERAPY IN NASOPHARYNGEAL CARCINOMA. J CANCER RES CLIN ONCOL. 2015?141:1845-1857", "literaturereference_normalized": "epstein barr virus targeted therapy in nasopharyngeal carcinoma", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20151016", "receivedate": "20151016", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11635393, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" } ]
{ "abstract": "Toxic epidermal necrolysis (TEN) is a potentially life-threatening muco-cutaneous disease, largely caused by an idiosyncratic reaction to medication or infectious disease, and is characterised by acute necrosis of the epidermis. No definitive consensus regarding the treatment of TEN has been agreed. A 60-year-old woman, diagnosed with multiple myeloma three months prior, was admitted with signs of TEN to the intensive care burns unit. She had been given ciprofloxacin to treat a urinary tract infection. She complained of malaise and pain, with maculopapular and bullous eruptions over her whole body on the third day of ciprofloxacin administration. Her supportive cares included intravenous immunoglobulins, pain control with analgesics, wound care, nutrition, and fluid support. Hyperbaric oxygen treatment (HBOT) was added on the second day of admission. The patient underwent 5 sessions of HBOT at 243.1 kPa (2.4 atmospheres absolute). Desquamation was noted to stop after the first session of HBOT and re-epithelisation commenced rapidly. The patient was discharged from the burn unit after 14 days of hospital admission. Improvement in this case was temporally related to the initiation of HBOT.", "affiliations": "University of Health Sciences, Hamidiye Medical Faculty, Department of Underwater and Hyperbaric Medicine, Istanbul, Turkey.;University of Health Sciences, Kartal Dr Lütfi Kirdar City Hospital, Department of Anesthesiology and Reanimation, Istanbul, Turkey.;University of Health Sciences, Kartal Dr Lütfi Kirdar City Hospital, Department of Underwater and Hyperbaric Medicine, Istanbul, Turkey.;University of Health Sciences, Kartal Dr Lütfi Kirdar City Hospital, Department of Infectious Diseases and Clinical Microbiology, Istanbul, Turkey.", "authors": "Gamze Sümen\|Selin\|S\|;Yakupoğlu\|Sezer\|S\|;Gümüş\|Tuna\|T\|;Benzonana\|Nur\|N\|", "chemical_list": "D010100:Oxygen", "country": "Australia", "delete": false, "doi": "10.28920/dhm51.2.216-219", "fulltext": null, "fulltext_license": null, "issn_linking": "1833-3516", "issue": "51(2)", "journal": "Diving and hyperbaric medicine", "keywords": "Case reports; Drugs; Hyperbaric medicine; Outcome; Side effects; Skin; Toxicity", "medline_ta": "Diving Hyperb Med", "mesh_terms": "D003422:Critical Care; D005260:Female; D006801:Humans; D006931:Hyperbaric Oxygenation; D008875:Middle Aged; D010100:Oxygen; D013262:Stevens-Johnson Syndrome", "nlm_unique_id": "101282742", "other_id": null, "pages": "216-219", "pmc": null, "pmid": "34157739", "pubdate": "2021-06-30", "publication_types": "D002363:Case Reports", "references": "17973540;19766401;28724844;3780308;27400826;27999358;11724089;28301358;16908399;15115708;10850900;23756299;9310730;31481319;13374196;8305780;20879700;28439852", "title": "Hyperbaric oxygen treatment for toxic epidermal necrolysis: A case report.", "title_normalized": "hyperbaric oxygen treatment for toxic epidermal necrolysis a case report" }	[ { "companynumb": "TR-TELIGENT, INC-20210700063", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "076754", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "URINARY TRACT INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN UNSPECIFIED" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Malaise", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Dermatitis bullous", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Pain", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SEZER YAKUPOLU. HYPERBARIC OXYGEN TREATMENT FOR TOXIC EPIDERMAL NECROLYSIS: A CASE REPORT. DIVING HYPERB MED. 2021?51(2):216?219", "literaturereference_normalized": "hyperbaric oxygen treatment for toxic epidermal necrolysis a case report", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "TR", "receiptdate": "20210719", "receivedate": "20210719", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19575478, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "TR-FRESENIUS KABI-FK202109150", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "GENTAMICIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "062356", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ENDOCARDITIS BACTERIAL", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GENTAMICIN (MANUFACTURER UNKNOWN)" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "URINARY TRACT INFECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VANCOMYCIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "062663", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ENDOCARDITIS BACTERIAL", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VANCOMYCIN (MANUFACTURER UNKNOWN)" } ], "patientagegroup": null, "patientonsetage": "60", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Klebsiella infection", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxic epidermal necrolysis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Acinetobacter infection", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "GAMZE SUMEN S, YAKUPOGLU S, GUMUS T, BENZONANA N. HYPERBARIC OXYGEN TREATMENT FOR TOXIC EPIDERMAL NECROLYSIS: A CASE REPORT. DIVING AND HYPERBARIC MEDICINE. 2021 JUN 30?51 (2):216?219.", "literaturereference_normalized": "hyperbaric oxygen treatment for toxic epidermal necrolysis a case report", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20210827", "receivedate": "20210827", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19761942, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "TR-FDC LIMITED-2118481", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "077568", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "URINARY TRACT INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN." } ], "patientagegroup": null, "patientonsetage": "60", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxic epidermal necrolysis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SUMEN SG, YAKUPOGLU S, GUMUS T, BENZONANA. HYPERBARIC OXYGEN TREATMENT FOR TOXIC EPIDERMAL NECROLYSIS: A CASE REPORT. DIVING AND HYPERBARIC MEDICINE 51: 216?219, NO. 2, 30 JUN 2021.URL: HTTP://DOI.ORG/10.28920/DHM51.2.216?219.", "literaturereference_normalized": "hyperbaric oxygen treatment for toxic epidermal necrolysis a case report", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20210917", "receivedate": "20210917", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 19843361, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20211014" } ]
{ "abstract": "A 17-year-old boy developed prominent mediastinal and subcutaneous emphysema while receiving treatment with 5-aminosalicylic acid (5-ASA) and oral corticosteroids for severe ulcerative colitis. We ruled out infection and initiated oral administration of tacrolimus, after which both the underlying disease and mediastinal and subcutaneous emphysema improved. However, he continued to experience repeated bouts of ulcerative colitis, so we ultimately opted for surgical intervention. Although mediastinal and subcutaneous emphysema is rare, it is one of the known extra-intestinal complications and can be particularly concerning. In this patient, mediastinal and subcutaneous emphysema might have been caused by the vulnerability of pulmonary alveolar walls to steroid medication and the increase of pulmonary alveolar pressure with abdominal pain and breath holding. Here, we report a case of inflammatory bowel disease with mediastinal and subcutaneous emphysema, along with a review of the literature.", "affiliations": "Department of Gastroenterology, Japanese Red Cross Kyoto Daiichi Hospital.", "authors": "Terasaki\|Kei\|K\|;Okuyama\|Yusuke\|Y\|;Ueda\|Tomohiro\|T\|;Matsuyama\|Kiichi\|K\|;Urata\|Yoji\|Y\|;Yoshida\|Norimasa\|N\|", "chemical_list": null, "country": "Japan", "delete": false, "doi": "10.11405/nisshoshi.113.457", "fulltext": null, "fulltext_license": null, "issn_linking": "0446-6586", "issue": "113(3)", "journal": "Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology", "keywords": null, "medline_ta": "Nihon Shokakibyo Gakkai Zasshi", "mesh_terms": "D000293:Adolescent; D003093:Colitis, Ulcerative; D006801:Humans; D008297:Male; D008478:Mediastinal Emphysema; D013352:Subcutaneous Emphysema", "nlm_unique_id": "2984683R", "other_id": null, "pages": "457-63", "pmc": null, "pmid": "26947047", "pubdate": "2016-03", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "A case report of severe ulcerative colitis with mediastinal and subcutaneous emphysema.", "title_normalized": "a case report of severe ulcerative colitis with mediastinal and subcutaneous emphysema" }	[ { "companynumb": "JP-TEVA-688949ISR", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MESALAMINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3600 MILLIGRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "COLITIS ULCERATIVE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MESALAZINE" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "89081", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MILLIGRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "COLITIS ULCERATIVE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": "17", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "40", "reaction": [ { "reactionmeddrapt": "Pneumomediastinum", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Subcutaneous emphysema", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "TERASAKI K, OKUYAMA Y, UEDA T, MATSUYAMA K, URATA Y, YOSHIDA N. A CASE REPORT OF SEVERE ULCERATIVE COLITIS WITH MEDIASTINAL AND SUBCUTANEOUS EMPHYSEMA. NIHON-SHOKAKIBYO-GAKKAI-ZASSHI 2016;113(3):457-63.", "literaturereference_normalized": "a case report of severe ulcerative colitis with mediastinal and subcutaneous emphysema", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20161101", "receivedate": "20160906", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12716490, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "JP-SHIRE-JP202033197", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MESALAMINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "022000", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK, UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "COLITIS ULCERATIVE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "476 (MESALAZINE/MESALAMINE)" } ], "patientagegroup": null, "patientonsetage": "17", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "39.91", "reaction": [ { "reactionmeddrapt": "Pneumomediastinum", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Subcutaneous emphysema", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "TERASAKI, K.? OKUYAMA ET AL. A CASE REPORT OF SEVERE ULCERATIVE COLITIS WITH MEDIASTINAL AND SUBCUTANEOUS EMPHYSEMA. THE JAPANESE JOURNAL OF GASTRO?ENTEROLOGY. 2016?113 (3):457", "literaturereference_normalized": "a case report of severe ulcerative colitis with mediastinal and subcutaneous emphysema", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20210423", "receivedate": "20201016", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18392943, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "JP-MYLANLABS-2016M1035444", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "PREDNISOLONE SODIUM PHOSPHATE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "COLITIS ULCERATIVE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MESALAMINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3600MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "COLITIS ULCERATIVE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MESALAZINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Subcutaneous emphysema", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pneumomediastinum", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "TERASAKI K, OKUYAMA Y, UEDA T, MATSUYAMA K, URATA Y, YOSHIDA N. A CASE REPORT OF SEVERE ULCERATIVE COLITIS WITH MEDIASTINAL AND SUBCUTANEOUS EMPHYSEMA. NIHON-SHOKAKIBYO-GAKKAI-ZASSHI 2016;113(3):457-63.", "literaturereference_normalized": "a case report of severe ulcerative colitis with mediastinal and subcutaneous emphysema", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20161118", "receivedate": "20160824", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12681133, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" } ]
{ "abstract": "Acute respiratory distress syndrome (ARDS) is the leading cause of mortality in hospitalized patients with coronavirus disease 2019 (COVID-19) because of limited effective therapies. During infection, the accumulation and activation of macrophages and monocytes in the lungs induce inflammatory mediators and contribute to tissue injury, leading to ARDS. However, therapeutic strategies that directly target activated macrophage and monocytes have not been reported. Combination treatment with etoposide (a cytotoxic agent) and a corticosteroid has been widely used for treating hemophagocytic lymphohistiocytosis characterized by the systemic activation of macrophages with overwhelming inflammation. Herein, we present five cases of COVID-19-associated ARDS treated with etoposide and corticosteroids. Three of the five patients were over 65 years of age and had various underlying diseases, including multiple myeloma. Four patients required invasive mechanical ventilation (MV), and one patient refused to be placed on MV due to underlying diseases. All patients were pre-treated with antiviral and/or other anti-inflammatory agents, but their condition deteriorated and hyperinflammation was noted. All five patients responded well to treatment and had an immediate response, as reflected by improvement in their respiratory condition and inflammatory marker levels and rapid resolution of fever after etoposide administration; however, some patients required a second dose of etoposide and longer course of steroids. All patients recovered, and there were no severe adverse events related to the drugs. Following successful treatment in these five patients, we plan to conduct a clinical trial to evaluate the efficacy and safety of combination therapy with etoposide and corticosteroid for treating COVID-19 patients in Japan.", "affiliations": "Department of Infectious Diseases, Internal Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.;Department of Infectious Diseases, Internal Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.;Department of Intelligent Network for Infection Control, Tohoku University Graduate School of Medicine, Sendai, Japan.;Department of Intensive Care Unit, Tohoku University Hospital, Sendai, Japan.;Department of Infectious Diseases, Internal Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.;Department of Infectious Diseases, Internal Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.;Department of Infectious Diseases, Internal Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.;Department of Intensive Care Unit, Tohoku University Hospital, Sendai, Japan.;Department of Infectious Diseases, Internal Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.;Department of Infectious Diseases, Internal Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.;Department of Infectious Diseases, Internal Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.;Department of Intensive Care Unit, Tohoku University Hospital, Sendai, Japan.;Department of Infectious Diseases, Internal Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.;Department of Infectious Diseases, Internal Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.", "authors": "Aoyagi\|Tetsuji\|T\|;Sato\|Yukio\|Y\|;Baba\|Hiroaki\|H\|;Shiga\|Takuya\|T\|;Seike\|Issei\|I\|;Niitsuma Sugaya\|Ikumi\|I\|;Takei\|Kentarou\|K\|;Iwasaki\|Yudai\|Y\|;Oshima\|Kengo\|K\|;Kanamori\|Hajime\|H\|;Yoshida\|Makiko\|M\|;Saito\|Koji\|K\|;Tokuda\|Koichi\|K\|;Kaku\|Mitsuo\|M\|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.3389/fmed.2021.718641", "fulltext": "\n==== Front\nFront Med (Lausanne)\nFront Med (Lausanne)\nFront. Med.\nFrontiers in Medicine\n2296-858X\nFrontiers Media S.A.\n\n10.3389/fmed.2021.718641\nMedicine\nCase Report\nCase Report: Successful Treatment of Five Critically Ill Coronavirus Disease 2019 Patients Using Combination Therapy With Etoposide and Corticosteroids\nAoyagi Tetsuji 1 2 \n\nSato Yukio 1\nBaba Hiroaki 2\nShiga Takuya 3\n\nSeike Issei 1\nNiitsuma Sugaya Ikumi 1\nTakei Kentarou 1\nIwasaki Yudai 3 4\n\nOshima Kengo 1 2\nKanamori Hajime 1 2\nYoshida Makiko 1 2\nSaito Koji 3\nTokuda Koichi 1 2\nKaku Mitsuo 1 5\n1Department of Infectious Diseases, Internal Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan\n2Department of Intelligent Network for Infection Control, Tohoku University Graduate School of Medicine, Sendai, Japan\n3Department of Intensive Care Unit, Tohoku University Hospital, Sendai, Japan\n4Department of Anaesthesiology and Perioperative Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan\n5Division of Infectious Diseases and Infection Control, Tohoku Medical and Pharmaceutical University, Sendai, Japan\nEdited by: Yimin Zhang, Zhejiang University, China\n\nReviewed by: Mohamed Gomaa Kamel, Minia University, Egypt; Ning Zhou, Central South University, China\n\nCorrespondence: Tetsuji Aoyagi [email protected]\nThis article was submitted to Infectious Diseases - Surveillance, Prevention and Treatment, a section of the journal Frontiers in Medicine\n\n23 9 2021\n2021\n23 9 2021\n8 71864101 6 2021\n30 8 2021\nCopyright © 2021 Aoyagi, Sato, Baba, Shiga, Seike, Niitsuma Sugaya, Takei, Iwasaki, Oshima, Kanamori, Yoshida, Saito, Tokuda and Kaku.\n2021\nAoyagi, Sato, Baba, Shiga, Seike, Niitsuma Sugaya, Takei, Iwasaki, Oshima, Kanamori, Yoshida, Saito, Tokuda and Kaku\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nAcute respiratory distress syndrome (ARDS) is the leading cause of mortality in hospitalized patients with coronavirus disease 2019 (COVID-19) because of limited effective therapies. During infection, the accumulation and activation of macrophages and monocytes in the lungs induce inflammatory mediators and contribute to tissue injury, leading to ARDS. However, therapeutic strategies that directly target activated macrophage and monocytes have not been reported. Combination treatment with etoposide (a cytotoxic agent) and a corticosteroid has been widely used for treating hemophagocytic lymphohistiocytosis characterized by the systemic activation of macrophages with overwhelming inflammation. Herein, we present five cases of COVID-19-associated ARDS treated with etoposide and corticosteroids. Three of the five patients were over 65 years of age and had various underlying diseases, including multiple myeloma. Four patients required invasive mechanical ventilation (MV), and one patient refused to be placed on MV due to underlying diseases. All patients were pre-treated with antiviral and/or other anti-inflammatory agents, but their condition deteriorated and hyperinflammation was noted. All five patients responded well to treatment and had an immediate response, as reflected by improvement in their respiratory condition and inflammatory marker levels and rapid resolution of fever after etoposide administration; however, some patients required a second dose of etoposide and longer course of steroids. All patients recovered, and there were no severe adverse events related to the drugs. Following successful treatment in these five patients, we plan to conduct a clinical trial to evaluate the efficacy and safety of combination therapy with etoposide and corticosteroid for treating COVID-19 patients in Japan.\n\nCOVID-19\nSARS-CoV-2\netoposide\ncorticosteroid\ncase series\nacute respiratory distress (ARDS)\nJapan Society for the Promotion of Science 10.13039/501100001691 Japan Agency for Medical Research and Development 10.13039/100009619\n==== Body\npmcIntroduction\n\nAcute respiratory distress syndrome (ARDS) is the leading cause of mortality among critically ill coronavirus disease 2019 (COVID-19) patients (1). Disease severity or mortality in COVID-19 patients is associated with elevated levels of pro-inflammatory cytokines and chemokines. Corticosteroid therapy is widely used to suppress inflammatory mediators in COVID-19 and has been reported to improve survival, especially in critically ill patients requiring invasive mechanical ventilation (MV) (2, 3). However, the associated mortality rate remains as high as 30% (2, 3).\n\nHemophagocytic lymphohistiocytosis (HLH) is a potentially life-threatening hyperinflammatory syndrome characterized by sustained activation of macrophages and elevated cytokine levels. Histologic evidence of secondary HLH (sHLH) has been observed in fatal respiratory infection with severe acute respiratory syndrome coronavirus 1, H5N1, and 2009H1N1pdm influenza virus (4–6). Recently, post-mortem analysis of COVID-19 patients with ARDS showed diffuse alveolar damage and hemophagocytosis with pulmonary hilar or mediastinal lymphadenopathy (7). Clinical data of severe COVID-19 patients revealed lymphopenia, hyperferritinemia, and elevated pro-inflammatory cytokine levels (8). Thus, macrophage-mediated inflammation might be involved in the pathogenesis of ARDS caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.\n\nHistorically, the HLH-94 protocol, etoposide (a cytotoxic agent), and a corticosteroid have been used to treat primary or secondary HLH (9). Etoposide is a chemotherapeutic drug that inhibits topoisomerase II, resulting in DNA synthesis errors that lead to apoptosis in rapidly dividing or activated cells. In this process of etoposide-induced cell death, etoposide can reduce the number of macrophages and monocytes in blood. We previously demonstrated that a combination therapy using etoposide and a low-dose corticosteroid, but not etoposide or a corticosteroid alone, reduced the mortality rate and lung injury in a fatal ARDS murine model, in which hypercytokinemia and highly activated macrophages with hemophagocytic activity were observed (10). Moreover, successful treatment with a combination of etoposide and corticosteroid has been reported in severe ARDS caused by H1N1/09 influenza virus (11). Recently, in a study of 11 patients with COVID-19 without invasive MV treated with etoposide as salvage therapy (12), all patients received methylprednisolone plus Tocilizmab (IL-6 inhibitor) or Ankinra (IL-1 inhibitor) before treatment with etoposide. Herein, we report the disease course of five critically ill COVID-19 patients on invasive MV who were treated with a combination of etoposide and corticosteroids.\n\nCase Description\n\nThe off-label use of etoposide and corticosteroid was approved by the Ethics Committee of Tohoku University Hospital. All patients received heparin (10,000–20,000 U/day) to prevent thrombosis. In patients undergoing invasive MV, prone positioning was performed. Figure 1; Table 1 show the clinical progress and clinical characteristics of five critically ill patients infected with SARS-CoV-2, respectively. We evaluated clinical indicators for activation of macrophages and monocytes using H-Score and COVID-19-associated hyperinflammatory syndrome (cHIS) score (Table 1). The median value of H-Score, excluding histological findings of bone marrow, was 54 (range: 33–97) on administration of etoposide and corticosteroid. All patients met 2–4 items of the cHIS criteria at the time of etoposide administration. The median sequential organ failure assessment (SOFA) score at the time of etoposide administration was 5.5 (range: 3–8), which improved by 0.5 (0–2) after a combination treatment with etoposide and prednisolone (PSL). Figure 2 shows the changes in white blood cell count before and after treatment with etoposide and corticosteroid.\n\nFigure 1 Timeline of clinical progress of COVID-19 patients after hospitalization and that after treatment with etoposide and corticosteroid. An 7 point ordinal clinical scale was used to assess pulmonary status consisting of the following values: 7, Ventilation in addition to extracorporeal membrane oxygen (ECMO); 6, Ventilation in addition to need for vasopressors (noradrenaline ≥ 0.1 μg/kg/min); 5, Intubation and mechanical ventilation; 4, Oxygen by mask or nasal prongs; 3, Hospitalization without oxygen supplementation; 2, Discharged from hospital either to home or to inpatient rehabilitation facility with supplemental oxygen; 1, Discharged to home without supplemental oxygen.\n\nTable 1 Patient background, laboratory parameter, time-course of admission, and assessment of clinical outcome after etoposide and corticosteroid.\n\n\tPatient 1\tPatient 2\tPatient 3\tPatient 4\tPatient 5\t\nAge\t58\t88\t71\t45\t69\t\nCo-morbidity\tNone\tMultiple myeloma, CKD, DM, HT\tBrain infarction, hemiplegia, atrial fibrillation, CHF, HT, DM\tChildhood asthma\tPost-CABG, stent graft for abdominal aortic aneurysm, brain infarction, HL, HT, DM\t\nCurrent or Ex-smoker\tYES\tNO\tYES\tNO\tYES\t\nSex\tFemale\tFemale\tMale\tMale\tMale\t\nFever (>38°C)\tYES\tYES\tYES\tYES\tYES\tYES\t\nPaO2/FiO2 (mmHg)\t134\t250\t90\t183\t150\t104\t\nFerritin (ng/ml)\t1,507\t538.6\t323.6\t855\t588.1\t580.3\t\nsoluble IL-2R (U/ml)\t630\t954\t1262\t1205\t883\t1,453\t\nCRP (mg/dl)\t3.91\t3.14\t15.93\t20.88\t19.16\t10.46\t\nLDH (U/L)\t509\t349\t306\t317\t288\t193\t\nD-dimer (μg/ml)\t1.7\t3.1\t1.3\t2.8\t1.1\t4.7\t\nCK (U/L)\t797\t55\t58\t62\t27\t144\t\nNeutrophils (/μl)\t6,240\t2,470\t10,490\t9,340\t10,390\t13,450\t\nLymphocytes (/μl)\t620\t1,530\t1,520\t1,480\t660\t760\t\nCytopenia > 2 Lines\tNO\tNO\tNO\tNO\tNO\tNO\t\nHepatomegaly or Splenomegaly\tNO\tNO\tNO\tNO\tSplenomegaly\tNO\t\nH-Score (without histological evidence of hemophagocytosis)\t96\t97\t33\t52\t56\t33\t\ncHIS score\t4/6\t3/6\t2/6\t3/6\t3/6\t3/6\t\nMechanical ventilation\tYES\tNO\tYES\tYES\tYES\tYES (ECMO)\t\nEtoposide (doses and times)\t80 mg/m2 × 1\t50 mg/m2 × 1\t80 mg/m2 × 1\t80 mg/m2 × 1\t80 mg/m2 × 2\t80 mg/m2 × 2\t\nPrednisolone (dose and duration)\t20 mg for 1 week → 10 mg for 1 week\t20 mg for 1 week → 10 mg for 1 week\t20 mg for 1 week → 10 mg for 1 week\t20 mg for 1 week → 10 mg for 1 week\t20 mg for 2 week → 15 mg for 3 days → 10 mg for 6 days\t20 mg for 1 week → 10 mg for 1 week\t\nPost etoposide and prednisolone PaO2/FiO2 (mmHg)\t480\t450\t396\t397\t450\t250\t\nA change in SOFA score (before and after etoposide and prednisolone)\t7 to 0\t4 to 0\t8 to 1\t7 to 1\t3 to 0\t4 to 2\t\nOutcome\tDischarge\tDischarge\tDischarge\tDischarge\tContinue rehabilitation\t\nInfection\tNO\tNO\tNO\tNO\tNO\tYES (perianal abscess)\t\n First course,\n\n** Second course.\n\nH-Score; (20).\n\ncHIS; (24).\n\nCKD, chronic kidney disease; DM, diabetes mellitus; HT, hypertension; CHF, chronic heart failure; HL, hyperlipidemia; CABG, Coronary artery bypass grafting; ECMO, extracorporeal membrane oxygenation; SOFA, sequential organ failure assessment.\n\nFigure 2 Changes in white blood cell count before and after treatment with etoposide and corticosteroid.\n\nPatient 1\n\nIn April 2020, a 58-year-old woman was transferred to our hospital with severe hypoxia (SpO2 90% on 8 L/min oxygen) 7 days after the onset of COVID-19 symptoms, which included general fatigue and cough. She was immediately transferred to our intensive care unit (ICU) and underwent endotracheal intubation and MV. Chest computed tomography (CT) showed bilateral ground-glass opacities and peripheral condensation. Partial pressure of oxygen in arterial blood (PaO2) was 80 mmHg while receiving FiO2 of 60%, which yielded a PaO2 to FiO2 ratio (P/F ratio) of 134 mmHg. She was treated with favipiravir (3,600 mg on day 1, followed by 1,800 mg from days 2 to 14). On day 2, noradrenaline was administered to maintain a mean blood pressure of >70 mmHg. On day 3, she still had fever (>38°C); her general condition deteriorated, with decreased urine output, and an increased dose of noradrenaline was required. Moreover, her laboratory data showed increased levels of soluble interleukin-2 receptor (sIL-2R), C-reactive protein (CRP), and creatine kinase (CK). We decided to treat her with etoposide (80 mg/m2) and PSL (20 mg/day) (instead of dexamethasone as PSL is the preferred corticosteroid in Japan). On the day following treatment with etoposide and corticosteroids, her respiratory and hemodynamic conditions improved dramatically, and the P/F ratio (312 mmHg) increased significantly. On day 7, 4 days after starting treatment, she was extubated. Because her general condition continued to be good and laboratory data showed decreased inflammatory marker levels, including sIL-2R and CRP, the PSL dose was tapered after 7 days of treatment. The patient was discharged home without supplemental oxygen after real-time polymerase chain reaction (RT-PCR) tests for SARS-CoV-2 on days 18 and 20 were confirmed to be negative.\n\nPatient 2\n\nAn 88-year-old woman with a history of recently diagnosed multiple myeloma (Bence-Jones protein λ, R-ISS III), diabetes mellitus, and chronic kidney failure (serum creatinine, 2.15 mg/dl) presented with low-grade fever and exertional dyspnea owing to COVID-19 pneumonia, with SpO2 of 95% on room air at presentation. Chest CT revealed bilateral multiple ground-glass opacities. Her renal function prevented the use of antiviral agents, including remdesivir. A single dose of 500 mg tocilizumab was administered on the day of admission. However, on day 4 of hospitalization, she developed fever (>38°C), and her respiratory condition progressively worsened (P/F ratio: 252 mmHg), but her family did not agree to MV. The patient was treated with etoposide and PSL (20 mg/day). The dose of etoposide was reduced from 80 to 50 mg/m2, considering her kidney failure and old age. After this treatment, her fever subsided and her respiratory condition gradually improved (P/F ratio: 452 mmHg). However, she still had exertional dyspnea, and CT showed progressive consolidation and parenchymal changes with pulmonary fibrosis. On day 28, she was discharged home with supplemental oxygen therapy. She was followed up in the outpatient clinic for 3 months with no evidence of exacerbation. However, she could not be weaned from home oxygen therapy.\n\nPatient 3\n\nA 71-year-old man with a history of hemiplegia owing to a stroke, atrial fibrillation, hypertension, chronic heart failure, and untreated diabetes mellitus was intubated and transferred to our hospital because of severe hypoxia and fever (>38°C) at 10 days after the laboratory diagnosis of asymptomatic SARS-CoV-2 infection following close contact with another patient. CT showed lung consolidation with bronchial distribution in multiple lobes and segments and thrombus formation in the left atrial appendage. He was immediately admitted to our ICU and required invasive MV for severe ARDS with a P/F ratio of 90 mmHg; noradrenalin was administered to maintain his blood pressure. Treatment with remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 4 additional days), etoposide (80 mg/m2), and PSL (20 mg/day) was started. On the day after etoposide administration, his fever subsided, respiratory and hemodynamic conditions improved dramatically, and P/F ratio increased to 152 mmHg. Noradrenalin was discontinued 5 days after treatment initiation. His general condition and laboratory data, including lactate dehydrogenase, CK, sIL-2R, and CRP levels, remarkably improved. The PSL dose was tapered after 7 days of treatment. RT-PCR tests for SARS-CoV-2 on days 10 and 11 were confirmed to be negative. However, on day 12, he developed high fever (>39°C), and circulatory agents, including noradrenalin and dobutamine, were required to maintain his hemodynamic condition because he had a history of atrial fibrillation and chronic heart failure; tracheostomy was performed. There was no evidence of superinfection. Several blood and sputum cultures were negative, and CT showed improved lung consolidation with no new infectious sites. There were clinical and biochemical features of cytokine-releasing syndrome, with increased levels of aspartate transaminase, lactate dehydrogenase, sIL-2R, ferritin, D-dimer, and CRP levels and increased peripheral monocytes. Thus, a second course of etoposide and PSL was administered for macrophage activation syndrome on day 18. The day after starting the second treatment course, his fever subsided and general and hemodynamic conditions improved immediately; the PSL dose was tapered 7 days after second course of etoposide. He was weaned from the MV 10 days post-second treatment course (on day 29) and discharged to an inpatient rehabilitation hospital with supplemental oxygen therapy on day 35. Four months later, he was discharged home without oxygen support.\n\nPatient 4\n\nA 45-year-old man with a history of childhood asthma presented with fever (>39°C), cough, and dyspnea 10 days after the onset of symptoms. His SpO2 was 90% on 10 L/min oxygen via a mask. Chest CT showed consolidation with a bronchial distribution in multiple lobes. SARS-CoV-2 infection was confirmed on a respiratory viral multiplex PCR test using a nasal swab sample. Dexamethasone (6.6 mg/day) and favipiravir were started immediately after diagnosis. On the day after treatment initiation, his respiratory condition deteriorated owing to ARDS and fever remained high (>39°C). He was transferred to our hospital for further management. He was intubated and admitted to the ICU, and favipiravir was replaced with remdesivir. On day 2, his respiratory condition had not improved (P/F ratio: 150 mmHg) and high fever persisted; thus, etoposide (80 mg/m2) and PSL (20 mg/day) were administered. His P/F ratio improved to 220 mmHg and fever subsided 2 days after combination treatment initiation. On day 6, he developed high fever (>39°C), and his P/F ratio worsened to 152 mmHg with no evidence of superinfection (negative blood and sputum cultures). On day 9, CT revealed worsening pulmonary consolidation, mediastinal lymphadenopathy, and splenomegaly. Laboratory test results showed increased sIL-2R (1506 U/ml), ferritin (991.3 ng/ml), CRP (24.4 mg/dl), and D-dimer (2.9 g/ml) levels in contrast to the levels before combination treatment initiation. Thus, we decided to administer a second dose of etoposide and continue the same dose of PSL for another week. His fever eventually subsided and P/F ratio improved to 220 mmHg 2 days after the second dose of etoposide; he was extubated on day 13. RT-PCR tests for SARS-CoV-2 on days 14 and 15 were confirmed to be negative. Because his general condition continued to be good and laboratory data showed decreased inflammatory marker levels, the PSL dose was gradually tapered after 14 days of treatment and stopped on day 20.\n\nHe was discharged home without supplemental oxygen on day 24.\n\nPatient 5\n\nA 68-year-old man with a history of coronary artery bypass surgery, endovascular aortic repair for an abdominal aortic aneurysm, stroke, diabetes mellitus, hypertension, and hyperlipidemia presented with general fatigue and dyspnea 5 days after the onset of symptoms including low-grade fever, cough, and rhinorrhea. His SpO2 was 94% on 1 L/min oxygen via a nasal tube. Chest CT showed bilateral multiple ground-glass opacities. Laboratory data showed an elevated D-dimer level (4.7 g/ml). Treatment with dexamethasone (6.6 mg/day), favipiravir, and heparin (10,000 U/day) was immediately started after SARS-CoV-2 infection was confirmed by respiratory viral multiplex PCR. However, his respiratory condition (SpO2 90–95% on 5 L/min oxygen via a mask) deteriorated 3 days after treatment initiation. He was transferred to our hospital for further management, and favipiravir was replaced with remdesivir. On day 2, he developed high fever (>39°C) and his SpO2 decreased to <90% on 10 L/min oxygen via a mask. Chest CT revealed progression of the pulmonary lesions in extent and density. He was transferred to our ICU and required invasive MV for severe ARDS with a P/F ratio of 105 mmHg. On day 3, his respiratory condition and laboratory data, including inflammatory marker levels, had not improved despite dexamethasone was being administered for 5 days; hence, etoposide (80 mg/m2) and PSL (20 mg/day) were administered. His P/F ratio improved to 237.5 mmHg and fever subsided 2 days after combination therapy initiation. On day 10, he developed high fever again, and laboratory data showed increased inflammatory marker levels, including sIL-2R (1741 U/ml), CRP (11.39 mg/dl), and D-dimer (5.1 g/ml), but no evidence of secondary infection or change in respiratory condition was noted. Thus, we administered a second dose of etoposide and tapered the PSL dose to 10 mg. After the second dose of etoposide, his fever subsided immediately; he was extubated on day 15. SARS-CoV-2 PCR tests were confirmed to be negative on days 16 and 17. On day 18, he developed septic shock and was re-intubated, and noradrenaline was administered. Blood and central catheter line samples were positive for Enterobacter aerogenes. On day 21, his respiratory condition worsened (P/F ratio: 100 mmHg) even though carbapenem and an aminoglycoside were administered, necessitating venovenous extracorporeal membrane oxygenation (ECMO). E. aerogenes was isolated several times from the blood culture, despite effective antimicrobial therapy and catheter replacement. Eventually, CT showed a perianal abscess. Drainage of the abscess and administration of antimicrobial agents improved his condition, and he was weaned off ECMO on day 40. Three months later, he was weaned off the mechanical ventilator and transferred to an inpatient rehabilitation hospital.\n\nDiscussion\n\nExpanding the treatment options for critically ill COVID-19 patients on MV will improve individual outcomes and reduce the burden on medical practitioners and healthcare staff leading to more effective use of medical resources. The COVID-19 mortality rate is particularly high in elderly patients requiring invasive MV (13). Combination treatment with etoposide and low-dose corticosteroid showed favorable outcomes in five cases of severe COVID-19, including four patients on invasive MV. Three of the five patients who received etoposide and corticosteroid were over 65 years of age and had various underlying diseases, but all of them recovered. The 88-year-old patient with multiple myeloma was not placed on invasive MV during treatment.\n\nPeripheral blood in patients with severe COVID-19 shows lymphopenia with increased CD14-positive monocyte and inflammatory cytokine levels, such as tumor necrosis factor (TNF)-α and interferon (IFN)-γ (14, 15). In severe COVID-19 pneumonia, TNF-α and IFN-γ induce nitric oxide synthase (iNOS), which produces cytotoxic nitric oxide in macrophages and plays a central role in tissue injury and mortality (16). Thus, macrophages and monocytes are implicated as potential therapeutic targets to reduce hyperinflammation and tissue injury. Using a lethal ARDS model, we demonstrated that combination therapy with etoposide and low-dose corticosteroids improved mortality and lung injury associated with suppressed macrophage/monocyte accumulation and high iNOS expression levels in the lungs rather than suppressed inflammatory cytokines (10). In our COVID-19 cases, treatment with etoposide and corticosteroid rapidly reduced the number of circulating monocytes (Figure 2) and improved the respiratory condition.\n\nEtoposide is an anti-cancer agent; thus, clinicians should be aware of its dose-dependent side effects. When the HLH-94 protocol is applied to adults with HLH, reducing the etoposide dose from 150 mg/m2 to 50–100 mg/m2 is recommended (9). Thus, we administered etoposide at a dose of 80 mg/m2 in all patients, except the one with impaired renal function. Secondary leukemia is one of the most serious side effects of etoposide, occurring in up to 18.4% of patients treated with cumulative doses ranging from 5,200 to 19,200 mg/m2 (17). We treated five COVID-19 patients with 50–80 mg/m2 of etoposide as one or two doses. This dose is much lower than the treatment dose for small lung cancer and that in the HLH-94 protocol. Reactive cytopenia and hepatotoxicity are other potential adverse events following etoposide administration. However, these potential side effects were not observed in any of our patients. We believe that etoposide can be used safely to treat patients with severe COVID-19 who are on invasive MV; however, a clinical trial is needed to validate the efficacy and safety of this regimen.\n\nDexamethasone is effective in severe COVID-19. The recommended dose of dexamethasone (6 mg/day) is equivalent to 40 mg/day of PSL. High-dose corticosteroid (>20 mg/day PSL) increases the risk of steroid toxicity, including diabetes mellitus and secondary infection (18). Further, the administration of high-dose corticosteroids to COVID-19 patients increases the risk of secondary infections, including bacteremia and pulmonary aspergillosis (3, 19). Therefore, we decided to administer low-dose corticosteroids (20 mg/day for 1 week, subsequently reduced to 10 mg/day for 1 week) based on animal experiment findings (10). One patient had perianal abscess-associated bacteremia, but the corticosteroid dose could be reduced by combining it with etoposide. Moreover, corticosteroids affect glycemic control in individuals with diabetes or hyperglycemia due to COVID-19 (3, 19). Three patients had underlying diabetes mellitus, and their glucose levels increased after combination treatment with etoposide and corticosteroids that could be controlled with insulin administration. The other two patients did not show abnormal glucoses levels during the therapy.\n\nPrevious studies demonstrated that ICU admission and corticosteroid treatment significantly delayed viral clearance (20, 21). All the four ICU patients had negative SARS-CoV-2 RT-PCR tests on days 10–18 after hospital admission (Figure 1). Among COVID-19 ICU patients, the median time to a negative SARS-CoV-2 RT-PCR test was 19–26 days post-ICU admission (22). Thus, it is unlikely that our combination therapy delayed viral clearance when compared with other immunosuppressive therapies.\n\nThe H-Score has been widely used to support the diagnosis of sHLH (23). However, none of our patients met the sHLH criterion using the H-Score upon etoposide and corticosteroid administration (Table 1). In a study of autopsy cases of H1N1/09 influenza, <50% with histological evidence of hemophagocytosis met the criteria for sHLH based on the H-S score (6). Moreover, the H-Score was low in COVID-19 patients with hemophagocytosis (7). These discrepancies may be explained by the fact that the lung is the initial site of hyperinflammation following respiratory virus infection, thus HLH occurs in the lung, but not always throughout the body as is observed in malignancies and autoimmune diseases. Recently, Webb et al. proposed a set of six clinical criteria for cHIS: fever, macrophage activation (hyperferritinemia), hematological dysfunction (neutrophil-to-lymphocyte ratio), hepatic injury (lactate dehydrogenase or aspartate aminotransferase), coagulopathy (D-dimer), and cytokinemia (C-reactive protein, interleukin-6, or triglycerides). Meeting two or more of the six cHIS items is generally associated with severe disease and high fatality rate (24). All our patients met more than two of the cHIS items at the time of etoposide administration. Although these criteria need to be validated, they may serve as an indicator for clinicians to consider life-saving immunotherapy, including etoposide and corticosteroid, in severe COVID-19.\n\nIn conclusion, in this preliminary experience, combination treatment with etoposide and low-dose corticosteroids resulted in an overall favorable outcome in patients with SARS-CoV-2 infection-associated ARDS. Recently, etoposide has been described as an effective treatment for severe COVID-19 patients who do not require MV (12, 25). We plan to conduct a clinical trial to evaluate the efficacy and safety of combination therapy with etoposide and low-dose corticosteroids in critically ill COVID-19 patients who are on invasive MV in Japan (jRCT2021210012).\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.\n\nEthics Statement\n\nThe off-label use of etoposide and corticosteroid was approved by the Ethics Committee of Tohoku University Hospital. Written informed consent was obtained from patients. If the patients with ARDS received mechanical ventilation under the sedation, and they were not able to make their decision by themselves, we obtained written informed consent from their legal proxy for medical decision making before treatment. Written informed consent was obtained from the individual(s) for publication of any potentially identifiable images or data included in this articles.\n\nAuthor Contributions\n\nTA, YS, and MK designed the study. TA and YS wrote the initial draft. HB, TS, IS, IN, KTa, YI, KO, HK, MY, KS, and KTo provided patient care and collected the data. This paper has been reviewed, edited, and approved by all authors.\n\nFunding\n\nThis study has been supported in part by Japanese Society for the Promotion of Science Grant-in-Aid for Scientific Research 18K08424 (TA). Department of Intelligent Network for Infection Control, Tohoku University Graduate School of Medicine (TA, HB, KO, HK, MY, KTo) is an endowment department, supported with an unrestricted grant from Kyosei Igaku Laboratory Co., Ltd. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nPublisher's Note\n\nAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.\n\nThe authors thank all of the medical staff members involved in treating this patient.\n\nSupplementary Material\n\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fmed.2021.718641/full#supplementary-material\n\nClick here for additional data file.\n==== Refs\nReferences\n\n1. Huang C Wang Y Li X Ren L Zhao J Hu Y . Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. (2020) 395:497-506. 10.1016/S0140-6736(20)30183-5 32502551\n2. Group RC Horby P Lim WS Emberson JR Mafham M Bell JL . Dexamethasone in hospitalized patients with Covid-19. N Engl J Med. (2021) 384:693-704. 10.1056/NEJMoa2021436 32678530\n3. Sterne JAC Murthy S Diaz JV Slutsky AS Villar J Angus DC . 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(2010) 376 :2116. 10.1016/S0140-6736(10)61345-1 21168053\n12. M MB L B I A P D E I F C . Etoposide treatment adjunctive to immunosuppressants for critically ill COVID-19 patients. J Infect. (2020) 81:452-82. 10.1016/j.jinf.2020.06.006 32579985\n13. Lim ZJ Subramaniam A Ponnapa Reddy M Blecher G Kadam U Afroz A . Case fatality rates for patients with COVID-19 requiring invasive mechanical ventilation. A meta-analysis. Am J Respir Crit Care Med. (2021) 203:54-66. 10.1164/rccm.202006-2405OC 33119402\n14. Wen W Su W Tang H Le W Zhang X Zheng Y . Immune cell profiling of COVID-19 patients in the recovery stage by single-cell sequencing. Cell Discov. (2020) 6 :31. 10.1038/s41421-020-0168-9 33941770\n15. Lucas C Wong P Klein J Castro TBR Silva J Sundaram M . Longitudinal analyses reveal immunological misfiring in severe COVID-19. Nature. (2020) 584:463-9. 10.1038/s41586-020-2588-y 32717743\n16. Karki R Sharma BR Tuladhar S Williams EP Zalduondo L Samir P . Synergism of TNF-alpha and IFN-gamma triggers inflammatory cell death, tissue damage, and mortality in SARS-CoV-2 infection and cytokine shock syndromes. Cell. (2021) 184:149-+. 10.1016/j.cell.2020.11.025 33278357\n17. Ezoe S . Secondary leukemia associated with the anti-cancer agent, etoposide, a topoisomerase II inhibitor. Int J Environ Res Public Health. (2012) 9:2444-53. 10.3390/ijerph9072444 22851953\n18. Youssef J Novosad SA Winthrop KL . Infection risk and safety of corticosteroid use. Rheum Dis Clin North Am. (2016) 42:157-76, ix-x. 10.1016/j.rdc.2015.08.004 26611557\n19. Cano EJ Fonseca Fuentes X Corsini Campioli C O'Horo JC Abu Saleh O Odeyemi Y . Impact of corticosteroids in coronavirus disease 2019 outcomes: systematic review and meta-analysis. Chest. (2021) 159:1019-40. 10.1016/j.chest.2020.10.054 33129791\n20. Wang J Yang W Chen P Guo J Liu R Wen P . 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Webb BJ Peltan ID Jensen P Hoda D Hunter B Silver A . Clinical criteria for COVID-19-associated hyperinflammatory syndrome: a cohort study. Lancet Rheumatol. (2020) 2:e754-63. 10.1016/S2665-9913(20)30343-X 33015645\n25. Patel M Dominguez E Sacher D Desai P Chandar A Bromberg M . Etoposide as salvage therapy for cytokine storm due to coronavirus disease 2019. Chest. (2021) 159:e7-11. 10.1016/j.chest.2020.09.077 32931823\n\n", "fulltext_license": "CC BY", "issn_linking": "2296-858X", "issue": "8()", "journal": "Frontiers in medicine", "keywords": "COVID-19; SARS-CoV-2; acute respiratory distress (ARDS); case series; corticosteroid; etoposide", "medline_ta": "Front Med (Lausanne)", "mesh_terms": null, "nlm_unique_id": "101648047", "other_id": null, "pages": "718641", "pmc": null, "pmid": "34631741", "pubdate": "2021", "publication_types": "D002363:Case Reports", "references": "21168053;26611557;33119402;32931823;32876694;32681166;16964257;33301059;32717743;24782338;32007143;33278357;32678530;33015645;33882090;33129791;22851953;32579985;30028782;33639375;31986264;30992265;12781536;26597256", "title": "Case Report: Successful Treatment of Five Critically Ill Coronavirus Disease 2019 Patients Using Combination Therapy With Etoposide and Corticosteroids.", "title_normalized": "case report successful treatment of five critically ill coronavirus disease 2019 patients using combination therapy with etoposide and corticosteroids" }	[ { "companynumb": "JP-MYLANLABS-2021M1086496", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "202179", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MILLIGRAM, QD, FOR 1 WEEK", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, 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Case Report: Successful Treatment of Five Critically Ill Coronavirus Disease 2019 Patients Using Combination Therapy With Etoposide and Corticosteroids. 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Case Report: Successful Treatment of Five Critically Ill Coronavirus Disease 2019 Patients Using Combination Therapy With Etoposide and Corticosteroids. 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FOR 1 WEEK", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19 pneumonia", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": "2", "drugtreatmentdurationunit": "803", "medicinalproduct": "PREDNISOLONE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": "080354", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM DAILY; FOR 1 WEEK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": "2", "drugtreatmentdurationunit": "803", "medicinalproduct": "PREDNISOLONE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "TOCILIZUMAB" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "SINGLE DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19 pneumonia", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOCILIZUMAB" } ], "patientagegroup": "6", "patientonsetage": "88", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Blood glucose increased", "reactionmeddraversionpt": "24.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Aoyagi T, Sato Y, Baba H, Shiga T, Seike I, Niitsuma Sugaya I, et al. Case Report: Successful Treatment of Five Critically Ill Coronavirus Disease 2019 Patients Using Combination Therapy With Etoposide and Corticosteroids. 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Case Report: Successful Treatment of Five Critically Ill Coronavirus Disease 2019 Patients Using Combination Therapy With Etoposide and Corticosteroids. Front-Med 2021;null:null.. 2021", "literaturereference_normalized": "case report successful treatment of five critically ill coronavirus disease 2019 patients using combination therapy with etoposide and corticosteroids", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20211124", "receivedate": "20211124", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 20110163, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220303" }, { "companynumb": "JP-TEVA-2021-JP-1982425", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": "74284", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MILLIGRAM DAILY; 1 WEEK", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": "2", "drugtreatmentdurationunit": "803", "medicinalproduct": "PREDNISOLONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM DAILY; 1 WEEK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": "2", "drugtreatmentdurationunit": "803", "medicinalproduct": "PREDNISOLONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "NOREPINEPHRINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Blood pressure management", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NOREPINEPHRINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "REMDESIVIR" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "LOADING DOSE ON DAY 1", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "REMDESIVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "REMDESIVIR" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "FOR UP TO 4 ADDITIONAL DAYS", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "REMDESIVIR" } ], "patientagegroup": "6", "patientonsetage": "71", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Blood glucose increased", "reactionmeddraversionpt": "24.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Aoyagi T, Sato Y, Baba H, Shiga T, Seike I, Niitsuma Sugaya I, et al. Case Report: Successful Treatment of Five Critically Ill Coronavirus Disease 2019 Patients Using Combination Therapy With Etoposide and Corticosteroids. Front-Med 2021;:.", "literaturereference_normalized": "case report successful treatment of five critically ill coronavirus disease 2019 patients using combination therapy with etoposide and corticosteroids", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20211202", "receivedate": "20211202", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20141703, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20220303" } ]
{ "abstract": "PML should be considered in patients with neurological symptoms following MM and in those who are immunosuppressed. Symptoms are diverse and often rapidly progressing. Prompt referral and early involvement of the multidisciplinary team are crucial.", "affiliations": "Department of Neurology NHS Lothian Western General Hospital Edinburgh UK.;Department of Haematology NHS Lothian Western General Hospital Edinburgh UK.;Department of Haematology NHS Lothian Western General Hospital Edinburgh UK.;Centre for Clinical Brain Sciences University of Edinburgh Edinburgh UK.", "authors": "Bennett\|Karina M\|KM\|https://orcid.org/0000-0001-9828-5558;Storrar\|Neill\|N\|;Johnson\|Peter\|P\|;Fernandes\|Peter M\|PM\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1002/ccr3.2612", "fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904 John Wiley and Sons Inc. Hoboken \n\n10.1002/ccr3.2612\nCCR32612\nCase Report\nCase Reports\nProgressive multifocal leukoencephalopathy (PML) following autologous peripheral blood stem cell transplantation for multiple myeloma\nBENNETT et al.Bennett Karina M. https://orcid.org/0000-0001-9828-5558\n1\[email protected] Storrar Neill \n2\n Johnson Peter \n2\n Fernandes Peter M. \n3\n \n1 \nDepartment of Neurology\nNHS Lothian\nWestern General Hospital\nEdinburgh\nUK\n\n\n2 \nDepartment of Haematology\nNHS Lothian\nWestern General Hospital\nEdinburgh\nUK\n\n\n3 \nCentre for Clinical Brain Sciences\nUniversity of Edinburgh\nEdinburgh\nUK\n\n* Correspondence\n\nKarina Bennett, Department of Neurology, NHS Lothian, Western General Hospital, Flat 4, 18 Royal Circus, Edinburgh. EH3 6SS, UK.\n\nEmail: [email protected]\n\n20 3 2020 \n6 2020 \n8 6 10.1002/ccr3.v8.6938 943\n12 7 2019 19 10 2019 29 10 2019 © 2020 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nPML should be considered in patients with neurological symptoms following MM and in those who are immunosuppressed. Symptoms are diverse and often rapidly progressing. Prompt referral and early involvement of the multidisciplinary team are crucial.\n\nPML should be considered in patients with neurological symptoms following MM and in those who are immunosuppressed. Symptoms are diverse and often rapidly progressing. Prompt referral and early involvement of the multidisciplinary team are crucial.\n\n\nautologous peripheral blood stem cell transplantationmultiple myelomaprogressive multifocal leukoencephalopathy source-schema-version-number2.0cover-dateJune 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.8.4 mode:remove_FC converted:19.06.2020\n\n\nBennett \nKM \n, \nStorrar \nN \n, \nJohnson \nP \n, \nFernandes \nPM \n. Progressive multifocal leukoencephalopathy (PML) following autologous peripheral blood stem cell transplantation for multiple myeloma\n. Clin Case Rep . 2020 ;8 :938 –943\n. 10.1002/ccr3.2612\n==== Body\n1 INTRODUCTION\nA 67‐year‐old man presented with left‐sided weakness and reduced left‐hand dexterity four months after autologous stem cell transplant (ASCT) for multiple myeloma (MM). Clinical neurological examination was felt to be normal. Three months later, he reported progressive worsening of this weakness; neurological examination showed mild left‐sided facial asymmetry.\n\nHe was diagnosed with IgG lambda MM in March 2016 during follow‐up of lytic lesions on a chest radiograph performed because of recurrent chest infections. His past medical history included chronic obstructive pulmonary disease and controlled hypertension. He was human immunodeficiency virus (HIV) negative. He underwent induction treatment with four cycles of bortezomib, thalidomide, and dexamethasone starting in April 2016, complicated by neutropenic sepsis requiring intensive care for high‐flow oxygen and granulocyte‐colony stimulating factor. He also developed thrombosis of his peripherally inserted central catheter, treated with low molecular weight heparin. ASCT with melphalan conditioning (200 mg/m2) was carried out in January 2017. On day 7 following ASCT, he developed neutropenic sepsis from urinary Escherichia coli. He took routine post‐transplant Pneumocystis jirovecii prophylaxis trimethoprim/sulfamethoxazole, which was switched to pentamidine in April 2017 because of slow platelet count recovery. This stopped in July 2017. In March 2017, he had an episode of herpes zoster affecting the left trunk.\n\nGeneral weakness is common in the months following transplant as the patient recovers from the intensive treatment, complications and hospital admission. The focal progressive symptoms and new findings on neurological examination are much more concerning. There is a wide differential diagnosis, including cerebrovascular disease, demyelinating illness and space occupying lesions.\n\nComputerized tomography (CT) scan of the head was performed which showed multiple areas of low attenuation (Figure 1).\n\nFigure 1 Computerized tomography (CT) scan of the head was performed which showed multiple areas of low attenuation, as shown by the white arrow\n\nThe radiological findings were thought to represent multiple areas of infarction, likely embolic in nature. The progressive nature of the weakness could represent multiple infarcts over time. The patient had several risk factors for stroke: smoking history, hypertension, malignancy, and treatment with chemotherapy. 1 The complication of peripherally inserted central catheter thrombosis could also point toward a predisposition for thrombosis.\n\nMagnetic Resonance Imaging (MRI) of the brain showed numerous hyper‐intense T2 lesions within the subcortical white matter of both cerebral hemispheres (Figure 2). The MRI was repeated one month later and showed interval progression in lesion size (Figure 3).\n\nFigure 2 Magnetic resonance imaging of the brain showed numerous hyper‐intense T2 lesions within the subcortical white matter of both cerebral hemispheres\n\nFigure 3 Magnetic resonance imaging (MRI) repeated one month after the MRI shown in Figure 1 shows interval progression in lesion size\n\nThe MRI head showed multiple areas T2 high signal in the white matter, in keeping with demyelination. This is a feature of several neurological conditions, including hypoxic/ ischemic insults, inflammation (multiple sclerosis, acute disseminated encephalomyelitis, vasculitis, and sarcoidosis), metabolic/toxic causes (carbon monoxide poisoning, vitamin B12 deficiency, central pontine myelinolysis, inherited leukodystrophies), and infections (HIV, syphilis, lyme disease, and progressive multifocal leukoencephalopathy (PML)).\n\nHis clinical symptoms continued to progress, and by September 2017, he was unable to walk 2 m unaided. He developed emotional lability and motion sickness. There was no alteration in sensation, sphincter or bulbar symptoms, and he had no weight loss, night sweats or fevers.\n\nExamination showed normal tone bilaterally. There was mild left‐sided weakness of the face and left‐sided hemiparesis, worse than previous. Reflexes in the legs were brisk with some spreading, and the left plantar response was up‐going. Gait was narrow‐based, stiff and hemiplegic. There were no cerebellar signs. Sensation was intact. Assessment of cognitive function with Addenbrooke's Cognitive Examination III‐revised (ACE III‐R) showed mild cognitive impairment with a score of 84/100 (attention 17/18, memory 21/26, fluency 7/14, language 26/26, and visuospatial 13/16).\n\nInterpretation of ACE III‐R scores is difficult, and repeated tests at different points in time are the best way to show cognitive decline. A score of less than 88 gives a significant likelihood of dementia 2; thus, in our patient, a score of 84 demonstrates probable cognitive impairment.\n\nFurther investigations were performed to determine the cause of the demyelination. A CT chest, abdomen, and pelvis showed no evidence of systemic disease, such as solid malignancy. Serum serology was negative for HIV, syphilis, and lyme disease. Connective tissue autoimmune screen was negative, with no evidence of systemic vasculitis, and vitamin B12 levels were normal. A lumbar puncture showed normal cell count (red blood cell 0 × 1012/L, white blood cell 2 × 109/L), protein (0.37 mg/dL), glucose (3.4 mg/dL), and no oligoclonal bands in serum or cerebrospinal fluid (CSF). Viral polymerase chain reaction was negative for enteroviruses, herpes simplex virus 1 & 2, parechovirus, and varicella zoster virus, and there were no abnormal cells on microscopy. John Cunningham polyomavirus virus (JCPyV), the causative agent of PML, was positive in serum (1.55 index value); CSF testing for JCPyV was strongly positive at a value of 830 000 copies/ml.\n\nSeropositivity for JCPyV in this patient was not unexpected as between 38% and 82% of the normal population have positive serology, but the virus should not be present in the CSF.3, 4 The positive CSF for JCPyV with compatible clinical and radiological findings fulfill the diagnostic criteria for PML,5 and there was no diagnostic need to perform a brain biopsy. This diagnosis was unexpected as the patient did not appear to be significantly immunocompromised following ASCT and PML is rare in this patient group.\n\nKey blood results before and after ASCT are shown in Table 1, and further measures of immune functioning were taken after the diagnosis of PML to evaluate scope for optimization of immune function (Table 2).\n\nTable 1 Table showing key blood results before, immediately after and 1, 2, and 3 months after ASCT\n\nTime\t\nIgG lambda paraprotein\n\n\n(g/L)\n\n\n\tIgA (g/L)\tIgM (g/L)\t\nHb\n\n\n(135‐180 g/L)\n\n\n\t\nWCC\n\n\n(4.0‐11 109/L)\n\n\n\t\nLymphocytes\n\n\n(1.5‐4\n\n\n109/L)\n\n\n\t\nNeutrophils\n\n\n(2.0‐7.5 109/L)\n\n\n\t\nPlatelets\n\n\n(150‐400 109/L)\n\n\n\t\nDiagnosed MM (March 2016)\t24\t0.36\t0.14\t‐\t‐\t‐\t‐\t‐\t\nBefore chemotherapy (April 2016)\t16\t \t \t130\t14.6\t0.23\t14.09\t143\t\nImmediately post ASCT (January 2017)\t<1\t1.25\t0.20\t117\t5.2\t0.13\t4.85\t141\t\n1 month (February 2017)\t<1\t \t \t95\t5.2\t0.85\t3.19\t39\t\n2 months (March 2017)\t<1\t \t \t92\t6.7\t0.52\t5.47\t100\t\n3 months (April 2017)\t<1\t0.87\t0.13\t98\t5.6\t0.67\t4.3\t57\t\nJohn Wiley & Sons, LtdTable 2 Measures of immune functioning at the time of diagnosis of PML\n\nImmune measure\tResult\t\nLymphocytes (1.5‐4 cells 109/L)\t0.41\t\nB cells (10%‐16%)\t43\t\nT‐cells (67%‐76%)\t40\t\nCD4 absolute (500‐1500 cells u/L)\t72\t\nCD4% (29%‐61%)\t18\t\nCD8 absolute (250‐750 cells u/L)\t90\t\nCD8% (14%‐44%)\t22\t\nCD4/CD8 ratio (0.9‐3.5)\t0.8\t\nNatural killer cells (10%‐15%)\t16\t\nC3 (0.81‐1.57 g/L)\t1.44\t\nC4 (0.13‐1.39 g/L)\t0.34\t\nIgA (6‐15 g/L)\t0.58\t\nIgG (0.8‐4.5 g/L)\t6.82\t\nIgM (0.35‐2.9 g/L)\t0.29\t\nJohn Wiley & Sons, LtdASCT improves the duration of remission and overall survival in patients with MM although most patients develop relapse of MM after a period of remission. 6, 7, 8 The recovery of different immune cells occurs at different time points post‐transplant. The reconstitution of innate immunity occurs rapidly, within 20‐30 days, while reconstitution of adaptive immunity can take 1 year. 9 Early recovery of absolute lymphocyte count (ALC) can be used as a prognostic indicator of overall survival and progression free survival. 10 The patient followed the usual pace of immune reconstitution, with neutrophil recovery at day + 12; implying good immune functioning. Reactivation of varicella zoster virus is common after ASCT 11 and does not suggest unusual immunodeficiency for this patient group. The CD4 count is low; in cases of HIV‐associated PML, there appears to be an association between CD4 count and PML. 5\n\n\nTreatment for JCPyV was commenced with mirtazapine 30mg once daily and intensive physiotherapy.\n\nTreatment for PML can be tackled in two ways: restoring the immune function and attacking the virus. Restoring the immune functioning in the patient was problematic as he did not appear to have reversible immune suppression beyond normal recovery post‐ASCT. No methods to restore immune function were thought feasible except for the possibility of performing a second ASCT using remaining stem cells cryopreserved prior to the first ASCT. Several experimental antiviral therapies were considered, including mirtazapine, which is thought to block virus entry into glial cells via 5HT2a serotonin receptors. 12 Recently, three groups have reported favorably on the use of immune‐checkpoint inhibitors to treat PML; immunotherapy appears promising but requires further study. 13, 14, 15\n\n\nDuring admission, his condition continued to worsen. He developed hospital acquired pneumonia (HAP) and deteriorated rapidly, dying 5 days later. His death was 18 months after diagnosis of MM, 10 months after ASCT, 14 days after diagnosis of PML and 10 days after mirtazapine had started. His death was before the second ASCT could be attempted.\n\nIt was very difficult to give a prognosis to the patient due to lack of comparable cases. His rapid deterioration from HAP was unexpected. This could reflect a weaker immune function than suggested by his blood test results. It was unlikely that a second stem cell infusion (without conditioning chemotherapy) would have promoted immune reconstitution, but equally seemed unlikely to cause harm.\n\n2 DISCUSSION\nPML is a rare demyelinating disorder of the central nervous system caused by reactivation of JCPyV virus, a neurotropic polyomavirus.16 The clinical presentation depends on the extent of demyelination and brain structures involved. Symptoms include muscle weakness, sensory deficit, hemianopia, cognitive dysfunction, aphasia, and coordination and gait difficulties. 17 JCPyV virus is present in 38%‐82% of the population 3, 4 but is usually well‐controlled by the immune system, resulting in asymptomatic latent infection. The kidney and bone marrow are the likely sites of latent infection,18 and there should be no JCPyV virus detectable in the CSF. PML primarily affects those with chronic and severely suppressed immune systems. 19 Three associations account for 90% of cases: (1) HIV; (2) immunosuppressing hematological malignancies, and (3) Multiple sclerosis patients treated with natalizumab, a monoclonal antibody to alpha‐4 integrin that prevents immune cells accessing the central nervous system. 20 PML is rarely associated with organ transplantation, solid malignancies, sarcoidosis, and autoimmune disorders.20\n\n\nTreatment for PML is via restoring immune function and/or attacking the virus. Restoring immune function can be achieved by reversal of the immunosuppression caused by a disease, for example antiretroviral drugs in HIV 21; removal of immunosuppressive treatment for example stopping Natalizumab 22 or speeding drug clearance through plasma exchange. 23 The second option is to attack the virus. Pavlovic et al 20 conducted a review of treatment options and divided them into 3 main groups: (1) antiviral agents (JCPyV cell entry inhibitors, retrograde transport inhibitors, inhibitors of DNA replication, antimalarials, poly‐ADP‐ribose polymerase‐1 inhibitors and tyrosine kinase inhibitors), (2) immune response modulators (cytokines and inflammation inhibitors), and (3) immunisation strategies (passive and active immunisation). Research supporting these options is limited to case studies and retrospective studies with no strong consensus. Identification of successful treatment is difficult due to lack of an adequate animal model, small patient numbers, and rapid disease progression.20\n\n\nPrognosis in PML is poor. In HIV, 70% are alive at one year and 50% at 2 years. In those with MS treated with Natalizumab, 77% are alive at three years, and in those with active immunosuppressing hematological malignancies, 10% are alive at 2 months. 20 A younger age at diagnosis, lower viral load of JCPyV, milder functional disability prior to PML diagnosis and more localized MRI brain involvement all appear to predict survival. 24\n\n\nDeveloping PML after MM is rare with 11 case reports in the literature. 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 Presentations varied in these patients depending on the location of the lesion and included: hemiparesis and hemiplegia, 25, 28, 29, 32, 35 numbness and tingling of the legs,29 rapid cognitive decline, 25, 27, 33 homonymous hemianopia, 27 ataxia, 27 speech difficulties, 26, 30, 31, 32, 35 incontinence, 26 apathy, 29 and memory impairment. 32, 33, 34\n. Trying to identify if an individual aspect of the MM treatment was responsible for the development of PML is difficult from these isolated case studies. Thalidomide has indirectly been related in this case and two others 29, 30 and lenalidomide in four cases. 25, 26, 27, 28 ASCT was used in all of the cases except two in which lenalidomide was used alone. 25, 28 Lenalidomide is an immunomodulatory drug with antiangiogenetic, anti‐inflammatory, and antiproliferative effects. Ying (2017) completed a systematic review and meta‐analysis of the risk of serious infection in patients with MM receiving lenalidomide and found that the overall incidence of high‐grade infection was 14.32%. Treatment for the PML varied in these case reports. Mirtazepine was used as a single agent in this case and 2 others; 26, 27 in these cases, the patients died within 2‐4 months. Yokokawa (2016) used mirtazepine in combination with mefloquine. In this case, the patient survived for more than one year from PML onset. Ripelino (2011) used mirtazapine in combination with cidofovir and the patient survived for more than two years after onset of PML. It is not possible to recommend the most appropriate therapy from these reports; however, the use of combined treatments may improve outcome. Treatment outcome may also be improved with early diagnosis.\n\nThere are difficult ethical questions about exposing patients to potentially harmful treatments when there is a lack of evidence of efficacy, even when prognosis is poor. Furthermore, any drug which is used must be able to cross the blood brain barrier and have acceptable side effects. There also needs to be consensus on how to measure outcome. Some possible measures include: survival, neurological examination, radiological lesion load and changes in JCPyV in the CSF. Until randomized control trials become available, the treatment of PML relies on case descriptions, retrospective studies, and informed discussions with patients.\n\nPML is a rare complication of MM therapy and is associated with high mortality and morbidity. Clinicians should consider this diagnosis when assessing patients with neurological symptoms and signs following treatment for MM. It is important that referrals are made promptly, and there is involvement of the multidisciplinary team with haematologists, neurologists, radiologists, virologists, and therapists.\n\nCONFLICT OF INTEREST\nNone declared.\n\nAUTHOR CONTRIBUTION\nKB, NS, PJ, and PMF: substantially contributed to conception and design, acquisition of data, or analysis and interpretation of data; drafted the article or revised it critically for important intellectual content; and finally approved the version to be published. Karina Bennett will act as guarantor for the content.\n==== Refs\nREFERENCES\n1 \n\nKristinsson \nSY \n, \nPfeiffer \nRM \n, \nBjörkholm \nM \n, et al. Arterial and venous thrombosis in monoclonal gammopathy of undetermined significance and multiple myeloma: a population‐based study\n. 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Progressive multifocal leukoencephalopathy associated with multiple myeloma\n. Acta Neuropathol . 1964 ;3 .\n35 \n\nYing \nLI \n, \nYinHui \nT \n, \nYunliang \nZ \n, \nSun \nH \n. Lenalidomide and the risk of serious infection in patients with multiple myeloma: a systematic review and meta‐analysis\n. Oncotarget . 2017 ;8 :46593 ‐46600\n.28423741\n\n", "fulltext_license": "CC BY", "issn_linking": "2050-0904", "issue": "8(6)", "journal": "Clinical case reports", "keywords": "autologous peripheral blood stem cell transplantation; multiple myeloma; progressive multifocal leukoencephalopathy", "medline_ta": "Clin Case Rep", "mesh_terms": null, "nlm_unique_id": "101620385", "other_id": null, "pages": "938-943", "pmc": null, "pmid": "32577238", "pubdate": "2020-06", "publication_types": "D002363:Case Reports", "references": "24492738;26600871;30969507;25227934;29507502;24834205;12031917;23568998;22701032;11468153;30969503;12424695;19741228;16956822;20299513;28423741;27909435;19434930;20506049;25771865;16977673;29690814;20298966;19188571;22890289;20190843;17005670;17674313;30969500;28278713;30704932;28039754;27538654;10025799", "title": "Progressive multifocal leukoencephalopathy (PML) following autologous peripheral blood stem cell transplantation for multiple myeloma.", "title_normalized": "progressive multifocal leukoencephalopathy pml following autologous peripheral blood stem cell transplantation for multiple myeloma" }	[ { "companynumb": "GB-ASPEN-GLO2020GB006835", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201604", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, 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PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) FOLLOWING AUTOLOGOUS PERIPHERAL BLOOD STEM CELL TRANSPLANTATION FOR MULTIPLE MYELOMA. CLINICAL CASE REPORTS. 2020?8:6:938?943", "literaturereference_normalized": "progressive multifocal leukoencephalopathy pml following autologous peripheral blood stem cell transplantation for multiple myeloma", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20200717", "receivedate": "20200717", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18036994, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "GB-TEVA-2020-GB-1809828", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BORTEZOMIB" }, 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null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PENTAMIDINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "201704", "drugenddateformat": "610", "drugindication": "ANTIFUNGAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRIMETHOPRIM/SULFAMETHOXAZOLE" } ], "patientagegroup": "6", "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Gait spastic", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dementia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hemiparesis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutropenic sepsis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cognitive disorder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Motion sickness", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Herpes zoster", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Progressive multifocal leukoencephalopathy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fine motor skill dysfunction", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Affect lability", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gait disturbance", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Escherichia infection", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "JC virus infection", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gait inability", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2017" } }, "primarysource": { "literaturereference": "BENNETT KM, STORRAR N, JOHNSON P, FERNANDES PM. PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) FOLLOWING AUTOLOGOUS PERIPHERAL BLOOD STEM CELL TRANSPLANTATION FOR MULTIPLE MYELOMA. CLIN?CASE?REP 2020?8(6):938?943.", "literaturereference_normalized": "progressive multifocal leukoencephalopathy pml following autologous peripheral blood stem cell transplantation for multiple myeloma", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20210628", "receivedate": "20200803", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18103917, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "GB-MYLANLABS-2020M1066945", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "040802", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK UNK, CYCLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PENTAMIDINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIFUNGAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PENTAMIDINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "THALIDOMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201604", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "THALIDOMIDE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200 MILLIGRAM/SQ. METER", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "201704", "drugenddateformat": "610", "drugindication": "ANTIFUNGAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRIMETHOPRIM SULFAMETHOXAZOLE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "BORTEZOMIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BORTEZOMIB." } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Progressive multifocal leukoencephalopathy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hemiparesis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gait spastic", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cognitive disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "JC virus infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Affect lability", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gait inability", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Escherichia infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gait disturbance", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dementia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Herpes zoster", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fine motor skill dysfunction", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutropenic sepsis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Motion sickness", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2017" } }, "primarysource": { "literaturereference": "BENNETT KM, STORRAR N, JOHNSON P, FERNANDES PM. PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) FOLLOWING AUTOLOGOUS PERIPHERAL BLOOD STEM CELL TRANSPLANTATION FOR MULTIPLE MYELOMA. CLIN?CASE?REP 2020?8(6):938?943.", "literaturereference_normalized": "progressive multifocal leukoencephalopathy pml following autologous peripheral blood stem cell transplantation for multiple myeloma", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20200727", "receivedate": "20200727", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18073280, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "GB-ASPEN-GLO2020GB007185", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "THALIDOMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "4 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201604", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "THALIDOMIDE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "4 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201604", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BORTEZOMIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201604", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BORTEZOMIB." } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neutropenic sepsis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2016" } }, "primarysource": { "literaturereference": "BENNETT KM, STORRAR N, JOHNSON P, FERNANDES PM.. PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) FOLLOWING AUTOLOGOUS PERIPHERAL BLOOD STEM CELL TRANSPLANTATION FOR MULTIPLE MYELOMA.. CLINICAL CASE REPORTS. 2020?8(6):938?943", "literaturereference_normalized": "progressive multifocal leukoencephalopathy pml following autologous peripheral blood stem cell transplantation for multiple myeloma", "qualification": "1", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20200728", "receivedate": "20200728", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 18079625, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "GB-FRESENIUS KABI-FK202007446", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "BORTEZOMIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201604", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BORTEZOMIB." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201701", "drugstartdateformat": "610", "drugstructuredosagenumb": "200", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "THALIDOMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201604", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "THALIDOMIDE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "084916", "drugbatchnumb": "UNKNOWN,UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201604", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE INJECTION (MANUFACTURER UNKNOWN)" } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Herpes zoster", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Device related thrombosis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Escherichia sepsis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "JC virus infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutropenic sepsis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Progressive multifocal leukoencephalopathy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201703" } }, "primarysource": { "literaturereference": "BENNETT K, STORRAR N, JOHNSON P, FERNANDES P. PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) FOLLOWING AUTOLOGOUS PERIPHERAL BLOOD STEM CELL TRANSPLANTATION FOR MULTIPLE MYELOMA. CLINICAL CASE REPORTS. 2020?8 (6):938?943.", "literaturereference_normalized": "progressive multifocal leukoencephalopathy pml following autologous peripheral blood stem cell transplantation for multiple myeloma", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20200722", "receivedate": "20200722", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18055433, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" } ]
{ "abstract": "BACKGROUND\nCytomegalovirus (CMV) infection is common in thoracic organ transplant recipients. Valganciclovir and ganciclovir are used for both prophylaxis and treatment of this infection, but intolerance and treatment failure are common. Letermovir has been demonstrated to reduce the risk of CMV infection when used for prophylaxis in allogeneic hematopoietic cell transplantation. However, there are no data on its efficacy in thoracic organ transplantation.\n\n\nMETHODS\nWe examined the use of letermovir for either CMV prophylaxis (primary and secondary) or treatment in heart and lung transplant recipients at our institution from February 1, 2018, through December 31, 2018.\n\n\nRESULTS\nNine total patients received letermovir at our institution (8 lung transplant, 1 heart transplant) during the study period. Letermovir was prescribed for CMV prophylaxis in eight patients (primary prophylaxis in two patients and secondary prophylaxis in 6 patients), and for treatment of CMV DNAemia in two cases. One patient received letermovir for both secondary prophylaxis and treatment on separate occasions. Three out of 8 (37.5%) patients receiving letermovir for prophylaxis developed CMV DNAemia during prophylaxis. One patient treated for CMV disease had clinical failure with a sharp rise in serum CMV DNA PCR. The other patient treated for low-grade CMV DNAemia initially had a slight rise in CMV DNA PCR, but has since had a sustained response. No major side effects were experienced, and 2 patients reported minor side effects.\n\n\nCONCLUSIONS\nLetermovir was well tolerated with only minor side effects reported; however, the rate of development of CMV DNAemia on prophylaxis was considerable. Further study of the dosing and efficacy of letermovir for CMV prophylaxis or treatment in thoracic organ transplant recipients is warranted.", "affiliations": "Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, Falls Church, Virginia.;Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, Falls Church, Virginia.;Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, Falls Church, Virginia.;Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, Falls Church, Virginia.;Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, Falls Church, Virginia.;Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, Falls Church, Virginia.;Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, Falls Church, Virginia.;Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, Falls Church, Virginia.;Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, Falls Church, Virginia.;Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, Falls Church, Virginia.;Advanced Heart Failure and Cardiac Transplant Program, Inova Fairfax Hospital, Falls Church, Virginia.;Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, Falls Church, Virginia.", "authors": "Aryal\|Shambhu\|S\|https://orcid.org/0000-0002-3753-4378;Katugaha\|Shalika B\|SB\|;Cochrane\|Adam\|A\|;Brown\|Anne Whitney\|AW\|;Nathan\|Steven D\|SD\|;Shlobin\|Oksana A\|OA\|;Ahmad\|Kareem\|K\|;Marinak\|Lauren\|L\|;Chun\|Jessica\|J\|;Fregoso\|Margaret\|M\|;Desai\|Shashank\|S\|;King\|Christopher\|C\|", "chemical_list": "D000085:Acetates; D000998:Antiviral Agents; D004279:DNA, Viral; D007166:Immunosuppressive Agents; D011799:Quinazolines; C000588473:letermovir", "country": "Denmark", "delete": false, "doi": "10.1111/tid.13166", "fulltext": null, "fulltext_license": null, "issn_linking": "1398-2273", "issue": "21(6)", "journal": "Transplant infectious disease : an official journal of the Transplantation Society", "keywords": "cytomegalovirus; heart transplantation; letermovir; lung transplantation", "medline_ta": "Transpl Infect Dis", "mesh_terms": "D000085:Acetates; D000328:Adult; D000368:Aged; D019072:Antibiotic Prophylaxis; D000998:Antiviral Agents; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D004279:DNA, Viral; D005260:Female; D006084:Graft Rejection; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D011799:Quinazolines; D055502:Secondary Prevention; D066027:Transplant Recipients; D016896:Treatment Outcome", "nlm_unique_id": "100883688", "other_id": null, "pages": "e13166", "pmc": null, "pmid": "31487755", "pubdate": "2019-12", "publication_types": "D016428:Journal Article", "references": null, "title": "Single-center experience with use of letermovir for CMV prophylaxis or treatment in thoracic organ transplant recipients.", "title_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients" }	[ { "companynumb": "US-STRIDES ARCOLAB LIMITED-2020SP003578", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "90687", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "90687", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "7.5 MILLIGRAM, UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "7.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LETERMOVIR" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "480 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "480", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETERMOVIR" } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cytomegalovirus infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cytomegalovirus viraemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA SB, COCHRANE A, BROWN AW, NATHAN SD, SHLOBIN OA, ET AL. SINGLE?CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS. TRANSPLANT INFECTIOUS DISEASE. 2019?21(6)", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200914", "receivedate": "20200914", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18263204, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "US-DRREDDYS-USA/USA/20/0120808", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "203511", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS VIRAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "090509", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "7.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cytomegalovirus viraemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukopenia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA S, COCHRANE A, BROWN A, NATHAN S, SHLOBIN O, AHMAD K, MARINAK L, CHUN J, FREGOSO M, DESAI S, KING C. SINGLE-CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS. TRANSPLANT INFECTIOUS DISEASE. 2019 DEC?21(6):1-6. DOI:10.1111/TID.13166", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200313", "receivedate": "20200313", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17537564, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "US-DRREDDYS-USA/USA/20/0120798", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "203511", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS VIRAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOSPORINE." } ], "patientagegroup": null, "patientonsetage": "60", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Leukopenia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA S, COCHRANE A, BROWN A, NATHAN S, SHLOBIN O, AHMAD K, MARINAK L, CHUN J, FREGOSO M, DESAI S, KING C. SINGLE-CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS. TRANSPLANT INFECTIOUS DISEASE. 2019 DEC?21(6):1-6. DOI:10.1111/TID.13166", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200313", "receivedate": "20200313", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17537434, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "US-APOTEX-2020AP008352", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "LETERMOVIR" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "240 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "240", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETERMOVIR" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "LETERMOVIR" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETERMOVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "065040", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, 100-150", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOSPORINE." } ], "patientagegroup": null, "patientonsetage": "60", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cytomegalovirus viraemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA S.B, COCHRANE A, BROWN A.W, NATHAN S.D. ET AL.. SINGLE-CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS. DOI:10.1111/TID.13166.. TRANSPLANT INFECTIOUS DISEASE. 2019?21:E13166:1-6", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200304", "receivedate": "20200304", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17491434, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "US-009507513-1904USA002788", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MILLIGRAM, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LETERMOVIR" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "209939", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK", "drugenddate": "2018", "drugenddateformat": "602", "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2018", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREVYMIS" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10?12, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2018" } }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA SB, COCHRANE A, BROWN AW, NATHAN SD, SHLOBIN OA, ET AL. SINGLE CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS.. TRANSPL INFECT DIS. 2019?21", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210629", "receivedate": "20190408", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16167277, "safetyreportversion": 4, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210716" }, { "companynumb": "NVSC2020US057315", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LETERMOVIR" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "480 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "480", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETERMOVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "65461", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "80336", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." } ], "patientagegroup": null, "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cytomegalovirus viraemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA SB, COCHRANE A, BROWN AW, NATHAN SD, SHLOBIN OA ET AL.. SINGLE-CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS. TRANSPLANT INFECTIOUS DISEASE. 2019?21(6):E13166", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200302", "receivedate": "20200302", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17485857, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "NVSC2020US057316", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "65461", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LETERMOVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETERMOVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "80336", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "7.5 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "7.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cytomegalovirus viraemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Oedema", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA SB, COCHRANE A, BROWN AW, NATHAN SD, SHLOBIN OA ET AL.. SINGLE-CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS.. TRANSPLANT INFECTIOUS DISEASE. 2019?21(6):E13166", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200303", "receivedate": "20200303", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17488397, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "US-TEVA-2020-US-1196956", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "GOAL TROUGH: 10-12", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "080356", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LETERMOVIR" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "480 MILLIGRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "480", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETERMOVIR" } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cytomegalovirus infection", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA SB, COCHRANE A, BROWN AW, NATHAN SD, SHLOBIN OA, ET AL. SINGLE-CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS. TRANSPL-INFECT-DIS 2019?21:NO. 6.", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200310", "receivedate": "20200310", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17524127, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200409" }, { "companynumb": "US-DRREDDYS-USA/USA/20/0120797", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "090509", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "203511", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS VIRAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." } ], "patientagegroup": null, "patientonsetage": "69", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Leukopenia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cytomegalovirus viraemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA S, COCHRANE A, BROWN A, NATHAN S, SHLOBIN O, AHMAD K, MARINAK L, CHUN J, FREGOSO M, DESAI S, KING C. SINGLE-CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS. TRANSPLANT INFECTIOUS DISEASE. 2019 DEC?21(6):1-6. DOI:10.1111/TID.13166", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200313", "receivedate": "20200313", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17537578, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "US-STRIDES ARCOLAB LIMITED-2020SP003571", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, 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"drugtreatmentdurationunit": null, "medicinalproduct": "LETERMOVIR" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "69", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA SB, COCHRANE A, BROWN AW, NATHAN SD, SHLOBIN OA, ET AL. SINGLE?CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS. TRANSPLANT INFECTIOUS DISEASE. 2019?21(6)", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200914", "receivedate": "20200914", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18261238, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20201103" }, { "companynumb": "PHHY2019US219908", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "050791", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG TRANSPLANT", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "(10-14)", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "050791", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "12.5 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "12.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": "48", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cytomegalovirus infection", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA BS, COCHRANE A, BROWN AW, NATHAN SD, SHLOBIN OA ET AL.. SINGLE-CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS. TRANSPLANT INFECTIOUS DISEASE. 2019?1-6", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190923", "receivedate": "20190923", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16840398, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191005" }, { "companynumb": "US-STRIDES ARCOLAB LIMITED-2020SP003579", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "LETERMOVIR" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS VIRAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETERMOVIR" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "90687", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LETERMOVIR" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "480 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "480", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETERMOVIR" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "90687", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cytomegalovirus viraemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA SB, COCHRANE A, BROWN AW, NATHAN SD, SHLOBIN OA, ET AL. SINGLE?CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS. TRANSPLANT INFECTIOUS DISEASE. 2019?21(6)", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200914", "receivedate": "20200914", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18263208, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20201103" }, { "companynumb": "US-TEVA-2020-US-1196955", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LETERMOVIR" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "480 MILLIGRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "480", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETERMOVIR" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "205220", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "080356", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "7.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "GOAL TROUGH: 10", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cytomegalovirus infection", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukopenia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Oedema", "reactionmeddraversionpt": "22.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA SB, COCHRANE A, BROWN AW, NATHAN SD, SHLOBIN OA, ET AL. SINGLE-CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS. TRANSPL-INFECT-DIS 2019?21:NO. 6.", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200310", "receivedate": "20200310", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17524126, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "US-009507513-1904USA002789", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LETERMOVIR" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "209939", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK", "drugenddate": "2018", "drugenddateformat": "602", "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2018", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREVYMIS" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "7.5 MILLIGRAM, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "7.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Oedema", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2018" } }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA SB, COCHRANE A, BROWN AW, NATHAN SD, SHLOBIN OA, ET AL. SINGLE CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS.. TRANSPL INFECT DIS. 2019?21 (6):E13166", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210607", "receivedate": "20190408", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16167276, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210716" }, { "companynumb": "US-DRREDDYS-USA/USA/20/0120812", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "090509", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "203511", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS VIRAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." } ], "patientagegroup": null, "patientonsetage": "33", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cytomegalovirus viraemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Gene mutation", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA S, COCHRANE A, BROWN A, NATHAN S, SHLOBIN O, AHMAD K, MARINAK L, CHUN J, FREGOSO M, DESAI S, KING C. SINGLE-CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS. TRANSPLANT INFECTIOUS DISEASE. 2019 DEC?21(6):1-6. DOI:10.1111/TID.13166", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200313", "receivedate": "20200313", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17537986, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "US-STRIDES ARCOLAB LIMITED-2020SP003574", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "90055", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MILLIGRAM, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", 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"drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." } ], "patientagegroup": null, "patientonsetage": "39", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA SB, COCHRANE A, BROWN AW, NATHAN SD, SHLOBIN OA, ET AL. SINGLE?CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS. TRANSPLANT INFECTIOUS DISEASE. 2019?21(6)", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200728", "receivedate": "20200728", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18079966, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20201103" }, { "companynumb": "US-MYLANLABS-2020M1023904", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "GOAL TROUGH: 10-12", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "080292", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cytomegalovirus infection", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA SB, COCHRANE A, BROWN AW, NATHAN SD, SHLOBIN OA, ET AL. SINGLE-CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS. TRANSPL-INFECT-DIS 2019?21:NO. 6.", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200305", "receivedate": "20200305", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17501169, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200409" }, { "companynumb": "US-TEVA-2020-US-1196954", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "205220", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "GOAL TROUGH:10-12", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LETERMOVIR" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "480 MILLIGRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "480", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETERMOVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "080356", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Leukopenia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cytomegalovirus infection", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA SB, COCHRANE A, BROWN AW, NATHAN SD, SHLOBIN OA, ET AL. SINGLE-CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS. TRANSPL-INFECT-DIS 2019?21:NO. 6.", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200311", "receivedate": "20200311", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17524609, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "US-DRREDDYS-USA/USA/20/0120801", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090509", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "12.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "203511", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." } ], "patientagegroup": null, "patientonsetage": "48", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Leukopenia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA S, COCHRANE A, BROWN A, NATHAN S, SHLOBIN O, AHMAD K, MARINAK L, CHUN J, FREGOSO M, DESAI S, KING C. SINGLE-CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS. TRANSPLANT INFECTIOUS DISEASE. 2019 DEC?21(6):1-6. DOI:10.1111/TID.13166", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200313", "receivedate": "20200313", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17537469, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "US-009507513-1904USA002791", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5-9, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LETERMOVIR" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "209939", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK", "drugenddate": "2018", "drugenddateformat": "602", "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2018", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREVYMIS" } ], "patientagegroup": null, "patientonsetage": "33", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2018" } }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA SB, COCHRANE A, WHITNEY BROWN A, NATHAN SD, SHLOBIN OA, ET AL. SINGLE CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS.. TRANSPL INFECT DIS. 2019", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20191016", "receivedate": "20190408", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16167269, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200122" }, { "companynumb": "US-STRIDES ARCOLAB LIMITED-2020SP003577", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "90687", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LETERMOVIR" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "480 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "480", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETERMOVIR" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MILLIGRAM, UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA SB, COCHRANE A, BROWN AW, NATHAN SD, SHLOBIN OA, ET AL. SINGLE?CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS. TRANSPLANT INFECTIOUS DISEASE. 2019?21(6)", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200914", "receivedate": "20200914", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18263209, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20201103" }, { "companynumb": "US-STRIDES ARCOLAB LIMITED-2020SP003580", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "90687", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEART TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "90687", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." } ], "patientagegroup": null, "patientonsetage": "33", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cytomegalovirus viraemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA SB, COCHRANE A, BROWN AW, NATHAN SD, SHLOBIN OA, ET AL. SINGLE?CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS. TRANSPLANT INFECTIOUS DISEASE. 2019?21(6)", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200914", "receivedate": "20200914", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18263202, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "US-009507513-2105USA006239", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LETERMOVIR" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "209939", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "480 MILLIGRAM, ONCE DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2018", "drugstartdateformat": "602", "drugstructuredosagenumb": "480", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREVYMIS" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": "69", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2018" } }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA SB, COCHRANE A, BROWN AW, NATHAN SD, SHLOBIN OA, ET AL.. SINGLE CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS.. TRANSPL INFECT DIS. 2019?21:E13166", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210527", "receivedate": "20210527", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19317362, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210717" }, { "companynumb": "US-DRREDDYS-USA/USA/20/0120800", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "180", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "203511", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS VIRAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "090509", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": "6", "patientonsetage": "68", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cytomegalovirus viraemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukopenia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA S, COCHRANE A, BROWN A, NATHAN S, SHLOBIN O, AHMAD K, MARINAK L, CHUN J, FREGOSO M, DESAI S, KING C. SINGLE-CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS. TRANSPLANT INFECTIOUS DISEASE. 2019 DEC?21(6):1-6. DOI:10.1111/TID.13166", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200317", "receivedate": "20200317", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17548410, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "US-009507513-2105USA005653", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MILLIGRAM, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10?14, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LETERMOVIR" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "209939", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "480 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2018", "drugstartdateformat": "602", "drugstructuredosagenumb": "480", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREVYMIS" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "39", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2018" } }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA SB, COCHRANE A, BROWN AW, NATHAN SD, SHLOBIN OA, ET AL.. SINGLE CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS.. TRANSPL INFECT DIS. 2019?21", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210527", "receivedate": "20210527", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19313830, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210717" }, { "companynumb": "US-DRREDDYS-USA/USA/20/0120809", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "7.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "203511", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS VIRAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090509", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cytomegalovirus infection", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Gene mutation", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA S, COCHRANE A, BROWN A, NATHAN S, SHLOBIN O, AHMAD K, MARINAK L, CHUN J, FREGOSO M, DESAI S, KING C. SINGLE-CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS. TRANSPLANT INFECTIOUS DISEASE. 2019 DEC?21(6):1-6. DOI:10.1111/TID.13166", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200313", "receivedate": "20200313", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17537510, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "US-DRREDDYS-USA/USA/20/0120802", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "090509", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "203511", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS VIRAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." } ], "patientagegroup": null, "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Leukopenia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cytomegalovirus viraemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA S, COCHRANE A, BROWN A, NATHAN S, SHLOBIN O, AHMAD K, MARINAK L, CHUN J, FREGOSO M, DESAI S, KING C. SINGLE-CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS. TRANSPLANT INFECTIOUS DISEASE. 2019 DEC?21(6):1-6. DOI:10.1111/TID.13166", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200313", "receivedate": "20200313", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17537515, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "US-009507513-2105USA006240", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "180 MILLIGRAM, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "180", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LETERMOVIR" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "209939", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "480 MILLIGRAM, ONCE DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2018", "drugstartdateformat": "602", "drugstructuredosagenumb": "480", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREVYMIS" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "68", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2018" } }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA SB, COCHRANE A, BROWN AW, NATHAN SD, SHLOBIN OA, ET AL.. SINGLE CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS.. TRANSPL INFECT DIS. 2019?21:E13166", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210527", "receivedate": "20210527", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19317185, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210717" }, { "companynumb": "US-009507513-1903USA012574", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "LETERMOVIR" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "209939", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "120 MILLIGRAM, UNK", "drugenddate": "2018", "drugenddateformat": "602", "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2018", "drugstartdateformat": "602", "drugstructuredosagenumb": "120", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREVYMIS" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100?150, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CICLOSPORIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "LETERMOVIR" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "209939", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK", "drugenddate": "2018", "drugenddateformat": "602", "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2018", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREVYMIS" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "LETERMOVIR" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "209939", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "240 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "240", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREVYMIS" } ], "patientagegroup": null, "patientonsetage": "60", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Fatigue", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2018" } }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA SB, COCHRANE A, BROWN AW, NATHAN SD, SHLOBIN OA, ET AL.. SINGLE CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS.. TRANSPL INFECT DIS. 2019?21", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210604", "receivedate": "20190408", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16167275, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210716" }, { "companynumb": "NVSC2020US057317", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LETERMOVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETERMOVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "65461", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "80336", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cytomegalovirus viraemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA SB, COCHRANE A, BROWN AW, NATHAN SD, SHLOBIN OA ET AL.. SINGLE-CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS. TRANSPLANT INFECTIOUS DISEASE. 2019?21(6):E13166", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200302", "receivedate": "20200302", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17484765, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "US-009507513-1904USA002790", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LETERMOVIR" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "209939", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK", "drugenddate": "2018", "drugenddateformat": "602", "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2018", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREVYMIS" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LETERMOVIR" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "209939", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK", "drugenddate": "2018", "drugenddateformat": "602", "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2018", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREVYMIS" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10?12, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2018" } }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA SB, COCHRANE A, BROWN AW, NATHAN SD, SHLOBIN OA, ET AL. SINGLE CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS.. TRANSPL INFECT DIS. 2019?21", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210604", "receivedate": "20190408", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16167265, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210716" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-285332", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10, GOAL TROUGH", "drugenddate": null, "drugenddateformat": null, "drugindication": "Immunosuppression", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "089247", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "7.5 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "Immunosuppression", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE" } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cytomegalovirus infection", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Aryal S, Katugaha S B, Cochrane A, Brown A W, Nathan A D, Shlobin O A. et al. Single-center experience with use of letermovir for CMV prophylaxis or treatment in thoracic organ transplant recipients. Transpl Infect Dis. 2019;Aug 21:e13166:1-6", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220215", "receivedate": "20210316", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19011595, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "US-STRIDES ARCOLAB LIMITED-2020SP003576", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, 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"drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "480 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "480", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETERMOVIR" } ], "patientagegroup": null, "patientonsetage": "48", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA SB, COCHRANE A, BROWN AW, NATHAN SD, SHLOBIN OA, ET AL. SINGLE?CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS. TRANSPLANT INFECTIOUS DISEASE. 2019?21(6)", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200728", "receivedate": "20200728", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18079951, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20201103" }, { "companynumb": "US-STRIDES ARCOLAB LIMITED-2020SP003575", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": null, "activesubstance": { 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SINGLE?CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS. 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SINGLE-CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS. TRANSPLANT INFECTIOUS DISEASE. 2019 DEC?21(6):1-6. DOI:10.1111/TID.13166", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200313", "receivedate": "20200313", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17537423, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" } ]
{ "abstract": "The aim of this study is to investigate the effective therapeutic combination of recombinant VIIa(Novoseven) and factor eight inhibitor bypass activity(FEIBA) drugs for the bleedings of adult hemophiliac patients with inhibitors.19 bleeding episodes of 5 hemophilia A patients who were using bypassing agents and followed-up between 2008 and 2016 in Hacettepe Hematology Department were analyzed retrospectively. In 11, 5 and 3 bleeding episodes, FEIBA, recombinant factor VIIa and FEIBA+recombinant factor VIIa were given to the patients, respectively. The treatment durations differed between 1 and 14 days depending on the bleeding and clinical course of the patients. Generally the treatment with bypassing agents was successful, and only in one patient who had elbow hematoma encountered serious bleeding which was taken under control by switching the bypass agent. We offer a different approach because of three reasons. Firstly, in our protocol we start the treatment with recombinant factor VIIa for the first three days. Secondly, our protocol is adjusted to consider health economics. Thirdly, we extended the time interval between doses of both bypassing agents without increasing bleeding risks because the half-life of both agents enables us to modify the protocol with more flexibility. To conclude, we have evaluated our clinic's data about hemophilia A patients with inhibitors and we offer a different protocol in the management of bleeding episodes for these patients.", "affiliations": "Hacettepe University, School of Medicine, Department of Hematology, Hacettepe Üniversitesi Tıp Fakültesi İç Hastalıkları ABD Hematoloji BD TR-06100 ANKARA-TURKEY, Postal Code: TR-06100, Ankara, Turkey.;Hacettepe University, School of Medicine, Department of Hematology, TR-06100, Ankara, Turkey.", "authors": "Malkan\|Umit Yavuz\|UY\|;Aksu\|Salih\|S\|", "chemical_list": null, "country": "Poland", "delete": false, "doi": "10.1515/med-2018-0090", "fulltext": "\n==== Front\nOpen Med (Wars)Open Med (Wars)medmedOpen Medicine2391-5463De Gruyter med-2018-009010.1515/med-2018-0090Regular ArticlesCombination of Novoseven and Feiba in Hemophiliac Patients with Inhibitors Malkan Umit Yavuz 1Aksu Salih 21 Hacettepe University, School of Medicine, Department of Hematology, Hacettepe Üniversitesi Tıp Fakültesi İç Hastalıkları ABD Hematoloji BD TR-06100 ANKARA-TURKEY, Postal Code: TR-06100, Ankara, Turkey2 Hacettepe University, School of Medicine, Department of Hematology, TR-06100, Ankara, Turkey Tel: +90-532-7780087, Fax: +90-312-3051614 [email protected] 12 2018 2018 13 618 621 08 6 2016 14 11 2018 © 2018 Umit Yavuz Malkan, Salih Aksu published by De Gruyter2018Umit Yavuz Malkan, Salih Aksu published by De GruyterThis work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License.Abstract\nThe aim of this study is to investigate the effective therapeutic combination of recombinant VIIa(Novoseven) and factor eight inhibitor bypass activity(FEIBA) drugs for the bleedings of adult hemophiliac patients with inhibitors.19 bleeding episodes of 5 hemophilia A patients who were using bypassing agents and followed-up between 2008 and 2016 in Hacettepe Hematology Department were analyzed retrospectively. In 11, 5 and 3 bleeding episodes, FEIBA, recombinant factor VIIa and FEIBA+recombinant factor VIIa were given to the patients, respectively. The treatment durations differed between 1 and 14 days depending on the bleeding and clinical course of the patients. Generally the treatment with bypassing agents was successful, and only in one patient who had elbow hematoma encountered serious bleeding which was taken under control by switching the bypass agent. We offer a different approach because of three reasons. Firstly, in our protocol we start the treatment with recombinant factor VIIa for the first three days. Secondly, our protocol is adjusted to consider health economics. Thirdly, we extended the time interval between doses of both bypassing agents without increasing bleeding risks because the half-life of both agents enables us to modify the protocol with more flexibility. To conclude, we have evaluated our clinic’s data about hemophilia A patients with inhibitors and we offer a different protocol in the management of bleeding episodes for these patients.\n\nKeywords\nHemophiliaInhibitorsFEIBARecombinant VIIA\n==== Body\n1 Introduction\nThe hemophilias are a group of associated bleeding disorders that are inherited most commonly. Hemophilia A refers to factor VIII deficiency. Cases with hemophilia encounter bleeding incidents that are treated with replacement of the absent factor. Development of an inhibitor is one of the complications of hemophilia treatment. It usually follows the initiation of replacement therapy. Actually, the inhibitors are antibodies (primarily IgG) directed against the specific absent factor. The development of inhibitors is more frequent in cases with hemophilia A than in those with hemophilia B. The inhibitors are more likely to develop in cases with severe disease. The degree of inhibitor response is detected in Bethesda units (BU). High responder patients generally have five or more Bethesda units and these inhibitor levels can persist for a long time even when there is no re-exposure [1,2]. On the other hand, low responder patients always have inhibitor levels less than 5 BU [3]. High responder patients generally need bypassing agents, whereas low responder cases usually have treatment answer to factor VIII replacement therapy [4]. In approximately 25 to 30 percent of cases with severe hemophilia A, Factor VIII inhibitors were detected [5,6]. Factor VIII inhibitors are not frequently encountered in moderate or mild hemophilia A cases [7]. The aim of this study is to investigate the effective therapeutic combination of recombinant VIIa (Novoseven) and factor eight inhibitor bypass activity (FEIBA) drugs for the bleedings of adult hemophiliac patients with inhibitors.\n\n2 Methods\n19 bleeding episodes of 5 hemophilia A patients who were using bypassing agents and followed-up between 2008 and 2016 in Hacettepe Hematology Department were analyzed retrospectively. All of the ethical considerations were strictly handled in accordance with the Helsinki Declaration. As a standard of care/action of the hospitals of Hacettepe Medical School, it was confirmed based on patient records that all of the study participants gave informed consent at the time of hospitalization and relevant diagnostic/therapeutic standards of care. All data were taken from Hacettepe University Medical School Hospital database. Patient records/information was anonymized prior to analysis. Parameters of age, bleeding site, bleeding complications, inhibitor levels, medication type and duration, bleeding complications were noted. In the study patients, evaluation of response to treatment depended upon the patients’ clinical condition. Physical examination was performed in every patient and depending on clinical condition X-ray or magnetic resonance imaging were performed in some patients also.\n\n3 Results\nA total of 19 bleeding episodes of 5 patients were analyzed. The median age of the patient group was 40 (28-78). All of the patients had diagnosis of hemophilia A and all patients were high responders. The median factor level was 1% (0-6%). Only one patient had mild hemophilia A, whereas other patients had severe hemophilia A. The median inhibitor level was 15.1 BU (9.3-56.0 BU). The characteristics of bleeding episodes and the treatment approaches are given in Table 1. There were 4 knee hematoma, 3 tooth extraction, 3 elbow hematoma, 2 prophylaxis, 2 major surgery, 1 psoas hematoma, 1 maxillary hematoma, 1 inguinal hematoma, 1 leg graft operation and 1 gastrointestinal bleeding episodes of hemophilia A patients with inhibitors. In 11, 5 and 3 bleeding episodes, FEIBA, recombinant factor VIIa and FEIBA + recombinant factor VIIa were given to the patients, respectively. The treatment durations differed between 1 and 14 days depending on the bleeding and clinical course of the patients. Generally the treatment with bypassing agents was successful, and only in one patient who had elbow hematoma encountered serious bleeding which was taken under control by switching the bypass agent.\n\nTable 1 The characteristics and treatment approaches of the bleeding episodes in adult hemophiliac patients with inhibitors\n\nClinical Condition\tNumber of patient\tBypassing Agents and Doses\tDays of dose given\t\nBleeds (n:11)\t3\tRecombinant factor VIIa, 3-4 x 90 μg.kg-1\t1-3\t\n\t7\tActivated prothrombin complex concentrate (FEIBA), 1-3 x 50-100 IU.kg-1\t1-5\t\n\t1\tFEIBA, 2 x 100 IU.kg-1 switched to Recombinant factor VIIa, 6 x 90 μg.kg-1\t14\t\nMinor Surgery (n:4)\t2\tRecombinant factor VIIa, 3-6 x 90 μg.kg-1\t3-7\t\n\t2\tFEIBA, 2 x 70 IU.kg-1\t14\t\nMajor Surgery\t2\t(Our proposed protocol) First 3 days Recombinant factor VIIa, 6 x 90 μg.kg-1and then FEIBA, 2 x 50 IU.kg-1\t14\t\nProphylaxis\t2\tFEIBA, 2 x 70 IU.kg-1\t2\t\n4 Discussion\nThe preparation of hemophilia A patients with inhibitors is compelling compared to patients without inhibitors. Two decades ago, elective surgery in hemophilia A patients with inhibitors is contraindicated because of the bleeding risks. However at the present time, with the help of new bypassing agents surgical operations are performed with success. Unlike hemophilia A patients without inhibitors, the factor 8 concentrates are ineffective because of circulating antibodies in patients with inhibitors. The two main bypassing agents are recombinant factor VIIa and activated prothrombin complex concentrate (FEIBA) which also contains vitamin K dependent factors (Factor 2, 7, 9, 10). In the literature the dosing of these agents are described (Table 2) [8]. In this paper, we offer a different approach to hemophilia A patients with inhibitors who will undergo surgical operation (Table 2). Bypassing agents eliminate the need of intrinsic pathway originated “tenase” complex which activates factor X. Recombinant factor VIIa directly activates factor X whereas FEIBA provides precursors for factor X, thus both agents bypass the pathways. FEIBA is considered to be an effective bypassing agent that controls bleeding episodes [9]. However since the activated proteases that provide the pro-coagulant activity of FEIBA have short half-life, initial hemostasis could be followed by breakthrough bleeding between doses that could lead to problems in maintaining hemostasis [10]. Moreover, FEIBA comes with a risk of thrombosis\n\nTable 2 The preparing methods for surgery in hemophilia A patients with inhibitors\n\n\tBypassing Agent\tPre-operative dosing\tPost-operative dosing\t\nIn the literature\tRecombinant factor VIIa\tBolus 90-120 μg.kg-1\t0-48 hours: 90 μg.kg-1/for each 2 hours,\n\n\n3-4 days: 90 μg.kg-1/for each 3 hours,\n\n\n5-7 days: 90 μg.kg-1/for each 4 hours,\n\n\n8th day-end of treatment: 90 μg.kg-1/for each 6 hours\n\n\n\t\nIn the literature\tActivated pro-thrombin complex concentrate\tBolus 75-100 IU.kg-1\t0-3 days: 70 IU.kg-1/for each 8 hours (for maximum dose of 200 IU.kg-1/per day).\n\n\n4th day-end of treatment: 50 IU.kg-1/for each 8 hours\n\n\t\nOur Method\tRecombinant factor VIIa+ Activated pro-thrombin complex concentrate\tBolus 90 μg.kg-1\tIn the post-operative 2, 4, 6, 8, 12, 16, 22, 30, 38, 46, 54, 62, 70 hours:\n\n\nRecombinant factor VIIa with dose of 90 μg.kg-1\n\n\n4th day-end of treatment: 2x50 IU.kg-1 Activated prothrombin complex concentrate (FEIBA).\n\n\nTreatment should stop in 7 or 14 days depending on patient’s clinical condition.\n\n\n\t\n*Reference number 8.\n\nthat is likely to occur with large doses [11]. Another problem about FEIBA is the absence of an in vitro assay that would confirm in vivo hemostatic efficacy. Thus, the treatment answer in bleeding episodes in each patient could be different [4]. The treatment approach for each patient should be personalized and it is accepted that if there is no treatment answer for any bypassing agent the other agent should be tried [4]. In the literature the optimal dose for FEIBA treatment was given as 50 to 100 units/kg and doses above 200 units/kg is not recommended because of the risk of disseminated intravascular coagulation development [4]. The optimal dosing frequency of FEIBA is every 8 to 12 hours; more frequent dosing is associated with increased thrombotic risk [4]. The usage of FEIBA for prophylaxis is also stated in the literature [12]. In our study FEIBA was effective for controlling the bleeding episodes in hemophilia A patients with inhibitors. On the other hand, in the literature it was stated that recombinant factor VIIa has excellent treatment response in majority of hemophilia A patients with inhibitors [13]. The difference of recombinant factor VIIa from FEIBA is that tissue factor is essential for factor VIIa to be effective therefore with recombinant factor VIIa treatment coagulation occurs only at local sites of hemostasis thus avoiding the risk of systemic coagulation that could happen with FEIBA treatment [11]. In the literature, the optimal dose for recombinant factor VIIa was given as 90 to 120 mcg/kg at two- to three-hour intervals until the bleeding was controlled [4]. The usage of recombinant factor VIIa for prophylaxis is stated in the literature [14]. The efficiency of recombinant factor VIIa and FEIBA was compared in the literature; both agents had 80-90% efficacy rate and neither agent shown to be superior in efficacy [15]. The usage of both agents together is shown to be very effective. However because of increased thrombotic risk, combination treatment is only recommended in serious life-threathening bleedings [16]. So, the risk of systemic coagulation is lower in rFVII than FEIBA. Although the bypassing agents provide a safe management of patients with inhibitors, the efficacy of these agents always remains lower than pure factor concentrates which are given to patients without inhibitors. As a result, hemophilia A patients with inhibitors have always a higher risk of bleeding than patients without inhibitors even in the presence of bypassing agents.\n\nAnother major concern about the management of hemophilia A patients with inhibitors is the cost of the treatment. Especially in the lower or middle income countries, the cost of bypassing agents is a great problem. In Turkey, the average cost for surgery preparation of a 70 kg hemophilia A patient with inhibitor is $267000, $114000 and $108000 with recombinant factor VIIa, FEIBA and our protocol, respectively. So, if there is a systemic coagulation risk generally rFVII should be preferred. The regular usage of both products at the same time is not recommended because of thrombosis risk. What we offer is to use rFVII in first 3 days and then switching to FEIBA with a different dosing protocol, which offers us a safer, cheaper and flexible control of the bleeding. We offer a different approach from the literature because of three main reasons. Firstly, in our protocol we start the treatment with recombinant factor VIIa for the first three days. The main reason for this choice is the short procoagulant half-life of bypassing agents and the need of frequent infusions to cover all hours of a day in order to quickly and safely achieve hemostasis. In our protocol we do not prefer FEIBA in the beginning because there is a risk of thrombosis if it is used more frequently than every 8 hour and there is a limit dose of 200 units/kg/day. In our protocol after safely achieving the initial hemostasis with recombinant factor VIIa ,we prefer to continue treatment with FEIBA till 7th or 14th days after bleeding. Secondly, our protocol is adjusted to consider health economics. Cost of recombinant factor VIIa is more than twice the cost of FEIBA. Therefore we prefer to use recombinant factor VIIa in first 3 days, the time interval where the bleeding risk is maximum and the homeostasis is the primary target. After achieving the initial hemostasis we set our preference to health economics first since the bleeding risk is decreased and the less frequent doses are sufficient to stabilize the clinical course of patient. Thirdly, we extended the time interval between doses of both bypassing agents without increasing bleeding risks because the half-life of both agents enables us to modify the protocol with more flexibility. This modification let us to control the drug costs without facing extra complications or bleeding risks. To conclude, in this paper we have evaluated our clinic’s data about hemophilia A patients with inhibitors and we offer a different protocol in the management of bleeding episodes for these patients.\n\nAcknowledgments\nUYM and SA designed the study, UYM collected and analyzed the data, UYM write the paper, UYM and SA approved the final version of the paper.\n\nConflict of interest\n\nConflict of interest statement: The authors of this paper have no conflicts of interest, including specific financial interests, relationships, and/or affiliations relevant to the subject matter or materials included.\n==== Refs\nReferences\n[1] White GC 2nd Rosendaal F Aledort LM Definitions in hemophilia. Recommendation of the scientific subcommittee on factor VIII and factor IX of the scientific and standardization committee of the International Society on Thrombosis and Haemostasis Thromb Haemost 2001 85 560 11307831 \n[2] Allain JP Frommel D Antibodies to factor VIII. V. Patterns of immune response to factor VIII in hemophilia A. Blood 1976 47 973 1276479 \n[3] Caram C de Souza RG de Sousa JC The long-term course of factor VIII inhibitors in patients with congenital haemophilia A without immune tolerance induction Thromb Haemost 2011 105 59 21057702 \n[4] Kempton CL White GC 2nd How we treat a hemophilia A patient with a factor VIII inhibitor Blood 2009 113 11 18820129 \n[5] Hoyer LW Scandella D Factor VIII inhibitors: structure and function in autoantibody and hemophilia A patients Semin Hematol 1994 31 1 \n[6] Lusher JM Arkin S Abildgaard CF Schwartz RS Recombinant factor VIII for the treatment of previously untreated patients with hemophilia A. Safety, efficacy, and development of inhibitors. Kogenate Previously Untreated Patient Study Group N Engl J Med 1993 328 453 8421474 \n[7] Fijnvandraat K Turenhout EA van den Brink EN The missense mutation Arg593 --> Cys is related to antibody formation in a patient with mild hemophilia A. Blood 1997 89 4371 \n[8] Mensah PK Gooding R Surgery in patients with inherited bleeding disorders. Anaesthesia 2015 Jan;70 Suppl 1 112 20 e39 40 10.1111/anae.12899 \n[9] Negrier C Goudemand J Sultan Y Multicenter retrospective study on the utilization of FEIBA in France in patients with factor VIII and factor IX inhibitors French FEIBA Study Group. Factor Eight Bypassing Activity. Thromb Haemost 1997 77 1113 \n[10] Lusher JM Use of prothrombin complex concentrates in management of bleeding in hemophiliacs with inhibitors-benefits and limitations Semin Hematol 1994 31 49 7939776 \n[11] Hough RE Hampton KK Preston FE Recombinant VIIa concentrate in the management of bleeding following prothrombin complex concentrate-related myocardial infarction in patients with haemophilia and inhibitors Br J Haematol 2000 111 974 11122162 \n[12] Leissinger C Gringeri A Antmen B Anti-inhibitor coagulant complex prophylaxis in hemophilia with inhibitors N Engl J Med 2011 365 1684 22047559 \n[13] O’Connell N Mc Mahon C Smith J Recombinant factor VIIa in the management of surgery and acute bleeding episodes in children with haemophilia and high responding inhibitors Br J Haematol 2002 116 632 11849223 \n[14] Konkle BA Ebbesen LS Erhardtsen E Randomized, prospective clinical trial of recombinant factor VIIa for secondary prophylaxis in hemophilia patients with inhibitors J Thromb Haemost 2007 5 1904 17723130 \n[15] Astermark J Donfield SM DiMichele DM A randomized comparison of bypassing agents in hemophilia complicated by an inhibitor: the FEIBA NovoSeven Comparative (FENOC) Study. Blood 2007 109 546 16990605 \n[16] Teitel J Berntorp E Collins P A systematic approach to controlling problem bleeds in patients with severe congenital haemophilia A and high-titre inhibitors Haemophilia 2007 13 256 17498074\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": null, "issue": "13()", "journal": "Open medicine (Warsaw, Poland)", "keywords": "FEIBA; Hemophilia; Inhibitors; Recombinant VIIA", "medline_ta": "Open Med (Wars)", "mesh_terms": null, "nlm_unique_id": "101672167", "other_id": null, "pages": "618-621", "pmc": null, "pmid": "30613789", "pubdate": "2018", "publication_types": "D016428:Journal Article", "references": "11122162;11307831;11849223;1276479;16990605;17498074;17723130;18820129;21057702;22047559;25440405;7524160;7939776;8421474;9192760;9241742", "title": "Combination of Novoseven and Feiba in Hemophiliac Patients with Inhibitors.", "title_normalized": "combination of novoseven and feiba in hemophiliac patients with inhibitors" }	[ { "companynumb": "TR-SHIRE-TR201902637", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "COAGULATION FACTOR VIIA RECOMBINANT HUMAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HAEMARTHROSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NOVOSEVEN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ANTI-INHIBITOR COAGULANT COMPLEX" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "101447", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "POWDER AND SOLVENT FOR SOLUTION FOR INFUSION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HAEMARTHROSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FEIBA NF" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "COAGULATION FACTOR VIIA RECOMBINANT HUMAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "FACTOR VIII DEFICIENCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NOVOSEVEN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PARACETAMOL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ANTI-INHIBITOR COAGULANT COMPLEX" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "101447", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "POWDER AND SOLVENT FOR SOLUTION FOR INFUSION", "drugdosagetext": "50 INTERNATIONAL UNIT/KILOGRAM, 2X/DAY:BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "FACTOR VIII DEFICIENCY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "028", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FEIBA NF" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MALKAN, U.Y.? AKSU, S.. COMBINATION OF NOVOSEVEN AND FEIBA IN HEMOPHILIAC PATIENTS WITH INHIBITORS. DE GRUYTER. 2018?13:618-621", "literaturereference_normalized": "combination of novoseven and feiba in hemophiliac patients with inhibitors", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20190215", "receivedate": "20190129", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15886373, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" } ]
{ "abstract": "Literature on the outcome of pregnancy after exposure to capecitabine and temozolomide during the first trimester is scarce. Chemotherapy administration in the first trimester is generally not recommended due the potential risks to the fetus including fetal death and major congenital malformations. Capecitabine and temozolomide are oral chemotherapy agents and pregnancy category D medications, thus the use of these agents in pregnancy is not recommended. We present the case of a 17-year-old female who while receiving cancer treatment, had unintentional exposure to capecitabine and temozolomide during the first trimester of pregnancy, and subsequently delivered a healthy infant.", "affiliations": "Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, United States. Electronic address: [email protected].;Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, GA, 30322, United States. Electronic address: [email protected].;Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX, 77030, United States. Electronic address: [email protected].;Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, United States. Electronic address: [email protected].", "authors": "Castellanos\|Maria I\|MI\|;Childress\|Krista J\|KJ\|;Ramirez\|Mildred\|M\|;Venkatramani\|Rajkumar\|R\|", "chemical_list": null, "country": "France", "delete": false, "doi": "10.1016/j.jogoh.2020.101881", "fulltext": null, "fulltext_license": null, "issn_linking": "2468-7847", "issue": null, "journal": "Journal of gynecology obstetrics and human reproduction", "keywords": "Cancer; Capecitabine; Chemotherapy; Fetus; Pregnancy; Temozolomide", "medline_ta": "J Gynecol Obstet Hum Reprod", "mesh_terms": null, "nlm_unique_id": "101701588", "other_id": null, "pages": "101881", "pmc": null, "pmid": "32712180", "pubdate": "2020-07-23", "publication_types": "D002363:Case Reports", "references": null, "title": "Fetal exposure to capecitabine and temozolomide during the first trimester: A case report.", "title_normalized": "fetal exposure to capecitabine and temozolomide during the first trimester a case report" }	[ { "companynumb": "US-009507513-2008USA002702", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CAPECITABINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1000 MG, TWICE DAILY X14 DAYS, 1 CYCLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CAPECITABINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "TEMOZOLOMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021029", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NEUROENDOCRINE CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TEMODAR" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "TEMOZOLOMIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "021029", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "250 MILLIGRAM, TWICE DAILY X 5 DAYS 1 CYCLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "250", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TEMODAR" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CAPECITABINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NEUROENDOCRINE CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CAPECITABINE." } ], "patientagegroup": null, "patientonsetage": "17", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Maternal exposure during pregnancy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CASTELLANOS MI, CHILDRESS KJ, RAMIREZ M, VENKATRAMANI R. FETAL EXPOSURE TO CAPECITABINE AND TEMOZOLOMIDE DURING THE FIRST TRIMESTER: A CASE REPORT. JOURNAL OF GYNECOLOGY OBSTETRICS AND HUMAN REPRODUCTION. 2020?101881", "literaturereference_normalized": "fetal exposure to capecitabine and temozolomide during the first trimester a case report", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200812", "receivedate": "20200812", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18137754, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20201103" }, { "companynumb": "NVSC2020US237541", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "76959", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG/M2 (EVERY CYCLE LASTING 21 DAYS, 4 CYCELS)", "drugenddate": null, "drugenddateformat": null, "drugindication": "FOETAL EXPOSURE DURING PREGNANCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CAPECITABINE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1000 MG, BID (FOR 14 DAYS, WITH EACH CYCLE LASTING 28 DAYS, 6 CYCLES)", "drugenddate": null, "drugenddateformat": null, "drugindication": "FOETAL EXPOSURE DURING PREGNANCY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CAPECITABINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "TEMOZOLOMIDE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "250 MG, BID (WITH EACH CYCLE LASTING 28 DAYS, 6 CYCLES)", "drugenddate": null, "drugenddateformat": null, "drugindication": "FOETAL EXPOSURE DURING PREGNANCY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "250", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TEMOZOLOMIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "175 MG/M2 (EVERY 21 DAYS, 4 CYCLES)", "drugenddate": null, "drugenddateformat": null, "drugindication": "FOETAL EXPOSURE DURING PREGNANCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "175", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PACLITAXEL." } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Jaundice neonatal", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Premature baby", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Low birth weight baby", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CASTELLANOS MI, CHILDRESS KJ, RAMIREZ M, VENKATRAMANI K. FETAL EXPOSURE TO CAPECITABINE AND TEMOZOLOMIDE DURING THE FIRST TRIMESTER: A CASE REPORT. 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FETAL EXPOSURE TO CAPECITABINE AND TEMOZOLOMIDE DURING THE FIRST TRIMESTER: A CASE REPORT. 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FETAL EXPOSURE TO CAPECITABINE AND TEMOZOLOMIDE DURING THE FIRST TRIMESTER: A CASE REPORT. 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"drugindication": "OVARIAN SERTOLI-LEYDIG CELL TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "EACH CYCLE LASTING FOR 21 DAYS", "drugenddate": null, "drugenddateformat": null, "drugindication": "OVARIAN SERTOLI-LEYDIG CELL TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "175", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PACLITAXEL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NEUROENDOCRINE CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." } ], "patientagegroup": null, "patientonsetage": "17", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pregnancy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CASTELLANOS M, CHILDRESS K, RAMIREZ M AND VENKATRAMANI R. FETAL EXPOSURE TO CAPECITABINE AND TEMOZOLOMIDE DURING THE FIRST TRIMESTER: A CASE REPORT. JOURNAL OF GYNECOLOGY OBSTETRICS AND HUMAN REPRODUCTION 2020 JUL 23?:101881?.", "literaturereference_normalized": "fetal exposure to capecitabine and temozolomide during the first trimester a case report", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210728", "receivedate": "20210728", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 19631887, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20211014" }, { "companynumb": "US-ROCHE-2655532", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CAPECITABINE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "020896", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "28", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CAPECITABINE." } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": "2.59", "reaction": [ { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Jaundice neonatal", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CASTELLANOS M, CHILDRESS K, RAMIREZ M AND VENKATRAMANI R. FETAL EXPOSURE TO CAPECITABINE AND TEMOZOLOMIDE DURING THE FIRST TRIMESTER: A CASE REPORT. JOURNAL OF GYNECOLOGY OBSTETRICS AND HUMAN REPRODUCTION 2020 JUL 23?:101881?.", "literaturereference_normalized": "fetal exposure to capecitabine and temozolomide during the first trimester a case report", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210728", "receivedate": "20210728", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 19631899, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20211014" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-256203", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TEMOZOLOMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TEMOZOLOMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CAPECITABINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "204668", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CAPECITABINE." } ], "patientagegroup": null, "patientonsetage": "17", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CASTELLANOS MI, CHILDRESS KJ, RAMIREZ M, VENKATRAMANI R. FETAL EXPOSURE TO CAPECITABINE AND TEMOZOLOMIDE DURING THE FIRST TRIMESTER: A CASE REPORT. J GYNECOL OBSTET HUM REPROD. 2020?101881:ONLINE AHEAD OF PRINT", "literaturereference_normalized": "fetal exposure to capecitabine and temozolomide during the first trimester a case report", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200812", "receivedate": "20200812", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18143761, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" } ]
{ "abstract": "BACKGROUND\nMusculoskeletal disorders are one of the most common reasons military servicemen seek medical care during their line of duty. This study aims to review the clinical profile and outcomes of military personnel with inflammatory arthritis (IA) referred to a specialist rheumatology center in Singapore.\n\n\nMETHODS\nConsecutive new case referrals from the Singapore Armed Forces medical centers during the study period January 1, 2010, to December 31, 2019, were retrospectively studied.\n\n\nRESULTS\nThere were 123 referrals, comprising 112 (91.1%) males, with the majority being Chinese (110, 89.4%). The mean age was 25.5 ± 11.1 years. The most common diagnoses were gout (including chronic tophaceous gout; 34, 27.6%), spondyloarthritis (18, 14.6%), palindromic rheumatism (8, 6.5%), rheumatoid arthritis (4, 3.3%), and juvenile idiopathic arthritis (4, 3.3%). Among servicemen with gout, all were male, the majority (31, 91.3%) were Chinese, and mean age was 34.1 ± 8.8 years. Mean body mass index (BMI) was 27.5 ± 3.9 kg/m2, of which 41.2% had moderate-risk and 47.1% high-risk BMI for cardiovascular disease and diabetes mellitus (DM). Comorbidities included hyperlipidemia (14), hypertension (6), and type 2 DM (3). Urate lowering therapy was initiated in 27 (79.4%) patients, comprising allopurinol (85.2%), probenecid (11.1%), and their combination (3.7%). One patient developed allopurinol-induced hepatitis; none had severe cutaneous adverse reactions. Among the remaining patients with IA, conventional synthetic disease-modifying antirheumatic drugs (DMARDs) used were sulfasalazine (8), methotrexate (4), hydroxychloroquine (4), and leflunomide (2). Biologic DMARDs used in five patients comprised adalimumab (3) and golimumab (2).\n\n\nCONCLUSIONS\nServicemen with IA and good functional status can still be physically fit and deployable into certain combat and service support vocations. This will optimize manpower resources in military organizations with a shrinking young workforce.", "affiliations": "Department of Rheumatology, Allergy and Immunology, Tan Tock Seng Hospital, 308433, Singapore.;Department of Rheumatology, Allergy and Immunology, Tan Tock Seng Hospital, 308433, Singapore.", "authors": "Chua\|Choon-Guan\|CG\|0000-0001-6166-4351;Thong\|Bernard Yu-Hor\|BY\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1093/milmed/usab246", "fulltext": null, "fulltext_license": null, "issn_linking": "0026-4075", "issue": null, "journal": "Military medicine", "keywords": null, "medline_ta": "Mil Med", "mesh_terms": null, "nlm_unique_id": "2984771R", "other_id": null, "pages": null, "pmc": null, "pmid": "34190324", "pubdate": "2021-06-30", "publication_types": "D016428:Journal Article", "references": null, "title": "Inflammatory Arthritis Among Military Servicemen From a Rheumatology Center in Singapore.", "title_normalized": "inflammatory arthritis among military servicemen from a rheumatology center in singapore" }	[ { "companynumb": "SG-INDOCO-000210", "fulfillexpeditecriteria": "1", "occurcountry": "SG", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALLOPURINOL" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "204467", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BLOOD URIC ACID DECREASED", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALLOPURINOL." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatitis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CHUA CG, THONG BY. INFLAMMATORY ARTHRITIS AMONG MILITARY SERVICEMEN FROM A RHEUMATOLOGY CENTER IN SINGAPORE. MIL MED. 2021 JUN 30:USAB246.", "literaturereference_normalized": "inflammatory arthritis among military servicemen from a rheumatology center in singapore", "qualification": "3", "reportercountry": "SG" }, "primarysourcecountry": "SG", "receiptdate": "20210716", "receivedate": "20210716", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19565457, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "SG-ACCORD-231881", "fulfillexpeditecriteria": "1", "occurcountry": "SG", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALLOPURINOL" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "203154", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BLOOD URIC ACID DECREASED", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALLOPURINOL." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatitis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CHUA CG, THONG BY. INFLAMMATORY ARTHRITIS AMONG MILITARY SERVICEMEN FROM A RHEUMATOLOGY CENTER IN SINGAPORE. MIL MED. 2021 JUN 30:USAB246.", "literaturereference_normalized": "inflammatory arthritis among military servicemen from a rheumatology center in singapore", "qualification": "3", "reportercountry": "SG" }, "primarysourcecountry": "SG", "receiptdate": "20210717", "receivedate": "20210717", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19573436, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" } ]

{ "abstract": "A 74-year-old woman with cT4aN2M0, cStage ⅢB gastric cancer underwent neoadjuvant chemotherapy comprising 2 courses of S-1 plus cisplatin, and the clinical response was determined as non-CR/non-PD according to RECIST ver 1.1. Although distal gastrectomy with D2 lymphadenectomy was planned, the tumor was considered as unresectable with peritoneal metastases during laparotomy. After the subsequent chemotherapy with 1 course of capecitabine plus cisplatin, tumor bleeding, and obstruction due to rapid tumor progression occurred. We performed palliative distal gastrectomy; however, the patient died 17 days after gastrectomy. A comprehensive genomic analysis using cancer-gene panel identified the tumor as a microsatellite instability-high(MSI-H). Recently post hoc analysis of the large-scale clinical trials showed no clinical benefit of perioperative chemotherapy in MSI-H gastric cancer. MSI status has a potential to optimize the perioperative treatment strategy in gastric cancer.", "affiliations": "Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences.", "authors": "Otani|Takahiro|T|;Ichikawa|Hiroshi|H|;Hanyu|Takaaki|T|;Ishikawa|Takashi|T|;Sakai|Takeshi|T|;Nemoto|Mariko|M|;Muneoka|Yusuke|Y|;Usui|Kenji|K|;Sudo|Natsuru|N|;Kano|Yosuke|Y|;Nagahashi|Masayuki|M|;Sakata|Jun|J|;Kobayashi|Takashi|T|;Kameyama|Hitoshi|H|;Wakai|Toshifumi|T|", "chemical_list": "D002945:Cisplatin", "country": "Japan", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0385-0684", "issue": "45(13)", "journal": "Gan to kagaku ryoho. Cancer & chemotherapy", "keywords": null, "medline_ta": "Gan To Kagaku Ryoho", "mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002945:Cisplatin; D019008:Drug Resistance, Neoplasm; D005260:Female; D005743:Gastrectomy; D006801:Humans; D053842:Microsatellite Instability; D020360:Neoadjuvant Therapy; D013274:Stomach Neoplasms", "nlm_unique_id": "7810034", "other_id": null, "pages": "1895-1897", "pmc": null, "pmid": "30692390", "pubdate": "2018-12", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Chemoresistance in Microsatellite Instability-High Gastric Cancer-A Case Report.", "title_normalized": "chemoresistance in microsatellite instability high gastric cancer a case report" }

[ { "companynumb": "JP-ACCORD-107986", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CAPECITABINE" }, "drugadditional": "2", "drugadministrationroute": null, "drugauthorizationnumb": "202593", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTRIC CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "3000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CAPECITABINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": "2", "drugadministrationroute": null, "drugauthorizationnumb": "206774", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTRIC CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "112", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN." } ], "patientagegroup": null, "patientonsetage": "74", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "54", "reaction": [ { "reactionmeddrapt": "Tumour haemorrhage", "reactionmeddraversionpt": "21.1", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "OTANI T, ICHIKAWA H, HANYU T, ISHIKAWA T, SAKAI T, NEMOTO M, ET. AL. CHEMORESISTANCE IN MICROSATELLITE INSTABILITY-HIGH GASTRIC CANCER-A CASE REPORT. VOLUME 45, NO. 13 DECEMBER 2018", "literaturereference_normalized": "chemoresistance in microsatellite instability high gastric cancer a case report", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190222", "receivedate": "20190222", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15993840, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" } ]

{ "abstract": "BACKGROUND\nExtensive data have been accumulated for adults who have undergone ABO-incompatible (ABOi)-living kidney transplantation (LKT). In contrast, available published data on pediatric recipients who underwent ABOi-LKT from the early to middle 2000s is very limited. Thus, pediatric ABOi-LKT has remained relatively rare, and there is a lack of large, multicenter data.\n\n\nMETHODS\nWe analyzed data from the Japanese Kidney Transplant Registry to clarify the patient and graft outcomes of pediatric recipients who underwent ABOi-LKT from 2002 to 2015. A total of 102 ABOi and 788 ABO-compatible (ABOc) recipients were identified in this study. All recipients had received basiliximab and a triple immunosuppressive protocol comprising calcineurin inhibitors, mycophenolate mofetil, and steroids. The ABOi recipients also received preconditioning therapies including B-cell depletion by a splenectomy or rituximab treatment and therapeutic apheresis.\n\n\nRESULTS\nDeath rates for ABOi and ABOc recipients were 0.17 versus 0.17 deaths per 100 patient-years. Graft loss rates for ABOi and ABOc recipients were 1.58 versus 1.45 events per 100 patient-years. No particular causes of death or graft loss predominantly affected ABOi or ABOc recipients.\n\n\nCONCLUSIONS\nThe results of this registry analysis suggest that pediatric ABOi-LKT can be performed efficiently. Although further studies are clearly required to perform pediatric ABOi-LKT more safely and less invasively, ABOi-LKT is now an acceptable treatment for pediatric patients with end-stage renal disease.", "affiliations": "Department of Pediatric Nephrology, Tokyo Women's Medical University, School of Medicine, Tokyo, Japan.;Department of Medical Informatics Center for Information, Jichi Medical University, Tochigi, Japan.;Department of Nephrology, Faculty of Medicine, Toho University, Tokyo, Japan.;Department of Nephrology, Faculty of Medicine, Toho University, Tokyo, Japan.;Department of Transplantation and Regenerative Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan.;National Center for Geriatrics and Gerontology, Aichi, Japan.;Niigata Organ Transplant Foundation, Niigata, Japan.;Kamata Minami-guchi Kidney Clinic, Tokyo, Japan.", "authors": "Hattori|Motoshi|M|;Mieno|Makiko|M|;Shishido|Seiichiro|S|;Aikawa|Atsushi|A|;Ushigome|Hidetaka|H|;Ohshima|Shinichi|S|;Takahashi|Kota|K|;Hasegawa|Akira|A|;|||", "chemical_list": "D000017:ABO Blood-Group System; D007166:Immunosuppressive Agents", "country": "United States", "delete": false, "doi": "10.1097/TP.0000000000002259", "fulltext": null, "fulltext_license": null, "issn_linking": "0041-1337", "issue": "102(11)", "journal": "Transplantation", "keywords": null, "medline_ta": "Transplantation", "mesh_terms": "D000017:ABO Blood-Group System; D000293:Adolescent; D000367:Age Factors; D001787:Blood Group Incompatibility; D002648:Child; D004359:Drug Therapy, Combination; D005260:Female; D006084:Graft Rejection; D006085:Graft Survival; D006648:Histocompatibility; D006801:Humans; D007166:Immunosuppressive Agents; D007564:Japan; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D019520:Living Donors; D008297:Male; D012042:Registries; D013156:Splenectomy; D013997:Time Factors; D016896:Treatment Outcome", "nlm_unique_id": "0132144", "other_id": null, "pages": "1934-1942", "pmc": null, "pmid": "29781948", "pubdate": "2018-11", "publication_types": "D016428:Journal Article", "references": null, "title": "Outcomes of Pediatric ABO-incompatible Living Kidney Transplantations From 2002 to 2015: An Analysis of the Japanese Kidney Transplant Registry.", "title_normalized": "outcomes of pediatric abo incompatible living kidney transplantations from 2002 to 2015 an analysis of the japanese kidney transplant registry" }

[ { "companynumb": "JP-ROCHE-2224520", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BASILIXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG WHEN BODY WEIGHT WAS {35 KG; 20 MG WHEN BODY WEIGHT WAS }35 KG", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BASILIXIMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "050722", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "600 TO 1200 MG/M2 PER DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOSPORIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "041", "drugauthorizationnumb": "103705", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INFUSION", "drugdosagetext": "150-375 MG/M2", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SULFAMETHOXAZOLE/TRIMETHOPRIM" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 TO 15 MG/KG", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cytomegalovirus infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Viral infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Polyomavirus-associated nephropathy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumocystis jirovecii pneumonia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Post procedural infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Adenoviral haemorrhagic cystitis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sepsis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bacterial infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrointestinal infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fungal infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Epstein-Barr virus associated lymphoproliferative disorder", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urinary tract infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": ", MIENO M, SHISHIDO S, ET AL OUTCOMES OF PEDIATRIC ABO-INCOMPATIBLE LIVING KIDNEY TRANSPLANTATIONS FROM 2002 TO 2015: AN ANALYSIS OF THE JAPANESE KIDNEY TRANSPLANT REGISTRY. TRANSPLANTATION 2018?102 (11):1934-1942.", "literaturereference_normalized": "outcomes of pediatric abo incompatible living kidney transplantations from 2002 to 2015 an analysis of the japanese kidney transplant registry", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190115", "receivedate": "20190102", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15780764, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" } ]

{ "abstract": "Spinal myoclonus following neuraxial anesthesia is rare. This report describes a case of myoclonus-like involuntary movement that occurred during the recovery from epidural anesthesia for a cesarean delivery. The patient's symptom improved with the administration of benzodiazepine, and the patient recovered with no neurological sequelae. In conclusion, epidural anesthesia can cause spinal myoclonus, which can be treated with a benzodiazepine.", "affiliations": "Department of Anesthesiology and Pain Medicine, Graduate School, Kyung Hee University.;Department of Anesthesiology and Pain Medicine, Graduate School, Kyung Hee University.;Department of Anesthesia and Pain Medicine, Kyung Hee University Hospital.;Department of Anesthesia and Pain Medicine, Kyung Hee University Hospital.;Department of Anesthesiology and Pain Medicine, Kyung Hee University Hospital at Gangdong.;Department of Anesthesiology and Pain Medicine, Graduate School, Kyung Hee University; Department of Anesthesia and Pain Medicine, Kyung Hee University Hospital.;Department of Anesthesiology and Pain Medicine, Graduate School, Kyung Hee University; Department of Anesthesiology and Pain Medicine, Kyung Hee University Hospital at Gangdong. Electronic address: [email protected].", "authors": "Kang|Hee Yong|HY|;Lee|Sang Wook|SW|;Hong|Eun Pyo|EP|;Sim|Yeo Hae|YH|;Lee|Su-Mi|SM|;Park|Sung Wook|SW|;Kang|Jong-Man|JM|", "chemical_list": "D000779:Anesthetics, Local; D000927:Anticonvulsants; D008012:Lidocaine; D000077554:Levobupivacaine; D008874:Midazolam; D002045:Bupivacaine", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0952-8180", "issue": "34()", "journal": "Journal of clinical anesthesia", "keywords": "Cesarean delivery; Epidural anesthesia; Involuntary movement; Spinal myoclonus", "medline_ta": "J Clin Anesth", "mesh_terms": "D061605:Administration, Intravenous; D000328:Adult; D000762:Anesthesia Recovery Period; D000767:Anesthesia, Epidural; D000773:Anesthesia, Obstetrical; D000779:Anesthetics, Local; D000927:Anticonvulsants; D002045:Bupivacaine; D002585:Cesarean Section; D005260:Female; D006801:Humans; D007268:Injections, Epidural; D000077554:Levobupivacaine; D008012:Lidocaine; D008874:Midazolam; D009207:Myoclonus; D011247:Pregnancy", "nlm_unique_id": "8812166", "other_id": null, "pages": "392-4", "pmc": null, "pmid": "27687419", "pubdate": "2016-11", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Myoclonus-like involuntary movements following cesarean delivery epidural anesthesia.", "title_normalized": "myoclonus like involuntary movements following cesarean delivery epidural anesthesia" }

[ { "companynumb": "KR-MYLANLABS-2016M1028187", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "EPHEDRINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EPHEDRINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LIDOCAINE" }, "drugadditional": null, "drugadministrationroute": "008", "drugauthorizationnumb": "091058", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "15 ML OF 2% INJECTION", "drugenddate": null, "drugenddateformat": null, "drugindication": "INDUCTION OF ANAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LIDOCAINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PHENYLEPHRINE\\PHENYLEPHRINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MICROG", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PHENYLEPHRINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LIDOCAINE" }, "drugadditional": null, "drugadministrationroute": "008", "drugauthorizationnumb": "091058", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "5 ML OF 2% INJECTION", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LIDOCAINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "EPHEDRINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EPHEDRINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEVOBUPIVACAINE" }, "drugadditional": null, "drugadministrationroute": "008", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "15 ML OF 0.75% INJECTION", "drugenddate": null, "drugenddateformat": null, "drugindication": "INDUCTION OF ANAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOBUPIVACAINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEVOBUPIVACAINE" }, "drugadditional": null, "drugadministrationroute": "008", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 ML OF 0.75% INJECTION", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOBUPIVACAINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "OXYTOCIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXYTOCIN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Myoclonus", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Maternal exposure during delivery", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KANG HY, LEE SW, HONG EP, SIM YH, LEE S-M, PARK SW, ET AL. MYOCLONUS-LIKE INVOLUNTARY MOVEMENTS FOLLOWING CESAREAN DELIVERY EPIDURAL ANESTHESIA. J-CLIN-ANESTH 2016;34:392-394.", "literaturereference_normalized": "myoclonus like involuntary movements following cesarean delivery epidural anesthesia", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20160707", "receivedate": "20160707", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12537712, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" }, { "companynumb": "KR-WATSON-2016-15763", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "EPHEDRINE" }, "drugadditional": null, "drugadministrationroute": "065", 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"drugdosageform": "UNK", "drugdosagetext": "15 ML, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "EPIDURAL ANAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "012", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LIDOCAINE (UNKNOWN)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEVOBUPIVACAINE" }, "drugadditional": null, "drugadministrationroute": "008", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "15 ML, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": 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"drugtreatmentdurationunit": null, "medicinalproduct": "PHENYLEPHRINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "OXYTOCIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXYTOCIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LIDOCAINE" }, "drugadditional": null, "drugadministrationroute": "008", "drugauthorizationnumb": "080377", "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNK", "drugdosagetext": "5 ML, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "012", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LIDOCAINE (UNKNOWN)" } ], "patientagegroup": null, "patientonsetage": "30", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "70", "reaction": [ { "reactionmeddrapt": "Myoclonus", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dysarthria", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KANG HY, LEE SW, HONG EP, SIM YH, LEE SM, PARK SW ET AL.. MYOCLONUS-LIKE INVOLUNTARY MOVEMENTS FOLLOWING CESAREAN DELIVERY EPIDURAL ANESTHESIA. J. CLIN. ANESTH.. 2016;(34):392-4.", "literaturereference_normalized": "myoclonus like involuntary movements following cesarean delivery epidural anesthesia", "qualification": "1", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20160720", "receivedate": "20160720", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12576295, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20161109" } ]

{ "abstract": "The genetically variable CYP450 isozymes are responsible for the metabolism of up to 80% of commonly used drugs, many of which are detected in cases of unexpected or suspicious death in Australia. The aim of this study was to examine the genetic profiles of individuals in a cohort of Australian deceased individuals dying of drug toxicity (219), natural disease (150), external injury (109) or unascertained (8) causes, to determine if there was an over-representation of individuals with a genetic predisposition to altered drug metabolism in cases attributed to drug toxicity compared with other causes. Single nucleotide polymorphisms (SNP) of CYP1A2, 2C9, 2C19, 2D6, 3A4 and 3A5 were analyzed. There were 27 cases (6.1%) that were CYP2D6 poor metabolizers (PM) and an additional 8 cases (1.7 %) that were CYP2C19 PMs. Around 31% of the cases were CYP2D6 intermediate-poor metabolizers, with a number of cases exhibiting drug combinations that were likely to have caused pharmacokinetic or pharmacodynamic interactions. There was no correlation between cause of death type and CYP2D6 metabolizer status. Increased enzyme activity was also indicated by the presence of hyperinducible variants such as CYP1A2*1F, which was observed at a frequency of 48%.", "affiliations": "Victorian Institute of Forensic Medicine, Department of Forensic Medicine, Monash University, 57-83 Kavanagh Street, Southbank 3006, Victoria, Australia. [email protected]", "authors": "Pilgrim|Jennifer L|JL|;Ruiz|Yarimar|Y|;Gesteira|Alejandro|A|;Cruz|Raquel|R|;Gerostamoulos|Dimitri|D|;Carracedo|Angel|A|;Drummer|Olaf H|OH|", "chemical_list": "D003577:Cytochrome P-450 Enzyme System", "country": "Netherlands", "delete": false, "doi": "10.2174/1389200211209050679", "fulltext": null, "fulltext_license": null, "issn_linking": "1389-2002", "issue": "13(5)", "journal": "Current drug metabolism", "keywords": null, "medline_ta": "Curr Drug Metab", "mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002423:Cause of Death; D003577:Cytochrome P-450 Enzyme System; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D011041:Poisoning; D020641:Polymorphism, Single Nucleotide; D014739:Victoria; D055815:Young Adult", "nlm_unique_id": "100960533", "other_id": null, "pages": "679-92", "pmc": null, "pmid": "22299824", "pubdate": "2012-06-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Characterization of single nucleotide polymorphisms of cytochrome p450 in an Australian deceased sample.", "title_normalized": "characterization of single nucleotide polymorphisms of cytochrome p450 in an australian deceased sample" }

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CHARACTERIZATION OF SINGLE NUCLEOTIDE POLYMORPHISMS OF CYTOCHROME P450 IN AN AUSTRALIAN DECEASED SAMPLE. 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CHARACTERIZATION OF SINGLE NUCLEOTIDE POLYMORPHISMS OF CYTOCHROME P450 IN AN AUSTRALIAN DECEASED SAMPLE. 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CHARACTERIZATION OF SINGLE NUCLEOTIDE POLYMORPHISMS OF CYTOCHROME P450 IN AN AUSTRALIAN DECEASED SAMPLE. 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CHARACTERIZATION OF SINGLE NUCLEOTIDE POLYMORPHISMS OF CYTOCHROME P450 IN AN AUSTRALIAN DECEASED SAMPLE. 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CHARACTERIZATION OF SINGLE NUCLEOTIDE POLYMORPHISMS OF CYTOCHROME P450 IN AN AUSTRALIAN DECEASED SAMPLE. 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CHARACTERIZATION OF SINGLE NUCLEOTIDE POLYMORPHISMS OF CYTOCHROME P450 IN AN AUSTRALIAN DECEASED SAMPLE. 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CHARACTERIZATION OF SINGLE NUCLEOTIDE POLYMORPHISMS OF CYTOCHROME P450 IN AN AUSTRALIAN DECEASED SAMPLE. 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CHARACTERIZATION OF SINGLE NUCLEOTIDE POLYMORPHISMS OF CYTOCHROME P450 IN AN AUSTRALIAN DECEASED SAMPLE. 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CHARACTERIZATION OF SINGLE NUCLEOTIDE POLYMORPHISMS OF CYTOCHROME P450 IN AN AUSTRALIAN DECEASED SAMPLE. 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CHARACTERIZATION OF SINGLE NUCLEOTIDE POLYMORPHISMS OF CYTOCHROME P450 IN AN AUSTRALIAN DECEASED SAMPLE. CURR DRUG METAB. 2012?13(5):679-692", "literaturereference_normalized": "characterization of single nucleotide polymorphisms of cytochrome p450 in an australian deceased sample", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20201215", "receivedate": "20201215", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18615462, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210114" }, { "companynumb": "AU-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-271145", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "FLUOXETINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "76990", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUOXETINE" } ], "patientagegroup": null, "patientonsetage": "90", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intentional self-injury", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PILGRIM JL, RUIZ Y, GESTEIRA A, CRUZ R, GEROSTAMOULOS D, CARRACEDO A, ET AL. CHARACTERIZATION OF SINGLE NUCLEOTIDE POLYMORPHISMS OF CYTOCHROME P450 IN AN AUSTRALIAN DECEASED SAMPLE. CURR DRUG METAB. 2012?13(5):679-692", "literaturereference_normalized": "characterization of single nucleotide polymorphisms of cytochrome p450 in an australian deceased sample", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20201215", "receivedate": "20201215", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18615460, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210114" }, { "companynumb": "AU-MYLANLABS-2020M1098886", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DIAZEPAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIAZEPAM." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CITALOPRAM HYDROBROMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "077042", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CITALOPRAM" } ], "patientagegroup": null, "patientonsetage": "53", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "PILGRIM JL, RUIZ Y, GESTEIRA A, CRUZ R, GEROSTAMOULOS D, CARRACEDO A, ET AL. CHARACTERIZATION OF SINGLE NUCLEOTIDE POLYMORPHISMS OF CYTOCHROME P450 IN AN AUSTRALIAN DECEASED SAMPLE. CURR-DRUG-METAB 2012?13(5):679-692.", "literaturereference_normalized": "characterization of single nucleotide polymorphisms of cytochrome p450 in an australian deceased sample", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20201202", "receivedate": "20201202", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18571630, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210114" }, { "companynumb": "AU-MYLANLABS-2020M1098867", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "MORPHINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "200824", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MORPHINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "TRAMADOL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAMADOL." } ], "patientagegroup": null, "patientonsetage": "29", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "PILGRIM JL, RUIZ Y, GESTEIRA A, CRUZ R, GEROSTAMOULOS D, CARRACEDO A, ET AL. CHARACTERIZATION OF SINGLE NUCLEOTIDE POLYMORPHISMS OF CYTOCHROME P450 IN AN AUSTRALIAN DECEASED SAMPLE. 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CHARACTERIZATION OF SINGLE NUCLEOTIDE POLYMORPHISMS OF CYTOCHROME P450 IN AN AUSTRALIAN DECEASED SAMPLE. CURRENT DRUG METABOLISM. 2012?13(5):679-92", "literaturereference_normalized": "characterization of single nucleotide polymorphisms of cytochrome p450 in an australian deceased sample", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20201127", "receivedate": "20201127", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18555085, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210114" }, { "companynumb": "AU-BAUSCH-BL-2020-033491", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CITALOPRAM HYDROBROMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CITALOPRAM" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALCOHOL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALCOHOL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DIAZEPAM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "020648", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIAZEPAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OXYCODONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXYCODONE" } ], "patientagegroup": null, "patientonsetage": "23", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Alcohol poisoning", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "PILGRIM J, RUIZ Y, GESTEIRA A, CRUZ R, GEROSTAMOULOS D, CARRACEDO A, DRUMMER O. CHARACTERIZATION OF SINGLE NUCLEOTIDE POLYMORPHISMS OF CYTOCHROME P450 IN AN AUSTRALIAN DECEASED SAMPLE. CURRENT DRUG METABOLISM. 2012?13 (5):679-692.", "literaturereference_normalized": "characterization of single nucleotide polymorphisms of cytochrome p450 in an australian deceased sample", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": null, "receiptdate": "20201125", "receivedate": "20201125", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18544935, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210114" }, { "companynumb": "AU-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-271158", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DIAZEPAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIAZEPAM." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ALCOHOL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALCOHOL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "NORDAZEPAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NORDIAZEPAM" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CITALOPRAM HYDROBROMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "77032", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CITALOPRAM" } ], "patientagegroup": null, "patientonsetage": "53", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Alcohol poisoning", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "PILGRIM JL, RUIZ Y, GESTEIRA A, CRUZ R, GEROSTAMOULOS D, CARRACEDO A, ET AL. CHARACTERIZATION OF SINGLE NUCLEOTIDE POLYMORPHISMS OF CYTOCHROME P450 IN AN AUSTRALIAN DECEASED SAMPLE. 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CHARACTERIZATION OF SINGLE NUCLEOTIDE POLYMORPHISMS OF CYTOCHROME P450 IN AN AUSTRALIAN DECEASED SAMPLE. 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CHARACTERIZATION OF SINGLE NUCLEOTIDE POLYMORPHISMS OF CYTOCHROME P450 IN AN AUSTRALIAN DECEASED SAMPLE. 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CHARACTERIZATION OF SINGLE NUCLEOTIDE POLYMORPHISMS OF CYTOCHROME P450 IN AN AUSTRALIAN DECEASED SAMPLE. 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CHARACTERIZATION OF SINGLE NUCLEOTIDE POLYMORPHISMS OF CYTOCHROME P450 IN AN AUSTRALIAN DECEASED SAMPLE. 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{ "abstract": "A 61-year-old man with a diagnosis of rectal cancer underwent assisted laparoscopic rectal amputation. Recurrence occurred, and treatment with FOLFIRI plus bevacizumab was initiated at our department. After 12 treatment courses, he developed abdominal pain at home. Emergency surgery was performed for the stoma perforation. We confirmed the diverticular perforation in the resected specimen. In our case, we found a para-stoma hernia and considered it to be the cause of perforation together with bevacizumab administration. Molecular-targeted drugs contribute to improving treatment outcomes in malignant tumors, but specific adverse events such as perforation have been reported. In addition, as causes of sigmoid colon perforation such as that of the stoma, cases associated with intestinal operation, constipation, and para-stoma hernia are suggested. In our case of hyperpolarization due to a para-stoma hernia, administration of bevacizumab was considered the cause of the perforation. This was a case that could be rescued with surgery.", "affiliations": "Dept. of Surgery, Toda Chuo General Hospital.", "authors": "Watanabe|Mitsuru|M|;Sumi|Tetsuo|T|;Udou|Ryutaro|R|;Enomoto|Masaya|M|;Matsudo|Takaaki|T|;Tachibana|Shingo|S|;Mimuro|Akihiro|A|;Katsumata|Kenji|K|;Tsuchida|Akihiko|A|", "chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000068258:Bevacizumab", "country": "Japan", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0385-0684", "issue": "46(1)", "journal": "Gan to kagaku ryoho. Cancer & chemotherapy", "keywords": null, "medline_ta": "Gan To Kagaku Ryoho", "mesh_terms": "D000074322:Antineoplastic Agents, Immunological; D000068258:Bevacizumab; D012809:Colon, Sigmoid; D003125:Colostomy; D006801:Humans; D007416:Intestinal Perforation; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D012004:Rectal Neoplasms", "nlm_unique_id": "7810034", "other_id": null, "pages": "148-150", "pmc": null, "pmid": "30765670", "pubdate": "2019-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "A Case of Diverticular Perforation of Sigmoid Colostomy during FOLFIRI plus BevacizumabTreatment.", "title_normalized": "a case of diverticular perforation of sigmoid colostomy during folfiri plus bevacizumabtreatment" }

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{ "abstract": "BACKGROUND\nInhibitors of dipeptidyl peptidase (DPP)-IV have been suspected in the onset of bullous pemphigoid for several years now. However, comparative studies assessing the link between DPP-IV inhibitor exposure and bullous pemphigoid have not yet been performed.\n\n\nOBJECTIVE\nTo detect, from the French Pharmacovigilance Database (FPVD), a signal of risk of bullous pemphigoid during DPP-IV inhibitor exposure by comparative study.\n\n\nMETHODS\nAll spontaneous reports of DPP-IV inhibitor-related bullous pemphigoid recorded in the FPVD between April 2008 and August 2014 were described. We conducted disproportionality analyses (case-noncase method) to assess the link between DPP-IV inhibitors and bullous pemphigoid, calculating reporting odds ratios (RORs). We also compared DPP-IV inhibitor-induced bullous pemphigoid reports rated per million defined daily doses dispensed during the study period.\n\n\nRESULTS\nAmong 217 331 spontaneous adverse drug reaction reports registered in the FPVD, 1297 involved DPP-IV inhibitors. Among these observations, 42 were bullous pemphigoid (vildagliptin, n = 31; sitagliptin, n = 10; saxagliptin, n = 1). The ROR for pooled DPP-IV inhibitors was 67·5 [95% confidence interval (CI) 47·1-96·9]. Disproportionality was also observed for each DPP-IV inhibitor: vildagliptin (ROR 225·3, 95% CI 148·9-340·9), sitagliptin (ROR 17·0, 95% CI 8·9-32·5) and saxagliptin (ROR 16·5, 95% CI 2·3-119·1). Analyses adjusted on dispensing data led to similar results.\n\n\nCONCLUSIONS\nThese data confirm a strong signal for an increased risk of bullous pemphigoid during DPP-IV inhibitor exposure. This adverse drug reaction is observed for each DPP-IV inhibitor, suggesting a class effect. The signal was higher with vildagliptin than with the other DPP-IV inhibitors.", "affiliations": "Centre Régional de Pharmacovigilance du Nord Pas-de-Calais, Univ.Lille, CHU Lille, F-59000, Lille, France.;Service de Médecine Interne, CHU de Toulouse, Toulouse, France.;Service de Dermatologie, CHU de Toulouse, Toulouse, France.;Centre Régional de Pharmacovigilance du Nord Pas-de-Calais, Univ.Lille, CHU Lille, F-59000, Lille, France.;Service Pharmacie, Centre Hospitalier de Valenciennes, Valenciennes, France.;Centre Régional de PharmacoVigilance, Hôpital Henri Mondor, Assistance Publique Hôpitaux de Paris, Créteil, France.;Centre Régional de PharmacoVigilance, Département de Pharmacologie Médicale et Toxicologie, Faculté de Médecine et CHRU, Montpellier, France.;Centre Régional de PharmacoVigilance, Service de Pharmacologie Clinique et Pharmacovigilance, Assistance Publique des Hôpitaux de Marseille, Aix Marseille Université, Marseille, France.;Centre Régional de Pharmacovigilance du Nord Pas-de-Calais, Univ.Lille, CHU Lille, F-59000, Lille, France.", "authors": "Béné|J|J|;Moulis|G|G|;Bennani|I|I|;Auffret|M|M|;Coupe|P|P|;Babai|S|S|;Hillaire-Buys|D|D|;Micallef|J|J|;Gautier|S|S|;|||", "chemical_list": "D054873:Dipeptidyl-Peptidase IV Inhibitors", "country": "England", "delete": false, "doi": "10.1111/bjd.14601", "fulltext": null, "fulltext_license": null, "issn_linking": "0007-0963", "issue": "175(2)", "journal": "The British journal of dermatology", "keywords": null, "medline_ta": "Br J Dermatol", "mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D054873:Dipeptidyl-Peptidase IV Inhibitors; D003875:Drug Eruptions; D005260:Female; D005602:France; D006801:Humans; D008297:Male; D008875:Middle Aged; D010391:Pemphigoid, Bullous; D060735:Pharmacovigilance; D012307:Risk Factors; D056737:Safety-Based Drug Withdrawals", "nlm_unique_id": "0004041", "other_id": null, "pages": "296-301", "pmc": null, "pmid": "27031194", "pubdate": "2016-08", "publication_types": "D003160:Comparative Study; D016428:Journal Article", "references": null, "title": "Bullous pemphigoid and dipeptidyl peptidase IV inhibitors: a case-noncase study in the French Pharmacovigilance Database.", "title_normalized": "bullous pemphigoid and dipeptidyl peptidase iv inhibitors a case noncase study in the french pharmacovigilance database" }

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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. BRITISH JOURNAL OF DERMATOLOGY. 2016?175:296-301", "literaturereference_normalized": "bullous pemphigoid and dipeptidyl peptidase iv inhibitors a case noncase study in the french pharmacovigilance database", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20191115", "receivedate": "20191115", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17036324, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "FR-MYLANLABS-2016M1058713", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VILDAGLIPTIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VILDAGLIPTIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALLOPURINOL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "018659", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALLOPURINOL." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pemphigoid", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "BENE J, MOULIS G, BENNANI I, AUFFRET M, COUPE P, BABAI S, ET AL. BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. BR-J-DERMATOL 2016;175(2):296-301.", "literaturereference_normalized": "bullous pemphigoid and dipeptidyl peptidase iv inhibitors a case noncase study in the french pharmacovigilance database", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20170110", "receivedate": "20170110", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13101668, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "FR-MYLANLABS-2016M1058755", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "075973", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VILDAGLIPTIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VILDAGLIPTIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pemphigoid", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "BENE J, MOULIS G, BENNANI I, AUFFRET M, COUPE P, BABAI S, ET AL. BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. BRITISH JOURNAL OF DERMATOLOGY. 2016?175(2):296-301", "literaturereference_normalized": "bullous pemphigoid and dipeptidyl peptidase iv inhibitors a case noncase study in the french pharmacovigilance database", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20191115", "receivedate": "20191115", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17037568, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "FR-MYLANLABS-2016M1058701", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "075973", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "SITAGLIPTIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SITAGLIPTIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pemphigoid", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "BENE J, MOULIS G, BENNANI I, AUFFRET M, COUPE P, BABAI S, ET AL. BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. BR-J-DERMATOL 2016;175(2):296-301.", "literaturereference_normalized": "bullous pemphigoid and dipeptidyl peptidase iv inhibitors a case noncase study in the french pharmacovigilance database", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20170105", "receivedate": "20170105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13088862, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "FR-JNJFOC-20161004731", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RISPERIDONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "020272", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RISPERIDONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pemphigoid", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BENE J, MOULIS G, BENNANI I, AUFFRET M, COUPE P, BABAI S, ET AL. BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. BRITISH JOURNAL OF DERMATOLOGY 2016;175(2):296-301.", "literaturereference_normalized": "bullous pemphigoid and dipeptidyl peptidase iv inhibitors a case noncase study in the french pharmacovigilance database", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20161007", "receivedate": "20161007", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12828332, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "NVSC2019FR035714", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "75965", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VILDAGLIPTIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "101706", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VILDAGLIPTIN" } ], "patientagegroup": null, "patientonsetage": "86", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pemphigoid", "reactionmeddraversionpt": "22.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "BENE J, MOULIS G, BENNANI I, AUFFRET M, COUPE P, BABAI S ET AL.. BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. BRITISH JOURNAL OF DERMATOLOGY. 2016?175:296-301", "literaturereference_normalized": "bullous pemphigoid and dipeptidyl peptidase iv inhibitors a case noncase study in the french pharmacovigilance database", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20191115", "receivedate": "20191115", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17036332, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "FR-TEVA-728007ISR", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "VILDAGLIPTIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VILDAGLIPTIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "75978", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pemphigoid", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "BENE J, MOULIS G, BENNANI I, AUFFRET M, COUPE P, BABAI S, ET AL. BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. BR-J-DERMATOL 2016;175(2):296-301.", "literaturereference_normalized": "bullous pemphigoid and dipeptidyl peptidase iv inhibitors a case noncase study in the french pharmacovigilance database", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20170111", "receivedate": "20170111", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13105982, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "FR-MYLANLABS-2016M1058767", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "VILDAGLIPTIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VILDAGLIPTIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "075973", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pemphigoid", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "BENE J, MOULIS G, BENNANI I, AUFFRET M, COUPE P, BABAI S, ET AL. BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. BR-J-DERMATOL 2016;175(2):296-301.", "literaturereference_normalized": "bullous pemphigoid and dipeptidyl peptidase iv inhibitors a case noncase study in the french pharmacovigilance database", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20170105", "receivedate": "20170105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13089662, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "NVSC2019FR035697", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACAMPROSATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACAMPROSATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREGABALIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREGABALIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VILDAGLIPTIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "101706", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VILDAGLIPTIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "75985", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pemphigoid", "reactionmeddraversionpt": "22.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Eosinophilia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BENE J, MOULIS G, BENNANI I, AUFFRET M, COUPE P, BABAI S ET AL.. BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. BRITISH JOURNAL OF DERMATOLOGY. 2016?175(2):296-301", "literaturereference_normalized": "bullous pemphigoid and dipeptidyl peptidase iv inhibitors a case noncase study in the french pharmacovigilance database", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20191115", "receivedate": "20191115", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17037602, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "FR-TEVA-728034ISR", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "75978", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "SITAGLIPTIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SITAGLIPTIN" } ], "patientagegroup": null, "patientonsetage": "45", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pemphigoid", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "BENE J, MOULIS G, BENNANI I, AUFFRET M, COUPE P, BABAI S, ET AL. BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. BR-J-DERMATOL 2016;175(2):296-301.", "literaturereference_normalized": "bullous pemphigoid and dipeptidyl peptidase iv inhibitors a case noncase study in the french pharmacovigilance database", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20170111", "receivedate": "20170111", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13106212, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "NVSC2019FR035702", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "VILDAGLIPTIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "101706", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VILDAGLIPTIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "75985", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": "75", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Eosinophilia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pemphigoid", "reactionmeddraversionpt": "22.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "BENE J, MOULIS G, BENNANI I, AUFFRET M, COUPE P, BABAI S, ET AL.. BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. BRITISH JOURNAL OF DERMATOLOGY. 2016?175(2):296-301", "literaturereference_normalized": "bullous pemphigoid and dipeptidyl peptidase iv inhibitors a case noncase study in the french pharmacovigilance database", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20191115", "receivedate": "20191115", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17036822, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "NVSC2019FR035709", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "75985", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VILDAGLIPTIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "101706", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VILDAGLIPTIN" } ], "patientagegroup": null, "patientonsetage": "80", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pemphigoid", "reactionmeddraversionpt": "22.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "BENE J, MOULIS G, BENNANI I, AUFFRET M, COUPE P, BABAI S ET AL.. BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. BRITISH JOURNAL OF DERMATOLOGY. 2016?175(2):296-301", "literaturereference_normalized": "bullous pemphigoid and dipeptidyl peptidase iv inhibitors a case noncase study in the french pharmacovigilance database", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20191115", "receivedate": "20191115", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17036340, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "FR-TEVA-728032ISR", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "75978", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "SITAGLIPTIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SITAGLIPTIN" } ], "patientagegroup": null, "patientonsetage": "65", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pemphigoid", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "BENE J, MOULIS G, BENNANI I, AUFFRET M, COUPE P, BABAI S, ET AL. BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. BR-J-DERMATOL 2016;175(2):296-301.", "literaturereference_normalized": "bullous pemphigoid and dipeptidyl peptidase iv inhibitors a case noncase study in the french pharmacovigilance database", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20170110", "receivedate": "20170110", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13101680, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "FR-MYLANLABS-2016M1058784", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "VILDAGLIPTIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VILDAGLIPTIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "075973", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pemphigoid", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "BENE J, MOULIS G, BENNANI I, AUFFRET M, COUPE P, BABAI S, ET AL. BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. BR-J-DERMATOL 2016;175(2):296-301.", "literaturereference_normalized": "bullous pemphigoid and dipeptidyl peptidase iv inhibitors a case noncase study in the french pharmacovigilance database", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20170105", "receivedate": "20170105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13089670, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "FR-TEVA-728021ISR", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "75978", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VILDAGLIPTIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VILDAGLIPTIN" } ], "patientagegroup": null, "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pemphigoid", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "BENE J, MOULIS G, BENNANI I, AUFFRET M, COUPE P, BABAI S, ET AL. BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. BR-J-DERMATOL 2016;175(2):296-301.", "literaturereference_normalized": "bullous pemphigoid and dipeptidyl peptidase iv inhibitors a case noncase study in the french pharmacovigilance database", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20170112", "receivedate": "20170112", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13109660, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "NVSC2019FR035715", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "75965", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VILDAGLIPTIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "101706", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VILDAGLIPTIN" } ], "patientagegroup": null, "patientonsetage": "70", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pemphigoid", "reactionmeddraversionpt": "22.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "BENE J, MOULIS G, BENNANI I, AUFFRET M, COUPE P, BABAI S ET AL.. BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. BRITISH JOURNAL OF DERMATOLOGY. 2016?175:296-301", "literaturereference_normalized": "bullous pemphigoid and dipeptidyl peptidase iv inhibitors a case noncase study in the french pharmacovigilance database", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20191115", "receivedate": "20191115", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17036330, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "FR-MYLANLABS-2016M1058714", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ESCITALOPRAM OXALATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESCITALOPRAM" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VILDAGLIPTIN" }, "drugadditional": "2", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VILDAGLIPTIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "075973", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RISPERIDONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RISPERIDONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pemphigoid", "reactionmeddraversionpt": "19.1", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "BENE J, MOULIS G, BENNANI I, AUFFRET M, COUPE P, BABAI S, ET AL. BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. BR-J-DERMATOL 2016;175(2):296-301.", "literaturereference_normalized": "bullous pemphigoid and dipeptidyl peptidase iv inhibitors a case noncase study in the french pharmacovigilance database", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20170105", "receivedate": "20170105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13089660, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "FR-TEVA-728020ISR", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "VILDAGLIPTIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VILDAGLIPTIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "75978", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": "80", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pemphigoid", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "BENE J, MOULIS G, BENNANI I, AUFFRET M, COUPE P, BABAI S, ET AL. BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. BR-J-DERMATOL 2016;175(2):296-301.", "literaturereference_normalized": "bullous pemphigoid and dipeptidyl peptidase iv inhibitors a case noncase study in the french pharmacovigilance database", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20170112", "receivedate": "20170112", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13109220, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "FR-MYLANLABS-2016M1058698", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "SITAGLIPTIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SITAGLIPTIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "075973", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pemphigoid", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BENE J, MOULIS G, BENNANI I, AUFFRET M, COUPE P, BABAI S, ET AL. BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE.. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. BR-J-DERMATOL 2016;175(2):296-301.", "literaturereference_normalized": "bullous pemphigoid and dipeptidyl peptidase iv inhibitors a case noncase study in the french pharmacovigilance database", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20170112", "receivedate": "20170112", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13109233, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "FR-TEVA-728036ISR", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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BULLOUS PEMPHIGOID AND DIPEPTIDYL PEPTIDASE IV INHIBITORS: A CASE-NONCASE STUDY IN THE FRENCH PHARMACOVIGILANCE DATABASE. 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{ "abstract": "The emergence of Multisystem Inflammatory Syndrome (MIS-C) following SARS-CoV-2 infection in children and adolescents provided a new diagnostic and management challenge as there is limited knowledge about this condition and its natural history. In existing literature on MIS-C, there are currently no data about long-term outcomes. We report the case of a 14-year-old boy, with no significant past medical history, who presented a condition of multiorgan dysfunction due to MIS-C, after a SARS CoV-2 infection, and subsequent clinical-laboratory signs of hepatic steatosis at short-term follow-up. The case suggests how hepatic steatosis may be a possible sequela following SARS-CoV-2 infection, MIS-C and its medical treatment. Therefore, a close and long-term follow-up is needed to establish the pathophysiology and the evolution of this condition in patients following MIS-C.", "affiliations": "Department of Pediatrics, University of Perugia, 06132 Perugia, Italy.;Department of Pediatrics, University of Perugia, 06132 Perugia, Italy.;Department of Pediatrics, University of Perugia, 06132 Perugia, Italy.;Department of Pediatrics, University of Perugia, 06132 Perugia, Italy.;Department of Pediatrics, University of Perugia, 06132 Perugia, Italy.", "authors": "Sica|Rossella|R|0000-0002-3990-4117;Pennoni|Serena|S|;Penta|Laura|L|;Di Cara|Giuseppe|G|;Verrotti|Alberto|A|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.3390/ijerph18136961", "fulltext": "\n==== Front\nInt J Environ Res Public Health\nInt J Environ Res Public Health\nijerph\nInternational Journal of Environmental Research and Public Health\n1661-7827\n1660-4601\nMDPI\n\n34209719\n10.3390/ijerph18136961\nijerph-18-06961\nCase Report\nNew Onset of Hepatic Steatosis Post-Severe Multisystem Inflammatory Syndrome in Children (MIS-C): A Case Report\nhttps://orcid.org/0000-0002-3990-4117\nSica Rossella *\nPennoni Serena\nPenta Laura\nDi Cara Giuseppe\nVerrotti Alberto\nTchounwou Paul B. Academic Editor\nDepartment of Pediatrics, University of Perugia, 06132 Perugia, Italy; [email protected] (S.P.); [email protected] (L.P.); [email protected] (G.D.C.); [email protected] (A.V.)\n* Correspondence: [email protected]\n29 6 2021\n7 2021\n18 13 696125 5 2021\n23 6 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nThe emergence of Multisystem Inflammatory Syndrome (MIS-C) following SARS-CoV-2 infection in children and adolescents provided a new diagnostic and management challenge as there is limited knowledge about this condition and its natural history. In existing literature on MIS-C, there are currently no data about long-term outcomes. We report the case of a 14-year-old boy, with no significant past medical history, who presented a condition of multiorgan dysfunction due to MIS-C, after a SARS CoV-2 infection, and subsequent clinical-laboratory signs of hepatic steatosis at short-term follow-up. The case suggests how hepatic steatosis may be a possible sequela following SARS-CoV-2 infection, MIS-C and its medical treatment. Therefore, a close and long-term follow-up is needed to establish the pathophysiology and the evolution of this condition in patients following MIS-C.\n\nMIS-C\nSARS-CoV-2\nhepatic steatosis\nultrasonography\ntransaminases\n==== Body\n1. Introduction\n\nSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was first identified in Wuhan, China, in December 2019 and then spread rapidly worldwide causing coronavirus disease 2019 (COVID-19) which became the first pandemic of the 21st century by number of deaths. Unlike adults, in which cytokine storm is frequently accompanied by severe respiratory involvement with development of acute respiratory distress syndrome, children with COVID-19 may be asymptomatic or only have mild symptoms. The most prevalent symptom of COVID-19 in pediatric population is fever, followed by cough, upper respiratory tract symptoms, diarrhea and nausea/vomiting. Only a small percentage of children with COVID-19 required Pediatric Intensive Care Unit (PICU) level care or mechanical ventilation [1]. Conversely, in the latter half of April 2020, reports from the UK [2] and Italy [3], followed by the U.S, described a novel syndrome whose features resembled those of known entities such as Kawasaki Disease (KD), toxic shock syndrome (TSS), and macrophage activation syndrome (MAS), which could lead to shock and multiple organ failure, requiring PICU. This novel syndrome is referred to interchangeably as Multisystem Inflammatory Syndrome in Children (MIS-C) associated with COVID 19 or Pediatric Inflammatory Multisystem Syndrome Temporally associated with SARS CoV-2 (PIMS TS). In a case series comparing children and adolescents with MIS-C vs. those with severe COVID-19, MIS-C was distinguished by having more severe cardiovascular or mucocutaneous involvement and extreme inflammation with a higher neutrophil/leucocyte ratio, higher c-reactive protein (CRP) level and more thrombocytopenia than patients with COVID-19 [4]. Initially, it was believed that this syndrome was specifically related to children and adolescents, but reports of cases of multisystem inflammatory syndrome in adults have recently been described, referring to this syndrome as Multisystem Inflammatory Syndrome in Adults Associated with SARS-CoV-2 Infection (MIS-A) [5]. These reports demonstrates that SARS-CoV-2 can cause this clinical manifestation in subjects of any age. The pathophysiology of this syndrome is under intense investigation but so far remains unclear. It is believed that this syndrome results from an abnormal immune response to the virus. Carter et al. performed a serum profiling of MIS-C patients that revealed high levels of interleukin-1β (IL-1β), IL-6, IL-8, IL-10, IL-17, interferon-γ and differential T and B cell subset lymphopenia in the acute phase. Moreover, high CD64 expression on neutrophils and monocytes, and high HLA-DR expression on γδ and CD4+CCR7+ T cells in the acute phase, suggested that these immune cell populations were activated. Antigen-presenting cells had low HLA-DR and CD86 expression, potentially indicative of impaired antigen presentation. All of these features normalized over the resolution phase [6]. In addition, the hyperinflammatory state was found to be different from that in adult severe COVID-19 and KD. Consiglio et al. performed a systems-level analysis of immune cells, cytokines and antibodies in the blood of children presenting with MIS-C as compared to children with mild SARS-CoV-2 infection and children with KD. They noticed that several details of the hyperinflammatory state in children with MIS-C were different from the hyperinflammation seen in adults and children with acute SARS-CoV-2 infection and that of children with KD as well. In particular, they found that IL-17 is most important in KD but it is significantly lower in MIS-C patients, indicating a difference in the underlying immunopathology [7]. Clinical features of MIS-C are variable and characterized mostly by persistent fever; mucocutaneous symptoms including conjunctivitis and rash; gastrointestinal symptoms, including vomiting, abdominal pain, and/or diarrhea; cardiac abnormalities such as myocardial dysfunction, myocardial infarction with increased serum concentrations of troponin and pro-B-type natriuretic peptide (proBNP), coronary artery dilation or aneurysm, arrhythmia and a compromised hemodynamic status which can lead to acute renal and hepatic failure; neurologic findings including headache, irritability and encephalopathy; and coagulopathy. On 13 May 2020, the Center for Disease Control (CDC) issued a case definition specifying that the patient should be <21 years old, have fever, with laboratory evidence of inflammation (including, but not limited to, 1 or more of the following: an elevated CRP, erythrocyte sedimentation rate, fibrinogen, procalcitonin, D-dimer, ferritin, lactate dehydrogenase, IL-6, elevated neutrophils, reduced lymphocytes and low albumin level), and evidence of clinically severe illness requiring hospitalization, with multisystem (>2) organ involvement (cardiac, renal, respiratory, haematological, gastrointestinal, dermatological or neurological), in the absence of an alternative plausible diagnosis, as well as evidence of SARS-CoV-2 infection or exposure [8]. In existing pediatric literature on MIS-C, only short-term outcomes were reported [9], as there are currently no published reports detailing long term outcomes in these patients.\n\n2. Case Report\n\nOn 1 March 2021, a 14-year-old boy was admitted to the Pediatric Emergency Department with compromised general status. He was found to be alert and oriented, febrile with 38.2 °C, tachycardic (118/beats/min), hypotensive (60/40 mmHg), saturating 100% on room air breathing 42 breaths per minute. Upon clinical examination, he was found to be dehydrated, with jaundiced skin, capillary refill 3–4 s, cold extremities with feeble peripheral pulses, palmoplantar erythema and edema, diffusely painful abdomen and palpable hepatosplenomegaly. He was in a condition of multiorgan failure: acute kidney injury, hepatosplenomegaly with increased inflammatory markers, in particular of IL-6 (144.6 pg/mL) and compromised hemodynamic status with reduction of left ventricular ejection fraction. We also noticed elevated values of alanine aminotransferase (ALT) (139 UI/L), aspartate aminotransferase (AST) (102 UI/L) and indices of cholestasis. Given the family history of SARS-CoV-2 infection and the positivity of SARS-CoV-2 IgG from serum, he was diagnosed with MIS-C. The patient’s compromised hemodynamic status required vasoactive support at the Cardiac Intensive Care Unit for the first 3–4 days of hospitalization. He was treated with intravenous immunoglobulin (2g/kg over 48 h) and pulse Methylprednisolone (10 mg/kg a bolus twice a day for 3 days and then progressively reduced). In consideration of the elevation of D-dimer (5734 ng/mL), a prophylactic antithrombotic therapy was started with low-molecular-weight heparin and aspirin (3 mg/kg/day). During hospital course, we noticed an improvement of his general conditions, with return to clinical baseline and progressive normalization of laboratory alterations, particularly of ALT and cholestatic indices. Ultrasonography of the abdomen was performed prior to discharge, and we found no abnormalities (Figure 1). He was discharged at day 14 with indication to continue therapy with Aspirin and Prednisone per os, in progressive decalage according to the tapering strategy.\n\nFollowing discharge, the patient was re-evaluated in a follow-up visit program (physical examination, laboratory tests and echocardiography) during which we started to taper off prednisone (until 1 mg/Kg/day). On 23 March, at the first follow-up visit, the patient was found to be in good conditions, without particular findings on the physical examination. The laboratory tests were normal except for the elevation of ALT (122 UI/L). On the second follow-up visit, 30 days following the onset of MIS-C, the patient was completely asymptomatic but clinical assessment revealed palpable hepatomegaly (2 cm below the costal margin) and further elevation of ALT (143 UI/L) on laboratory testing. AST, serum bilirubin and all the other lab parameters were normal. Ultrasonography of the abdomen was performed and revealed that hepatomegaly was secondary to hepatic steatosis (Figure 1), with absence of pre-existing obesity (BMI 19.2) and signs of Nonalcoholic Fatty Liver Disease (NAFLD). Moreover, any other existing or previous inflammatory pathology was excluded. The following follow-up visits, laboratory tests (Figure 2) and ultrasonographies of the abdomen showed data suggesting hepatic steatosis as well. We did not introduce a drug therapy but we started a lifestyle approach including dietary improvements and increasing physical activity. Our patient was referred to a Pediatric Gastroenterologist. Currently, the patient is in good general clinical condition, with an optimal recovery of cardiac and renal function and not on drug therapy, as steroid therapy was withdrawn during the follow-up visit program. Nevertheless, our patient still has hepatic steatosis which was also confirmed by ultrasonography of the abdomen performed during the most recent follow-up visit on 27 May.\n\n3. Discussion\n\nSARS-CoV-2 may cause a systemic disease with possible involvement of other organs besides the respiratory system, including the liver, because of ubiquitous distribution of the main viral entry receptor, namely angiotensin converting enzyme 2 (ACE2). In particular, the virus spike protein binds ACE2 to gain cell entry and transmembrane serine protease 2 (TMPRSS2) and paired basic amino acid cleaving enzyme (FURIN) are also important for infection. Therefore, the expression of these receptors provided early clues for putative hepatic permissive cells [10]. A study of Pirola et al. demonstrates that gene expression levels for ACE2 are highest in cholangiocytes compared with alveolar type 2 cells, followed in turn by sinusoidal endothelial cells and hepatocytes, thus supporting the possibility that SARS-CoV-2 may cause direct liver injury by viral cytopathic effect. The cytopathic effect may be due to a direct mechanism such as lysis or by necrotic and/or apoptotic effects. Furthermore, the expression pattern in cell clusters associated with numerous active immune pathways, for example, inflammatory macrophages, natural killer cells, plasma cells, mature B cells and cells of the liver endothelial microenvironment, opens the possibility of SARS-CoV-2 immune-mediated liver damage [11]. Therefore, the pathophysiology of the liver involvement in COVID-19 and MIS-C is still unclear, but it is believed that the injury might be caused by hepatocellular infection with direct cytopathic effects of SARS-CoV-2 or an immune-mediated response with inflammatory damage. In addition, hypoxic/shock-related circulatory compromise, endothelial dysfunction, microthrombi formation and drug-induced liver injury (e.g., corticosteroids, lopinavir, ritonavir, tocilizumab and remdesivir) may be involved [12]. COVID-19-associated liver injury is defined as any liver damage occurring during disease course and treatment of COVID-19 patients, with or without pre-existing liver disease [13] and typically leads to a temporary moderate elevation of liver tests without significant hepatic synthetic function impairment. Patients with SARS-CoV-2 infection and elevated ALT are at risk of a more severe disease course including longer hospitalization and ICU stays [14]. Patients with greater elevations in serum ALT levels often have high levels of CRP, which is synthesized by the liver, D- dimer, ferritin and IL-6. IL-6 is produced by monocytes, macrophages and T cells in response to activation of the innate and adaptive immune system, and is the most important driver of CRP production, and high IL-6 levels are associated with liver injury in COVID-19 [10]. Hepatitis is also common in children with MIS-C, and it is associated with a more severe presentation of the syndrome [15]. COVID-19-associated hepatocellular injury is characterized by moderate steatosis, lobular and portal inflammation, apoptotic and/or necrotic foci and elevation of plasma ALT and AST [16]. Microvesicular and macrovesicular steatosis have been observed in liver autopsies of COVID-19 patients who presented with SARS-CoV-2 infection and, in some cases, SARS-CoV-2 hepatocellular infection has been proven [16,17]. Induction of host de novo lipogenesis might be crucial for SARS-CoV-2 life cycle as enhanced de novo lipogenesis could supply the virus with sufficient amounts of lipids to generate the vesicular systems required for viral replication and exocytosis [16]. Moreover, steatosis might be caused by SARS-CoV-2 induced mitochondrial dysfunction and Endoplasmic reticulum (ER) stress, which can induce de novo lipogenesis [16,18]. There are observations that suggest that SARS-CoV-2 affects mitochondrial activity, for instance, mitochondrial crista abnormalities were found in liver specimen of COVID-19 patients [17]. In addition, electron microscopy examinations proved SARS-CoV-2 hepatocellular infection and reported a pathological ER dilatation in infected hepatocytes, which is the most probable cause of ER stress [17]. In addition, the coronavirus S protein might play a key role in ER stress induction [19]. SARS-CoV-2 infection might also activate mTOR, inducing de novo lipogenesis and eventually inhibiting autophagy (as a mechanism of viral degradation) and facilitating viral escape from the immune system [16]. Moreover, significantly increased mTOR activity has been revealed upon IL-6 stimulation [20], and IL-6 is one of the most important cytokines involved in MIS-C. Additionally, it is important to differentiate hepatic lipid accumulation as a result of SARS-CoV-2 infection and MIS-C from pre-existing NAFLD, which has been shown to increase the risk for poor outcome [21]. Therefore, we hypothesize that hepatic steatosis in our patient might be caused by SARS-COV-2 infection, COVID-19 and MIS-C. We do not exclude that liver damage and consequent steatosis might be caused by an immune-mediated inflammatory response to the virus or by hypoxic/shock-related circulatory compromised status, endothelial dysfunction and/or microthrombi formation. Furthermore, drug-induced liver damage should not be excluded. In a retrospective chart review of a cohort of children treated with a multidisciplinary approach and consensus-driven algorithm, the short-term outcomes of these patients were found to be generally favorable [9]. However, in existing literature on MIS-C, there are no data concerning the mid-long-term outcomes of these patients. Although much of the discussion around MIS-C and its outcomes has centered on cardiac manifestations and sequelae, such as left ventricular (LV) dysfunction and coronary aneurysms, providers must be aware of the hepatic damage which might be caused either by SARS-CoV-2 infection and immune-mediated response. We suggest that close follow-up for these patients would be needed to assess the evolution of hepatic damage following MIS-C.\n\n4. Conclusions\n\nThe emergence of MIS-C following SARS-CoV-2 infection in children and adolescents provided new diagnostic, therapeutic and follow-up challenges as there is limited knowledge about this condition and its natural history. The hepatic consequences of SARS- CoV-2 infection are due to possible direct cytopathic effect, systemic inflammation and immune dysfunction and are an important component of both COVID-19 and MIS-C. Moreover, pre-existing NAFLD should be distinguished from hepatic lipid accumulation as a result of SARS-CoV-2 infection and MIS-C. Currently, there are no data reporting mid-long-term outcomes in patients following MIS-C. We report a case with an excellent cardiac and renal outcome but with a new onset of hepatic steatosis. New onset of hepatic steatosis might be one of the sequelae following SARS-CoV-2 infection, MIS-C and its treatment, mainly the prolonged use of corticosteroids. Furthermore, we suggest that hepatic steatosis after COVID-19 and MIS-C might be underdiagnosed as few patients do undergo abdominal ultrasonography monitoring. Diagnosis of hepatic steatosis is easily accessible through an abdominal ultrasound, which is a low-cost, non-invasive examination. We suggest that it can be very useful to identify this potential damage early. Therefore, more studies are needed to establish the pathophysiology and the evolution of this condition in patients following MIS-C. We suggest that long-term follow-up is needed and would be essential to define the late outcomes of these patients.\n\nAuthor Contributions\n\nConceptualization and methodology R.S., S.P. and L.P.; validation, A.V. and G.D.C.; writing—original draft preparation, R.S. and S.P.; writing—review and editing, R.S., S.P. and L.P.; supervision, A.V. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research received no external funding.\n\nInstitutional Review Board Statement\n\nNot applicable.\n\nInformed Consent Statement\n\nInformed consent was obtained from the subject involved in the study.\n\nConflicts of Interest\n\nThe authors declare no conflict of interest.\n\nFigure 1 (a) Ultrasonography of the abdomen performed at discharge demonstrating normal dimension of the liver and a homogenous pattern. (b) Ultrasonography of the liver performed during follow-up demonstrating hepatomegaly and a hyperechoic liver, suggestive of hepatic steatosis.\n\nFigure 2 Graphic representation of the ALT and AST levels over time which demonstrates the decrease in ALT and AST during hospitalization (A) and then a new rise of the ALT with stable low AST levels during follow-up visits (B).\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Mantovani A. Rinaldi E. Zusi C. Beatrice G. Saccomani M.D. Dalbeni A. Coronavirus disease 2019 (COVID-19) in children and/or adolescents: A meta-analysis Pediatr. Res. 2021 89 733 737 10.1038/s41390-020-1015-2 32555539\n2. Riphagen S. Gomez X. Gonzalez-Martinez C. Wilkinson N. Theocharis P. Hyperinflammatory shock in children during COVID-19 pandemic Lancet 2020 39 1607 1608 10.1016/S0140-6736(20)31094-1\n3. Verdoni L. Mazza A. Gervasoni A. Martelli L. Ruggeri M. Ciuffreda M. Bonanomi E. D’Antiga L. An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: An observational cohort study Lancet 2020 395 1771 1778 10.1016/S0140-6736(20)31103-X 32410760\n4. Feldstein L.R. Tenforde M.W. Friedman K.G. Rose E.B. Dapul H. Soma V.L. Maddux A.B. Mourani P.M. Bowens C. Maamari M. Characteristics and Outcomes of US Children and Adolescents with Multisystem Inflammatory Syndrome in Children (MIS-C) Compared with Severe Acute COVID-19 JAMA 2021 325 1074 1087 10.1001/jama.2021.2091 33625505\n5. Morris S.B. Schwartz N.G. Patel P. Abbo L. Beauchamps L. Balan S. Lee E.H. Paneth-Pollak R. Geevarughese A. Lash M.K. Case Series of Multisystem Inflammatory Syndrome in Adults Associated with SARS-CoV-2 Infection—United Kingdom and United States, March–August 2020 MMWR 2020 69 1450 1456 10.15585/mmwr.mm6940e1 33031361\n6. Carter M.J. Fish M. Jennings A. Doores K.J. Wellman P. Seow J. Acors S. Graham C. Timms E. 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Med. 2020 1 4 10.1007/s42399-020-00631-3 33173850\n\n", "fulltext_license": "CC BY", "issn_linking": "1660-4601", "issue": "18(13)", "journal": "International journal of environmental research and public health", "keywords": "MIS-C; SARS-CoV-2; hepatic steatosis; transaminases; ultrasonography", "medline_ta": "Int J Environ Res Public Health", "mesh_terms": "D000293:Adolescent; D000086382:COVID-19; D002648:Child; D005234:Fatty Liver; D006801:Humans; D008297:Male; D000086402:SARS-CoV-2; D018746:Systemic Inflammatory Response Syndrome", "nlm_unique_id": "101238455", "other_id": null, "pages": null, "pmc": null, "pmid": "34209719", "pubdate": "2021-06-29", "publication_types": "D002363:Case Reports", "references": "32437830;33826804;32170806;32386565;32966765;17670839;32352224;32410760;33692570;33211859;33173850;33206767;32810894;33031361;19081072;32555539;30213506;33190346;33625505;32812012", "title": "New Onset of Hepatic Steatosis Post-Severe Multisystem Inflammatory Syndrome in Children (MIS-C): A Case Report.", "title_normalized": "new onset of hepatic steatosis post severe multisystem inflammatory syndrome in children mis c a case report" }

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NEW ONSET OF HEPATIC STEATOSIS POST?SEVERE MULTISYSTEM INFLAMMATORY SYNDROME IN CHILDREN (MIS?C): A CASE REPORT. 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"METHYLPREDNISOLONE" }, "drugadditional": "2", "drugadministrationroute": "065", "drugauthorizationnumb": "202691", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "PULSE METHYLPREDNISOLONE (10 MG/KG A BOLUS TWICE A DAY FOR 3 DAYS)", "drugenddate": "202103", "drugenddateformat": "610", "drugindication": null, "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "12", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "20210301", "drugstartdateformat": "102", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, 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null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "14", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatomegaly", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Hepatic steatosis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20210323" } }, "primarysource": { "literaturereference": "SICA R, PENNONI S, PENTA L, DI CARA G, VERROTTI A. NEW ONSET OF HEPATIC STEATOSIS POST?SEVERE MULTISYSTEM INFLAMMATORY SYNDROME IN CHILDREN (MIS?C): A CASE REPORT. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH. 2021?18(13):ARTICLE NUMBER 6961. DOI: 10.3390/IJERPH18136961.", "literaturereference_normalized": "new onset of hepatic steatosis post severe multisystem inflammatory syndrome in children mis c a case report", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "IT", "receiptdate": "20210730", "receivedate": "20210730", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19638723, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" } ]

{ "abstract": "To investigate the inter-individual variability in duration of anti-vascular endothelial growth factor (VEGF) treatment effect in neovascular age-related macular degeneration (nvAMD).\n\n\n\nProspective observational multi-centered study.\n\n\n\nForty-eight patients with nvAMD treated with anti-VEGF injections were included. Both treatment naive (n=25) as well as patients who had previously received treatment with ranibizumab (n=23) more than one month prior to their enrollment were recruited.\n\n\n\nPatients received injection with ranibizumab (0.5 mg/0.05 ml) and were followed weekly for 4 weeks with spectral-domain OCT (SD-OCT) assessing the time to maximal reduction of central retinal thickness (CRT) and the presence of intraretinal and subretinal fluid. Other data collected included age, gender, visual acuity, axial length, lens status, and previous injections. The Shapiro-Wilk test was used to examine normal distributions for all variables. Correlations were examined by calculating Spearman's correlation coeficient. Distributions of quantitative variables are described as means (±SD). Qualitative variables are summarized by counts and percentage.\n\n\n\nTime to maximal reduction of CRT and intra- and subretinal fluid after ranibizumab injection.\n\n\n\nA total of 48 eyes of 48 patients (age 74.8±8.3 years, 62.5% female, 52% treatment naive, 35.4% pseudophakic) were assessed. Two-thirds (64.6%) reached maximal CRT reduction earlier than the standard 4-week interval: 6.3% at 1 week postinjection, 22.9% at 2 weeks postinjection, and 35.4% at 3 weeks postinjection. Only 35.4% of patients had maximal CRT reduction at 4 weeks. Twenty percent of treatment-naive and 34.8% of non-naive patients had a week-4 CRT that was >35 μm thicker than the earlier occuring lowest CRT value (nadir). The time to maximal CRT reduction was not related to axial length, age, lens status, or history of injections.\n\n\n\nOptimal dosing interval for maximal CRT reduction may be less than 4 weeks for a significant proportion of patients. Most patients will be classified as complete responders if intervals less than 4 weeks are used to assess anti-VEGF treatment response. Disease load rather than eye size appears to be the driver of anti-VEGF treatment duration and therefore, dosing interval needs to be optimized in the cohort of short-term responders.", "affiliations": "Department of Ophthalmology, University of Crete, Heraklion, Greece; Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts; Korgialenio Benakio General Hospital, Athens, Greece.;Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts.;Department of Ophthalmology, University of Crete, Heraklion, Greece.;Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts.;OMMA Eye Institute, Athens, Greece.;Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts.;Korgialenio Benakio General Hospital, Athens, Greece.;Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts.;Department of Ophthalmology, University of Crete, Heraklion, Greece.;Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts. Electronic address: [email protected].", "authors": "Bontzos|Georgios|G|;Bagheri|Saghar|S|;Ioanidi|Larissa|L|;Kim|Ivana|I|;Datseris|Ioannis|I|;Gragoudas|Evangelos|E|;Kabanarou|Stamatina|S|;Miller|Joan|J|;Tsilimbaris|Miltiadis|M|;Vavvas|Demetrios G|DG|", "chemical_list": "D020533:Angiogenesis Inhibitors; D042461:Vascular Endothelial Growth Factor A; D000069579:Ranibizumab", "country": "United States", "delete": false, "doi": "10.1016/j.oret.2019.11.004", "fulltext": null, "fulltext_license": null, "issn_linking": "2468-6530", "issue": "4(12)", "journal": "Ophthalmology. Retina", "keywords": null, "medline_ta": "Ophthalmol Retina", "mesh_terms": "D000368:Aged; D020533:Angiogenesis Inhibitors; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D058449:Intravitreal Injections; D008297:Male; D011446:Prospective Studies; D000069579:Ranibizumab; D013997:Time Factors; D041623:Tomography, Optical Coherence; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A; D014792:Visual Acuity; D057135:Wet Macular Degeneration", "nlm_unique_id": "101695048", "other_id": null, "pages": "1138-1145", "pmc": null, "pmid": "31937473", "pubdate": "2020-12", "publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study", "references": "17021318;23929309;23352196;21791509;21282580;22374154;28660277;25882328;28527040;21526923;16581423;16483659;22818800;23538578;20920825;23901256;21733918;25217857;30269186;26447985;26309891;19516114;29769445;15671306;19815292;19118696;18408176;23966368;28469938;17386270;28893454;18930553;23084240;17021319;28926193;23453513;29142592;26981331;24143065;24084496;15885778", "title": "Nonresponders to Ranibizumab Anti-VEGF Treatment Are Actually Short-term Responders: A Prospective Spectral-Domain OCT Study.", "title_normalized": "nonresponders to ranibizumab anti vegf treatment are actually short term responders a prospective spectral domain oct study" }

[ { "companynumb": "GR-ROCHE-2534228", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RANIBIZUMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "125156", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "0.5MG/0.5ML", "drugenddate": null, "drugenddateformat": null, "drugindication": "NEOVASCULAR AGE-RELATED MACULAR DEGENERATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RANIBIZUMAB." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neovascular age-related macular degeneration", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PRIVACY, BAGHERI S, LOANIDI L, KIM I, DATSERIS I, GRAGOUDAS E ET AL. NONRESPONDERS TO RANIBIZUMAB ANTI-VEGF TREATMENT ARE ACTUALLY SHORT-TERM RESPONDERS: A PROSPECTIVE SPECTRAL-DOMAIN OCT STUDY.. OPTHALMOLOGY RETINA. 2020?:1-8.", "literaturereference_normalized": "nonresponders to ranibizumab anti vegf treatment are actually short term responders a prospective spectral domain oct study", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20200319", "receivedate": "20200130", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17350900, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" } ]

{ "abstract": "Metformin-associated lactic acidosis [MALA] is a potentially fatal condition characterized by an elevation in serum lactate in patients with metformin exposure. An 82-year-old man with no prior renal history was brought to hospital after being found by his family in a confused state. He had a history of type 2 diabetes mellitus, and his medications included regular metformin. On arrival to our hospital he was conscious but confused and noted recent decreased oral intake. Initial investigations revealed severe acidemia (pH <6.75, undetectable bicarbonate), with elevated serum lactate, urea, creatinine, and hyperkalemia. He was treated with intravenous dextrose, crystalloids, and bicarbonate and underwent urgent hemodialysis. The patient responded well to supportive therapies and achieved full renal recovery one week after admission. He was discharged feeling well, with a new antihyperglycemic medication regimen. This case highlights the potential for life-threatening acidemia in cases of MALA. The case is further unique in that the patient was conscious and responded to questions on arrival, despite the serious metabolic disturbance, and recovered completely. From a safety standpoint, health care providers should advise and educate their patients about discontinuing metformin and other potentially harmful medications in the context of acute illness with volume contraction.", "affiliations": "Department of Medicine, The Ottawa Hospital, University of Ottawa, Ottawa, ON, Canada.;Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, ON, Canada.;Department of Medicine, Division of Nephrology, Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada.", "authors": "Gershkovich|Benjamin|B|0000-0001-7914-9067;McCudden|Christopher|C|;Burns|Kevin D|KD|0000-0002-1482-5826", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1155/2018/4696182", "fulltext": "\n==== Front\nCase Rep NephrolCase Rep NephrolCRINCase Reports in Nephrology2090-66412090-665XHindawi 10.1155/2018/4696182Case ReportA Unique Case of Metformin-Associated Lactic Acidosis http://orcid.org/0000-0001-7914-9067Gershkovich Benjamin \n1\nMcCudden Christopher \n2\nhttp://orcid.org/0000-0002-1482-5826Burns Kevin D. [email protected]\n3\n\n1Department of Medicine, The Ottawa Hospital, University of Ottawa, Ottawa, ON, Canada\n2Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, ON, Canada\n3Department of Medicine, Division of Nephrology, Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, CanadaAcademic Editor: Ze'ev Korzets\n\n2018 15 11 2018 2018 46961829 10 2018 30 10 2018 Copyright © 2018 Benjamin Gershkovich et al.2018This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Metformin-associated lactic acidosis [MALA] is a potentially fatal condition characterized by an elevation in serum lactate in patients with metformin exposure. An 82-year-old man with no prior renal history was brought to hospital after being found by his family in a confused state. He had a history of type 2 diabetes mellitus, and his medications included regular metformin. On arrival to our hospital he was conscious but confused and noted recent decreased oral intake. Initial investigations revealed severe acidemia (pH <6.75, undetectable bicarbonate), with elevated serum lactate, urea, creatinine, and hyperkalemia. He was treated with intravenous dextrose, crystalloids, and bicarbonate and underwent urgent hemodialysis. The patient responded well to supportive therapies and achieved full renal recovery one week after admission. He was discharged feeling well, with a new antihyperglycemic medication regimen. This case highlights the potential for life-threatening acidemia in cases of MALA. The case is further unique in that the patient was conscious and responded to questions on arrival, despite the serious metabolic disturbance, and recovered completely. From a safety standpoint, health care providers should advise and educate their patients about discontinuing metformin and other potentially harmful medications in the context of acute illness with volume contraction.\n\nUniversity of Ottawa\n==== Body\n1. Introduction\nMetformin, a medication of the biguanide class, is a commonly used first line oral agent for the treatment of type II diabetes mellitus [DM2] [1]. Metformin improves glycemic control in DM2 via several complex mechanisms, including an increase in peripheral insulin sensitivity, improvement in peripheral glucose uptake, and a decrease in hepatic gluconeogenesis [2–4]. Since metformin is primarily excreted in the urine, dose adjustments are recommended for estimated glomerular filtration rate levels of 45 mL/minute/1.73 m2 or less [5]. The most common adverse effects of chronic metformin use are gastrointestinal complaints, including nausea, bloating, and diarrhea [6].\n\nThe rarest and most dangerous complication of metformin use is metformin-associated lactic acidosis [MALA]. The incidence of MALA in patients without renal disease is low, with a reported estimate of 5 cases per 100,000 patient-years [7]. The pathophysiology of MALA is thought to be multifactorial in nature. In rat models, metformin has been shown to promote lactate production in enterocytes [8]. Additionally, given that lactate is one of the substrates for hepatic gluconeogenesis, an accumulation of lactate may occur when this process is inhibited by metformin [9].\n\nVarious reports have documented high mortality rates for MALA. A case series of 49 patients with MALA reported an overall mortality rate of 45% [10]. The same study found that the degree of serum lactate elevation and serum metformin concentration do not appear to play prognostic roles. A separate retrospective study, involving 42 patients admitted to the intensive care unit, concluded that MALA related to intentional metformin overdose portends a much more favorable prognosis compared with MALA related to incidental metformin accumulation with concurrent medical illness [11]. Higher mortality was associated with increased age, lower arterial pH, elevated prothrombin time, and need for mechanical ventilation and vasoactive medications.\n\nHere we describe a case of MALA in an elderly patient, who presented with confusion and unremarkable vital signs, despite demonstrating a profound depression in arterial pH and serum bicarbonate concentration. The patient fully recovered with fluid resuscitation, bicarbonate administration, and institution of hemodialysis therapy.\n\n2. Case Presentation\nAn 82-year-old man who lived alone was brought to a regional hospital from his home after being found by his family in a confused state. His past medical history was significant for DM2, hypertension, dyslipidemia, benign prostatic hyperplasia, and chronic back pain. His medications consisted of metformin 1000 mg p.o. BID, sitagliptin 50 mg p.o. BID, ramipril 10 mg p.o. daily, tamsulosin 0.4 mg p.o. daily, hydrochlorothiazide 25 mg p.o. daily, and meloxicam 7.5 mg p.o. daily. He had no known prior history of cardiac or renal disease, and baseline serum creatinine [Cr] was 79 μmol/L.\n\nOn initial assessment, the patient was in no acute distress, although he was disoriented and confused [Glasgow Coma Scale 14]. He complained of mild nausea with recent decreased oral intake, but there was no history of diarrhea. He had no history of infectious symptoms, toxic ingestions, recent medication changes, or witnessed seizure activity. On physical examination he had normal cardiorespiratory findings and no focal neurologic signs. His initial vital signs were blood pressure 150/83 mm Hg, heart rate 124/min, respiratory rate 33/min, oxygen saturation 100% on room air, and temperature 34.9° Celsius. His initial bloodwork results revealed a profound metabolic acidosis and acute kidney injury [Table 1].\n\nA chest X-ray was unremarkable, and his electrocardiogram showed a wide QRS complex, prolonged PR interval, and peaked T waves.\n\nHe was initially treated with intravenous [i.v.] dextrose, a crystalloid bolus, and calcium gluconate, and his potassium was shifted intracellularly with inhaled salbutamol and i.v insulin. He also received one ampule of i.v. sodium bicarbonate. Given his profound metabolic disturbances, he was urgently transferred by ambulance to the local tertiary care centre for expedited management and consideration of dialysis. Upon arrival to the Emergency Department of the tertiary care hospital, he was oriented to person and place but not time, and vital signs were: blood pressure 110/80 mm Hg, heart rate 80/min, respiratory rate 20/min, and oxygen saturation 100% on room air. Within 30 minutes of arrival his mean arterial pressure [MAP] dropped to <65 mm Hg, and he required norepinephrine and vasopressin infusions as well as consultation with the intensive care unit [ICU]. At this time he also received a bolus of 1.5 litres of normal saline, and his axillary temperature was measured as 32.1° Celsius. An arterial blood gas [ABG] revealed profound metabolic acidemia (Table 2).\n\nBlood cultures and serum toxicology screen for ethanol, methanol, isopropanol, acetone, ethylene glycol, acetaminophen, salicylates, and tricyclic antidepressants were negative. His remaining metabolic workup, including plasma thyroid stimulating hormone and plasma cortisol, was normal. Computerized tomography of the head, abdomen, and pelvis were negative for acute findings with no evidence of urinary obstruction or hydronephrosis. An assay for serum metformin level was unfortunately not available at our institution.\n\nThe patient's level of consciousness remained stable, and he consistently protected his airway. He required infusion of vasoactive agents for approximately 20 hours to maintain adequate blood pressure. He was heated externally using warming blankets, and his urine output during the first 24 hours of admission was 205 mL. In addition to treatment with i.v. crystalloid and bicarbonate, he underwent urgent hemodialysis treatment [dialysate HCO3− concentration of 36 mEq/L] via central venous access, which was repeated the next day. After two days he was transferred out of the ICU and went on to achieve renal recovery [serum Cr 95 μmol/L on day 8 of hospitalization] with restoration of urine output, acid-base and electrolyte balance. His functional status at the time of discharge was at his baseline. The metformin was discontinued from the day of admission, and he was prescribed a new regimen of oral antihyperglycemic medications for his diabetes.\n\n3. Discussion\nThis patient presented with acute kidney injury associated with severe hyperkalemia, hypoglycemia, and a profound metabolic acidemia with elevated anion gap and serum lactate levels. The patient's high anion gap metabolic acidosis was likely due to lactic acidosis and acute kidney injury, and he demonstrated appropriate respiratory compensation. Despite having severely depressed pH and HCO3− levels however, the patient maintained consciousness throughout and did not require ventilatory support. Although a serum metformin assay was not available at our institution, other causes of elevated serum lactate including sepsis and tissue ischemia were ruled out, and there was no evidence of hepatic disease or toxic ingestions. Although the patient's transient hypotension may have contributed to his lactic acidosis, his serum lactate was significantly elevated on initial presentation, prior to the requirement of vasoactive agents. Overall, his presentation was in keeping with MALA.\n\nIn this case, it is unclear what precipitated the patient's rapid decline and initial presentation to hospital, as history was limited. However, based on his medication profile and laboratory findings, it is possible that he developed acute kidney injury secondary to extracellular volume contraction in the setting of nonsteroidal anti-inflammatory [meloxicam] and ACE inhibitor [ramipril] use, with resultant hypoglycemia and severe lactic acidosis secondary to metformin accumulation. Thus, this case illustrates the potential danger of volume contraction in elderly patients with DM2 who are treated with renin-angiotensin blockade, nonsteroidal anti-inflammatories and metformin, which can set off a cascade of events leading to life-threatening MALA.\n\nThis case was unique for several other reasons. Firstly, the patient's initial clinical appearance and findings on exam were not suggestive of critical illness, and very much out of keeping with his abnormal biochemical profile. Despite having undetectably low serum pH and bicarbonate values, he was able to maintain an acceptable level of mentation, and consistently protected his airway without the need for intubation. In this regard, a correlation exists between low pH and altered mental status, with progression to coma frequently seen in patients with serum pH <6.9 [12].\n\nAdditionally, although mortality rate is high in cases of MALA [10, 11], this patient had an unusually favorable clinical outcome. His advanced age, requirement of vasopressor therapy, elevated prothrombin time, and extent of acute kidney injury placed him at increased risk of death, yet remarkably he experienced renal recovery and had returned to his baseline functional status by the time of hospital discharge.\n\nHypothermia in MALA has been described previously in several case reports [13–15]. While there does not appear to be a direct relationship between metformin and thermoregulation, it has been hypothesized that hypothermia in cases of severe MALA may be a consequence of systemic vasodilation, which is induced by acidemia [13]. Hypoglycemia is also known to cause hypothermia [16] as a result of decreased available substrate for cellular respiration and heat production. In our patient, the combination of acidemia and hypoglycemia can explain his significant hypothermia, given that central, infectious, traumatic, and other endocrine causes of hypothermia were ruled out.\n\nThe patient's coagulopathy on presentation cannot be explained by liver disease, clotting factor deficiencies, or recent use of anticoagulant medications. It is possible that he may have developed vitamin K deficiency given his history of decreased oral intake. However, his INR and PTT corrected within 12 hours of admission, which is sooner than expected for reversal of a vitamin K deficiency. In human and animal models, acidemia has been shown to inhibit clot formation, which may be due to increased fibrinogen consumption [17, 18]. Additionally, hypothermia inhibits thrombin generation in vitro [19, 20], which may result in the clinical finding of elevated PT and PTT values. Therefore, it is most likely that our patient developed a coagulopathy as a result of the combined effects of hypothermia and acidemia, which corrected shortly after warming and treatment with bicarbonate and hemodialysis.\n\nFinally, an interesting aspect of this case was the result of the ABG that was performed after the patient arrived at the tertiary care centre. The arterial pH and bicarbonate were reported as “<6.75” and “No result”, respectively. These values reflect the fact that the patient's true serum pH and bicarbonate were below the detectable limit for our institution's blood gas analyzer. On a typical blood gas analyzer, pH is measured by detecting the potential difference across a hydrogen-selective membrane. The potential difference is converted to hydrogen ion concentration using the Nernst equation. Bicarbonate is then calculated from pH and pCO2 using the Henderson-Hasselbalch equation [21].\n\nIn contrast, on a typical automated chemistry analyzer, bicarbonate measurement is based on a series of coupled enzyme reactions to convert bicarbonate to other compounds, such as malate. In the process there is a decrease in levels of nicotinamide adenine dinucleotide [NADH], which is measured spectrophotometrically by absorbance at 405 nm. The decrease in NADH concentration is then used to calculate the bicarbonate concentration, as there is a direct proportional relationship between the two variables [22]. Based on the Henderson-Hasselbalch equation, a serum bicarbonate concentration of 0 mmol/L is theoretically not possible. In fact, a set of serum electrolytes done at the time of the above blood gas confirmed a serum bicarbonate of 4 mmol/L in our patient, highlighting the need for vigilance in interpreting the ABG in such settings.\n\nThis case demonstrates the importance of early recognition of MALA in patients taking metformin who present with an unexplained high anion gap metabolic acidosis with elevated lactate levels. Such patients may present with clinical findings that do not correlate with their metabolic derangements and are at risk of rapid deterioration. Despite his advanced age and severe metabolic derangements, our patient had a very favorable outcome, perhaps as a result of prompt medical intervention, coupled with his relatively few medical comorbidities. Additionally, this case highlights the need for healthcare providers to educate patients about the importance of temporarily discontinuing metformin and other potentially nephrotoxic medications in the settings of acute illness and extracellular volume contraction.\n\nAcknowledgments\nFunding for this case report was provided by unrestricted research funds at the Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa.\n\nConsent\nPatient written informed consent for the writing and publication of this case report was obtained on May 6, 2018.\n\nConflicts of Interest\nThe authors declare that there are no conflicts of interest regarding the publication of this article.\n\nTable 1 Initial laboratory results [normal values in parentheses].\n\nHb [g/L]\t130 [140-180]\t\nWBC [x109/L]\t\n17.3 [4.0 – 11.0]\t\nPlatelets [x109/L]\t286 [150 – 400]\t\npH [Venous]\t\n6.85 [7.33 – 7.46]\t\npCO2 [Venous] [mmHg]\t\n19.3 [40.0 – 50.0]\t\nHCO3− [Venous] [mmol/L]\t\n3.4 [22.0 – 27.0]\t\nNa+ [mmol/L]\t145 [135 – 145]\t\nK+ [mmol/L]\t\n8.3 [3.5 – 5.1]\t\nCl− [mmol/L]\t101 [100 – 110]\t\nAnion Gap [mmol/L]\t\n40.6 [5 – 12]\t\nAlbumin [g/L]\t28 [34 – 46]\t\nGlucose [mmol/L]\t\n1.4 [4.0 – 11.0]\t\nCreatinine [µmol/L]\t\n967 [58 – 110]\t\nUrea [mmol/L]\t\n31.2 [2.5 – 7.0]\t\nPO4−2 [mmol/L]\t\n3.68 [0.80 – 1.45]\t\nCa2+ [mmol/L]\t2.43 [2.20 – 2.52]\t\nMg2+ [mmol/L]\t0.84 [0.65 – 0.90]\t\nBilirubin [µmol/L]\t6 [3 – 17]\t\nALT [Alanine Aminotransferase] [U/L]\t22 [20 - 70]\t\nAST [Aspartate Aminotransferase] [U/L]\t32 [15 – 45]\t\nALP [Alkaline Phosphatase] [U/L]\t44 [40 – 115]\t\naPTT [Activated Partial Thromboplastin Time] [s]\t\n45 [22-30]\t\nPT [Prothrombin Time] [s]\t\n21.3 [10.1 – 14.6]\t\nINR [International Normalized Ratio]\t\n1.9 [0.9 – 1.2]\t\nLipase [U/L]\t351 [45 – 300]\t\nLactate [mmol/L]\t\n14.9 [0.5 – 2.2]\t\nCK [Creatinine Kinase] [U/L]\t65 [30 – 200]\t\nTroponin I [ng/L]\t32 [<30]\t\nTable 2 Arterial blood gas, serum lactate level, and serum electrolyte panel.\n\npH [Arterial]\t\n<6.75 [7.38 – 7.46]\t\npCO2 [Arterial] [mmHg]\t\n<12 [32 – 45]\t\nHCO3− [Arterial] [mmol/L]\t\n“No result” [22 - 27]\t\nLactate [mmol/L]\t\n16.0 [0.5 – 2.5]\t\nNa+ [mmol/L]\t142 [136 – 145]\t\nK+ [mmol/L]\t\n5.6 [3.5 – 5.1]\t\nCl− [mmol/L]\t107 [98 – 107]\t\nAnion Gap [mmol/L]\t\n31 [5 – 12]\t\nGlucose [mmol/L]\t13.7 [4.0 – 11.0]\t\nCreatinine [µmol/L]\t\n794 [49 – 93]\t\nUrea [mmol/L]\t\n33.0 [2.1 – 8.0]\n==== Refs\n1 Foretz M. Guigas B. Bertrand L. Pollak M. Viollet B. Metformin: from mechanisms of action to therapies Cell Metabolism 2014 20 6 953 966 10.1016/j.cmet.2014.09.018 25456737 \n2 Rena G. Hardie D. G. Pearson E. R. The mechanisms of action of metformin Diabetologia 2017 60 9 1577 1585 2-s2.0-85026840123 10.1007/s00125-017-4342-z 28776086 \n3 Madiraju A. K. Erion D. M. Rahimi Y. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase Nature 2014 510 7506 542 546 10.1038/nature13270 2-s2.0-84901558868 24847880 \n4 An H. He L. Current understanding of metformin effect on the control of hyperglycemia in diabetes Journal of Endocrinology 2016 228 R97 R106 10.1530/joe-15-0447 26743209 \n5 Lipska K. J. Bailey C. J. Inzucchi S. E. Use of metformin in the setting of mild-to-moderate renal insufficiency Diabetes Care 2011 34 6 1431 1437 2-s2.0-80051978747 10.2337/dc10-2361 21617112 \n6 McCreight L. J. Bailey C. J. Pearson E. R. Metformin and the gastrointestinal tract Diabetologia 2016 59 3 426 435 2-s2.0-84957440490 10.1007/s00125-015-3844-9 26780750 \n7 Salpeter S. R. Greyber E. Pasternak G. A. Salpeter E. E. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus Cochrane Database of Systematic Reviews 2006, https://www-cochranelibrary-com.proxy.bib.uottawa.ca/cdsr/doi/10.1002/14651858.CD002967.pub2/abstract \n8 Bailey C. J. Wilcock C. Day C. Effect of metformin on glucose metabolism in the splanchnic bed British Journal of Pharmacology 1992 105 4 1009 1013 2-s2.0-0026606805 10.1111/j.1476-5381.1992.tb09093.x 1504710 \n9 Sirtori C. R. Pasik C. Re-evaluation of a biguanide, metformin: mechanism of action and tolerability Pharmacological Research 1994 30 3 187 228 2-s2.0-0028139101 10.1016/1043-6618(94)80104-5 7862618 \n10 Lalau J.-D. Race J.-M. Lactic acidosis in metformin-treated patients. Prognostic value of arterial lactate levels and plasma metformin concentrations Drug Safety 1999 20 4 377 384 2-s2.0-0032917623 10.2165/00002018-199920040-00006 10230584 \n11 Seidowsky A. Nseir S. Houdret N. Fourrier F. Metformin-associated lactic acidosis: A prognostic and therapeutic study Critical Care Medicine 2009 37 7 2191 2196 2-s2.0-67649801964 10.1097/CCM.0b013e3181a02490 19487945 \n12 Edge J. A. Roy Y. Bergomi A. Conscious level in children with diabetic ketoacidosis is related to severity of acidosis and not to blood glucose concentration Pediatr Diabetes 2006 7 1 11 5 \n13 Ahmad S. Beckett M. Recovery from ph 6.38: Lactic acidosis complicated by hypothermia Emergency Medicine Journal 2002 19 2 169 171 2-s2.0-0036203620 10.1136/emj.19.2.169 11904273 \n14 Mustafa E. Lai L. Lien Y.-H. H. Rapid recovery from acute kidney injury in a patient with metformin-associated lactic acidosis and hypothermia American Journal of Medicine 2012 125 2 e1 e2 2-s2.0-84856086173 10.1016/j.amjmed.2011.06.016 22269627 \n15 Zibar L. Zibar K. Hemodialysis-refractory metformin-associated lactate acidosis with hypoglycemia, hypothermia, and bradycardia in a diabetic patient with belated diagnosis and chronic kidney disease International Journal of Clinical Pharmacology and Therapeutics 2017 55 4 348 351 2-s2.0-85017318639 10.5414/CP202686 28139970 \n16 Strauch B. S. Felig P. Baxter J. D. Schimpff S. C. Hypothermia in Hypoglycemia Journal of the American Medical Association 1969 210 2 345 346 2-s2.0-1842678553 10.1001/jama.1969.03160280085028 \n17 Engström M. Schött U. Romner B. Reinstrup P. Acidosis impairs the coagulation: A thromboelastographic study Journal of Trauma - Injury Infection and Critical Care 2006 61 3 624 628 2-s2.0-33748747205 10.1097/01.ta.0000226739.30655.75 16966998 \n18 Martini W. Z. Holcomb J. B. Acidosis and coagulopathy: The differential effects on fibrinogen synthesis and breakdown in pigs Annals of Surgery 2007 246 5 831 835 2-s2.0-35648942694 10.1097/SLA.0b013e3180cc2e94 17968176 \n19 Martini W. Z. Pusateri A. E. Uscilowicz J. M. Independent contributions of hypothermia and acidosis to coagulopathy in swine Journal of Trauma - Injury Infection and Critical Care 2005 58 5 1002 1010 2-s2.0-20144368558 10.1097/01.TA.0000156246.53383.9F 15920416 \n20 Martini W. Z. Coagulopathy by hypothermia and acidosis: mechanisms of thrombin generation and fibrinogen availability The Journal of Trauma and Acute Care Surgery 2009 67 1 202 209 10.1097/ta.0b013e3181a602a7 2-s2.0-67651184083 \n21 ABL800 FLEX blood gas analyzer - Radiometer 2018, https://www.radiometeramerica.com/en-us/products/blood-gas-testing/abl800-flex-blood-gas-analyzer?ref=rmed&_ga=2.108419777.271826494.1535327976-1954082072.1535327976&ref=rmed&_ga=2.108419777.271826494.1535327976-1954082072.1535327976 \n22 Saleem M. Dimeski G. Bourne L. Coates P. Artifactually elevated serum bicarbonate results caused by elevated serum lactate dehydrogenase concentrations Annals of Clinical Biochemistry 2013 50 4 365 367 2-s2.0-84890167365 10.1177/0004563212474562 23605134\n\n", "fulltext_license": "CC BY", "issn_linking": "2090-665X", "issue": "2018()", "journal": "Case reports in nephrology", "keywords": null, "medline_ta": "Case Rep Nephrol", "mesh_terms": null, "nlm_unique_id": "101598418", "other_id": null, "pages": "4696182", "pmc": null, "pmid": "30581638", "pubdate": "2018", "publication_types": "D002363:Case Reports", "references": "10230584;11904273;1504710;15920416;16489969;16966998;17968176;19487945;19590336;20091535;21617112;22269627;23605134;24847880;25456737;26743209;26780750;28139970;28776086;7862618", "title": "A Unique Case of Metformin-Associated Lactic Acidosis.", "title_normalized": "a unique case of metformin associated lactic acidosis" }

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A UNIQUE CASE OF METFORMIN?ASSOCIATED LACTIC ACIDOSIS. J?AM?SOC?NEPHROL 2019?30:157 ABSTR. 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BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "DYSLIPIDAEMIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SITAGLIPTIN/SITAGLIPTIN PHOSPHATE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "079148", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1000 MG P.O. 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DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "BENIGN PROSTATIC HYPERPLASIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TAMSULOSIN/TAMSULOSIN HYDROCHLORIDE" } ], "patientagegroup": "6", "patientonsetage": "82", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "GERSHKOVICH B, MCCUDDEN C, BURNS KD. A UNIQUE CASE OF METFORMIN-ASSOCIATED LACTIC ACIDOSIS. CASE REP NEPHROL. 2018 NOV 15?2018:4696182.", "literaturereference_normalized": "a unique case of metformin associated lactic acidosis", "qualification": "3", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20190108", "receivedate": "20190108", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15799531, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "US-MYLANLABS-2021M1001775", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LIRAGLUTIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.2 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "DIABETES MELLITUS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.2", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LIRAGLUTIDE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "075973", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 GRAM, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "DIABETES MELLITUS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypoxia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypothermia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Mental status changes", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Dysarthria", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "AHUJA AC. A UNIQUE CASE OF METFORMIN?ASSOCIATED LACTIC ACIDOSIS. J?AM?SOC?NEPHROL 2019?30:157 ABSTR. TH?PO176.", "literaturereference_normalized": "a unique case of metformin associated lactic acidosis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210119", "receivedate": "20210119", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18755801, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210419" }, { "companynumb": "US-GLENMARK PHARMACEUTICALS-2021GMK051625", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "078170", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 GRAM, BID (EVERY 12 HOURS)", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LIRAGLUTIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.2 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.2", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LIRAGLUTIDE" } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Enterococcal infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urosepsis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Aerococcus urinae infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Myxoedema coma", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "AHUJA AC.. A UNIQUE CASE OF METFORMIN?ASSOCIATED LACTIC ACIDOSIS. JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY. 2019?30:157", "literaturereference_normalized": "a unique case of metformin associated lactic acidosis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210122", "receivedate": "20210122", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18771213, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20210419" } ]

{ "abstract": "Jaw-opening oromandibular dystonia (O-OMD) is a clinical subtype of OMD, commonly resistant to treatment. Here, we report a distinct case of tardive O-OMD with a characteristic sensory trick, successfully treated with high-dose botulinum toxin (BTX) injection. A 34-year-old male patient presented with involuntary jaw opening, tongue protrusion, dysarthria, and mild cervical dystonia. The patient reported improved abilities to talk and close his mouth after putting something, like a cigarette, between his teeth. After an unsuccessful treatment with anticholinergic medications, the patient received electromyography-guided BTX injection to the lateral pterygoids (through an extraoral approach), sternocleidomastoids, trapezius, tongue, and platysma muscles. Following the injection, the patient reported marked improvements in his ability to talk and close his mouth without using his sensory trick. One month later, we detected a 58.2% improvement in the Abnormal Involuntary Movement Scale score. Therefore, high-dose BTX injection may be an effective alternative in refractory O-OMD.", "affiliations": "Department of Neurology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.;Medical Research Center, Faculty of Medicine, Ain Shams University, Cairo, Egypt.;Internal Medicine Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt.;Department of Psychiatry, Faculty of Medicine, Ain Shams University, Cairo, Egypt.;Department of Neurology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.", "authors": "Shalash|Ali S|AS|;Abushouk|Abdelrahman Ibrahim|AI|;Elsherbeny|Mohammed Yasser|MY|;Elrassas|Hanan|H|;Kamel|Taha|T|", "chemical_list": "D009465:Neuromuscular Agents; D001905:Botulinum Toxins", "country": "India", "delete": false, "doi": "10.4103/0028-3886.266235", "fulltext": null, "fulltext_license": null, "issn_linking": "0028-3886", "issue": "67(4)", "journal": "Neurology India", "keywords": "Botulinum toxin; case report; oromandibular dystonia; sensory trick", "medline_ta": "Neurol India", "mesh_terms": "D000328:Adult; D001905:Botulinum Toxins; D020821:Dystonic Disorders; D005152:Facial Muscles; D006801:Humans; D008297:Male; D009059:Mouth Diseases; D009465:Neuromuscular Agents; D014103:Torticollis", "nlm_unique_id": "0042005", "other_id": null, "pages": "1110-1111", "pmc": null, "pmid": "31512647", "pubdate": "2019", "publication_types": "D002363:Case Reports", "references": null, "title": "Refractory Open Jaw Oromandibular Tardive Dystonia with a Sensory Trick, Treated with Botulinum Toxin: A Case Report.", "title_normalized": "refractory open jaw oromandibular tardive dystonia with a sensory trick treated with botulinum toxin a case report" }

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{ "abstract": "Kaposi sarcoma (KS) is the most common tumor in patients with human immunodeficiency virus (HIV), and its frequency is increasing after organ transplantation in HIV-negative patients. A 28-year-old woman had preemptive kidney transplantation from her 48-year-old mother. In the postoperative ninth month, an exophytic mass was found in the upper medial conjunctiva of the right eye. The lesion was excised under local anesthesia, and cryotherapy was applied to the surgical area. The biopsy result was reported as KS. Treatment with tacrolimus was switched to everolimus (EVO), but EVO was discontinued because of pneumonitis. The patient was followed without any recurrences after the excision of the conjunctival lesion. No local or systemic recurrence was observed in the 14th month after surgical excision and local cryotherapy. Local treatment and the reduction of immunosuppressive therapy may be effective in the treatment of conjunctival KS.", "affiliations": "Department of Nephrology, University of Health Sciences, Gazi Yasargil Training and Research Hospital, Diyarbakir, Turkey. Electronic address: [email protected].;Department of Ophthalmology, University of Health Sciences, Gazi Yasargil Training and Research Hospital, Diyarbakir, Turkey.", "authors": "Gunay|Emrah|E|;Oncul|Hasan|H|", "chemical_list": "D007166:Immunosuppressive Agents; D000068338:Everolimus; D016559:Tacrolimus", "country": "United States", "delete": false, "doi": "10.1016/j.transproceed.2019.12.005", "fulltext": null, "fulltext_license": null, "issn_linking": "0041-1345", "issue": "52(2)", "journal": "Transplantation proceedings", "keywords": null, "medline_ta": "Transplant Proc", "mesh_terms": "D000328:Adult; D003230:Conjunctival Neoplasms; D000068338:Everolimus; D005260:Female; D015658:HIV Infections; D006801:Humans; D016867:Immunocompromised Host; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D012514:Sarcoma, Kaposi; D016559:Tacrolimus", "nlm_unique_id": "0243532", "other_id": null, "pages": "622-624", "pmc": null, "pmid": "32035672", "pubdate": "2020-03", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Successful Treatment of Conjunctival Kaposi Sarcoma in a Human Immunodeficiency Virus-Negative Kidney Transplant Recipient: A Case Report.", "title_normalized": "successful treatment of conjunctival kaposi sarcoma in a human immunodeficiency virus negative kidney transplant recipient a case report" }

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SUCCESSFUL TREATMENT OF CONJUNCTIVAL KAPOSI SARCOMA IN A HUMAN IMMUNODEFICIENCY VIRUS-NEGATIVE KIDNEY TRANSPLANT RECIPIENT: A CASE REPORT. TRANSPLANTATION PROCEEDINGS. 2020?1-3", "literaturereference_normalized": "successful treatment of conjunctival kaposi sarcoma in a human immunodeficiency virus negative kidney transplant recipient a case report", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20200214", "receivedate": "20200214", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17420514, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200409" }, { "companynumb": "TR-BAUSCH-BL-2020-006178", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "40070", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLIC ACID." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "REDUCED DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLIC ACID." } ], "patientagegroup": null, "patientonsetage": "28", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Conjunctival neoplasm", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Kaposi^s sarcoma", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "GUNAY E, ONCUL H. SUCCESSFUL TREATMENT OF CONJUNCTIVAL KAPOSI SARCOMA IN A HUMAN IMMUNODEFICIENCY VIRUS?NEGATIVE KIDNEY TRANSPLANT RECIPIENT: A CASE REPORT.. TRANSPLANTATION PROCEEDINGS. 2020?1?3. DOI:HTTPS://DOI.ORG/10.1016/J.TRANSPROCEED.2019.12.005", "literaturereference_normalized": "successful treatment of conjunctival kaposi sarcoma in a human immunodeficiency virus negative kidney transplant recipient a case report", "qualification": "1", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20200826", "receivedate": "20200310", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17523738, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201102" }, { "companynumb": "TR-TEVA-2020-TR-1224726", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "65457", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLIC ACID." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "080354", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "EVEROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "210050", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EVEROLIMUS." } ], "patientagegroup": null, "patientonsetage": "28", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Respiratory distress", "reactionmeddraversionpt": "23.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Kaposi^s sarcoma", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pneumonitis", "reactionmeddraversionpt": "23.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "GUNAY E, ONCUL H. SUCCESSFUL TREATMENT OF CONJUNCTIVAL KAPOSI SARCOMA IN A HUMAN IMMUNODEFICIENCY VIRUS-NEGATIVE KIDNEY TRANSPLANT RECIPIENT: A CASE REPORT. TRANSPLANT-PROC 2020?52(2):622-624.", "literaturereference_normalized": "successful treatment of conjunctival kaposi sarcoma in a human immunodeficiency virus negative kidney transplant recipient a case report", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20200421", "receivedate": "20200421", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17687476, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200714" }, { "companynumb": "TR-PBT-000029", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "090802", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": "5", "patientonsetage": "28", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Kaposi^s sarcoma", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "GUNAY E, ONCUL H. SUCCESSFUL TREATMENT OF CONJUNCTIVAL KAPOSI SARCOMA IN A HUMAN IMMUNODEFICIENCY VIRUS-NEGATIVE KIDNEY TRANSPLANT RECIPIENT: A CASE REPORT. TRANSPLANT PROC. 2020 FEB 5. PII: S0041-1345(19)31579-9. DOI: 10.1016/J.TRANSPROCEED.2019.12.005", "literaturereference_normalized": "successful treatment of conjunctival kaposi sarcoma in a human immunodeficiency virus negative kidney transplant recipient a case report", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20200225", "receivedate": "20200225", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17455040, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "TR-ACCORD-174028", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "091195", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "202555", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL/MYCOPHENOLATE SODIUM/MYCOPHENOLIC ACID" } ], "patientagegroup": null, "patientonsetage": "28", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Conjunctival neoplasm", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Kaposi^s sarcoma", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "GUNAY E, ONCUL H. SUCCESSFUL TREATMENT OF CONJUNCTIVAL KAPOSI SARCOMA IN A HUMAN IMMUNODEFICIENCY VIRUS-NEGATIVE KIDNEY TRANSPLANT RECIPIENT: A CASE REPORT. TRANSPLANTATION PROCEEDINGS. 2020.", "literaturereference_normalized": "successful treatment of conjunctival kaposi sarcoma in a human immunodeficiency virus negative kidney transplant recipient a case report", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20200228", "receivedate": "20200228", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17472053, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20200409" } ]

{ "abstract": "BACKGROUND\nRectus sheath haematomas associated with anticoagulation are often self limiting. When large, however, they can even extend into the pelvis and cause compression of adjacent organs such as the bladder. A combined endovascular and surgical approach can decrease the operative exposure necessary to treat this occurrence.\n\n\nMETHODS\nA 42 year old morbidly obese African American female on warfarin treatment for pulmonary embolism presented outside the hospital with pneumonia. During her hospitalisation, she developed a spontaneous right rectus abdominis haematoma below the level of the umbilicus with active bleeding in the extraperitoneal space causing mass compression of the bladder. She developed acute renal failure and became anuric. Following endovascular embolisation of the inferior epigastric artery, surgical exploration was successfully performed to remove the haematoma and relieve the urinary obstruction. Diuresis resumed and renal function normalised without any further evidence of bleeding.\n\n\nCONCLUSIONS\nA large rectus sheath haematoma that extends into the bladder causing renal obstruction can be treated by endovascular embolisation and surgical exploration to limit operative risks and exposure in morbidly obese patients.", "affiliations": "Division of General, Minimally Invasive, and Robotic Surgery, University of Illinois at Chicago, Chicago, IL, USA.;Department of General Surgery Residency Program, University of Illinois at Chicago, Chicago, IL, USA.;Division of Interventional Radiology, University of Illinois at Chicago, Chicago, IL, USA.", "authors": "Gangemi|A|A|;Mashbari|H N|HN|;Bui|J T|JT|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1016/j.ejvssr.2017.02.001", "fulltext": "\n==== Front\nEJVES Short RepEJVES Short RepEJVES Short Reports2405-6553Elsevier S2405-6553(17)30003-810.1016/j.ejvssr.2017.02.001Case ReportObstructive Uropathy because of a Large Rectus Sheath Haematoma: A Case Report of Combined Interventional Radiology and Surgical Approach Gangemi A. [email protected]∗Mashbari H.N. bBui J.T. ca Division of General, Minimally Invasive, and Robotic Surgery, University of Illinois at Chicago, Chicago, IL, USAb Department of General Surgery Residency Program, University of Illinois at Chicago, Chicago, IL, USAc Division of Interventional Radiology, University of Illinois at Chicago, Chicago, IL, USA∗ Corresponding author. Division of General, Minimally Invasive, and Robotic Surgery, University of Illinois at Chicago, 840 S. Wood Street, Suite 435E, Chicago, IL 60612, USA.Division of General, Minimally Invasive, and Robotic SurgeryUniversity of Illinois at Chicago840 S. Wood StreetSuite 435EChicagoIL60612USA [email protected] 3 2017 2017 17 3 2017 34 24 27 25 9 2016 20 2 2017 22 2 2017 © 2017 The Authors2017This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Introduction\nRectus sheath haematomas associated with anticoagulation are often self limiting. When large, however, they can even extend into the pelvis and cause compression of adjacent organs such as the bladder. A combined endovascular and surgical approach can decrease the operative exposure necessary to treat this occurrence.\n\nReport\nA 42 year old morbidly obese African American female on warfarin treatment for pulmonary embolism presented outside the hospital with pneumonia. During her hospitalisation, she developed a spontaneous right rectus abdominis haematoma below the level of the umbilicus with active bleeding in the extraperitoneal space causing mass compression of the bladder. She developed acute renal failure and became anuric. Following endovascular embolisation of the inferior epigastric artery, surgical exploration was successfully performed to remove the haematoma and relieve the urinary obstruction. Diuresis resumed and renal function normalised without any further evidence of bleeding.\n\nDiscussion\nA large rectus sheath haematoma that extends into the bladder causing renal obstruction can be treated by endovascular embolisation and surgical exploration to limit operative risks and exposure in morbidly obese patients.\n\nHighlights\n• Rectus heath haematoma (RSH) is uncommon and usually arises from disruption of a branch of the inferior epigastric artery (IEA).\n\n• Obstructive uropathy leading to acute post-renal failure can be a rare presentation.\n\n• Embolisation of the IEA and staged surgical evacuation of the large compressive RSH may be feasible and effective.\n\n\n\nKeywords\nRectus sheath haematomaAcute renal failureObstructive uropathyAnticoagulant therapy\n==== Body\nIntroduction\nRectus sheath haematomas (RSHs) are uncommon and can arise from disruption of a branch of the inferior epigastric artery at its insertion into the rectus abdominis muscle combined with an inability to tamponade the bleeding, especially below the arcuate line. RSHs have been found to be associated with severe bouts of coughing, anticoagulation therapy, subcutaneous abdominal injection of insulin, pregnancy, and connective tissue disorders. Pain and anemia are the most common manifestations. Most RSHs are self limiting and the majority does not cause hypovolemic shock requiring emergency medical or surgical intervention.1 Herein is reported a rare rectus sheath haematoma complicated by compressive obstructive uropathy leading to acute post-renal failure that was successfully treated by a combined endovascular and surgical approach.\n\nReport\nA 42 year old African American female with past medical history significant for morbid obesity (body mass index 63.8 kg/m2), hypertension, systemic lupus erythematosus (SLE), pulmonary emboli on warfarin, and recent diagnosis of pneumonia, presented to an outside hospital with recurrent shortness of breath, severe cough, and new onset diarrhea. On presentation, the patient a had fever (39.4○C) and was tachycardic (106 beats per minute). She had mildly elevated serum creatinine (sCrea; 1.32 mg/dl) (baseline 0.8–0.9 mg/dl), normal haemoglobin (Hb; 10.2 mg/dl), and a normal international normalised ratio (INR; 1.0). Sputum culture revealed influenza A virus subtype H1N1, and stool culture was positive for Clostridium difficile attributable to her recent antibiotic use for the pneumonia. Her influenza infection was treated with oseltamivir and her C. difficile with vancomycin/cefepime. On her first hospital day, the patient began complaining of abdominal pain. CT abdomen/pelvis with contrast showed right rectus abdominis haematoma below the level of the umbilicus with active arterial bleeding in the extraperitoneal pelvis causing mass compression (Figure 1, Figure 2, Figure 3). On the following day, the Hb level was on a downward trend, from 10.2 to 7.7 mg/dl. Two units of fresh frozen plasma (FFP) were given, two units of packed red blood cells were ordered, and the patient was transferred to the tertiary care medical centre. She was admitted to the intensive care unit and found to be anuric, tachycardic, and hypotensive but responsive to intravenous fluid resuscitation (heart rate ranging between 90 and 100 per minutes and systolic blood pressure ranging between 90 and 120 mm Hg with the mean arterial pressure (MAP) > 65 mm Hg). Renal ultrasound showed right hydronephrosis (Fig. 3). Repeat laboratory tests upon transfer showed acute renal failure (sCrea 5.56 mg/dl) and the Hb level going down further from 7.7 to 7.2 mg/dl. The serum vancomycin level was 8.1 μg/ml (normal low 4 μg/ml; normal high 40 μg/ml). Anti-double stranded DNA antibody (anti-dsDNA) IgG and anti-nuclear antibodies (ANAs) for SLE in the serum were not detected. A Foley catheter was placed, and critically elevated bladder pressures (∼50 mmHg) were measured that raised a concern of abdominal compartment syndrome. An emergency surgical consultation was requested. Abdominal examination showed significant tenderness, notably in the suprapubic, right lower, and right upper quadrant over a palpable haematoma. The patient had no urine output for almost 20 hours, with worsening and severe suprapubic pressure and pain. The decision was made to take the patient to the interventional radiology (IR) suite for coil embolisation of the inferior epigastric artery first followed by transfer to the operating room (OR) for evacuation of the compressive right pelvic haematoma.Figure 1 Active arterial haemorrhage into the rectus sheath. Axial computed tomography of the pelvis with contrast shows active arterial haemorrhage into right rectus sheath (white arrowhead) and large haematoma with layering of blood in the pelvis (black arrow).\n\nFigure 1Figure 2 Large rectus sheath haematoma extending into pelvis and compressing the bladder. Sagittal computed tomography abdomen and pelvis shows the haematoma extending into the extraperitoneal pelvis causing displacement and obscuration of the bladder due to the size of the haematoma. Notice the active arterial haemorrhage (white arrowhead).\n\nFigure 2Figure 3 Hydronephrosis. Renal ultrasound shows right hydronephrosis.\n\nFigure 3\n\nIn IR, embolisation of the right inferior epigastric artery was performed. Real time ultrasound guidance was used to access the contralateral femoral artery with placement of a 5F vascular sheath; a reverse curve catheter SOS1 was used to select the right common iliac artery under fluoroscopy. Over a guidewire, this catheter was exchanged for a 5F angled glide catheter that was positioned at the right external iliac artery. An angiogram showed diffusely small arteries related to the hypovolemic state. Then via a coaxial renegade high flow microcatheter and guidewire, the right inferior epigastric artery (RIEA) was selected; the angiogram showed no active arterial bleeding but compressive effects of the haematoma. Embolisation of the RIEA was performed with 0.018 inch tornado microcoils (Fig. 4). Additionally, given the extent of haematoma and the plan for immediate surgical exploration, the right circumflex iliac artery was selected and prophylactic embolisation was performed. The patient was transferred to the OR.Figure 4 Embolisation of right inferior epigastric artery. Coaxial microcatheter into the right inferior epigastric artery shows proximal embolisation with several microcoils.\n\nFigure 4\n\nA lower midline skin incision was performed and a flap was dissected on the right side to separate the skin and subcutaneous layers from the fascial layer. The haematoma was confirmed to be a rectus sheath haematoma by palpation and indirect visualisation through the rectus sheath (Fig. 5). A longitudinal incision over the rectus sheath fascia to the right of the margin of the rectus muscle was performed. The large haematoma was found to extend for at least 25 cm from lateral to medial and from cephalad to caudal, approaching the Retzius space and sitting on top of the bladder and to its right side. The haematoma was then scooped out with a fingers and hand manoeuvre. haemostasis of the oozing surfaces of the surgical field was successfully achieved.Figure 5 Intra-operative evacuation of haematoma. Intra-operative picture showing rectus sheath haematoma visible through the rectus sheath.\n\nFigure 5\n\nThe urinary bladder wall could be visualised through the peritoneal reflection and seemed quite ecchymotic but overall viable. The anterior rectus sheath was re-approximated with interrupted PDS0 sutures. The skin layer was re-approximated. Intra-operatively, clots were noted inside the Foley catheter.\n\nOn the same post-operative day (Day 0), she underwent haemodialysis with ultrafiltration of 500 ml. Her urinary output started to improve immediately and reached 2.6 l/24 hours by the second post-operative day. The sCrea level normalised to 0.99 mg/dl, and post-operative renal ultrasound showed resolution of hydronephrosis (Fig. 6). The patient was restarted on warfarin without any further bleeding. The patient was discharged to a long-term acute care facility and had uneventful clinic follow-up 2 weeks later after having fully recovered.Figure 6 Resolution of hydronephrosis. Post-operative right renal ultrasound shows interval resolution of hydronephrosis.\n\nFigure 6\n\nDiscussion\nThis case supports prior evidence that rectus sheath haematomas developing below the arcuate line tend to bleed more and dissect more extensively because of the lack of tamponade exercised by the posterior sheath and the tendinous inscriptions that are indeed present above the arcuate line. Obstructive uropathy secondary to large RSHs is very rare and usually presents in the setting of hypovolemic shock.2, 3, 4\n\nThe management of RSHs including large ones has shifted over the past few years from an aggressive surgical approach5 to non-operative treatment that is based on withdrawal of anticoagulants and immediate reversal of anticoagulation, with prothrombin complex concentrates being preferred over FFP administration.6 However, this patient developed acute post-renal failure with critically elevated bladder pressures, severe suprapubic pain that was not responsive to analgesics, and right hydronephrosis ipsilateral to the side of the injury. With the degree of renal failure, if left untreated the condition would have led inexorably to irreversible renal damage and possible chronic renal failure. A temporising treatment option could have been nephrostomy tube placement, but this would not have addressed the underlying cause of the obstructive uropathy from the pelvic haematoma. The increased intra-abdominal pressure, hypovolemia, co-existing medical condition (SLE), and the use of nephrotoxic drugs (vancomycin) might have contributed to the onset of acute renal failure although the patient's MAP and serum levels of vancomycin were within normal limits and anti-dsDNA and ANA for SLE were not detected. Furthermore, the critically elevated bladder pressure recorded prior to surgical exploration, the concomitant hydronephrosis on the same side as the RSH, and the prompt restarting of the urinary output post-operatively seem to support the idea that the mass compression of the bladder by this very large haematoma was the cause of the acute renal syndrome. This interpretation of the aetiology is also substantiated by the repeat renal US after surgery which showed resolution of hydronephrosis (Fig. 6).\n\nIt is not known if the chronic treatment with warfarin might have played a role in the aetiology of the RSH since the patient's INR was found to be within normal limits (1.0). Rather, it is believed that the aetiology of the RSH was probably traumatic because of the severe coughing the patient experienced for several days as a result of her pneumonia.\n\nEndovascular embolisation of the inferior epigastric artery has been successfully and effectively performed7 and may prevent further bleeding at the time of the surgical exploration to remove, and at least partially tamponade, the large haematoma.\n\nThis combined approach is of further value when considering that the surgical exploration might fail to find the bleeding source, obligating the surgeon to ligate the inferior epigastric artery at its origin from the femoral artery in close proximity to the inguinal ligament area. A long skin incision extending through the entire lower abdomen and reaching into the groin is potentially associated with suboptimal cosmetic outcome, greater intra-operative blood loss, and peri-operative pain and an overall longer recovery time. One potential disadvantage of the combined endovascular and surgical approach is represented by the unavailability of an endovascular specialist at a local level or lack of available staff after office hours and the need for close coordination with the surgical team so that the patient can be transferred from the endovascular suite to the OR for the staged surgical treatment. At this institution, IR is available 24/7 and works closely with the surgical team; therefore, this consideration did not represent a concern in this case.\n\nConclusion\nA combined approach based on embolisation of the inferior epigastric artery and staged surgical evacuation of a large compressive rectus sheath haematoma leading to acute post-renal failure is feasible and should be considered as an alternative to aggressive surgical intervention requiring ligation of the inferior epigastric artery at its origin. Further studies are needed to provide definitive evidence in favour of this innovative and effective approach that was carried out on this isolated case.\n\nConflict of Interest\nNone.\n\nFunding\nNone.\n==== Refs\nReferences\n1 Hatjipetrou A. Anyfantakis D. Kastanakis M. Rectus sheath hematoma: a review of the literature Int J Surg 13 2015 267 25529279 \n2 Toyonaga J. Tsuruya K. Masutani K. Maeda H. Nakamura K. Taniguchi M. Hemorrhagic shock and obstructive uropathy due to a large rectus sheath hematoma in a patient on anticoagulant therapy Intern Med 48 24 2009 2119 2122 20009404 \n3 Dangle P.P. Patel M.B. Terán M. Chehval M.J. Obstructive uropathy secondary to rectus sheath hematoma W V Med J 109 2 2013 32 33 \n4 Masson J.C. Bollack C. Renaud R. Gandar R. Obstructive uropathy due to hematoma of the sheath of the rectus abdominis muscles J Urol Nephrol (Paris) 81 3 1975 246 249 125349 \n5 Jone T.W. Merendino K.A. The deep epigastric artery: rectus muscle syndrome Am J Surg 103 1962 159 169 14452343 \n6 Berna J.D. Zuazu I. Madrigal M. Garcia-Medina V. Fernandez C. Guirado F. Conservative treatment of large rectus sheath hematoma in patients undergoing anticoagulant therapy Abdom Imaging 25 2000 230 234 10823439 \n7 Magill S.T. del Prado G. Chiovaro J. Embolization of hemorrhaging rectus sheath hematoma J Gen Intern Med 29 2 2014 408 409 24002622\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2405-6553", "issue": "34()", "journal": "EJVES short reports", "keywords": "Acute renal failure; Anticoagulant therapy; Obstructive uropathy; Rectus sheath haematoma", "medline_ta": "EJVES Short Rep", "mesh_terms": null, "nlm_unique_id": "101695075", "other_id": null, "pages": "24-27", "pmc": null, "pmid": "28856329", "pubdate": "2017", "publication_types": "D002363:Case Reports", "references": "125349;24002622;20009404;23600103;14452343;10823439;25529279", "title": "Obstructive Uropathy because of a Large Rectus Sheath Haematoma: A Case Report of Combined Interventional Radiology and Surgical Approach.", "title_normalized": "obstructive uropathy because of a large rectus sheath haematoma a case report of combined interventional radiology and surgical approach" }

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OBSTRUCTIVE UROPATHY BECAUSE OF A LARGE RECTUS SHEATH HAEMATOMA: A CASE REPORT OF COMBINED INTERVENTIONAL RADIOLOGY AND SURGICAL APPROACH. 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OBSTRUCTIVE UROPATHY BECAUSE OF A LARGE RECTUS SHEATH HAEMATOMA: A CASE REPORT OF COMBINED INTERVENTIONAL RADIOLOGY AND SURGICAL APPROACH. EJVES-SHORT-REP 2017;34:24-27.", "literaturereference_normalized": "obstructive uropathy because of a large rectus sheath haematoma a case report of combined interventional radiology and surgical approach", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170424", "receivedate": "20170424", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13473831, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" } ]

{ "abstract": "To perform meta-analyses of studies evaluating the risk of pre-eclampsia in high-risk insulin-resistant women taking metformin prior to, or during pregnancy.\n\n\n\nA search was conducted of the Medline, EMBASE, Web of Science and Scopus databases. Both randomized controlled trials and prospective observational cohort studies of metformin treatment vs. placebo/control or insulin either prior to or during pregnancy were selected. The main outcome measure was the incidence of pre-eclampsia in each treatment group.\n\n\n\nOverall, in five randomized controlled trials comparing metformin treatment (n = 611) with placebo/control (n = 609), no difference in the risk of pre-eclampsia was found [combined/pooled risk ratio (RR), 0.86 (95% CI 0.33-2.26); P = 0.76; I2 = 66%]. Meta-analysis of four cohort studies again showed no significant effect [RR, 1.21 (95% CI 0.56-2.61); P = 0.62; I2 = 30%]. A meta-analysis of eight randomized controlled trials comparing metformin (n = 838) with insulin (n = 836), however, showed a reduced risk of pre-eclampsia with metformin [RR, 0.68 (95% CI 0.48-0.95); P = 0.02; I2 = 0%]. No heterogeneity was present in the metformin vs. insulin analysis of randomized controlled trials, whereas high levels of heterogeneity were present in studies comparing metformin with placebo/control. Pre-eclampsia was a secondary outcome in most of the studies. The mean weight gain from time of enrolment to delivery was lower in the metformin group (P = 0.05, metformin vs. placebo; P = 0.004, metformin vs. insulin).\n\n\n\nIn studies randomizing pregnant women to glucose-lowering therapy, metformin was associated with lower gestational weight gain and a lower risk of pre-eclampsia compared with insulin.", "affiliations": "Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.;Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.;Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.;Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.;Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.;Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.;Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.", "authors": "Alqudah|A|A|;McKinley|M C|MC|;McNally|R|R|;Graham|U|U|;Watson|C J|CJ|;Lyons|T J|TJ|;McClements|L|L|0000-0002-4911-1014", "chemical_list": "D007004:Hypoglycemic Agents; D007328:Insulin; D008687:Metformin", "country": "England", "delete": false, "doi": "10.1111/dme.13523", "fulltext": null, "fulltext_license": null, "issn_linking": "0742-3071", "issue": "35(2)", "journal": "Diabetic medicine : a journal of the British Diabetic Association", "keywords": null, "medline_ta": "Diabet Med", "mesh_terms": "D000328:Adult; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2; D016640:Diabetes, Gestational; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents; D007328:Insulin; D007333:Insulin Resistance; D008687:Metformin; D008875:Middle Aged; D064887:Observational Studies as Topic; D011225:Pre-Eclampsia; D011247:Pregnancy; D011254:Pregnancy in Diabetics; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors; D016896:Treatment Outcome; D015430:Weight Gain; D055815:Young Adult", "nlm_unique_id": "8500858", "other_id": null, "pages": "160-172", "pmc": null, "pmid": "29044702", "pubdate": "2018-02", "publication_types": "D016428:Journal Article; D017418:Meta-Analysis; D013485:Research Support, Non-U.S. Gov't; D000078182:Systematic Review", "references": null, "title": "Risk of pre-eclampsia in women taking metformin: a systematic review and meta-analysis.", "title_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis" }

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DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "PK", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735494, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2018-00931", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2-2.55 G/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "POLYCYSTIC OVARIES", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETICMEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "US", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735544, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "PK-ALKEM LABORATORIES LIMITED-PK-ALKEM-2018-00894", "fulfillexpeditecriteria": "2", "occurcountry": "PK", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, AND INCREASED UP TO 2500 MG IN 3 DIVIDED DOSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "INSULIN NOS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INSULIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "PK", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735487, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "IT-ALKEM LABORATORIES LIMITED-IT-ALKEM-2018-00944", "fulfillexpeditecriteria": "2", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1700-3000 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERINSULINAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "IT", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735337, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "PK-ALKEM LABORATORIES LIMITED-PK-ALKEM-2018-00895", "fulfillexpeditecriteria": "1", "occurcountry": "PK", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, AND INCREASED UP TO 2500 MG IN 3 DIVIDED DOSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypoglycaemia neonatal", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "PK", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735488, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2018-00933", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2-2.55 G/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "POLYCYSTIC OVARIES", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETICMEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "US", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735548, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "GH-ALKEM LABORATORIES LIMITED-GH-ALKEM-2018-00979", "fulfillexpeditecriteria": "2", "occurcountry": "GH", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, INCREASED GRADUALLY OVER TWO (2) WEEKS, TO MEET GLYCEMIC TARGETS", "drugenddate": null, "drugenddateformat": null, "drugindication": "GESTATIONAL DIABETES", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GH", "receiptdate": "20181217", "receivedate": "20181217", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15729698, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "PK-ALKEM LABORATORIES LIMITED-PK-ALKEM-2018-00908", "fulfillexpeditecriteria": "2", "occurcountry": "PK", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, AND INCREASED UP TO 2500 MG IN 3 DIVIDED DOSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "PK", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735498, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "PK-ALKEM LABORATORIES LIMITED-PK-ALKEM-2018-00883", "fulfillexpeditecriteria": "2", "occurcountry": "PK", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, AND INCREASED UP TO 2500 MG IN 3 DIVIDED DOSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Gastrointestinal disorder", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "PK", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735478, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "IT-ALKEM LABORATORIES LIMITED-IT-ALKEM-2018-00943", "fulfillexpeditecriteria": "2", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1700-3000 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERINSULINAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "IT", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735326, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "PK-ALKEM LABORATORIES LIMITED-PK-ALKEM-2018-00906", "fulfillexpeditecriteria": "1", "occurcountry": "PK", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "INSULIN NOS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INSULIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, AND INCREASED UP TO 2500 MG IN 3 DIVIDED DOSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypoglycaemia neonatal", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "PK", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735486, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "PK-ALKEM LABORATORIES LIMITED-PK-ALKEM-2018-00905", "fulfillexpeditecriteria": "1", "occurcountry": "PK", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, AND INCREASED UP TO 2500 MG IN 3 DIVIDED DOSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "INSULIN NOS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INSULIN" } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypoglycaemia neonatal", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "PK", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735496, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "IT-ALKEM LABORATORIES LIMITED-IT-ALKEM-2018-00937", "fulfillexpeditecriteria": "2", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1700-3000 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERINSULINAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "IT", "receiptdate": "20181217", "receivedate": "20181217", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15729729, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "PK-ALKEM LABORATORIES LIMITED-PK-ALKEM-2018-00885", "fulfillexpeditecriteria": "2", "occurcountry": "PK", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, AND INCREASED UP TO 2500 MG IN 3 DIVIDED DOSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrointestinal disorder", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "PK", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735479, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2018-00935", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2-2.55 G/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "POLYCYSTIC OVARIES", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETICMEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "US", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735549, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "GH-ALKEM LABORATORIES LIMITED-GH-ALKEM-2018-00980", "fulfillexpeditecriteria": "2", "occurcountry": "GH", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, INCREASED GRADUALLY OVER TWO (2) WEEKS, TO MEET GLYCEMIC TARGETS", "drugenddate": null, "drugenddateformat": null, "drugindication": "GESTATIONAL DIABETES", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GH", "receiptdate": "20181217", "receivedate": "20181217", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15729699, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "PK-ALKEM LABORATORIES LIMITED-PK-ALKEM-2018-00897", "fulfillexpeditecriteria": "1", "occurcountry": "PK", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, AND INCREASED UP TO 2500 MG IN 3 DIVIDED DOSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypoglycaemia neonatal", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "PK", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735489, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "PK-ALKEM LABORATORIES LIMITED-PK-ALKEM-2018-00889", "fulfillexpeditecriteria": "2", "occurcountry": "PK", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, AND INCREASED UP TO 2500 MG IN 3 DIVIDED DOSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "INSULIN NOS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INSULIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "PK", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735482, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "PK-ALKEM LABORATORIES LIMITED-PK-ALKEM-2018-00904", "fulfillexpeditecriteria": "1", "occurcountry": "PK", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, AND INCREASED UP TO 2500 MG IN 3 DIVIDED DOSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "INSULIN NOS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INSULIN" } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypoglycaemia neonatal", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "PK", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735492, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "IT-ALKEM LABORATORIES LIMITED-IT-ALKEM-2018-00940", "fulfillexpeditecriteria": "2", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1700-3000 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERINSULINAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "IT", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735332, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "GH-ALKEM LABORATORIES LIMITED-GH-ALKEM-2018-00983", "fulfillexpeditecriteria": "2", "occurcountry": "GH", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "INSULIN NOS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GESTATIONAL DIABETES", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INSULIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "INSULIN NOS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INSULIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, INCREASED GRADUALLY OVER TWO (2) WEEKS, TO MEET GLYCEMIC TARGETS", "drugenddate": null, "drugenddateformat": null, "drugindication": "GESTATIONAL DIABETES", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GH", "receiptdate": "20181217", "receivedate": "20181217", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15729702, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "PK-ALKEM LABORATORIES LIMITED-PK-ALKEM-2018-00886", "fulfillexpeditecriteria": "2", "occurcountry": "PK", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, AND INCREASED UP TO 2500 MG IN 3 DIVIDED DOSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Gastrointestinal disorder", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "PK", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735480, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "GH-ALKEM LABORATORIES LIMITED-GH-ALKEM-2018-00981", "fulfillexpeditecriteria": "2", "occurcountry": "GH", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, INCREASED GRADUALLY OVER TWO (2) WEEKS, TO MEET GLYCEMIC TARGETS", "drugenddate": null, "drugenddateformat": null, "drugindication": "GESTATIONAL DIABETES", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GH", "receiptdate": "20181217", "receivedate": "20181217", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15729700, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "PK-ALKEM LABORATORIES LIMITED-PK-ALKEM-2018-00910", "fulfillexpeditecriteria": "2", "occurcountry": "PK", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, AND INCREASED UP TO 2500 MG IN 3 DIVIDED DOSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "PK", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735500, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "PK-ALKEM LABORATORIES LIMITED-PK-ALKEM-2018-00903", "fulfillexpeditecriteria": "1", "occurcountry": "PK", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "INSULIN NOS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INSULIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, AND INCREASED UP TO 2500 MG IN 3 DIVIDED DOSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypoglycaemia neonatal", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "PK", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735495, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "IT-ALKEM LABORATORIES LIMITED-IT-ALKEM-2018-00936", "fulfillexpeditecriteria": "2", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1700-3000 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERINSULINAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "IT", "receiptdate": "20181219", "receivedate": "20181219", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15738165, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "IT-ALKEM LABORATORIES LIMITED-IT-ALKEM-2018-00942", "fulfillexpeditecriteria": "2", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1700-3000 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERINSULINAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "IT", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735335, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2018-00932", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2-2.55 G/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "POLYCYSTIC OVARIES", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETICMEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "US", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735545, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "PK-ALKEM LABORATORIES LIMITED-PK-ALKEM-2018-00887", "fulfillexpeditecriteria": "2", "occurcountry": "PK", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, AND INCREASED UP TO 2500 MG IN 3 DIVIDED DOSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "GESTATIONAL DIABETES", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrointestinal disorder", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "PK", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735481, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "PK-ALKEM LABORATORIES LIMITED-PK-ALKEM-2018-00900", "fulfillexpeditecriteria": "1", "occurcountry": "PK", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, AND INCREASED UP TO 2500 MG IN 3 DIVIDED DOSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypoglycaemia neonatal", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "PK", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735491, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "GH-ALKEM LABORATORIES LIMITED-GH-ALKEM-2018-00982", "fulfillexpeditecriteria": "2", "occurcountry": "GH", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, INCREASED GRADUALLY OVER TWO (2) WEEKS, TO MEET GLYCEMIC TARGETS", "drugenddate": null, "drugenddateformat": null, "drugindication": "GESTATIONAL DIABETES", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GH", "receiptdate": "20181217", "receivedate": "20181217", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15729701, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "PK-ALKEM LABORATORIES LIMITED-PK-ALKEM-2018-00891", "fulfillexpeditecriteria": "2", "occurcountry": "PK", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, AND INCREASED UP TO 2500 MG IN 3 DIVIDED DOSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "INSULIN NOS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INSULIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "PK", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735483, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "PK-ALKEM LABORATORIES LIMITED-PK-ALKEM-2018-00909", "fulfillexpeditecriteria": "2", "occurcountry": "PK", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, AND INCREASED UP TO 2500 MG IN 3 DIVIDED DOSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETIC MEDICINE. 2018?35(2):160-172", "literaturereference_normalized": "risk of pre eclampsia in women taking metformin a systematic review and meta analysis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "PK", "receiptdate": "20181218", "receivedate": "20181218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15735503, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "IT-ALKEM LABORATORIES LIMITED-IT-ALKEM-2018-00938", "fulfillexpeditecriteria": "2", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1700-3000 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERINSULINAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALQUDAH A, MCKINLEY MC, MCNALLY R, GRAHAM U, ET AL.. RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. 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RISK OF PRE-ECLAMPSIA IN WOMEN TAKING METFORMIN: A SYSTEMATIC REVIEW AND META-ANALYSIS. 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{ "abstract": "BACKGROUND Metformin has a longstanding reputation as the first-line treatment for glycemic control in the setting of diabetes mellitus type 2. A contributing factor to this reputation is metformin having a low risk of inducing hypoglycemia compared to other oral hypoglycemics or insulin. There are no case reports of hypoglycemia while on conventional or therapeutic doses of metformin. This case report is of a patient who developed symptomatic hypoglycemia while being treated with a therapeutic dose of metformin. CASE REPORT A 58-year-old man with history including diabetes mellitus type 2, hypertension, and schizoaffective disorder was dismissed early from work due to symptoms of severe weakness, confusion, diaphoresis, dizziness, shortness of breath, palpitations, and a sensation of feeling hot. Continuous glucose monitoring revealed hypoglycemic episodes up to 4% of the time. The hypoglycemic events appeared to occur primarily between midnight and 7 A.M., with the second likely time frame being between 7A.M. and noon. Within 2 weeks of discontinuing metformin, there were no further \"attacks\", and the chronic daytime fatigue and somnolence significantly improved. CONCLUSIONS This case report suggests that there is a risk of symptomatic hypoglycemia with therapeutic doses of metformin. Although advised to be taken with meals to avoid gastrointestinal upset, patients should also be educated to take metformin with meals to reduce the risk of metformin-associated hypoglycemia.", "affiliations": "Department of Internal Medicine and Psychiatry, Altru Health System, Grand Forks, ND, USA.", "authors": "Joseph|Chenelle M C|CMC|", "chemical_list": "D001786:Blood Glucose; D007004:Hypoglycemic Agents; D008687:Metformin", "country": "United States", "delete": false, "doi": "10.12659/AJCR.931311", "fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923\nInternational Scientific Literature, Inc.\n\n34075013\n10.12659/AJCR.931311\n931311\nArticles\nSymptomatic Hypoglycemia During Treatment with a Therapeutic Dose of Metformin\nJoseph Chenelle M.C. EF\nDepartment of Internal Medicine and Psychiatry, Altru Health System, Grand Forks, ND, U.S.A.\nCorresponding Author: Chenelle M.C. Joseph, e-mail: [email protected]\nAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\n2021\n02 6 2021\n22 e931311-1e931311-4\n26 1 2021\n18 4 2021\n28 4 2021\n© Am J Case Rep, 2021\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)\nPatient: Male, 58-year-old\n\nFinal Diagnosis: Diabetes mellitus type 2\n\nSymptoms: Confusion • diaphoresis • dizziness • dyspnea • palpitation • weakness\n\nMedication: Metformin\n\nClinical Procedure: —\n\nSpecialty: Endocrinology and Metabolic • General and Internal Medicine • Psychiatry\n\nObjective:\n\nUnusual clinical course\n\nBackground:\n\nMetformin has a longstanding reputation as the first-line treatment for glycemic control in the setting of diabetes mellitus type 2. A contributing factor to this reputation is metformin having a low risk of inducing hypoglycemia compared to other oral hypoglycemics or insulin. There are no case reports of hypoglycemia while on conventional or therapeutic doses of metformin. This case report is of a patient who developed symptomatic hypoglycemia while being treated with a therapeutic dose of metformin.\n\nCase Report:\n\nA 58-year-old man with history including diabetes mellitus type 2, hypertension, and schizoaffective disorder was dismissed early from work due to symptoms of severe weakness, confusion, diaphoresis, dizziness, shortness of breath, palpitations, and a sensation of feeling hot. Continuous glucose monitoring revealed hypoglycemic episodes up to 4% of the time. The hypoglycemic events appeared to occur primarily between midnight and 7 A.M., with the second likely time frame being between 7A.M. and noon. Within 2 weeks of discontinuing metformin, there were no further “attacks”, and the chronic daytime fatigue and somnolence significantly improved.\n\nConclusions:\n\nThis case report suggests that there is a risk of symptomatic hypoglycemia with therapeutic doses of metformin. Although advised to be taken with meals to avoid gastrointestinal upset, patients should also be educated to take metformin with meals to reduce the risk of metformin-associated hypoglycemia.\n\nKeywords:\n\nDiabetes Mellitus\nHypoglycemia\nMetformin\n==== Body\nBackground\n\nMetformin has a longstanding reputation as the first-line treatment for glycemic control in the setting of diabetes mellitus type 2. A contributing factor to this reputation is metformin having a low risk of inducing hypoglycemia compared to other oral hypoglycemics or insulin. Metformin is a biguanide, which reduces blood glucose levels by decreasing glucose production by the liver, decreasing intestinal absorption of glucose, and improving insulin sensitivity [1–6]. The more common adverse effects of metformin include nausea, vomiting, flatulence, abdominal pain, and diarrhea, which is why it is advised to take metformin with food [6,7]. Metformin-associated lactic acidosis (MALA) is a rare adverse effect reported in postmarking cases, the majority of which were linked to metformin toxicity and/or predisposing conditions such as hypovolemia, infection or sepsis, acute or chronic kidney disease, or liver cirrhosis [1,4]. There are reports of metformin overdose or toxicity triggering hypoglycemia, but in only 2% of the cases [5]. There are no case reports of hypoglycemia while on conventional or therapeutic doses of metformin. This case report is of a patient who developed symptomatic hypoglycemia while being treated with a therapeutic dose of metformin. Given that the risk of hypoglycemia is rare but not zero, patients should be advised to take metformin with food, not only to minimize potential gastrointestinal adverse effects, but to also minimize the risk of hypoglycemia.\n\nCase Report\n\nA 58-year-old man presented to the clinic 1 day after experiencing what had historically been labelled a “schizophrenic attack”. The symptoms included severe weakness, confusion, diaphoresis, dizziness, shortness of breath, palpitations, and a sensation of feeling hot. This specific “attack” occurred in the morning while he was at work, and lasted approximately 3 hours. During that time, the patient was allowed to rest and was provided snacks. His medical history included diabetes mellitus type 2, hypertension, hyperlipidemia, gastroesophageal reflux disease, and schizoaffective disorder. His medications included aspirin 81 mg daily, lisinopril 10 mg daily, pantoprazole 40 mg daily, immediate-release metformin 500 mg twice daily, simvastatin 20 mg nightly, lurasidone 120 mg daily, sertraline 50 mg daily, and clozapine 250 mg daily.\n\nOn examination during the clinic visit, there were no physical abnormalities. The vital signs were within normal limits, with blood pressure of 118/70 mmHg, heart rate of 87 beats per minute, and oxygen saturation of 96%. He was mildly obese with a body mass index of 30.83. There were no subjective or objective findings indicative of active depression or mania. The patient was not internally stimulated, denied any visual hallucinations, and reported no change in his chronic auditory hallucinations that tell him that he is God. According to the patient’s wife, he had not voiced any recent paranoid or delusional statements, and continued to talk to himself as usual, with no change in behavior.\n\nThe complete blood count revealed normal cell counts, including white blood cell count of 6.30 K/uL with an absolute neutro-phil count of 3490 K/ul and red blood cell count of 5.02 M/uL. The clozapine level was within therapeutic range at 265 ng/mL with a normal combination clozapine + norclozapine level of 432 ng/mL. The comprehensive metabolic panel showed normal electrolytes, and normal liver and kidney function tests, without acidosis. The non-fasting blood glucose was 107 mg/dl. Inflammatory markers (CRP, sedimentation rate), thyroid-stimulating hormone (TSH), brain natriuretic peptide (BNP), and creatine phosphokinase (CPK) were all within normal limits. The serum C-peptide was elevated at 10.3 ng/mL, but the serum insulin and beta-hydroxybutyrate levels were normal at 11.4 mcIU/mL and 0.1 mmol/L, respectively. A CT scan of the abdomen and pelvis with contrast was normal, including no adrenal, pancreatic, or hepatic abnormalities. A transthoracic echocardiogram showed normal left ventricular ejection fraction of 55–60%, mild grade I diastolic dysfunction, and no wall motion or valvular abnormalities.\n\nGiven that the “attack” mimicked symptomatic hypoglycemia, continuous glucose monitor was performed as an out-patient. The monitor was worn for 15 days (from March 25 2020 through April 8 2020), with 100% active continuous glucose monitoring during that time. Most (96%) of the readings were within the target range (70–180 mg/dl), with 4% of the readings being in the hypoglycemic range (54–69 mg/dl). (Figure 1). The average reading was 92 mg/dl. The hypoglycemic events appeared to occur primarily between midnight and 7 A.M., with the second likely time frame being between 7A.M. and noon (Figure 2).\n\nGiven the documented hypoglycemia, metformin was subsequently discontinued. Approximately 1 month after the last “attack”, and approximately 2 weeks after discontinuing metformin, the patient and his wife reported noticing significant improvements. Both parties denied any further “attacks” of any severity. The patient’s wife stated that the patient was no longer “sleeping all the time”, a complaint for which previous sleep studies ruled out obstructive or central sleep apnea. The patient stated that he no longer had to consume “1 to 2 pots of coffee” to combat daytime fatigue. Unfortunately, his insurance would not cover repeat continuous glucose monitoring to reassess for ongoing hypoglycemia. However, repeat fasting blood tests were within normal limits, including glucose of 117 mg/dl, C-peptide 5.0 ng/mL, and creatinine of 0.8 mg/ dl with a GFR of greater than 60 mL/min/1.73 sq m.\n\nDiscussion\n\nMedical and psychiatric evaluations did not support active schizoaffective disorder, orthostatic hypotension, hypoxia, myocarditis, cardiac valvular disorder, an infectious process, or thyroid dysfunction as contributing factors to this patient’s “attack”. Gastrointestinal pathology including insulinoma was also ruled out. Collateral information, including the metformin refill history through the pharmacy, as well as collateral information from his wife (who managed his medications) and from his social worker, verified that metformin use did not exceed the daily dose prescribed. There were no other residents in the home, and his wife was not on any diabetes medications. The initially elevated serum C-peptide level (with normal serum insulin level) were likely due to insulin insensitivity in the setting of type 2 diabetes mellitus and obesity. Due to the time of day of the majority of the hypoglycemic episodes (fasting state overnight), and an inability to perform a blood draw at or adjacent to his workplace, there was no way to capture his insulin level or his glucose level during a hypoglycemic episode.\n\nThe patient’s social worker estimated that he experienced 1 of these “attacks” at least once a month for several years and were attributed to his diagnosis of schizoaffective disorder, bipolar type. However, his wife estimated that he experienced an “attack” at least once or twice a week, at various levels of severity. His wife reported routinely bringing snacks to his work place in an effort to prevent these “attacks”. To her, the “attacks” were attributed to not eating before work, in combination with overexertion at work.\n\nThere are case reports estimating no more than 2% rate of hypoglycemia secondary to metformin overdose or toxicity [4,5], but hypoglycemia at a therapeutic metformin dose is thought to be rare. Several hypotheses have been proposed for metformin-induced hypoglycemia, but are currently controversial. Metformin-induced hypoglycemia hypotheses include a direct link to its mechanism of action – decreased hepatic glucose production and decreased glucose absorption [2]. However, it is thought that additional confounding circumstance(s) are required for hypoglycemia to occur. ACE-inhibitors are hypothesized to cause hypoglycemia by increasing insulin sensitivity, leading to vasodilation in the muscles with increased muscle uptake of glucose. The combination of ACE-inhibitor with 1 or more oral hypoglycemic agents, including metformin, is thought to increase the risk of hypoglycemia [8–10]. However, the risk does not appear to be significant, as ACE-inhibitors in combination with metformin is commonly prescribed in type 2 diabetes mellitus due the ACE-inhibitors’ protective benefits towards diabetic nephropathy. Also, a recent study of the ACE-inhibitors and ARBs with metformin and other oral hypoglycemics revealed no drug-drug interaction causing hypoglycemia (instead, it showed significant increase in total cholesterol and LDL) [11]. A pharmacy review update of medications commonly prescribed in the management of type 2 diabetes mellitus also did not report any hypoglycemic risk with ACE-inhibitors, nor of a significant drug-drug interaction between metformin and ACE-inhibitors [7,12].\n\nOther hypotheses include concurrent presence of a fasting state, alcohol use, and/or strenuous activity [1,2]. Given that this patient has never consumed alcohol, in this case, the hypoglycemia appears to be multifactorial, including treatment with metformin combined with inadequate oral intake and overexertion at work. There were no drug-drug interactions identified between metformin and the following medications: aspirin, pantoprazole, simvastatin [6,13–15]. His psychotropic regimen, both individual medications and as a whole, (clozapine, lurasidone, sertraline), carries a risk of hyperglycemia (but not hypoglycemia) [6,16–18]. They each also carry the potential to minimize the glucose-reducing effects of metformin, while having no direct interaction with metformin. The initial diagnosis of diabetes mellitus type 2 and the initial treatment of immediate-release metformin was in March 2007 based on a fasting glucose 131 mg/dl. Our patient’s A1c had historically been between 5.4% and 6.0% while on metformin, and has ranged from 5.7% to 5.9% after the discontinuation of metformin.\n\nThe patient denied any other diabetic treatments or any previous adjustments in metformin since its initiation. Controlled studies would best determine risk factors for hypoglycemia regarding metformin. However, the rarity of such cases limits the ability to pursue such studies. Genetic studies on individuals who have experienced therapeutically-dosed metformin-induced hypoglycemia could be an alternate area of study.\n\nConclusions\n\nThis case report supports that there is a risk of symptomatic hypoglycemia with therapeutic doses of metformin. Although advised to be taken with meals to avoid gastrointestinal upset, patients should be educated to take metformin with meals to reduce the risk of metformin-associated hypoglycemia, especially in individuals who frequently engage in strenuous activities.\n\nFigure 1. Composition of glucose readings during continuous glucose monitoring.\n\nFigure 2. Frequency and timing of hypoglycemic events throughout a 24-hour period.\n\nDepartment and Institution Where Work Was Done\n\nDepartment of Internal Medicine and Psychiatry, Altru Health System, Grand Forks, ND, U.S.A.\n\nConflict of Interest\n\nNone.\n==== Refs\nReferences:\n\n1. Bodmer M Meier C Krahenbuhl S Metformin, sulfonylureas, or other antidiabetes drugs and the risk of lactic acidosis or hypoglycemia: A nested case-control analysis Diabetes Care 2008 31 2086 91 18782901\n2. Gasim GI Hypoglycemia induced by therapeutic doses of metformin in the absence of other anti-diabetic drugs FS J Pharm 2013 4 1 2\n3. Nasri H Rafieian-Kopaei M Metformin: Current knowledge J Res Med Sci 2014 19 7 658 64 25364368\n4. Jacob T Garrick R Goldberg M Recurrent lactic acidosis and hypoglycemia with inadvertent metformin use: a case of look-alike pills Endocrinol Diabetes Metab Case Rep 2018 2018 17 0148\n5. Aldobeaban S Mzahim B Ali Alshehri A Recurrent hypoglycemia secondary to metformin toxicity in the absence of co-ingestions: A case report J Med Case Rep 2018 12 223 30119705\n6. Metformin: Drug Information UpToDate Lexicomp Wolters Kluwer Health, Inc Riverwoods, IL http://online.lexi.com. [Accessed March 5 2021]\n7. Triplitt C Drug interactions of medications commonly used in diabetes Diabetes Spectrum 2006 19 4 202 11\n8. Elshimy G Techathaveewat P Alysayed M Simple reason for hypoglycemia: ACE inhibitor-induced severe recurrent hypoglycemia in a non-diabetic patient Cureus 2019 11 8 e5449 31489273\n9. May M Schindler C Clinically and pharmacologically relevant interactions of antidiabetic drugs Ther Adv Endocrinol Metab 2016 7 2 69 83 27092232\n10. Vue MH Setter SM Drug-induced glucose alterations part 1: Drug induced hypoglycemia Diabetes Spectrum 2011 24 3 171 77\n11. Daoud N Qadi O Al-talhi D Al-sharabi H Effect of anti-hypertensive agents on Biochemical Parameters in Diabetic Patients in Taif – KSA International Journal of Diabetes and Clinical Research 2019 6 113\n12. Lisinopril: Drug Information UpToDate Wolters Kluwer Health, Inc Riverwoods, IL http://online.lexi.com [Accessed March 5 2021]\n13. Simvastatin: Drug Information UpToDate Wolters Kluwer Health, Inc Riverwoods, IL http://online.lexi.com [Accessed March 5 2021]\n14. Pantoprazole: Drug Information UpToDate Wolters Kluwer Health, Inc Riverwoods, IL http://online.lexi.com [Accessed March 5 2021]\n15. Aspirin: Drug Information UpToDate Wolters Kluwer Health, Inc Riverwoods, IL http://online.lexi.com [Accessed March 5 2021]\n16. Clozapine: Drug Information UpToDate Wolters Kluwer Health, Inc Riverwoods, IL http://online.lexi.com. [Accessed March 5 2021]\n17. Lurasidone: Drug Information UpToDate Wolters Kluwer Health, Inc Riverwoods, IL http://online.lexi.com. [Accessed March 5 2021]\n18. Sertraline: Drug Information UpToDate Wolters Kluwer Health, Inc Riverwoods, IL http://online.lexi.com [Accessed March 5 2021]\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "1941-5923", "issue": "22()", "journal": "The American journal of case reports", "keywords": null, "medline_ta": "Am J Case Rep", "mesh_terms": "D001786:Blood Glucose; D015190:Blood Glucose Self-Monitoring; D003924:Diabetes Mellitus, Type 2; D004359:Drug Therapy, Combination; D006801:Humans; D007003:Hypoglycemia; D007004:Hypoglycemic Agents; D008297:Male; D008687:Metformin; D008875:Middle Aged", "nlm_unique_id": "101489566", "other_id": null, "pages": "e931311", "pmc": null, "pmid": "34075013", "pubdate": "2021-06-02", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "31489273;30119705;25364368;18782901;27092232;29340159", "title": "Symptomatic Hypoglycemia During Treatment with a Therapeutic Dose of Metformin.", "title_normalized": "symptomatic hypoglycemia during treatment with a therapeutic dose of metformin" }

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"literaturereference": "JOSEPH CMC. SYMPTOMATIC HYPOGLYCEMIA DURING TREATMENT WITH A THERAPEUTIC DOSE OF METFORMIN. AMERICAN JOURNAL OF CASE REPORTS. 2021?22:E931311:1?4", "literaturereference_normalized": "symptomatic hypoglycemia during treatment with a therapeutic dose of metformin", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210628", "receivedate": "20210628", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19466670, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" } ]

{ "abstract": "BACKGROUND\nA previously repaired right popliteal artery aneurysm via a medial approach with proximal and distal ligation and interval bypass re-presented 7 years after the initial repair with a ruptured 9 × 25.5 cm right popliteal aneurysm.\n\n\nMETHODS\nSurgical repair was complex due to the large size of the aneurysm. Technique and management of popliteal aneurysm repair are discussed, along with a review of the current literature.\n\n\nRESULTS\nA 58-year-old male with a 3.5 cm popliteal artery aneurysm was initially treated with end-to-end prosthetic bypass and proximal/distal aneurysm ligation from a medial-approach without complication. Seven years later, he presented with a 9-cm popliteal aneurysm rupture. Posterior approach endoaneurysmorrhaphy repair was far more complicated than expected with massive blood loss. Despite this, he was discharged without complication POD #5, but on POD #19 presented with cellulitis and underwent incision and drainage of retained hematoma with cultures positive for Strep dysgalactiae. With appropriate treatment, he was healed in 3 months.\n\n\nCONCLUSIONS\nSurgical repair of large popliteal aneurysms can be challenging, but continued aneurysmal degeneration is a potential consequence if the sac continues to be pressurized from patent geniculate arteries. Surgical repair of large popliteal artery aneurysms is complex and requires adjunctive techniques to maximize success. A posterior approach is described and the literature reviewed to support recommendations for primary popliteal artery aneurysm repair and repair of large degenerated popliteal artery aneurysms. We recommend primary popliteal artery aneurysm repair from a posterior approach with endoaneurysmorrhaphy and an interposition bypass. For ruptured large popliteal artery aneurysms, there is a high risk of hemorrhage and wound complications. Therefore, we recommend the use of a tourniquet, surgical drain and to consider the collection of intraoperative cultures to guide potential antibiotic management.", "affiliations": "Spectrum Health Grand Rapids, Michigan State University, College of Human Medicine, Grand Rapids, MI. Electronic address: [email protected].;Spectrum Health Grand Rapids, Michigan State University, College of Human Medicine, Grand Rapids, MI.;Spectrum Health Grand Rapids, Michigan State University, College of Human Medicine, Grand Rapids, MI.", "authors": "Lu|Joyce J|JJ|;Cuff|Robert F|RF|;Chambers|Christopher M|CM|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.avsg.2020.10.018", "fulltext": null, "fulltext_license": null, "issn_linking": "0890-5096", "issue": "72()", "journal": "Annals of vascular surgery", "keywords": null, "medline_ta": "Ann Vasc Surg", "mesh_terms": "D000783:Aneurysm; D017542:Aneurysm, Ruptured; D019917:Blood Vessel Prosthesis Implantation; D018450:Disease Progression; D006801:Humans; D008026:Ligation; D008297:Male; D008875:Middle Aged; D011150:Popliteal Artery; D012086:Reoperation; D013997:Time Factors; D016896:Treatment Outcome", "nlm_unique_id": "8703941", "other_id": null, "pages": "665.e9-665.e13", "pmc": null, "pmid": "33227480", "pubdate": "2021-04", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Open Endoaneurysmorrhaphy of 9-cm Ruptured Popliteal Aneurysm 7 Years after Initial Repair.", "title_normalized": "open endoaneurysmorrhaphy of 9 cm ruptured popliteal aneurysm 7 years after initial repair" }

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{ "abstract": "Rivaroxaban is an oral anticoagulant that acts as a direct, competitive factor Xa inhibitor. Large randomized clinical trials have shown that, at a daily dose of 20 mg, Rivaroxaban is at least as effective as dose-adjusted warfarin for the prevention of stroke or other embolic complications in patients with nonvalvular atrial fibrillation (AF). The safety and efficacy of combining Rivaroxaban with an antiplatelet agent for secondary stroke prevention has not been established. We report the case of an elderly patient with permanent AF and coronary heart disease, who had already suffered an ischemic stroke while on warfarin treatment, and was consequently switched to treatment with an association of Rivaroxaban and Aspirin. Her CHA2DS2-VASc score was 9. The patient developed a severe recurrent disabling ischemic stroke. This case goes to show that the novel direct anticoagulants may fail to prevent recurrent stroke in patients at particularly high risk, even when associated with antiplatelet drugs.", "affiliations": "Internal Medicine Clinic, Coagulopathy Section, Department of Cardiovascular and Thoracic Sciences, Padua University, Padua, Italy - [email protected].", "authors": "Bilora|Franca|F|;Adamo|Angelo|A|;Pomerri|Fabio|F|;Prandoni|Paolo|P|", "chemical_list": "D000925:Anticoagulants; D000069552:Rivaroxaban; D001241:Aspirin", "country": "Italy", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0026-4725", "issue": "64(4)", "journal": "Minerva cardioangiologica", "keywords": null, "medline_ta": "Minerva Cardioangiol", "mesh_terms": "D000368:Aged; D000925:Anticoagulants; D001241:Aspirin; D001281:Atrial Fibrillation; D002545:Brain Ischemia; D005260:Female; D006801:Humans; D000069552:Rivaroxaban; D020521:Stroke; D014057:Tomography, X-Ray Computed; D017211:Treatment Failure", "nlm_unique_id": "0400725", "other_id": null, "pages": "494-6", "pmc": null, "pmid": "27228488", "pubdate": "2016-08", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Failure of old and new anticoagulants to prevent ischemic stroke in high-risk atrial fibrillation: a case report.", "title_normalized": "failure of old and new anticoagulants to prevent ischemic stroke in high risk atrial fibrillation a case report" }

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FAILURE OF OLD AND NEW ANTICOAGULANTS TO PREVENT ISCHEMIC STROKE IN HIGH-RISK ATRIAL FIBRILLATION: A CASE REPORT. 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FAILURE OF OLD AND NEW ANTICOAGULANTS TO PREVENT ISCHEMIC STROKE IN HIGH-RISK ATRIAL FIBRILLATION: A CASE REPORT. MINERVA CARDIOANGIOL. 2016;64 (4):494-496", "literaturereference_normalized": "failure of old and new anticoagulants to prevent ischemic stroke in high risk atrial fibrillation a case report", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20160613", "receivedate": "20160613", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12461386, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": 1, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" }, { "companynumb": "IT-CIPLA LTD.-2016IT17026", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "WARFARIN SODIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "90935", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ISCHAEMIC HEART DISEASE PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN SODIUM." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BILORA F, ADAMO A, POMERRI F, PRANDONI P. FAILURE OF OLD AND NEW ANTICOAGULANTS TO PREVENT ISCHEMIC STROKE IN HIGH-RISK ATRIAL FIBRILLATION: A CASE REPORT. MINERVA CARDIOANGIOL. 2016;64 (4):494 TO 496", "literaturereference_normalized": "failure of old and new anticoagulants to prevent ischemic stroke in high risk atrial fibrillation a case report", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20160816", "receivedate": "20160816", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12653809, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" }, { "companynumb": "IT-IPCA LABORATORIES LIMITED-IPC201608-000685", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "200104", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DEEP VEIN THROMBOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2012", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "200104", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ATRIAL FIBRILLATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" } ], "patientagegroup": null, "patientonsetage": "77", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Ischaemic stroke", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "BILORA F,ADAMO A,POMERRI F,PRANDONI P. FAILURE OF OLD AND NEW ANTICOAGULANTS TO PREVENT ISCHEMIC STROKE IN HIGH-RISK ATRIAL FIBRILLATION: A CASE REPORT. MINERVA CARDIOANGIOL 2016 AUG;64(4):494-6.", "literaturereference_normalized": "failure of old and new anticoagulants to prevent ischemic stroke in high risk atrial fibrillation a case report", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20160822", "receivedate": "20160822", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12674291, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" } ]

{ "abstract": "BACKGROUND\nHealth Care Workers (HCWs) are at risk of occupational transmission of HIV, Hepatitis B and Hepatitis C, which can be minimized by following guidelines for standard precautions as well as taking Post Exposure Prophylaxis (PEP) measures. There are limited studies from India documenting details of PEP for HIV and Hepatitis B.\n\n\nOBJECTIVE\nWe aimed to study the efficacy, tolerance, details of PEP regimens used among HCWs exposed to HIV and Hepatitis B as well as vaccination status and (Anti-Hepatitis B Surface Antigen) anti-HBS Antibody Titre Level Among HCWs exposed Hepatitis B.\n\n\nMETHODS\nThis retrospective observational study was done at a rural based tertiary care teaching centre of Western India.\n\n\nMETHODS\nHospital Infection Control Committee of our institute was maintaining a record of all reported incidences of HIV and Hepatitis B positive exposures since 2003. We analysed reported incidences of exposures to HIV and Hepatitis B positive source occurred during the period of January 2003 to December 2015.\n\n\nRESULTS\nOf the total 96 exposures, 48 were to HIV and 48 were to Hepatitis B. Of the 48 exposures to HIV, PEP was warranted in 39. Of 39 exposures, only 14 (35.9%) received PEP within two hours. Basic regimen was used in 22 and expanded in 17 exposures. Only 12 (31.6%) reported side effects to PEP. Zidovudine based regimen was less well tolerated. All side effects were reported by female HCWs only. Of the 48 exposed to Hepatitis B, 33 (68.6%) were completely vaccinated. Out of 33, titre result was not available for eight. Three (12.0%) of remaining 25 were having low titre (<10mIU/ml) of anti-HBS antibody. Five of six with incomplete vaccination status demonstrated anti HBS antibody titre > 100mIU/ml. Of the 48, in 17 (35.4%) incidences no action was required; 23 (47.9%) were managed with booster dose of Hepatitis B vaccine and eight (16.7%) with Hepatitis B immunoglobulin. No cases of sero-conversion was reported either for HIV or Hepatitis B from available data.\n\n\nCONCLUSIONS\nInspite of high incidences of exposures to HIV or Hepatitis B positive source, good efficacy of PEP was observed with no sero-conversion. PEP for HIV was well tolerated; female HCWs were less tolerant. Study emphasized the need for creating awareness about timely reporting of incidence, achieving maximum vaccination against Hepatitis B for all HCWs and need for anti-HBS antibody titre.", "affiliations": "Professor, Department of Medicine, Pramukh Swami Medical College , Karamsad, Gujarat, India .;Professor, Department of Medicine, Pramukh Swami Medical College , Karamsad, Gujarat, India .;Professor and HOD, Department of Medicine, Pramukh Swami Medical College , Karamsad, Gujarat, India .", "authors": "Sheth|Sanket Pranjivan|SP|;Leuva|Alpa C|AC|;Mannari|Jyoti G|JG|", "chemical_list": null, "country": "India", "delete": false, "doi": "10.7860/JCDR/2016/19876.8387", "fulltext": null, "fulltext_license": null, "issn_linking": "0973-709X", "issue": "10(8)", "journal": "Journal of clinical and diagnostic research : JCDR", "keywords": "Anti-HBS antibody titre; Hepatitis B immunoglobulin; Hepatitis B vaccination; Occupational transmission; Tenofovir; Zidovudine", "medline_ta": "J Clin Diagn Res", "mesh_terms": null, "nlm_unique_id": "101488993", "other_id": null, "pages": "OC39-44", "pmc": null, "pmid": "27656485", "pubdate": "2016-08", "publication_types": "D016428:Journal Article", "references": "22308136;26559816;25366873;25577991;23188932;25043080;24278151;25879442;23508479;20606925;26092496;25745570;24432275;21493989;20418554;19172059;23437024;22248951;22058270;16195697;21799569;25368534;22639503;25815093;26545721;27080795;10835856;23616912;20061757;23705668;22684185;24352112;11442229", "title": "Post Exposure Prophylaxis for Occupational Exposures to HIV and Hepatitis B: Our Experience of Thirteen Years at a Rural Based Tertiary Care Teaching Hospital of Western India.", "title_normalized": "post exposure prophylaxis for occupational exposures to hiv and hepatitis b our experience of thirteen years at a rural based tertiary care teaching hospital of western india" }

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POST EXPOSURE PROPHYLAXIS FOR OCCUPATIONAL EXPOSURES TO HIV AND HEPATITIS B: OUR EXPERIENCE OF THIRTEEN YEARS AT A RURAL BASED TERTIARY CARE TEACHING HOSPITAL OF WESTERN INDIA.. 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POST EXPOSURE PROPHYLAXIS FOR OCCUPATIONAL EXPOSURES TO HIV AND HEPATITIS B: OUR EXPERIENCE OF THIRTEEN YEARS AT A RURAL BASED TERTIARY CARE TEACHING HOSPITAL OF WESTERN INDIA.. 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POST EXPOSURE PROPHYLAXIS FOR OCCUPATIONAL EXPOSURES TO HIV AND HEPATITIS B: OUR EXPERIENCE OF THIRTEEN YEARS AT A RURAL BASED TERTIARY CARE TEACHING HOSPITAL OF WESTERN INDIA. 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{ "abstract": "BACKGROUND\nProton pump inhibitors are usually safe, although serious adverse effects can occur. We report the first case of rhabdomyolysis associated with single-dose intravenous esomeprozole administration.\n\n\nMETHODS\nA 45-year-old Korean male visited our emergency room because of persistent lower chest discomfort that started 10 hours before. He had been diagnosed with diabetes and coronary heart disease, but discontinued oral hypoglycemic agents 1 month earlier. He continued to take medications for coronary heart disease. There was no abnormality on an electrocardiogram or in cardiac enzymes. Initial laboratory findings did not show abnormalities for muscle enzymes. Esomeprozole 40 mg was administrated intravenously for the control of his ambiguous chest discomfort. Then, 12 hours later, he complained of abrupt severe right buttock pain. An area of tender muscle swelling 8 cm in diameter was seen on his right buttock area. Creatine kinase and lactate dehydrogenase were elevated to 40,538 and 1326 U/L, respectively. A bone scan using 20 mCi of Tc-hydroxymethylene diphosphonate was compatible with rhabdomyolysis.\n\n\nRESULTS\nHis muscular symptoms, signs, and laboratory findings improved markedly with conservative management, including hydration and urine alkalinization. He is being followed in the outpatient department with no evidence of recurrence.\n\n\nCONCLUSIONS\nWe should keep in mind that single-dose intravenous administration of esomeprazole can induce rhabdomyolysis.", "affiliations": "Department of Internal Medicine, Gyeongsang National University Hospital, Jinju Department of Internal Medicine, Changwon Gyeongsang National University Hospital, Changwon Department of Internal Medicine, Gyeongsang National University School of Medicine, Internal Medicine Institute of Health Science, Gyeongsang National University, Jinju, South Korea.", "authors": "Jeon|Dae-Hong|DH|;Kim|Yire|Y|;Kim|Min Jeong|MJ|;Cho|Hyun Seop|HS|;Bae|Eun Jin|EJ|;Chang|Se-Ho|SH|;Park|Dong Jun|DJ|", "chemical_list": "D054328:Proton Pump Inhibitors; D064098:Esomeprazole", "country": "United States", "delete": false, "doi": "10.1097/MD.0000000000004313", "fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 2744268010.1097/MD.0000000000004313043135200Research ArticleClinical Case ReportRhabdomyolysis associated with single-dose intravenous esomeprazole administration A case reportJeon Dae-Hong MDaKim Yire MDaKim Min Jeong MDaCho Hyun Seop MDaBae Eun Jin MDbChang Se-Ho MD, PhDacdPark Dong Jun MD, PhDbcd∗Mubarak. Muhammed a Department of Internal Medicine, Gyeongsang National University Hospital, Jinjub Department of Internal Medicine, Changwon Gyeongsang National University Hospital, Changwonc Department of Internal Medicine, Gyeongsang National University School of Medicine, Internal Medicined Institute of Health Science, Gyeongsang National University, Jinju, South Korea.∗ Correspondence: Dong Jun Park, Department of Internal Medicine, Changwon Gyeongsang National University Hospital, Internal Medicine, 11, Samjeongja-ro, Seongsan-gu, Changwon-si, Gyeongsangnam-do, South Korea (e-mail: [email protected]).7 2016 22 7 2016 95 29 e431328 4 2016 19 6 2016 29 6 2016 Copyright © 2016 the Author(s). Published by Wolters Kluwer Health, Inc. All rights reserved.2016This is an open access article distributed under the Creative Commons Attribution License 4.0, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nBackground:\nProton pump inhibitors are usually safe, although serious adverse effects can occur. We report the first case of rhabdomyolysis associated with single-dose intravenous esomeprozole administration.\n\nMethods:\nA 45-year-old Korean male visited our emergency room because of persistent lower chest discomfort that started 10 hours before. He had been diagnosed with diabetes and coronary heart disease, but discontinued oral hypoglycemic agents 1 month earlier. He continued to take medications for coronary heart disease. There was no abnormality on an electrocardiogram or in cardiac enzymes. Initial laboratory findings did not show abnormalities for muscle enzymes. Esomeprozole 40 mg was administrated intravenously for the control of his ambiguous chest discomfort. Then, 12 hours later, he complained of abrupt severe right buttock pain. An area of tender muscle swelling 8 cm in diameter was seen on his right buttock area. Creatine kinase and lactate dehydrogenase were elevated to 40,538 and 1326 U/L, respectively. A bone scan using 20 mCi of 99mTc-hydroxymethylene diphosphonate was compatible with rhabdomyolysis.\n\nResults:\nHis muscular symptoms, signs, and laboratory findings improved markedly with conservative management, including hydration and urine alkalinization. He is being followed in the outpatient department with no evidence of recurrence.\n\nConclusion:\nWe should keep in mind that single-dose intravenous administration of esomeprazole can induce rhabdomyolysis.\n\nKeywords\nacute kidney injuryproton pump inhibitorrhabdomyolysisOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nEsomeprazole, the (S)-isomer of omeprazole,[1,2] is available in both oral and intravenous formulations; it is usually indicated for the treatment of gastroesophageal reflux disease (GERD), Helicobacter pylori eradication, and the prevention of nonsteroidal anti-inflammatory drug induced gastric ulcers.[3–5] Numerous clinical trials including many patients have demonstrated that esomeprazole is tolerable and safe for both short- and long-term use.[6–8] Esomeprazole, like other proton pump inhibitors (PPIs), has few adverse effects, with reported rates of adverse effects ranging from 1% to 5%. The most common side effects include headache, diarrhea, abdominal pain, and nausea. These adverse effects, excluding diarrhea, are usually not related with age, dosage, or duration of treatment. Mean changes in laboratory measurements due to esomeprazole are usually small and not clinically meaningful.[5] In addition, esomeprazole did not cause clinically significant electrocardiographic (ECG) changes.[9]\n\nRhabdomyolysis is induced by skeletal muscle breakdown, leading to the leakage of muscle cell contents, such as myoglobin, electrolytes, and other sarcoplasmic proteins, into the circulation.[10,11] Acute kidney injury (AKI) complicated by rhabdomyolysis is quite common, representing about 7% to 10% of all cases of AKI in the United States.[12,13] Eight categories of events are well known to provoke rhabdomyolysis: trauma, exertion, muscle hypoxia, genetic defects, infections, body temperature changes, metabolic and electrolyte disorders, and drugs and toxins.[11,12,14] Rhabdomyolysis associated with PPIs has been reported sporadically.[15–17] However, there has been no report of a PPI associated with rhabdomyolysis after single-dose intravenous administration. Thus, here we report the first case of rhabdomyolysis occurring after single-dose intravenous esomeprazole administration.\n\n2 Case presentation\nA 45-year-old male patient visited the emergency room (ER) because of lower chest discomfort starting 6 hours earlier. He also complained of thirst and limb numbness. His medical history included diabetes mellitus, bronchial asthma, and unstable angina for 4 years, 2 years, and 1 year, respectively. He had been taking aspirin (100 mg/d), clopidogrel (75 mg/d), atorvastatin (10 mg/d), and candesartan (8 mg/d) for 1 year without changes. He took those medicines on the morning of his admission. He regularly used a Symbicort Turbuhaler® (AstraZeneca Korea, Seoul, Republic of Korea) (160/4.5 μg) for asthma management. One month before the present admission, he discontinued the oral hypoglycemic agents prescribed by his primary physician. He denied recent alcohol consumption and had quit smoking 1 year earlier. Except for these symptoms, he initially had no complaints, such as muscular pain, fever, upper respiratory symptoms, or signs, on visiting the ER. He had no history of excessive physical activity or recent trauma.\n\nOn initial physical examination in the ER, his vital signs were as follows: blood pressure, 100/60 mm Hg; heart rate, 71 beats/min; respiratory rate, 20 times/min; and body temperature, 36.6 °C. On chest auscultation, no abnormal sounds, such as rales or wheezing, were audible, and his heartbeat was regular without murmur. His general skin turgor was decreased, and his tongue was dry. His conjunctivae were not anemic and sclerae were not icteric. There were no palpable lymph nodes in the head or neck area. Organomegaly was not seen in the abdomen. No pretibial pitting edema, muscular swelling, or skin color changes were detected on either lower extremity. There was no tenderness in the upper or lower extremities. His muscle power was within normal limits.\n\nCompared with a previous ECG, the rhythm and voltage were unchanged. His initial troponin-I was less than 0.1 ng/mL, creatinine kinase (CK) was 144 U/L (0–190 U/L), lactate dehydrogenase (LDH) was 220 U/L (135–225 U/L), and CK-MB, subunit of CK, was 3.5 ng/mL. Other initial laboratory data were hematocrit 45% (39%–52%), hemoglobin 14.5 g/dL (13–17 g/dL), white blood cell count 11,280/mm3 (4000–10,000/mm3, neutrophils: 68.2%, lymphoid cells: 25.6%, and monocytes: 4.5%), and platelet count 256,000/mm3 (130,000–400,000/mm3). Liver function tests were as follows: alkaline phosphatase 84 IU/L (35–130 IU/L), aspartate aminotransferase (AST) 21 IU/L (0–37 IU/L), alanine aminotransferase (ALT) 42 IU/L (0–41 IU/L), and glucose 696 mg/dL. Hemoglobin A1c (HbA1c) was 9.3% (4.2%–5.9%). Blood urea nitrogen (BUN) and creatinine were 19.9 mg/dL (6.0–20.0 mg/dL) and 1.11 mg/dL (0.6–1.2 mg/dL), respectively. Electrolyte results were sodium 123 mmol/L (135–145 mmol/L), potassium 4.7 mmol/L (3.3–5.1 mmol/L), and chloride 80 mmol/L (98–110 mmol/L). Serum osmolality was 296 mOsm/kg. Urinalysis with micro revealed no protein or blood on a dipstick and red blood cell 1 to 4/high-power field.\n\nContinuous intravenous insulin and hydration with normal saline were started. In addition, 40 mg of esomeprazole was infused intravenously under a suspicion of GERD. Glucose levels, measured by a blood sugar meter, decreased to 240 mg/dL and chest discomfort improved 6 hours after this management. In the mean time, there were no other oral, intramuscular, and intravenous drug therapies except for oral lactulose for his constipation. He felt mild discomfort in the right buttock at that time but did not complain to the medical team. However, he complained of severe right buttock pain 12 hours after the esomeprazole infusion. Tender muscle swelling of 8 cm in diameter was seen in the right buttock area and a reddish skin color change was noted (Fig. 1). Serum CK and LDH levels increased to 40,533 and 1326 U/L, respectively, and AST and ALT levels also increased to 320 and 83 IU/L, respectively. BUN and creatinine levels were 23.9 and 1.49 mg/dL, respectively. We started vigorous hydration through isotonic saline infusion and urine alkalinization by intravenous bicarbonate infusion. Another 40 mg of esomeprazole was administered because we did not regard esomeprazole as the causative agent of the rhabdomyolysis at that time. Serum CK, LDH, AST, and ALT levels were 84,226, 1943, 603, and 171 IU/L, respectively, 24 hours later. On the third day in hospital, he was admitted to the nephrology ward. Esomeprazole was ended, and hydration and alkalinization were continued. Serum CK and LDH levels decreased gradually (Fig. 2A and B), and his muscular symptoms and swelling in the buttock area improved gradually. A bone scan using 20 mCi of 99mTc-hydroxymethylene diphosphonate was performed on the seventh day in hospital and revealed multiple and diffuse uptake in the soft tissues of the right buttock and both lower legs (Fig. 3). His clinical manifestations and laboratory findings improved, so he was discharged on the 12th day. We added oral hypoglycemic agents, linagliptin 5 mg and metformin 500 mg, to his previous drugs (aspirin, clopidogrel, candesartan, and atorvastatin). He is being followed in our outpatient department with no recurrence of rhabdomyolysis at 6 months.\n\nFigure 1 Red and swollen right buttock which is 8 cm in diameter (encircled area).\n\nFigure 2 (A) and (B) The change of serum creatinine kinase, lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase.\n\nFigure 3 Bone scan showing multiple uptakes in both tibia and fibula and right buttock area.\n\n3 Discussion\nWe report here the first case of rhabdomyolysis associated with single-dose esomeprazole intravenous administration. Our patient initially did not show clinical or laboratory evidence of rhabdomyolysis before esomeprazole administration in the ER. He was still in the ER when muscular pain and swelling presented after esomeprazole administration, but we did not suspect a relationship between rhabdomyolysis and esomeprazole, leading to administration of a second esomeprazole dose on the second day. We finally confirmed that esomeprazole was associated with rhabdomyolysis and ended the infusion of esomeprazole after he moved to the ward.\n\nFrom the case reports in VigiBase and in the literature, Clark and Strandell[18] reported 35 cases of rhabdomyolysis associated with PPIs in the literature, a serious reaction to the drugs. They also showed that a statin was taken concomitantly in 12 cases. Other drugs, such as lovastatin, amlodipine, and diazepam, were also taken, although no dates were given. Rhabdomyolysis occurred within the first week in 9 cases, between after 14 days and 3 months of treatment in 4 cases, and between 1.5 and 10 years in 3 additional cases. Time to onset was unknown in 19 cases. However, there are limitations to the report: VigiBase reports are not homogenous with respect to origin or to the probability that a pharmaceutical product caused the adverse reaction. Thus, no pure causal relationship between rhabdomyolysis and PPIs was evident. In our case, the causal relationship seems particularly prominent, in that esomeprazole was intravenously administered without other concomitant medicines except for intravenous insulin in the ER, and muscular symptoms and laboratory changes were confirmed immediately. We think that the administration of insulin is very unlikely to be one of the reasons for the rhabdomyolysis.\n\nFrom PubMed research, 2 cases of rhabdomyolysis associated with esomeprazole have been reported.[19,20] One case occurred in a patient with chronic heart failure and the other was in a patient taking atorvastatin and clarithromycin. The former patient also underwent aortic valve replacement and coronary artery bypass surgery and was administered several other medications including propofol, sufentanil, furosemide, amiodarone, meropenem, linezolid, and cathecholamines. Esomeprazole was administered intravenously (40–80 mg/d) for 1 month. They proposed that the dose of esomeprazole was correlated with rhabdomyolysis.[19] However, his serum CK level was not elevated (although his serum myoglobin level was), but they did not mention the discordance between CK and myoglobin levels. Furthermore, there seemed to be no prominent correlation between esomeprazole withdrawal and restoration of myoglobin levels. The latter patient had a long medication history of atorvastatin (>1 year), a 6-week history of esomeprazole, and received 3 500-mg doses of clarithromycin just before admission.[20] Thus, the rhabdomyolysis seemed not to be associated with esomeprazole, but with clarithromycin.\n\nMost PPIs are metabolized to varying degrees by the hepatic cytochrome P450 enzymatic system, and drug metabolism may be altered by induction or inhibition of the cytochrome P enzymes.[21] According to in vitro studies, esomeprazole was a weak inhibitor of cytochrome P450 (CYP3A4, -2B6, -2D6, -2C9, -2C8, and -1A2), but a potent inhibitor of CYP2C19 in human liver microsomes, compared with other PPIs, and esomeprazole might not reach the plasma concentrations needed to inhibit CYP3A4 in the normal clinical setting.[22] Andersen et al extensively reviewed the pharmacokinetic drug interaction potential of esomeprazole. They showed that esomeprazole did not have clinically relevant interactions with 3A4 substrates, such as quinidine and clarithromycin, or the 2C9 substrate, (S)-warfarin. However, esomeprazole had different interaction with 2C19 substrates including (R)-warfarin, diazepam, and phenytoin.[22]\n\nOne report showed that 3- or 30-minute intravenous esomeprazole (40 mg) provides similar levels of intragastric acid control to the oral formulation,[23,24] although little is known about the pharmacokinetic profile of esomeprazole after intravenous administration (whereas that of the oral formulation is well characterized).[1,2] Niazi et al[25] demonstrated that a higher infusion rate of intravenous esomeprazole showed higher Cmax values, but did not affect other values such as the plasma concentration–time curve, plasma elimination half-life (t1/2), or plasma clearance in healthy volunteers. A previous study also showed that Cmax values were higher after intravenous dosing than after oral dosing.[26] Although the exact mechanism of rhabdomyolysis in our patient with a single-dose injection remains to be determined, an abrupt increase in Cmax after intravenous infusion and drugs, which the patient had taken, might be associated with an elevation of the plasma level of esomeprazole, which might in turn be correlated with toxicity. Other possibility includes an idiosyncratic drug reaction, leading to some myopathy in the way that toxicity may occur after only single-dose use. Lastly, direct toxicity to muscle might be one of the mechanisms that can’t be ignored.[27]\n\nIn conclusion, physicians should keep in mind that a single-dose infusion of esomeprazole might be associated with rhabdomyolysis, directly or indirectly. Early recognition and intervention is important to reduce complications.\n\nAbbreviations: AKI = acute kidney injury, ALT = alanine aminotransferase, AST = aspartate aminotransferase, BUN = blood urea nitrogen, CK = creatinine kinase, ECG = electrocardiograph, ER = emergency room, GERD = gastroesophageal reflux disease, LDH = lactate dehydrogenase, PPI = proton pump inhibitor.\n\nEthics committee approval: Informed consent was obtained from the patient, but this case report did not require an ethics committee approval according to the current laws in our hospital.\n\nThe authors have no funding and conflicts of interest to disclose.\n==== Refs\nReferences\n1 Andersson T Hassa-Alin M Hasselgren G \nPharmacokinetic studies with esomeprazole, the (S)-isomer of omeprazole . Clin Pharmacokinet \n2001 ; 40 :411 –426 .11475467 \n2 Andersson T Rohss K Bredberg E \nPharmacokinetics and pharmacodynamics of esomeprazole, the S-isomer of omeprazole . Aliment Pharmacol Ther \n2001 ; 15 :1563 –1569 .11563995 \n3 Shi S Klotz U \nProton pump inhibitors: an update of their clinical use and pharmacokinetics . Eur J Clin Pharmacol \n2008 ; 64 :935 –951 .18679668 \n4 Blume H Donath F Warnke A \nPharmacokinetic drug interaction profiles of proton pump inhibitors . Drug Safety \n2006 ; 29 :769 –784 .16944963 \n5 Morgner A Miehlke S Labenz J \nEsomeprazole: prevention and treatment of NSAID-induced symptoms and ulcers . Expert Opin Pharmacother \n2007 ; 8 :975 –988 .17472543 \n6 Richter JE Kahrilas PJ Johanson J \nEsomeprazole Study Investigators . Efficacy and safety of esomeprazole compared with omeprazole in GERD patients with erosive esophagitis: a randomized controlled trial . Am J Gastroenterol \n2001 ; 96 :656 –665 .11280530 \n7 Maton PN Vakil NB Levine JG \nEsomeprazole Study Investigators . Safety and efficacy of long term esomeprazole therapy in patients with healed erosive oesophagitis . Drug Saf \n2001 ; 24 :625 –635 .11480494 \n8 Vakil NB Shaker R Johnson DA \nThe new proton pump inhibitor esomeprazole is effective as a maintenance therapy in GERD patients with healed erosive oesophagitis: a 6-month, randomized, double-blind, placebo-controlled study of efficacy and safety . Aliment Pharmacol Ther \n2001 ; 5 :927 –935 .\n9 Hasselgren B Claar-Nillson C Hasselgren C \nStudies in healthy volunteers do not show any electrocardiographic effects with esomeprazole . Clin Drug Invest \n2000 ; 20 :425 –431 .\n10 Warren JD Blumbergs PC Thompson PD \nRhabdomyolysis: a review . Muscle Nerve \n2002 ; 25 :332 –347 .11870710 \n11 Bosch X Poch E Grau JM \nRhabdomyolysis and acute kidney injury . N Engl J Med \n2009 ; 361 :62 –72 .19571284 \n12 Bagley WH Yang H Shah KH \nRhabdomyolysis . Intern Emerg Med \n2007 ; 2 :210 –218 .17909702 \n13 Holt SG Moore KP \nPathogenesis and treatment of renal dysfunction in rhabdomyolysis . Intensive Care Med \n2001 ; 27 :803 –811 .11430535 \n14 Allison RC Bedsole DL \nThe other medical causes of rhabdomyolysis . Am J Med Sci \n2003 ; 326 :79 –88 .12920439 \n15 Nozaki M Suzuki T Hirano M \nRhabdomyolysis associated with omeprazole . J Gastroenterol \n2004 ; 39 :86 .\n16 Bebarta VS King JA McDonough M \nProton pump inhibitor-induced rhabdomyolysis and hyponatremic delirium . Am J Emerg Med \n2008 ; 26 :519.e1 –519.e2 .\n17 Tanaka K Nakada TA Abe R \nOmeprazole-associated rhabdomyolysis . Crit Care \n2014 ; 18 :462 .25184508 \n18 Clark DW Strandell J \nMyopathy including polymyositis: a likely class adverse effect of proton pump inhibitors? \nEur J Clin Pharmacol \n2006 ; 62 :473 –479 .16758264 \n19 Tröger U Reiche I Jepsen MS \nEsomeprazole-induced rhabdomyolysis in a patient with heart failure . Intensive Care Med \n2010 ; 36 :1278 –1279 .20229039 \n20 Sipe BE Jones RJ Bokhart GH \nRhabdomyolysis causing AV blockade due to possible atorvastatin, esomeprazole, and clarithromycin interaction . Ann Pharmacother \n2003 ; 37 :808 –811 .12773066 \n21 Zvyaga T Chang SY Chen C \nEvaluation of six proton pump inhibitors as inhibitors of various human cytochromes P450: focus on cytochrome P450 2C19 . Drug Metab Dispos \n2012 ; 40 :1698 –1711 .22648560 \n22 Andersson T Hassan-Alin M Hasselgren G \nDrug interaction studies with esomeprazole, the (S)-isomer of omeprazole . Clin Pharmacokinet \n2001 ; 40 :523 –537 .11510629 \n23 Wilder-Smith C Röhss K Bondarov P \nEsomeprazole 40 mg administered intravenously (IV) as a 3-min. injection or 30-min. infusion provides the same effective acid control in healthy subjects . Gastroenterology \n2003 ; 124 :A233 .\n24 Röhss K Bondarov P Lundin C \nEsomeprazole 40 mg administered as a 30-minute intravenous infusion provides the same effective acid control as oral administration in healthy subjects . Gastroenterology \n2003 ; 124 \nsuppl 1 :A231 .\n25 Niazi M Ahlbom H Bondarov P \nPharmacokinetics of esomeprazole following varying intravenous administration rates . Basic Clin Pharmacol Toxicol \n2005 ; 97 :351 –354 .16364049 \n26 Hassan-Alin M Andersson T Bredberg E \nPharmacokinetics of esomeprazole after oral and intravenous administration of single and repeated doses to healthy subjects . Eur J Clin Pharmacol \n2000 ; 56 :665 –670 .11214773 \n27 Sivakumar K Dalakas MC \nAutoimmune syndrome induced by omeprazole . Lancet \n1994 ; 344 :619 –620 .\n\n", "fulltext_license": "CC BY", "issn_linking": "0025-7974", "issue": "95(29)", "journal": "Medicine", "keywords": null, "medline_ta": "Medicine (Baltimore)", "mesh_terms": "D000328:Adult; D002637:Chest Pain; D000072700:Conservative Treatment; D064098:Esomeprazole; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D054328:Proton Pump Inhibitors; D012206:Rhabdomyolysis", "nlm_unique_id": "2985248R", "other_id": null, "pages": "e4313", "pmc": null, "pmid": "27442680", "pubdate": "2016-07", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "11421866;11563995;16758264;18410837;16364049;17909702;16944963;20229039;11480494;12920439;11280530;7914991;18679668;11510629;11430535;11214773;17472543;19571284;12773066;11870710;14767743;22648560;25184508;11475467", "title": "Rhabdomyolysis associated with single-dose intravenous esomeprazole administration: A case report.", "title_normalized": "rhabdomyolysis associated with single dose intravenous esomeprazole administration a case report" }

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MEDICINE (BALTIMORE). 2016 JUL;95(29):E4313.", "literaturereference_normalized": "rhabdomyolysis associated with single dose intravenous esomeprazole administration a case report", "qualification": "1", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20160829", "receivedate": "20160806", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12627788, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20161109" }, { "companynumb": "KR-MYLANLABS-2016M1036859", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUDESONIDE\\FORMOTEROL FUMARATE DIHYDRATE" }, 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null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CONSTIPATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LACTULOSE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "INSULIN NOS" }, "drugadditional": "3", "drugadministrationroute": "041", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INSULIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ATORVASTATIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG/ DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ATORVASTATIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ESOMEPRAZOLE" }, "drugadditional": "1", "drugadministrationroute": "041", "drugauthorizationnumb": "078936", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MG INITIAL, ANOTHER 40 MG WAS GIVEN LATER", "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROOESOPHAGEAL REFLUX DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESOMEPRAZOLE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "75 MG/ DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOPIDOGREL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SODIUM CHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SODIUM CHLORIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG/ DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN /00002701/" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CANDESARTAN CILEXETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "8 MG/ DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CANDESARTAN CILEXETIL." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Rhabdomyolysis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "JEON D-H, KIM Y, KIM MJ, CHO HS, BAE EJ, CHANG S-H, ET AL. RHABDOMYOLYSIS ASSOCIATED WITH SINGLE-DOSE INTRAVENOUS ESOMEPRAZOLE ADMINISTRATION: A CASE REPORT. MEDICINE 2016;95(29):E4313.", "literaturereference_normalized": "rhabdomyolysis associated with single dose intravenous esomeprazole administration a case report", "qualification": "1", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20160831", "receivedate": "20160831", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12704182, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" } ]

{ "abstract": "The patient was a 55-year-old male who had prominent fasciculation and muscle cramps. Muscle weakness and atrophy of the trunk, respiratory system, and extremities gradually progressed. On the basis of these features, we diagnosed this patient as having amyotrophic lateral sclerosis (ALS), however, the upper motor neuron signs were not significant. Following the detection of the anti-voltage gated potassium channel (VGKC) complex antibody at 907.5 pM (normal < 100 pM) and repetitive discharge in a nerve conduction study, immunotherapy with intravenous immunoglobulin, methylprednisolone (mPSL), double filtration plasmapheresis (DFPP), ciclosporin, and rituximab was introduced. mPSL and DFPP showed only tentative effectiveness for fasciculation and muscle cramps, respectively. Thereafter, muscle weakness progressed. The patient died of type II respiratory failure at the age of 57 years, about 2 years after the onset of the disease. At autopsy, a histopathological diagnosis of ALS with lower-motor-predominant degeneration was made. Characteristic cellular features, including Bunina bodies in the remaining lower motor neurons and phosphorylated TAR DNA-binding protein 43-kDa (pTDP-43)-immunopositive inclusions in both upper and lower motor neuron systems, were evident. At present, an immunological role of the anti-VGKC complex antibody in the development of cramp-fasciculation syndrome has been speculated. In this ALS patient, the antibodies might be associated with pathomechanisms underlying the characteristic symptoms.", "affiliations": "Department of Neurology, Niigata City General Hospital.", "authors": "Sato|Aki|A|;Sakai|Naoko|N|;Shinbo|Junsuke|J|;Hashidate|Hideki|H|;Igarashi|Shuichi|S|;Kakita|Akiyoshi|A|;Yamazaki|Motoyoshi|M|", "chemical_list": "D001323:Autoantibodies; D024642:Potassium Channels, Voltage-Gated", "country": "Japan", "delete": false, "doi": "10.5692/clinicalneurol.54.32", "fulltext": null, "fulltext_license": null, "issn_linking": "0009-918X", "issue": "54(1)", "journal": "Rinsho shinkeigaku = Clinical neurology", "keywords": null, "medline_ta": "Rinsho Shinkeigaku", "mesh_terms": "D000690:Amyotrophic Lateral Sclerosis; D001323:Autoantibodies; D001344:Autopsy; D005207:Fasciculation; D006801:Humans; D008297:Male; D008875:Middle Aged; D024642:Potassium Channels, Voltage-Gated", "nlm_unique_id": "0417466", "other_id": null, "pages": "32-7", "pmc": null, "pmid": "24429646", "pubdate": "2014", "publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article", "references": null, "title": "An autopsy case of amyotrophic lateral sclerosis with prominent muscle cramps, fasciculation, and high titer of anti-voltage gated potassium channel (VGKC) complex antibody.", "title_normalized": "an autopsy case of amyotrophic lateral sclerosis with prominent muscle cramps fasciculation and high titer of anti voltage gated potassium channel vgkc complex antibody" }

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"activesubstancename": "CYCLOSPORINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "065017", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CICLOSPORIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "065017", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "AMYOTROPHIC LATERAL SCLEROSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CICLOSPORIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "60 MG,PER DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "AMYOTROPHIC LATERAL SCLEROSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "HUMAN IMMUNOGLOBULIN G" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201001", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IMMUNOGLOBULIN I.V" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "HUMAN IMMUNOGLOBULIN G" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "AMYOTROPHIC LATERAL SCLEROSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201002", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IMMUNOGLOBULIN I.V" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "041", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "RILUZOLE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RILUZOLE." } ], "patientagegroup": null, "patientonsetage": "55", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "55.5", "reaction": [ { "reactionmeddrapt": "Respiratory failure", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Disease progression", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Therapeutic response decreased", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Muscular weakness", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SATO A, SAKAI N, SHINBO J, HASHIDATE H, IGARASHI S, KAKITA A ET AL.. AN AUTOPSY CASE OF AMYOTROPHIC LATERAL SCLEROSIS WITH PROMINENT MUSCLE CRAMPS, FASCICULATION, AND HIGH TITER OF ANTI-VOLTAGE GATED POTASSIUM CHANNEL (VGKC) COMPLEX ANTIBODY. CLINICAL NEUROLOGY. 2014;54 (1):32-37", "literaturereference_normalized": "an autopsy case of amyotrophic lateral sclerosis with prominent muscle cramps fasciculation and high titer of anti voltage gated potassium channel vgkc complex antibody", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20141013", "receivedate": "20140213", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 9893544, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150529" } ]

{ "abstract": "BACKGROUND\nIn this study, the data of eight new patients in conjunction with previously reported cases with piperacillin-induced immune hemolytic anemia (PIHA) are described.\n\n\nMETHODS\nFive patients with cystic fibrosis and three patients with other disorders developed massive hemolysis after administration of piperacillin. Serologic tests were carried out using standard techniques. Tests for drug-dependent antibodies (ddab) were performed in the presence and absence of piperacillin and its ex vivo antigens (urine of patients treated with piperacillin).\n\n\nRESULTS\nHemolysis was acute and severe in all eight patients. The direct antiglobulin test was positive in all cases. Sera from four patients reacted with red blood cells (RBCs) in the presence of piperacillin as well as its ex vivo antigens. Sera from three patients showed positive reactivity with untreated RBCs in the presence of piperacillin, and the serum from the remaining patient was reactive only in the presence of piperacillin ex vivo antigens. Other patients with PIHA have been reported in the literature. Three of these patients also had cystic fibrosis.\n\n\nCONCLUSIONS\nTo date approximately 26 patients with PIHA have been described and at least eight of these patients had cystic fibrosis. It is unclear whether patients with cystic fibrosis might be susceptible in developing PIHA.", "affiliations": "Institute for Transfusion Medicine, Charité-University Medicine, Berlin, Germany.", "authors": "Mayer|Beate|B|;Yürek|Salih|S|;Salama|Abdulgabar|A|", "chemical_list": "D000900:Anti-Bacterial Agents; D010878:Piperacillin", "country": "United States", "delete": false, "doi": "10.1111/j.1537-2995.2009.02544.x", "fulltext": null, "fulltext_license": null, "issn_linking": "0041-1132", "issue": "50(5)", "journal": "Transfusion", "keywords": null, "medline_ta": "Transfusion", "mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000744:Anemia, Hemolytic, Autoimmune; D000900:Anti-Bacterial Agents; D005260:Female; D006801:Humans; D008297:Male; D010878:Piperacillin", "nlm_unique_id": "0417360", "other_id": null, "pages": "1135-8", "pmc": null, "pmid": "20051057", "pubdate": "2010-05", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Piperacillin-induced immune hemolysis: new cases and a concise review of the literature.", "title_normalized": "piperacillin induced immune hemolysis new cases and a concise review of the literature" }

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{ "abstract": "Central nervous system (CNS) histoplasmosis occurs in 5-20% of all cases and is most commonly seen in immunosuppressed patients who have acquired immunodeficiency syndrome (AIDS) or have received organ transplant. The prevalence of histoplasmosis in patients greater than 65 years old between the years of 1999-2008 in the state of Texas was about 2-3 cases per 100,000 patients year. Since 1990 with the discovery of Triazoles, itraconazole (ICZ) has become the standard initial and suppressive therapy in patients with mild-moderate histoplasmosis without CNS involvement. However, poor penetration of ICZ into the brain, in vitro fluconazole resistance and lack of controlled-trials pose challenge in the treatment of cerebral histoplasmosis.", "affiliations": "Internal Medicine, The University of Texas Health Science Center/Christus Good Shepherd Medical Center, Longview, USA.;Internal Medicine, The University of Texas Health Science Center/Christus Good Shepherd Medical Center, Longview, USA.;Internal Medicine, The University of Texas Health Science Center/Christus Good Shepherd Medical Center, Longview, USA.;Internal Medicine, The University of Texas Health Science Center/Christus Good Shepherd Medical Center, Longview, USA.;Internal Medicine, Methodist Richardson Medical Center, Richardson, USA.", "authors": "Peddi|Prashanth|P|;Challa|Tejo|T|;Meegada|Sreenath|S|;Annakula|Madhavi|M|;Mar|Evan|E|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.7759/cureus.7064", "fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.7064\nInternal Medicine\nHIV/AIDS\nInfectious Disease\nA Case of Histoplasmosis with Central Nervous System Relapse after Itraconazole Therapy Needs Further Research\nMuacevic Alexander Adler John R Peddi Prashanth 1 Challa Tejo 1 Meegada Sreenath 1 Annakula Madhavi 1 Mar Evan 2 \n1 \nInternal Medicine, The University of Texas Health Science Center/Christus Good Shepherd Medical Center, Longview, USA \n\n2 \nInternal Medicine, Methodist Richardson Medical Center, Richardson, USA \n\nSreenath Meegada [email protected]\n21 2 2020 \n2 2020 \n12 2 e706416 2 2020 21 2 2020 Copyright © 2020, Peddi et al.2020Peddi et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/28211-a-case-of-histoplasmosis-with-central-nervous-system-relapse-after-itraconazole-therapy-needs-further-researchCentral nervous system (CNS) histoplasmosis occurs in 5-20% of all cases and is most commonly seen in immunosuppressed patients who have acquired immunodeficiency syndrome (AIDS) or have received organ transplant. The prevalence of histoplasmosis in patients greater than 65 years old between the years of 1999-2008 in the state of Texas was about 2-3 cases per 100,000 patients year. Since 1990 with the discovery of Triazoles, itraconazole (ICZ) has become the standard initial and suppressive therapy in patients with mild-moderate histoplasmosis without CNS involvement. However, poor penetration of ICZ into the brain, in vitro fluconazole resistance and lack of controlled-trials pose challenge in the treatment of cerebral histoplasmosis.\n\nhistoplasmosisitraconazoletreatment failurecns penetrationring enhancing lesionsThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nHistoplasmosis is a fungal infection caused by Histoplasma capsulatum which is one of the common fungal respiratory infections, endemic in Africa, Latin America, Asia, central and southeastern states of the United States [1]. Most of the documented histoplasmosis infections are asymptomatic in immunocompetent individuals, and are self-resolving. Symptomatic cases of infections are seen in patients who are immunocompromised like acquired immunodeficiency syndrome (AIDS), transplant patients on immunosuppressants, patients with ventriculoperitoneal shunts, and patients on steroids [1]. Here we present a patient with history of adrenal histoplasmosis status post bilateral adrenalectomy presenting with central nervous system (CNS) histoplasmosis despite being on itraconazole (ICZ) therapy.\n\nCase presentation\nA 56-year-old white male from Texas with history of adrenal histoplasmosis status post bilateral adrenalectomy who had completed two weeks of Amphotericin-B and one year of ICZ treatment presented to us with encephalopathy for one day and weight loss for two months. The patient’s wife was present and stated that the patient had a shuffled walk, poor memory, and when the wife attempted to walk the patient he would be falling to his left side repeatedly. The patient had immediate and remote memory intact. However, his recent memory was diminished and he was not capable of remembering the past 1.5 days. It was noticed that the patient had trouble with repetition in speech, and his fluency appeared to be slowed. In regards to cerebellar function, a patient is capable of performing rapid alternating movements but experiences some difficulty in performing finger-to-nose test and hesitation towards the end when attempting to touch a finger. The patient had initial computed tomography (CT) imaging performed which showed multiple areas of vasogenic edema involving the frontal lobes bilaterally and the left parietal lobe. Shortly after initial imaging, the patient had a magnetic resonance imaging (MRI) brain, which revealed ring enhancing lesions throughout the brainstem, cerebellum and cerebral hemispheres (Figures 1-3).\n\nFigure 1 MRI brain with IV contrast showing ring enhancing lesions in cerebral cortex, one lesion close to ventricle (Arrows pointing)\nFigure 2 MRI brain showing ring enhancing lesion in cerebellar hemisphere (Arrow pointing)\nFigure 3 MRI brain different slice showing ring enhancing lesions in cerebral hemispheres (Arrows pointing)\nThe patient was started on IV Decadron whilst further workup was started and Infectious Disease was consulted. The patient was found to have an elevated erythrocyte sedimentation rate (ESR) of 48 mm/hr and C-reactive protein (CRP) of 19 mg/dL and urinary histoplasma antigen was positive. The patient was initially started on: Amphotericin B liposomal, Leucovorin, Pyrimethamine and Sulfadiazine. The patient also had negative toxoplasmosis and human immunodeficiency virus (HIV) workup. All treatments other than Amphotericin B liposomal were discontinued. An initial stereotactic brain biopsy and histoplasma polymerase chain reaction (PCR) were obtained, but after being examined both in house and after being sent to Washington University in St. Louis, MO, the sample was not able to decipher the diagnosis after 3-4 weeks. Tissue culture was positive for Histoplasma capsulatum per DNA probe. The patient experienced acute renal failure believed to be from Amphotericin B, so for a period of about two weeks before definitive diagnosis the patient was switched to IV fluconazole with resolution of his acute renal failure. Almost one month after the initial stereotactic biopsy, an open window brain biopsy of a granuloma occurred. Intraoperative pathology of the biopsy showed yeast consistent with histoplasmosis (Figure 4).\n\nFigure 4 Patient’s open window brain biopsy with Gomori methenamine silver stain positive for histoplasma\nSubsequent tissue cultures confirmed the diagnosis. He was treated with Amphotericin-B for six weeks followed by long-term fluconazole. His neurological impairment improved considerably and he is now back to his baseline mental status.\n\nDiscussion\nThe diagnosis of isolated CNS histoplasmosis can be quite challenging particularly in immunocompetent patients. However, a combination of high index of suspicion, clinical features, imaging studies and testing spinal fluid or urine for Histoplasma antigen might be useful. Identifying the histoplasma in the brain either by stereotactic or open biopsy remains gold standard for diagnosis of CNS histoplasma [1]. Patients with CNS histoplasmosis can present with chronic meningitis, encephalitis, hydrocephalus, parenchymal lesions involving the brain and spinal cord resulting in stroke, seizures, confusion, memory impairment [1,2]. Due to rarity of the CNS histoplasmosis and due to lack of randomized or comparative trials definitive treatment for CNS histoplasmosis in immunocompetent persons remains unclear. However, updated clinical practice guidelines issued in 2007 offered us guidance based on clinical experience and descriptive studies and provided two level III B recommendations which include 1) Liposomal amphotericin B (5.0 mg/kg daily for a total of 175 mg/kg given over 4-6 weeks) followed by itraconazole (200 mg two or three times daily) for at least one year and until resolution of CSF abnormalities, including Histoplasma antigen levels and 2) Blood levels of itraconazole (ICZ) should be obtained to ensure adequate drug exposure [3]. Checking the serum levels after initiation of therapy and monitoring clinical response by serial lumbar punctures, checking serum and urinary antigens is of paramount importance while patients undergoing proper treatment. With lack of treatment trials it is unclear what azole is preferred treatment for CNS histoplasmosis. Although ICZ has been found to be more active against H. capsulatum, it has poor penetration into the brain. P-glycoprotein-mediated efflux mechanism markedly limits the accumulation of itraconazole in brain tissue [4]. This results in sanctuary sites in the CNS and relapse while ICZ is used as maintenance treatment after amp-B induction in disseminated histoplasmosis, which might be the cause of CNS relapse in our patient. Fluconazole achieves excellent concentration of drugs into the CSF as well as brain parenchyma [5]. Review of the literature identified few reports where the use of fluconazole was highly successful despite its lower efficacy and high chance of developing resistance than itraconazole [6-8]. Patients who do not tolerate itraconazole, or unable to achieve adequate blood levels with either preparation, or are receiving concomitant medications that lead to serious drug interactions with itraconazole, fluconazole may be alternative option like our patient who relapsed while on ICZ therapy which could be either patient non-compliance or intolerance due to drug. Newer azoles (posaconazole, voriconazole) also demonstrate in vitro activity against H. capsulatum similar to itraconazole; absence of in vivo data makes them less favorable [9]. Until more research is done to establish the safety and efficacy of these new azole medications, these drugs are not encouraged to treat the CNS histoplasmosis. New drug delivery systems using nano-particle technology to achieve high concentrations of ICZ into brain tissue might be an option in the near future [10,11].\n\nConclusions\nPatients with disseminated histoplasmosis should be screened for CNS histoplasmosis as it may help to determine the type of treatment. Fluconazole has higher CSF and brain penetration. There are reported cases of successful treatment of CNS histoplasmosis with fluconazole. While it remains an alternative option for patients who do not tolerate itraconazole or fail to achieve target serum drug levels, more studies are needed to establish dosing, safety and efficacy. Newer azoles like posaconazole, voriconazole with in vitro activity against H. capsulatum and new drug delivery systems to achieve better CSF penetration show promise for treatment options in the future. Our case report highlights the need for further research in terms of standard of care for CNS histoplasmosis treatment.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Histoplasmosis with deep CNS involvement: case presentation with discussion and literature review J Neurol Surg Rep Hariri OR Minasian T Quadri SA Dyurgerova A Farr S Miulli DE Siddiqi J 167 172 76 2015 \n2 Central nervous system histoplasmosis: multicenter retrospective study on clinical features, diagnostic approach and outcome of treatment Medicine (Baltimore) Wheat J Myint T Guo Y 245 97 2018 \n3 Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America Clin Infect Dis Wheat LJ Freifeld AG Kleiman MB Baddley JW McKinsey DS Loyd JE Kauffman CA 807 825 45 2007 17806045 \n4 Clinical relevance of the pharmacokinetic interactions of azole antifungal drugs with other coadministered agents Clin Infect Dis Brüggemann RJ Alffenaar JW Blijlevens NM 1441 1458 48 2009 19361301 \n5 Diagnosis and management of central nervous system histoplasmosis Clin Infect Dis Wheat LJ Musial CE Jenny-Avital E 844 852 40 2005 15736018 \n6 A case of HIV-associated cerebral histoplasmosis successfully treated with fluconazole Eur J Clin Microbiol Infect Dis Knapp S Turnherr M Dekan G Willinger B Stingl G Rieger A 658 661 18 1999 10534189 \n7 Fluconazole therapy for histoplasmosis Clin Infect Dis McKinsey DS Kauffman CA Pappas PG 996 1001 23 1996 8922792 \n8 Disseminated histoplasmosis treated by boluses of fluconazole. (Article in French) Med Sante Trop Mandengue Ebenye C Takuefou Mfangam B Nouédoui C Atangana PJA 110 111 25 2015 24854365 \n9 Activity of newer triazoles against Histoplasma capsulatum from patients with AIDS who failed fluconazole J Antimicrob Chemother Wheat LJ Connolly P Smedema M 1235 1239 57 2006 16627592 \n10 Targeted brain delivery of itraconazole via RVG29 anchored nanoparticles J Drug Targeting Chen W Zhan C Gu B Meng Q Wang H Lu W Hou H 228 234 19 2011 \n11 Formulation and delivery of itraconazole to the brain using a nanolipid carrier system Int J Nanomed Lim WM Rajinikanth PS Mallikarjun C Kang Y 2117 2126 9 2014\n\n", "fulltext_license": "CC BY", "issn_linking": "2168-8184", "issue": "12(2)", "journal": "Cureus", "keywords": "cns penetration; histoplasmosis; itraconazole; ring enhancing lesions; treatment failure", "medline_ta": "Cureus", "mesh_terms": null, "nlm_unique_id": "101596737", "other_id": null, "pages": "e7064", "pmc": null, "pmid": "32226666", "pubdate": "2020-02-21", "publication_types": "D002363:Case Reports", "references": "19361301;8922792;24833900;24854365;29595679;17806045;20540685;10534189;16627592;26251798;15736018", "title": "A Case of Histoplasmosis with Central Nervous System Relapse after Itraconazole Therapy Needs Further Research.", "title_normalized": "a case of histoplasmosis with central nervous system relapse after itraconazole therapy needs further research" }

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{ "abstract": "To analyze patterns of response in soft tissue sarcomas exposed to pazopanib using CT-morphologic and textural features and their suitability for evaluating therapeutic response.\nRetrospective evaluation of CT response and texture patterns in 33 patients (23 female; mean age: 61.2 years, range, 30-85 years) with soft tissue sarcomas treated with pazopanib from October 2008 to July 2017. Response evaluation was based on modified (m)CHOI-criteria and RECISTv.1.1 and classified as partial response (PR), stable disease (SD), progressive disease (PD). The following CT-texture (CTTA)-parameters were calculated: mean, entropy and uniformity of intensity/average/skewness/entropy of co-occurrence matrix and contrast of neighboring-gray-level-dependence-matrix.\nFollowing mCHOI-criteria, 12 patients achieved PR, 7 SD and 14 PD. As per RECISTv.1.1 9 patients obtained PR, 9 SD and 15 PD. Frequent patterns of response were tumor liquefaction and necrosis (n=4/33, 12.1% each). Further patterns included shrinkage and cavitation (n=2/33, 6.1% each). In responders, differences in mean heterogeneity (p=0.01), intensity (p=0.03), average (p=0.03) and entropy of skewness (p=0.01) were found at follow-up whereas in non-responders, CTTA-parameters did not change significantly. Baseline-CTTA-features differed between responders and non-responders in terms of uniformity of skewness (p=0.045). Baseline-CTTA-parameters did not correlate with any morphologic response pattern.\nMost frequent patterns of response to pazopanib were tumor liquefaction and necrosis. Single CT-textural features show strong association with the response to pazopanib-although limited in relation to specific response patterns.\nTumor liquefication and necrosis are important patterns of response to pazopanib. CT-texture analysis has limited associations with specific response patterns.", "affiliations": "Department of Diagnostic and Interventional Radiology, Eberhard-Karls-University, Hoppe-Seyler-Str.3, 72076 Tübingen, Germany.;Department of Diagnostic and Interventional Radiology, Ulm University, Albert-Einstein-Allee 23, 89081 Ulm, Germany.;Department of Diagnostic and Interventional Radiology, Eberhard-Karls-University, Hoppe-Seyler-Str.3, 72076 Tübingen, Germany.;Department of Diagnostic and Interventional Radiology, Eberhard-Karls-University, Hoppe-Seyler-Str.3, 72076 Tübingen, Germany.;Department of Diagnostic and Interventional Radiology, Eberhard-Karls-University, Hoppe-Seyler-Str.3, 72076 Tübingen, Germany.;Department of Diagnostic and Interventional Radiology, Eberhard-Karls-University, Hoppe-Seyler-Str.3, 72076 Tübingen, Germany.;Department of Diagnostic and Interventional Radiology, Eberhard-Karls-University, Hoppe-Seyler-Str.3, 72076 Tübingen, Germany.", "authors": "Esser|Michael|M|;Kloth|Cristopher|C|;Thaiss|Wolfgang M|WM|;Reinert|Christian P|CP|;Kraus|Mareen S|MS|;Gast|Gabriel Cc|GC|;Horger|Marius|M|", "chemical_list": "D000970:Antineoplastic Agents; D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib", "country": "England", "delete": false, "doi": "10.1259/bjr.20190158", "fulltext": null, "fulltext_license": null, "issn_linking": "0007-1285", "issue": "92(1103)", "journal": "The British journal of radiology", "keywords": null, "medline_ta": "Br J Radiol", "mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D005260:Female; D006801:Humans; D007191:Indazoles; D008297:Male; D008875:Middle Aged; D011743:Pyrimidines; D012189:Retrospective Studies; D012509:Sarcoma; D012983:Soft Tissue Neoplasms; D013449:Sulfonamides; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome", "nlm_unique_id": "0373125", "other_id": null, "pages": "20190158", "pmc": null, "pmid": "31509443", "pubdate": "2019-11", "publication_types": "D016428:Journal Article", "references": "19097774;23093486;20456972;29800950;25526682;23714556;19451427;29857858;29846498;25302110;26500539;23079473;23857966;25793653;29230829;25143189;23109517;25798275;29404187;28652049;27663525;25953002;29152166;29127700;30292263;31113389;26119045;29550245;28898189;20610543;28807589;28895916;19261927;24346105", "title": "CT-morphologic and CT-textural patterns of response in inoperable soft tissue sarcomas treated with pazopanib-a preliminary retrospective cohort study.", "title_normalized": "ct morphologic and ct textural patterns of response in inoperable soft tissue sarcomas treated with pazopanib a preliminary retrospective cohort study" }

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CT-MORPHOLOGIC AND CT-TEXTURAL PATTERNS OF RESPONSE IN INOPERABLE SOFT TISSUE SARCOMAS TREATED WITH PAZOPANIB-A PRELIMINARY RETROSPECTIVE COHORT STUDY. 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CT-MORPHOLOGIC AND CT-TEXTURAL PATTERNS OF RESPONSE IN INOPERABLE SOFT TISSUE SARCOMAS TREATED WITH PAZOPANIB-A PRELIMINARY RETROSPECTIVE COHORT STUDY. 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CT-MORPHOLOGIC AND CT-TEXTURAL PATTERNS OF RESPONSE IN INOPERABLE SOFT TISSUE SARCOMAS TREATED WITH PAZOPANIB-A PRELIMINARY RETROSPECTIVE COHORT STUDY. 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CT-MORPHOLOGIC AND CT-TEXTURAL PATTERNS OF RESPONSE IN INOPERABLE SOFT TISSUE SARCOMAS TREATED WITH PAZOPANIB-A PRELIMINARY RETROSPECTIVE COHORT STUDY. 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CT-MORPHOLOGIC AND CT-TEXTURAL PATTERNS OF RESPONSE IN INOPERABLE SOFT TISSUE SARCOMAS TREATED WITH PAZOPANIB-A PRELIMINARY RETROSPECTIVE COHORT STUDY. 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{ "abstract": "Chronic leg ulceration is a frequent condition in elderly patients. Chronic wounds that are nonresponsive to 3-month therapy affect approximately 6.5 million people in the United States with a prevalence of 1% and costs estimated at 25 billion dollars per year. Although the main causes are venous insufficiency, lower extremity arterial disease and diabetes, in many cases the etiology is multi-factorial. Approximately 20-23% of non-healing wounds that are refractory to vascular intervention have other etiologies including vasculitis, rheumatoid arthritis and Sjögren syndrome. Adverse drug interactions are the least commonly considered, especially those which involve disease-modifying anti-rheumatic drugs. The authors present a report on a female patient with reported Sjögren syndrome, multiple morbidities and non-healing lower limb ulceration that developed during treatment with methotrexate, and no significant improvement after discontinuation of the drug and after vascular surgery. Microvascular deterioration caused by beta-blockers was considered decisive. Calcium-blocker replacement brought complete healing in the follow-up.", "affiliations": "Department of Geriatrics, National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland.;Department of Geriatrics, National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland.;Department of Geriatrics, National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland.;Department of Geriatrics, National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland.", "authors": "Sławiński|Piotr|P|;Radkowski|Marcin|M|;Lewandowicz|Andrzej|A|;Targowski|Tomasz|T|", "chemical_list": null, "country": "Poland", "delete": false, "doi": "10.5114/reum.2019.86429", "fulltext": "\n==== Front\nReumatologiaReumatologiaRUReumatologia0034-62332084-9834Narodowy Instytut Geriatrii, Reumatologii i Rehabilitacji w Warszawie 8642910.5114/reum.2019.86429Case ReportMixed-etiology leg ulcers in a patient on long-term glucocorticoid therapy Sławiński Piotr Radkowski Marcin Lewandowicz Andrzej Targowski Tomasz Department of Geriatrics, National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, PolandAddress for correspondence: Piotr Sławiński, Department of Geriatrics, National Institute of Geriatrics, Rheumatology and Rehabilitation, 1 Spartańska St., 02-637 Warszawa, Poland. e-mail: [email protected] 6 2019 2019 57 3 173 177 26 2 2019 28 5 2019 Copyright: © 2019 Narodowy Instytut Geriatrii, Reumatologii i Rehabilitacji w Warszawie2019This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License, allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.Chronic leg ulceration is a frequent condition in elderly patients. Chronic wounds that are nonresponsive to 3-month therapy affect approximately 6.5 million people in the United States with a prevalence of 1% and costs estimated at 25 billion dollars per year. Although the main causes are venous insufficiency, lower extremity arterial disease and diabetes, in many cases the etiology is multi-factorial. Approximately 20–23% of non-healing wounds that are refractory to vascular intervention have other etiologies including vasculitis, rheumatoid arthritis and Sjögren syndrome. Adverse drug interactions are the least commonly considered, especially those which involve disease-modifying anti-rheumatic drugs.\n\nThe authors present a report on a female patient with reported Sjögren syndrome, multiple morbidities and non-healing lower limb ulceration that developed during treatment with methotrexate, and no significant improvement after discontinuation of the drug and after vascular surgery. Microvascular deterioration caused by beta-blockers was considered decisive. Calcium-blocker replacement brought complete healing in the follow-up.\n\nmicrocirculation disordersleg ulcerschronic ulcersbeta-blockers\n==== Body\nIntroduction\nChronic ulceration of lower limbs is a frequent condition with a prevalence of 3–5% in the population over 65 [1] and about 8% of elderly patients aged 85 and over. Around 50–70% of treated ulcers heal within 4–6 months, and 8% heal over the next 5 years [2]. Chronic wounds that are unresponsive to 3 months of appropriate wound care affect approximately 6.5 million people in the United States of America (US) with a prevalence of 1% and costs estimated at 25 billion dollars per year [3]. Although the main causes are venous insufficiency, lower extremity arterial disease and diabetes, in many cases the etiology is multi-factorial. In a study in the London population of patients with leg ulcers, venous disease was diagnosed simultaneously with arterial disease, diabetes, lymphedema and rheumatoid arthritis; in 35% of cases more than one cause of leg ulcers occurred [4].\n\nLegs ulcers are a frequent problem in patients with rheumatoid arthritis (RA) and in patients with systemic sclerosis. Approximately 10% of patients with RA experienced leg ulceration. Larger studies have found that at least half of the ulcers in these patients are of multifactorial etiology. Approximately 10% of patients with RA are affected by leg ulcers while as many as 10% of leg ulcers can be associated with RA [5]. Approximately 20–23% of non-healing wounds that are refractory to vascular intervention have other etiology including vasculitis, RA, scleroderma, systemic lupus erythematosus, psoriasis, pyoderma gangrenosum [6], and Sjögren syndrome [7]. Thus, for proper treatment of patients with leg ulcers, it is important to be aware of the differential diagnosis of leg ulceration.\n\nThis article presents a patient with diagnosis of Sjögren’s syndrome, multiple other morbidities and non-healing lower limb ulceration of mixed etiology and highlights the importance of drug selection to optimize microcirculation in anti-ulcerative treatment.\n\nCase report\nAn 82-year-old woman with a long history of sicca syndrome diagnosis, metabolic syndrome comprising obesity, arterial hypertension, and hyperlipidemia, as well as Hashimoto thyroiditis with thyroid insufficiency, congestive heart failure, chronic kidney disease, bilateral cataract and lower limb ulcers, was admitted to the Department of Geriatrics in July 2016 due to symptoms of acute circulatory failure with pitting edema of lower limbs.\n\nIn the last 10-year period, the patient had undergone long-term glucocorticosteroid treatment for Sjögren syndrome. There was no available medical documentation for this period. In 2014, the patient had been hospitalized in the rheumatology department because of acute exacerbation of arthralgia and myalgia shortly after a sudden glucocorticosteroids withdrawal. There were symmetrical hand arthralgias without other signs of inflammation but with an elevated erythrocyte sedimentation rate and C-reactive protein concentration, with negative rheumatoid factor (RF), negative anti-cyclic citrullinated peptide antibodies (ACPA) and antinuclear antibodies (ANA) titer 1 : 80 (Table I). Comparative hand (Fig. 1) and feet radiograms and spine radiograms showed mainly osteoarthritic changes with multiple geodes. Radiograms also revealed calcifications in arterial walls. Schirmer’s test showed decrease of tear secretion (3 mm/5 min in both eyes); there were signs and symptoms of conjunctivitis sicca.\n\nTable I Results of laboratory tests\n\nParameter\tMay 2014\tMarch 2016\tJuly 2016\tOctober 2016\tJuly 2018\t\nRF\t20.0 IU/ml\t20.0 IU/ml\tNo data\tNo data\tNo data\t\nACPA\t< 7.00 U/ml\t< 7.00 U/ml\tNo data\tNo data\tNo data\t\nANA\t1 : 80\t1 : 640\tNo data\tNo data\tNo data\t\nCRP\t58 mg/l\n552.39 nmol/l\t33 mg/l\n314.29 nmol/l\t45 mg/l\n428.58 nmol/l\t19 mg/l\n180.96 nmol/l\t11 mg/l\n104.76 nmol/l\t\nESR\t56 mm/h\t83 mm/h\t95 mm/h\t107 mm/h\t56 mm/h\t\nCreatinine\t0.7 mg/dl\n53.38 μmol/l\t2.0 mg/dl\n152.50 μmol/l\t1.0 mg/dl\n76.25 μmol/l\t0.9 mg/dl\n68.63 μmol/l\t1.10 mg/d\nl83.88 μmol/l\t\nNT-proBNP\tNo data\tNo data\t1100 pg/ml\n130.06 pmol/l\t936.8 pg/ml\n110.77 pmol/l\t783.5 pg/ml\n92.64 pmol/l\t\nRF – rheumatoid factor, ACPA – anti-cyclic citrullinated peptide antibodies, ANA – antinuclear antibodies, CRP – C-reactive protein, ESR – erythrocyte sedimentation rate, NT-proBNP – N-terminal pro-brain natriuretic peptide.\n\nFig. 1 Hands radiogram – osteoarthritic changes with geodes.\n\nThere was no objective confirmation of mouth dryness. The described patient did not agree to a biopsy of the minor salivary glands. The patient did not meet ACR/EULAR 2010 [8] criteria for diagnosis of RA. The patient was diagnosed with unclassified arthritis and successfully treated with methotrexate in an initial dose of 10 mg per week which was increased to 15 mg per week and a small dose of methylprednisolone.\n\nIn March 2016, the patient was re-hospitalized in the same department because of lower limb, shoulder girdle and knee pain, and calf edema. The patient reported night leg pain. Physical examination did not reveal symptoms of joint inflammation but extensive ulcers in both legs with purulent exudation were presented. Laboratory inflammatory markers were elevated, which is presented in Table I.\n\nUltrasonography of the joints and radiography findings matched osteoarthritis and did not support arthritis diagnosis at that moment. Therefore, methotrexate was discontinued and the patient was treated with antibiotics according to the wound culture. After the start of treatment outpatient care was recommended.\n\nDuring the next hospitalization to the Department of Geriatrics in July 2016, the patient reported weakness, dyspnea, orthopnea, mouth and eye dryness, night pain of both lower limbs resulting in sleeplessness and excessive consumption of non-steroid anti-inflammatory analgesics. Due to general weakness and pain the patient spent most time in bed. The list of medications taken by the patient included bisoprolol, ramipril, indapamide, L-thyroxine, allopurinol, naproxen, tramadol, acetaminophen, omeprazole, ibandronic acid and cholecalciferol.\n\nThe examination revealed two extensive ulcerations of lower limbs covering around 2/3 of the right and half of the left calf circumference (Fig. 2A). The patient was hypotonic and hypervolemic. There was crepitation on both lung bases indicating heart failure. The peripheral arterial pulse was hardly palpable. Laboratory tests revealed anemia, elevated inflammatory markers, hyponatremia, and elevated N-terminal pro-brain natriuretic peptide (NT-proBNP) (results summarized in Table I).\n\nFig. 2 Legs ulcerations – healing progress. (A) 13.07.2016, (B) 13.10.2016, (C) 27.01.2017, (D) 19.10.2017.\n\nKlebsiella pneumoniae and Serratia marcescens strains were cultured from the ulcers. Chronic heart failure exacerbation (NYHA III/IV), chronic kidney disease exacerbation, anemia of chronic disease and mixed-etiology leg ulcers were diagnosed.\n\nWounds were debrided, topical and systemic (empirical and targeted) antibiotics were used, analgesics, diuretics were administered and dressings were applied. Due to a significant reduction in hemoglobin concentration and to improve healing conditions it was necessary to transfuse the red blood cell concentrate. No evident positive effect was achieved in treatment of legs ulcers, which remained deep, inflamed, with purulent discharge. Resting lower limb pain persisted. The Doppler ultrasound revealed occlusion of the right femoral artery. The patient was referred for surgery in which femoral-popliteal bypass surgery was performed. A significant reduction in leg edema was observed. Pain complaints resolved almost completely.\n\nIn October 2016, about 3 months after the bypass surgery, the patient was admitted to a regional hospital with critical ischemia of the right lower limb suspected, with accompanying inflammation. Leg amputation was considered, but the patient did not agree to such radical treatment. Therefore the patient was transferred to the Department of Geriatrics for conservative treatment. On admission physical examination revealed extensive deep ulceration of 2/3 of the right calf circumference and two ulcerations on the outer surface of the left calf with dimensions comparable to those during the previous discharge (Fig. 2B), palpable right inguinal lymph nodes, which were confirmed in ultrasound, and large subcutaneous edema, especially of the right limb.\n\nBased on a repeated wound smear culture, targeted ceftazidime was administered intravenously for 11 days. A very slow healing process was noted, and microvascular disorders were taken into consideration as a decisive factor for the impaired healing. Actual cardiology treatment was modified – beta-blocker treatment was replaced with a non-dihydropyridine calcium channel blocker because of a suspected mechanism of peripheral microvascular deterioration by beta-receptor inhibition. Also a vasodilatory drug (bencyclane) was added.\n\nIn the next two weeks a significant reduction in the depth and dimensions of ulcers was observed. Control wound smear cultures were negative. The patient learned to walk with crutches and was discharged to outpatient care. The patient was informed about proper, intensified wound hygiene and change of dressings.\n\nIn the next few weeks, the healing of the left leg ulcer was complete and the right leg ulcer reduced to superficial and 1/3 of the previous size in a follow-up after several months (Figs. 2C and 2D). At the follow-up in July 2018, both legs were cicatrized, the patient was self-reliant in basic daily activities, walking on crutches, painless.\n\nDiscussion\nContemporary medicine offers a broad choice of therapies in leg ulcer healing, varying from conservative treatment with vasodilatory drugs, more and more sophisticated wound dressings, through more aggressive therapy for underlying autoimmune using disease-modifying antirheumatic drugs and biological agents such as TNF-α inhibitors and rituximab as treatment for RA-associated leg ulcers [6], to vascular surgery and split skin grafting [5].\n\nThis case report is intended to underline the role of differential diagnosis in the decision-making process of selecting the appropriate therapy in lower limb ulcers. The proper diagnosis of all factors in ulcer pathogenesis leads to the selection of a suitable therapy and successful healing. Studies showed that glucocorticoids may predispose to skin fragility and thus serve as a risk factor for ulceration in patients with RA and potential other autoimmune diseases as Sjögren’s syndrome. Sometimes it can be difficult to differentiate whether the cause of ulceration is the effect of the disease itself or an adverse effect of the treatment applied for this disease.\n\nIn Sjögren syndrome, leg ulcers may occur as a consequence of leukocytoclastic vasculitis [7]. In such cases, skin biopsy should be performed and other systemic vasculitides should be considered in the differential diagnosis. Laboratory testing for component of complement, anti-neutrophil antibodies and cryoglobulins is indicated. Signs of inflammatory vasculitis ulcers are very similar or the same as in more often ischemic or venous ulcers.\n\nIn this case, the diagnosis of Sjögren syndrome remains controversial. Unfortunately, there is no available objective medical documentation prior to 2014, and all data come from the anamnesis. The patient refused a salivary gland biopsy in the past. Moreover, starting from 2014, the patient did not fulfill the criteria of primary Sjögren syndrome at any stage of the therapy. Rheumatoid factor was negative, ANA titer was initially negative, only in 2016 they were 1 : 640 but without specificity. Anti-Ro/SSA, La/SSB and other ENA antibodies were not detected by dot-blot method in particular [8]. Maślińska et al. [9] describe a positive correlation between ANA titer, anti-Ro, anti-La antibodies and erythrocyte sedimentation rate (ESR) in patients with primary Sjögren syndrome, as important factors in the inflammatory process. Elevated C-reactive protein (CRP) and ESR in the present case were not associated with an autoimmune disease, but with a bacterial wound infection. Thus, we did not perform a skin biopsy and other immune tests. It is worth remembering that a geriatric patient can be afebrile even in a serious infection, and the only signs and symptoms could be discrete changes of mental state, weakness, falls, etc.\n\nWe believe that the reported mouth and eye dryness along with the positive Schirmer’s test were consequences of polypragmasy and the aging process. Smidt et al. [10] found in their cohort study that oral and ocular dryness in older people is correlated with the number of medications used and the number of comorbidities. A diagnosis of more than four diseases was related to 19.7% prevalence of oral and 16.4% prevalence of ocular dryness; the use of more than 6 medications was related to 19.6% prevalence of both. High prevalence and odds ratios for mouth dryness was associated with metabolic diseases (31%), intake of thyroid hormones (27%), beta-blockers (11.8%), paracetamol, and opioids (33.3%), proton pump inhibitors (15.9%), bisphosphonates (25%), diuretics (12.8%) and ACE inhibitors (12%). The patient described was treated with a majority of medications mentioned above.\n\nLeg ulcers emerged about six months after the treatment with methotrexate had started. This immunosuppressive agent changes the immune response to microbes, which in our opinion was crucial for this patient. Even a small injury to the skin exposed to glucocorticosteroids for many years could become easily infected. Unfavorable healing conditions, such as atherosclerotic ischemia, impaired venous flow and immobilization caused by pain promote deep and infected ulcerations. Unfortunately, in 2014, the clinical and radiological image was too unclear to definitely exclude autoimmune arthritis, and the patient was lost from observation for the next two years.\n\nAll these factors resulted in a “net disease” with ulcers of complex etiology as a main symptom. Although the patient received multidisciplinary treatment, a simple change of pharmacotherapy could rupture the net.\n\nMany studies evaluate positive effects of different approaches, but there are very few publications addressing adverse effects of joint therapies which may have detrimental effect on healing. One of our considerations is deterioration of microcirculation caused by the use of beta-blockers. While there is no doubt as to the beneficial influence of this pharmacological class on the circulatory system, we want to point out some specific situations, when these drugs could be harmful. Especially the population of elderly patients, with the burden of atherosclerosis involving small blood vessels, could be prone to deterioration of blood flow due to the blockade of peripheral β-1 receptors, even despite the use of a cardioselective drug (nebivolol) with a vasodilatory component, as we observed in the case described herein.\n\nConclusions\nIt seems that despite the lack of clear recommendations concerning this issue [11–13], replacing the beta blocker with a non-dihydropyridine calcium channel blocker could be critical for healing leg ulcers in some groups of elderly patients.\n\nThe authors declare no conflicts of interest.\n\nAcknowledgments\nThe authors would like to thank Professor Iwona Sudoł-Szopińska, Head of the Radiology Department in the National Institute of Geriatrics, Rheumatology and Rehabilitation for providing them with access to the radiology imaging, and would like to address words of particular gratitude to Doctor Agnieszka Skoczylas for her valuable comments concerning their paper.\n==== Refs\nReferences\n1 Mekkes JR Loots MA Van Der Wal AC Bos JD Causes, investigation and treatment of leg ulceration Br J Dermatol 2003 148 388 401 12653729 \n2 Tendera M Aboyans V Barterlink ML and ESC Committee for Practice Guidelines. ESC Guidelines on the diagnosis and treatment of peripheral artery diseases: Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries: the Task Force on the Diagnosis and Treatment of Peripheral Artery Diseases of the European Society of Cardiology (ESC) Eur Heart J 2011 32 2851 2906 21873417 \n3 Shanmugam VK Angra D Rahim H McNish S Vasculitic and autoimmune wounds J Vasc Surg Venous Lymphat Disord 2017 5 280 292 28214498 \n4 Moffatt CJ Franks PJ Doherty DC Prevalence of leg ulceration in a London population QIM 2004 97 431 471 \n5 Hafne J Schneider E Burg G Cassina PC Management of leg ulcers in patients with rheumatoid arthritis or systemic sclerosis: The importance of concomitant arterial and venous disease J Vasc Surg 2000 32 322 329 10917993 \n6 Shanmugam VK Vasculitic Diseases and Prothrombotic States Contributing to Delayed Healing in Chronic Wounds Curr Dermatol Rep 2016 5 270 277 27833788 \n7 Chapnick SL Merkel PA Skin ulcers in a patient with Sjogren’s Syndrome Arthritis Care Res (Hoboken) 2010 62 1040 1046 20235199 \n8 Aletaha D Neogi T Silman AJ 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative Arthritis Rheum 2010 62 2569 2581 20872595 \n9 Maślińska M Kontny E Kwiatkowska B The relationship between the presence of autoantibodies, indicators of local and systemic inflammation, the serum concentration of B-cell activating factor (BAFF) and the intensity of salivary gland infiltration in patients with primary Sjögren’s syndrome – a preliminary study Reumatologia 2015 53 321 327 27407265 \n10 Smidt D Torpet LA Nauntofte B Associations between oral and ocular dryness, labial and whole salivary flow rates, systemic diseases and medications in a sample of older people Community Debt Oral Epidemiol 2011 39 276 288 \n11 Frołow M Leśniak W Masłowski L Przewlekłe niedokrwienie kończyn dolnych Interna Szczeklika, Medycyna Praktyczna, Kraków 2018 496 503 \n12 Paravastu SC Mendonca DA Da Silva A Beta blockers for peripheral arterial disease Cochrane Database Syst Rev 2013 CD005508 24027118 \n13 Csiki Z Garai I Shemirani AH The effect of metoprolol alone and combined metoprolol-felodipin on the digital microcirculation of patients with primary Raynaud’s syndrome Microvasc Res 2011 82 84 87 21515290\n\n", "fulltext_license": "CC BY-NC-SA", "issn_linking": "0034-6233", "issue": "57(3)", "journal": "Reumatologia", "keywords": "beta-blockers; chronic ulcers; leg ulcers; microcirculation disorders", "medline_ta": "Reumatologia", "mesh_terms": null, "nlm_unique_id": "20130190R", "other_id": null, "pages": "173-177", "pmc": null, "pmid": "31462834", "pubdate": "2019", "publication_types": "D002363:Case Reports", "references": "10917993;12653729;15208431;20235199;20872595;21070322;21515290;21873417;24027118;27407265;27833788;28214498", "title": "Mixed-etiology leg ulcers in a patient on long-term glucocorticoid therapy.", "title_normalized": "mixed etiology leg ulcers in a patient on long term glucocorticoid therapy" }

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"medicinalproduct": "BISOPROLOL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBANDRONATE SODIUM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBANDRONATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RAMIPRIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RAMIPRIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "INDAPAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INDAPAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TRAMADOL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAMADOL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVOTHYROXINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "L-THYROXINE /00068001/" } ], "patientagegroup": null, "patientonsetage": "82", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Dry eye", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Insomnia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Pain in extremity", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dry mouth", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Impaired healing", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SLAWINSKI P, RADKOWSKI M, LEWANDOWICZ A, TARGOWSKI T. MIXED-ETIOLOGY LEG ULCERS IN A PATIENT ON LONG-TERM GLUCOCORTICOID THERAPY. REUMATOLOGIA 2019?57(3):173-177.", "literaturereference_normalized": "mixed etiology leg ulcers in a patient on long term glucocorticoid therapy", "qualification": "3", "reportercountry": "PL" }, "primarysourcecountry": "PL", "receiptdate": "20190808", "receivedate": "20190808", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16683308, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20191004" }, { "companynumb": "PL-ROCHE-2389340", "fulfillexpeditecriteria": "1", "occurcountry": "PL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PARACETAMOL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CHOLECALCIFEROL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CHOLECALCIFEROL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "NAPROXEN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NAPROXEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBANDRONIC ACID" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021455", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBANDRONIC ACID." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN,UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ARTHRITIS", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "INDAPAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INDAPAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVOTHYROXINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOTHYROXINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TRAMADOL HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAMADOL HYDROCHLORIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BISOPROLOL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BISOPROLOL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN,UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ALLOPURINOL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALLOPURINOL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RAMIPRIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RAMIPRIL." } ], "patientagegroup": null, "patientonsetage": "82", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Asthenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Serratia infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pain in extremity", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Orthopnoea", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dyspnoea", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dry mouth", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Skin ulcer", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Insomnia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dry eye", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Klebsiella infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201603" } }, "primarysource": { "literaturereference": "STAWINSKI P, RADKOWSKI M, LEWANDOWICZ A AND TARGOWSKI T. MIXED?ETIOLOGY LEG ULCERS IN A PATIENT ON LONG?TERM GLUCOCORTICOID THERAPY. REUMATOLOGIA 2019?57 (3):173?7.", "literaturereference_normalized": "mixed etiology leg ulcers in a patient on long term glucocorticoid therapy", "qualification": "1", "reportercountry": "PL" }, "primarysourcecountry": "PL", "receiptdate": "20191022", "receivedate": "20191022", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16944388, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20201105" }, { "companynumb": "PL-JNJFOC-20190804474", "fulfillexpeditecriteria": "1", "occurcountry": "PL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBANDRONIC ACID" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBANDRONIC ACID." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ARTHRITIS", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "201509", "drugstartdateformat": "610", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "DOSE INCREASED", "drugenddate": "201603", "drugenddateformat": "610", "drugindication": null, "drugintervaldosagedefinition": "803", 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"602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ALLOPURINOL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALLOPURINOL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CHOLECALCIFEROL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CHOLECALCIFEROL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "019872", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PARACETAMOL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RAMIPRIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RAMIPRIL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "NAPROXEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NAPROXEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVOTHYROXINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOTHYROXINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "INDAPAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INDAPAMIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "BISOPROLOL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BISOPROLOL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TRAMADOL HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAMADOL HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": "82", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Dry eye", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dry mouth", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201607" } }, "primarysource": { "literaturereference": "SLAWINSKI P, RADKOWSKI M, LEWANDOWICZ A, TARGOWSKI T. MIXED?ETIOLOGY LEG ULCERS IN A PATIENT ON LONG?TERM GLUCOCORTICOID THERAPY. REUMATOLOGIA. 2019?57 (3):173?177.", "literaturereference_normalized": "mixed etiology leg ulcers in a patient on long term glucocorticoid therapy", "qualification": "1", "reportercountry": "PL" }, "primarysourcecountry": "PL", "receiptdate": "20200615", "receivedate": "20190813", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16695796, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20201104" }, { "companynumb": "PL-ACCORD-149475", "fulfillexpeditecriteria": "1", "occurcountry": "PL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "SMALL DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2016", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RAMIPRIL" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "202392", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RAMIPRIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CHOLECALCIFEROL" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "COLECALCIFEROL" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "040716", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201509", "drugstartdateformat": "610", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PARACETAMOL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBANDRONIC ACID" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "206058", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBANDRONIC ACID." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVOTHYROXINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOTHYROXINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "INDAPAMIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INDAPAMIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "BISOPROLOL" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BISOPROLOL" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "040716", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DOSE INCREASED", "drugenddate": "201603", "drugenddateformat": "610", "drugindication": "ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TRAMADOL" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAMADOL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALLOPURINOL" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALLOPURINOL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "NAPROXEN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NAPROXEN." } ], "patientagegroup": null, "patientonsetage": "82", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Serratia infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Dry mouth", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Skin ulcer", "reactionmeddraversionpt": "23.1", "reactionoutcome": "4" }, { "reactionmeddrapt": "Dry eye", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Klebsiella infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201603" } }, "primarysource": { "literaturereference": "SLAWINSKI P, RADKOWSKI M, LEWANDOWICZ A, TARGOWSKI T. MIXED?ETIOLOGY LEG ULCERS IN A PATIENT ON LONG?TERM GLUCOCORTICOID THERAPY. REUMATOLOGIA. 2019?57(3):173?177.", "literaturereference_normalized": "mixed etiology leg ulcers in a patient on long term glucocorticoid therapy", "qualification": "1", "reportercountry": "PL" }, "primarysourcecountry": "PL", "receiptdate": "20190806", "receivedate": "20190730", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16646289, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201104" }, { "companynumb": "PL-TEVA-2019-PL-1093605", "fulfillexpeditecriteria": "1", "occurcountry": "PL", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "BISOPROLOL" }, "drugadditional": "1", "drugadministrationroute": "065", 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"reactionmeddrapt": "Skin ulcer", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Impaired healing", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SLAWINSKI P, RADKOWSKI M, LEWANDOWICZ A, TARGOWSKI T. MIXED?ETIOLOGY LEG ULCERS IN A PATIENT ON LONG?TERM GLUCOCORTICOID THERAPY. 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"drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NAPROXEN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DOSE INCREASED", "drugenddate": "201603", "drugenddateformat": "610", "drugindication": null, "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." } ], "patientagegroup": null, "patientonsetage": "82", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Skin ulcer", "reactionmeddraversionpt": "23.1", "reactionoutcome": "4" }, { "reactionmeddrapt": "Chronic kidney disease", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Infected skin ulcer", "reactionmeddraversionpt": "23.1", "reactionoutcome": "4" }, { "reactionmeddrapt": "Cardiac failure chronic", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Impaired healing", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Klebsiella infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Anaemia of chronic disease", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Serratia infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2016" } }, "primarysource": { "literaturereference": "SLAWINSKI P, RADKOWSKI M. MIXED?ETIOLOGY LEG ULCERS IN A PATIENT ON LONG?TERM GLUCOCORTICOID THERAPY. REUMATOLOGIA. 2019?57(3):173?7.", "literaturereference_normalized": "mixed etiology leg ulcers in a patient on long term glucocorticoid therapy", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": null, "receiptdate": "20190801", "receivedate": "20190729", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16641860, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201104" }, { "companynumb": "PL-PFIZER INC-2019320250", "fulfillexpeditecriteria": "1", "occurcountry": "PL", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, WEEKLY (INITIAL DOSE OF 10 MG PER WEEK)", "drugenddate": null, "drugenddateformat": null, "drugindication": "ARTHRITIS", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "201509", "drugstartdateformat": "610", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEVOTHYROXINE SODIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOTHYROXINE SODIUM." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "15 MG, WEEKLY DOSE INCREASED (15 MG,1 IN 1 WK)", "drugenddate": "201603", "drugenddateformat": "610", "drugindication": null, "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "011153", "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK (SMALL DOSE)", "drugenddate": null, "drugenddateformat": null, "drugindication": "ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2016", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TRAMADOL HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAMADOL HYDROCHLORIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "BISOPROLOL FUMARATE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BISOPROLOL FUMARATE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CHOLECALCIFEROL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CHOLECALCIFEROL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RAMIPRIL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RAMIPRIL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "NAPROXEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NAPROXEN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "INDAPAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INDAPAMIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ALLOPURINOL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALLOPURINOL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "IBANDRONIC ACID" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBANDRONIC ACID." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PARACETAMOL" } ], "patientagegroup": null, "patientonsetage": "82", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Skin ulcer", "reactionmeddraversionpt": "23.0", "reactionoutcome": "4" }, { "reactionmeddrapt": "Klebsiella infection", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Dry eye", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dry mouth", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Insomnia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Serratia infection", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pain in extremity", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201603" } }, "primarysource": { "literaturereference": "SLAWINSKI, P.. MIXED-ETIOLOGY LEG ULCERS IN A PATIENT ON LONG-TERM GLUCOCORTICOID THERAPY. REUMATOLOGIA. 2019?57(3):173-177", "literaturereference_normalized": "mixed etiology leg ulcers in a patient on long term glucocorticoid therapy", "qualification": "1", "reportercountry": "PL" }, "primarysourcecountry": "PL", "receiptdate": "20200619", "receivedate": "20190730", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16647200, "safetyreportversion": 8, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200713" }, { "companynumb": "PL-SA-2019SA199741", "fulfillexpeditecriteria": "1", "occurcountry": "PL", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "BISOPROLOL" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BISOPROLOL SALT NOT SPECIFIED" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVOTHYROXINE SODIUM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK UNK, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOTHYROXINE SODIUM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBANDRONIC ACID" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBANDRONIC ACID." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALLOPURINOL" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALLOPURINOL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CHOLECALCIFEROL" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CHOLECALCIFEROL" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "15 MG, QW DOSE INCREASED", "drugenddate": "201603", "drugenddateformat": "610", "drugindication": null, 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"drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RAMIPRIL." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Insomnia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Renal failure", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intentional product misuse", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Crepitations", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiac failure", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Asthenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypervolaemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dry mouth", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Klebsiella infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Serratia infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pain", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Peripheral swelling", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pain in extremity", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Dyspnoea", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Orthopnoea", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hyponatraemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiac failure chronic", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Skin ulcer", "reactionmeddraversionpt": "23.1", "reactionoutcome": "4" }, { "reactionmeddrapt": "Hypotonia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dry eye", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201603" } }, "primarysource": { "literaturereference": "SLAWINSKI P., RADKOWSKI M., LEWANDOWICZ A., TARGOWSKI T. MIXED?ETIOLOGY LEG ULCERS IN A PATIENT ON LONG?TERM GLUCOCORTICOID THERAPY. REUMATOLOGIA. 2019?57(3):173?177", "literaturereference_normalized": "mixed etiology leg ulcers in a patient on long term glucocorticoid therapy", "qualification": "1", "reportercountry": "PL" }, "primarysourcecountry": "PL", "receiptdate": "20200611", "receivedate": "20190731", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16654003, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201104" }, { "companynumb": "PL-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-216546", "fulfillexpeditecriteria": "1", "occurcountry": "PL", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "201749", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SJOGREN^S SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SJOGREN^S SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Skin ulcer", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SLAWINSKI P, RADKOWSKI M, LEWANDOWICZ A, TARGOWSKI T. MIXED-ETIOLOGY LEG ULCERS IN A PATIENT ON LONG-TERM GLUCOCORTICOID THERAPY. REUMATOLOGIA. 2019?57(3):173-177", "literaturereference_normalized": "mixed etiology leg ulcers in a patient on long term glucocorticoid therapy", "qualification": "3", "reportercountry": "PL" }, "primarysourcecountry": "PL", "receiptdate": "20190812", "receivedate": "20190812", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16691533, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191004" } ]

{ "abstract": "Congenital chylothorax (CC) can result from a congenital malformation or an acquired obstruction or disruption of the thoracic duct. Recently, oral administration of the phosphodiesterase-5 inhibitor, sildenafil, was reported to be effective in resolving non-pulmonary lymphatic malformations in infants and young children. We report a case of CC in a late preterm infant with congenital pulmonary lymphangiectasia where octreotide was not effective, but management with oral sildenafil was successful.", "affiliations": "Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA.;Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA.", "authors": "Malleske|D T|DT|;Yoder|B A|BA|", "chemical_list": "D058986:Phosphodiesterase 5 Inhibitors; D000068677:Sildenafil Citrate", "country": "United States", "delete": false, "doi": "10.1038/jp.2015.10", "fulltext": null, "fulltext_license": null, "issn_linking": "0743-8346", "issue": "35(5)", "journal": "Journal of perinatology : official journal of the California Perinatal Association", "keywords": null, "medline_ta": "J Perinatol", "mesh_terms": "D002916:Chylothorax; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007235:Infant, Premature, Diseases; D008168:Lung; D008171:Lung Diseases; D008200:Lymphangiectasis; D058986:Phosphodiesterase 5 Inhibitors; D000068677:Sildenafil Citrate; D014057:Tomography, X-Ray Computed", "nlm_unique_id": "8501884", "other_id": null, "pages": "384-6", "pmc": null, "pmid": "25917021", "pubdate": "2015-05", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": "22024836;24656411;21364190;22564297;23257321;19019226;17855621;22276841;24997116;15798894;16801173;21538325;15109074;24446440;24372911", "title": "Congenital chylothorax treated with oral sildenafil: a case report and review of the literature.", "title_normalized": "congenital chylothorax treated with oral sildenafil a case report and review of the literature" }

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{ "abstract": "Lamotrigine overdose usually follows a benign pattern, and the majority of cases reported involve a co-ingestant. Prior reports have suggested the possible use of intravenous lipid emulsion in cases of severe sodium channel blockade. We describe the electrocardiographic changes in a massive lamotrigine overdose treated with intravenous lipid emulsion. A 36-year-old male with bipolar disorder ingested 13.5 g of lamotrigine in a suicidal attempt. The lamotrigine level was 78.0 μg/mL. Comprehensive drug screen was negative for all screened compounds. The electrocardiogram demonstrated a prolonged QRS complex and signs suggestive of sodium channel blockade. Refractory to treatment with sodium bicarbonate was treated with intravenous lipid emulsion, with immediate resolution of the electrocardiographic changes. Lamotrigine inhibits the voltage-gated sodium channel opening, attenuating the release of excitatory neurotransmitters. Cardiac intraventricular conduction could be delayed in cases of lamotrigine overdose resulting in QRS and QTc prolongation and R waves >3 mm in leads I and aVR. A potential role for intravenous lipid emulsion therapy has been described in patients with toxic levels of lamotrigine and electrocardiographic changes refractory to the treatment with sodium bicarbonate. Intravenous lipid emulsion has been successfully used in the treatment of lamotrigine cardiac toxicity.", "affiliations": "Division of Cardiology, St. Luke's - Roosevelt Hospital Center, Mount Sinai Health System, Icahn School of Medicine, New York, NY, 10025, USA.;Department of Medicine, St. Luke's - Roosevelt Hospital Center, Mount Sinai Health System, Icahn School of Medicine, 1111 Amsterdam Avenue, New York, NY, 10025, USA. [email protected].;Division of Cardiology, St. Luke's - Roosevelt Hospital Center, Mount Sinai Health System, Icahn School of Medicine, New York, NY, 10025, USA.", "authors": "Chavez|Patricia|P|;Casso Dominguez|Abel|A|;Herzog|Eyal|E|", "chemical_list": "D018692:Antimanic Agents; D014227:Triazines; D061567:Voltage-Gated Sodium Channel Blockers; D000077213:Lamotrigine", "country": "United States", "delete": false, "doi": "10.1007/s12012-014-9300-0", "fulltext": null, "fulltext_license": null, "issn_linking": "1530-7905", "issue": "15(4)", "journal": "Cardiovascular toxicology", "keywords": "Electrocardiogram; Intravenous lipid emulsion; Intraventricular conduction delay; Lamotrigine", "medline_ta": "Cardiovasc Toxicol", "mesh_terms": "D000328:Adult; D018692:Antimanic Agents; D001145:Arrhythmias, Cardiac; D001714:Bipolar Disorder; D062787:Drug Overdose; D004562:Electrocardiography; D006329:Heart Conduction System; D006339:Heart Rate; D006801:Humans; D000077213:Lamotrigine; D008297:Male; D013406:Suicide, Attempted; D013997:Time Factors; D016896:Treatment Outcome; D014227:Triazines; D061567:Voltage-Gated Sodium Channel Blockers", "nlm_unique_id": "101135818", "other_id": null, "pages": "394-8", "pmc": null, "pmid": "25448877", "pubdate": "2015-10", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Evolving Electrocardiographic Changes in Lamotrigine Overdose: A Case Report and Literature Review.", "title_normalized": "evolving electrocardiographic changes in lamotrigine overdose a case report and literature review" }

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EVOLVING ELECTROCARDIOGRAPHIC CHANGES IN LAMOTRIGINE OVERDOSE: A CASE REPORT AND LITERATURE REVIEW. 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"drugstartdateformat": null, "drugstructuredosagenumb": "90", "drugstructuredosageunit": "032", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMOTRIGINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RALTEGRAVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HIV INFECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RALTEGRAVIR." } ], "patientagegroup": null, "patientonsetage": "36", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Electrocardiogram QRS complex prolonged", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Suicide attempt", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intentional overdose", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DOMINGUEZ A, CHAVEZ P, HERZOG E. EVOLVING ELECTROCARDIOGRAPHIC CHANGES IN LAMOTRIGINE OVERDOSE: A CASE REPORT AND LITERATURE REVIEW. CARDIOVASCULAR TOXICOLOGY. 2015;15:394-398.", "literaturereference_normalized": "evolving electrocardiographic changes in lamotrigine overdose a case report and literature review", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160722", "receivedate": "20160722", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 12581587, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20161109" }, { "companynumb": "US-TEVA-605133USA", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LAMOTRIGINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "76420", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MILLIGRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "BIPOLAR DISORDER", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMOTRIGINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RALTEGRAVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HIV INFECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RALTEGRAVIR." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TENOFOVIR DISOPROXIL FUMARATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "HIV INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TENOFOVIR DISOPROXIL FUMARATE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LAMOTRIGINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "76420", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "90 TABLETS OF 150MG (13.5G INGESTION)", "drugenddate": null, "drugenddateformat": null, "drugindication": "OVERDOSE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMOTRIGINE." } ], "patientagegroup": null, "patientonsetage": "36", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Critical illness myopathy", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Suicide attempt", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Electrocardiogram QT prolonged", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Electrocardiogram QRS complex prolonged", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CHAVEZ P, CASSO DOMINGUEZ A, HERZOG E. EVOLVING ELECTROCARDIOGRAPHIC CHANGES IN LAMOTRIGINE OVERDOSE: A CASE REPORT AND LITERATURE REVIEW. CARDIOVASC-TOXICO 2015? 15(4):394-398.", "literaturereference_normalized": "evolving electrocardiographic changes in lamotrigine overdose a case report and literature review", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20151103", "receivedate": "20151103", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11694417, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160304" }, { "companynumb": "US-GLAXOSMITHKLINE-US2014GSK038849", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LAMOTRIGINE" }, "drugadditional": null, 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"drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EPINEPHRINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "NOREPINEPHRINE\\NOREPINEPHRINE BITARTRATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NOREPINEPHRINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "EGG PHOSPHOLIPIDS\\SAFFLOWER OIL\\SOYBEAN OIL" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100-ML BOLUS OF 20% LIPID EMULSION", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "012", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FAT EMULSION NOS" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Circulatory collapse", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Acute lung injury", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Tremor", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sinus tachycardia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Generalised tonic-clonic seizure", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pneumonia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Ventricular fibrillation", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pineal gland cyst", "reactionmeddraversionpt": "18.1", "reactionoutcome": null }, { "reactionmeddrapt": "Ventricular tachycardia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pulmonary oedema", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pleural effusion", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Memory impairment", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Coordination abnormal", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intentional overdose", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cerebral disorder", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Brain injury", "reactionmeddraversionpt": "18.1", "reactionoutcome": null }, { "reactionmeddrapt": "Lung consolidation", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Fine motor skill dysfunction", "reactionmeddraversionpt": "18.1", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "DOMINGUEZ A, CHAVEZ P AND HERZOG E. EVOLVING ELECTROCARDIOGRAPHIC CHANGES IN LAMOTRIGINE OVERDOSE: A CASE REPORT AND LITERATURE REVIEW. CARDIOVASC TOXICOL. 2015?15:394-398", "literaturereference_normalized": "evolving electrocardiographic changes in lamotrigine overdose a case report and literature review", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20151019", "receivedate": "20151019", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11639942, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160304" }, { "companynumb": "US-GLENMARK PHARMACEUTICALS EUROPE LIMITED-2015GMK020132", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LAMOTRIGINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "079099", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "13.5 G, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "13.5", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMOTRIGINE." } ], "patientagegroup": null, "patientonsetage": "36", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Intentional overdose", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Electrocardiogram QRS complex prolonged", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Suicide attempt", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CHAVEZ P, CASSO DOMINGUEZ A, HERZOG E. EVOLVING ELECTROCARDIOGRAPHIC CHANGES IN LAMOTRIGINE OVERDOSE: A CASE REPORT AND LITERATURE REVIEW.. CARDIOVASCULAR TOXICOLOGY.. 2015?15(4):394-398", "literaturereference_normalized": "evolving electrocardiographic changes in lamotrigine overdose a case report and literature review", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20151020", "receivedate": "20151020", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11642872, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" }, { "companynumb": "US-JUBILANT CADISTA PHARMACEUTICALS-2015JUB00354", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LAMOTRIGINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "079132", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "13.5 G, ONCE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "13.5", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMOTRIGINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TENOFOVIR" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TENOFOVIR" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RALTEGRAVIR" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG, 2X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RALTEGRAVIR." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LAMOTRIGINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "079132", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "150 MG, 2X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMOTRIGINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "EMTRICITABINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EMTRICITABINE" } ], "patientagegroup": null, "patientonsetage": "36", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cardiotoxicity", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Electrocardiogram QT prolonged", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Intentional overdose", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Quadriplegia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "4" }, { "reactionmeddrapt": "Suicide attempt", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Sinus tachycardia", "reactionmeddraversionpt": "18.1", "reactionoutcome": null }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "18.1", "reactionoutcome": "4" }, { "reactionmeddrapt": "Critical illness myopathy", "reactionmeddraversionpt": "18.1", "reactionoutcome": "4" }, { "reactionmeddrapt": "Bundle branch block right", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "18.1", "reactionoutcome": null }, { "reactionmeddrapt": "Electrocardiogram QRS complex prolonged", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Mental status changes", "reactionmeddraversionpt": "18.1", "reactionoutcome": "4" } ], "summary": null }, "primarysource": { "literaturereference": "CHAVEZ P, CASSO DOMINGUEZ A, HERZOG E. EVOLVING ELECTROCARDIOGRAPHIC CHANGES IN LAMOTRIGINE OVERDOSE: A CASE REPORT AND LITERATURE REVIEW. CARDIOVASC TOXICOL (DOI:10.1007/S12012-014-9300-0). 2015?15(4):394-398", "literaturereference_normalized": "evolving electrocardiographic changes in lamotrigine overdose a case report and literature review", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20151109", "receivedate": "20151109", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11714842, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": 1, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20160304" }, { "companynumb": "US-MYLANLABS-2015M1036200", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "RALTEGRAVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "HIV INFECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RALTEGRAVIR." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TENOFOVIR DISOPROXIL FUMARATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "HIV INFECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TENOFOVIR DISOPROXIL FUMARATE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LAMOTRIGINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "077420", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "150 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "BIPOLAR DISORDER", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMOTRIGINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LAMOTRIGINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "077420", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "90 TABLETS OF 150MG (13.5G INGESTION)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMOTRIGINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Intentional overdose", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Electrocardiogram QRS complex prolonged", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Electrocardiogram QT prolonged", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Suicide attempt", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Critical illness myopathy", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CHAVEZ P, CASSO DOMINGUEZ A, HERZOG E. EVOLVING ELECTROCARDIOGRAPHIC CHANGES IN LAMOTRIGINE OVERDOSE: A CASE REPORT AND LITERATURE REVIEW. CARDIOVASC-TOXICO 2015? 15(4):394-398.", "literaturereference_normalized": "evolving electrocardiographic changes in lamotrigine overdose a case report and literature review", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20151026", "receivedate": "20151026", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11662072, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160304" }, { "companynumb": "US-CIPLA LTD.-2015US07961", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LAMOTRIGINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "077783", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "275 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "TEMPORAL LOBE EPILEPSY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "275", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMOTRIGINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Vertigo", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Craniocerebral injury", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Electrocardiogram abnormal", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Ataxia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Altered state of consciousness", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Nystagmus", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hyporeflexia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Fall", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CHAVEZ P, DOMINGUEZ A AND HERZOG E. EVOLVING ELECTROCARDIOGRAPHIC CHANGES IN LAMOTRIGINE OVERDOSE: A CASE REPORT AND LITERATURE REVIEW. CARDIOVASC TOXICOL. 2015?15:394-398", "literaturereference_normalized": "evolving electrocardiographic changes in lamotrigine overdose a case report and literature review", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20151015", "receivedate": "20151015", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11631930, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160304" }, { "companynumb": "US-ZYDUS-009336", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LAMOTRIGINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "078009", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "ESTIMATED AMOUNT INGESTED AS UP TO 13.5 G (90 TABLETS OF 150 MG)", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": [ { "drugrecuraction": "Conduction disorder" }, { "drugrecuraction": "Myopathy" }, { "drugrecuraction": "Status epilepticus" }, { "drugrecuraction": "Overdose" }, { "drugrecuraction": "Generalised tonic-clonic seizure" }, { "drugrecuraction": "Quadriplegia" } ], "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMOTRIGINE." } ], "patientagegroup": null, "patientonsetage": "36", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Generalised tonic-clonic seizure", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Conduction disorder", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Myopathy", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Quadriplegia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CHAVEZ P, CASSO DOMINGUEZ A, HERZOG E. EVOLVING ELECTROCARDIOGRAPHIC CHANGES IN LAMOTRIGINE OVERDOSE: A CASE REPORT AND LITERATURE REVIEW. CARDIOVASCULAR TOXICOLOGY. 2015 OCT?15(4):394-398.", "literaturereference_normalized": "evolving electrocardiographic changes in lamotrigine overdose a case report and literature review", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20151101", "receivedate": "20151101", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11688540, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" }, { "companynumb": "US-CIPLA LTD.-2015US07956", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "AMITRIPTYLINE" }, "drugadditional": null, 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"patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypoglycaemia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Shock", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CHAVEZ P, DOMINGUEZ A AND HERZOG E. EVOLVING ELECTROCARDIOGRAPHIC CHANGES IN LAMOTRIGINE OVERDOSE: A CASE REPORT AND LITERATURE REVIEW. CARDIOVASC TOXICOL. 2015?15:394-398", "literaturereference_normalized": "evolving electrocardiographic changes in lamotrigine overdose a case report and literature review", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20151019", "receivedate": "20151019", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11639930, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" }, { "companynumb": "US-CIPLA LTD.-2015US07955", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LAMOTRIGINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMOTRIGINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DULOXETINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DULOXETINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "EGG PHOSPHOLIPIDS\\SAFFLOWER OIL\\SOYBEAN OIL" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 GM/DL CONCENTRATION OF LIPID EMULSION BOLUS", "drugenddate": null, "drugenddateformat": null, "drugindication": "SHOCK", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FAT EMULSION NOS" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VERAPAMIL HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VERAPAMIL" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Shock", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hyperlipidaemia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CHAVEZ P, DOMINGUEZ A AND HERZOG E. EVOLVING ELECTROCARDIOGRAPHIC CHANGES IN LAMOTRIGINE OVERDOSE: A CASE REPORT AND LITERATURE REVIEW. CARDIOVASC TOXICOL. 2015?15:394-398", "literaturereference_normalized": "evolving electrocardiographic changes in lamotrigine overdose a case report and literature review", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20151019", "receivedate": "20151019", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11639915, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" }, { "companynumb": "US-DRREDDYS-USA/USA/14/0045096", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "RALTEGRAVIR" }, "drugadditional": null, 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"Suicide attempt", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bundle branch block right", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CHAVEZ P, CASSO DOMINGUEZ A, HERZOG E. EVOLVING ELECTROCARDIOGRAPHIC CHANGES IN LAMOTRIGINE OVERDOSE: A CASE REPORT AND LITERATURE REVIEW. CARDIOVASC TOXICOL. 2015?15(4):394-8.", "literaturereference_normalized": "evolving electrocardiographic changes in lamotrigine overdose a case report and literature review", "qualification": "3", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "US", "receiptdate": "20151109", "receivedate": "20141224", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10673731, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" } ]

{ "abstract": "In GM1 gangliosidosis the lack of function of β-galactosidase results in an accumulation of GM1 ganglioside and related glycoconjugates in visceral organs, and particularly in the central nervous system, leading to severe disability and premature death. In the type 2 form of the disease, early intervention would be important to avoid precocious complications. To date, there are no effective therapeutic options in preventing progressive neurological deterioration. Substrate reduction therapy with Miglustat, a N-alkylated sugar that inhibits the enzyme glucosylceramide synthase, has been proposed for the treatment of several lysosomal storage disorders such as Gaucher type 1 and Niemann Pick Type C diseases. However, data on Miglustat therapy in patients with GM1 gangliosidosis are still scarce.\n\n\n\nWe report here the results of Miglustat administration in four Italian children (average age: 55 months, range 20-125) affected by GM1 gangliosidosis type 2 treated in three different Italian pediatric hospitals specialized in metabolic diseases.\n\n\n\nThis treatment was safe and relatively well tolerated by all patients, with stabilization and/or slowing down of the neurological progression in three subjects.", "affiliations": "Clinical Genetics Unit, Department of Pediatric Medicine, Giovanni XXIII Children's Hospital, Bari, Italy.;Department of Biomedical Science and Human Oncology, Pediatric Unit, University of Bari \"Aldo Moro\", Bari, Italy.;Unit of Child Neuropsychiatry, Clinical and Surgical Neurosciences Department, IRCCS Institute Giannina Gaslini, Genoa, Italy.;Unit of Child Neuropsychiatry, Clinical and Surgical Neurosciences Department, IRCCS Institute Giannina Gaslini, Genoa, Italy.;Radiology Unit, Pediatric Hospital Giovanni XXIII, Bari, Italy.;Radiology Unit, Pediatric Hospital Giovanni XXIII, Bari, Italy.;Unit of Rare Diseases, IRCCS Institute Giannina Gaslini, Genoa, Italy.;Department of Clinical Sciences, Division of Pediatrics, Polytechnic University of Marche, OspedaliRiuniti, Presidio Salesi, Ancona, Italy.;Department of Biomedical Science and Human Oncology, Pediatric Unit, University of Bari \"Aldo Moro\", Bari, Italy.;Clinical Genetics Unit, Department of Pediatric Medicine, Giovanni XXIII Children's Hospital, Bari, Italy.;Department of Biomedical Science and Human Oncology, Pediatric Unit, University of Bari \"Aldo Moro\", Bari, Italy.;Department of Medical Translational Sciences Section of Pediatrics, University Federico II Naples, Napoli, Italy.;Department of Medical Translational Sciences Section of Pediatrics, University Federico II Naples, Napoli, Italy.;Neuroradiology Unit, IRCCS Institute Giannina Gaslini, Genoa, Italy.;Paediatric Neurology Unit and Laboratories, Neuroscience Department, Meyer Children's Hospital, Florence, Italy.;Department of Biomedical Science and Human Oncology, Pediatric Unit, University of Bari \"Aldo Moro\", Bari, Italy.", "authors": "Fischetto|Rita|R|;Palladino|Valentina|V|0000-0002-3976-6463;Mancardi|Maria M|MM|;Giacomini|Thea|T|;Palladino|Stefano|S|;Gaeta|Alberto|A|;Di Rocco|Maja|M|0000-0001-9677-880X;Zampini|Lucia|L|;Lassandro|Giuseppe|G|;Favia|Vito|V|;Tripaldi|Maria E|ME|;Strisciuglio|Pietro|P|;Romano|Alfonso|A|;Severino|Mariasavina|M|;Morrone|Amelia|A|0000-0003-2890-8179;Giordano|Paola|P|", "chemical_list": "D065089:Glycoside Hydrolase Inhibitors; D017485:1-Deoxynojirimycin; C059896:miglustat; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase", "country": "United States", "delete": false, "doi": "10.1002/mgg3.1371", "fulltext": "\n==== Front\nMol Genet Genomic Med\nMol Genet Genomic Med\n10.1002/(ISSN)2324-9269\nMGG3\nMolecular Genetics & Genomic Medicine\n2324-9269 John Wiley and Sons Inc. Hoboken \n\n10.1002/mgg3.1371\nMGG31371\nClinical Report\nClinical Reports\nSubstrate reduction therapy with Miglustat in pediatric patients with GM1 type 2 gangliosidosis delays neurological involvement: A multicenter experience\nFISCHETTO et al.Fischetto Rita \n1\[email protected] Palladino Valentina https://orcid.org/0000-0002-3976-6463\n2\n Mancardi Maria M. \n3\n Giacomini Thea \n3\n Palladino Stefano \n4\n Gaeta Alberto \n4\n Di Rocco Maja https://orcid.org/0000-0001-9677-880X\n5\n Zampini Lucia \n6\n Lassandro Giuseppe \n2\n Favia Vito \n1\n Tripaldi Maria E. \n2\n Strisciuglio Pietro \n7\n Romano Alfonso \n7\n Severino Mariasavina \n8\n Morrone Amelia https://orcid.org/0000-0003-2890-8179\n9\n Giordano Paola \n2\n \n1 \nClinical Genetics Unit\nDepartment of Pediatric Medicine\nGiovanni XXIII Children's Hospital\nBari\nItaly\n\n\n2 \nDepartment of Biomedical Science and Human Oncology\nPediatric Unit\nUniversity of Bari “Aldo Moro”\nBari\nItaly\n\n\n3 \nUnit of Child Neuropsychiatry, Clinical and Surgical Neurosciences Department\nIRCCS Institute Giannina Gaslini\nGenoa\nItaly\n\n\n4 \nRadiology Unit\nPediatric Hospital Giovanni XXIII\nBari\nItaly\n\n\n5 \nUnit of Rare Diseases\nIRCCS Institute Giannina Gaslini\nGenoa\nItaly\n\n\n6 \nDepartment of Clinical Sciences\nDivision of Pediatrics\nPolytechnic University of Marche\nOspedaliRiuniti\nPresidio Salesi\nAncona\nItaly\n\n\n7 \nDepartment of Medical Translational Sciences Section of Pediatrics\nUniversity Federico II Naples\nNapoli\nItaly\n\n\n8 \nNeuroradiology Unit\nIRCCS Institute Giannina Gaslini\nGenoa\nItaly\n\n\n9 \nPaediatric Neurology Unit and Laboratories\nNeuroscience Department\nMeyer Children's Hospital\nFlorence\nItaly\n\n* Correspondence\n\nRita Fischetto, Clinical Genetics Unit, Department of Pediatric Medicine, Giovanni XXIII Children's Hospital, Bari, Italy.\n\nEmail: [email protected]\n\n11 8 2020 \n10 2020 \n8 10 10.1002/mgg3.v8.10e137106 3 2020 30 4 2020 01 6 2020 © 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Abstract\nBackground\nIn GM1 gangliosidosis the lack of function of β‐galactosidase results in an accumulation of GM1 ganglioside and related glycoconjugates in visceral organs, and particularly in the central nervous system, leading to severe disability and premature death. In the type 2 form of the disease, early intervention would be important to avoid precocious complications. To date, there are no effective therapeutic options in preventing progressive neurological deterioration. Substrate reduction therapy with Miglustat, a N‐alkylated sugar that inhibits the enzyme glucosylceramide synthase, has been proposed for the treatment of several lysosomal storage disorders such as Gaucher type 1 and Niemann Pick Type C diseases. However, data on Miglustat therapy in patients with GM1 gangliosidosis are still scarce.\n\nMethods\nWe report here the results of Miglustat administration in four Italian children (average age: 55 months, range 20–125) affected by GM1 gangliosidosis type 2 treated in three different Italian pediatric hospitals specialized in metabolic diseases.\n\nConclusion\nThis treatment was safe and relatively well tolerated by all patients, with stabilization and/or slowing down of the neurological progression in three subjects.\n\nIn GM1 gangliosidosis the lack of function of β‐galactosidase results in an accumulation of GM1 gangliosides and related glycoconjugates in visceral organs, especially the central nervous system, leading to severe disability and premature death. In the type 2 form of the disease, early intervention would be important to avoid precocious complications. We report here the results of Miglustat administration in four Italian children (average age: 55 months, range 20–125) affected by GM1 gangliosidosis type 2. This treatment was safe and relatively well tolerated by all patients, with stabilization and/or slowing down of the neurological progression in three subjects.\n\n\nGM1 gangliosidosisMiglustatpediatric source-schema-version-number2.0cover-dateOctober 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.3 mode:remove_FC converted:28.10.2020\n\n\nFischetto \nR \n, \nPalladino \nV \n, \nMancardi \nMM \n, et al. Substrate reduction therapy with Miglustat in pediatric patients with GM1 type 2 gangliosidosis delays neurological involvement: A multicenter experience\n. Mol Genet Genomic Med . 2020 ;8 :e1371\n10.1002/mgg3.1371\n==== Body\n1 INTRODUCTION\nGM1 gangliosidosis is an autosomal recessive disorder caused by the deficiency of β‐galactosidase (GLB1), a lysosomal hydrolase that removes the terminal β‐galactosyl residues from GM1 gangliosides, glycoproteins, and glycosaminoglycans. Lack of β‐galactosidase function results in an accumulation of GM1 ganglioside and related glycoconjugates in visceral organs, and particularly in the central nervous system (CNS) (Sandhoff & Harzer, 2013). The incidence of GM1 gangliosidosis is estimated to be 1 in 100.000–200.000 live births, although prevalence widely differs in the world (Brunetti‐Pierri & Scaglia, 2008).\n\nβ‐galactosidase is encoded by GLB1, a gene located on chromosome 3p21.33 (Yamamoto et al., 1990). To date, more than 200 mutations have been identified (HGMD professional database 2015.3; https://portal.biobase‐international.com/cgibin/portal/login.cgi), differing in the residual enzyme activity that inversely correlates with the clinical severity (Suzuki, Nakamura, & Fukuoka, 1978). Despite the large genetic variability, currently, three main clinical forms have been identified: type 1 (infantile), type 2 (late infantile and juvenile), and type 3 (adult). GM1 gangliosidosis type 1 is characterized by early psychomotor deterioration, visceromegaly, macular cherry‐red spot, skeletal deformities, and death within the first 2 years of life (Suzuki & Oshima, 1993). Type 2 form presents with slowly progressive neurological signs as early locomotor problems, strabismus, muscle weakness, seizures, recurrent bronchopneumonia, and less severe dysmorphisms and skeletal involvement than in type 1. GM1 gangliosidosis type 2 can be divided into a late infantile and a juvenile form. In the late infantile form death occurs within adolescence while patients with the juvenile form can survive longer, with great individual clinical variability (Regier & Tifft, 2013). The adult form (type 3) is characterized by a less severe course and late onset, usually in juvenile age (Cox, 2015; Jarnes Utz et al., 2017; Regier, Proia, D'Azzo, & Tifft, 2016). Data on neuroimaging findings in the different forms of GM1 gangliosidosis are scarce; the reported patterns are nonspecific, including diffuse atrophy and white matter abnormalities (Chen et al., 1998; De Grandis, Di Rocco, Pessagno, Veneselli, & Rossi, 2009; Di Rocco et al., 2005; Gururaj et al., 2005). Type 1 may also present with delayed myelination and hyposignal on T2‐weighted images in the thalami, while type 2 may be associated with T2 hypointensity in the globi pallidi, and type 3 shows T2 hyperintensity within the putamina (Chen et al., 1998; De Grandis et al., 2009; Di Rocco et al., 2005; Erol, Alehan, Pourbagher, Canan, & Vefa, 2006; Gururaj et al., 2005).\n\nTo date, there are no effective drugs for the management of GM1 gangliosidosis that is mainly based on palliative treatments. Especially in the infantile and juvenile forms of GM1 gangliosidosis, early intervention would be important to avoid severe disability and premature death. However, the failure to access glycolipid storage products in CNS cells during critical developmental periods and the absence of clinical markers to evaluate treatment efficacy have hindered progress in developing effective therapies (Jarnes Utz et al., 2017).\n\nRecently, the application of a substrate reduction therapy (SRT) has been evaluated in several lysosomal storage disorders (Hollak & Wijburg, 2014; Parenti, Andria, & Valenzano, 2015). The rationale of SRT is based on the use of synthesis inhibitors of substrates accumulated in lysosomes using specific iminosugars (Jeyakumar, Butters, Dwek, & Platt, 2002). NB‐DNJ (Miglustat, Zavesca®) is a N‐alkylated sugar that is a reversible competitive inhibitor of the glucosylceramide synthase, an enzyme catalyzing the first committed step in the synthesis of lacto‐ and globo‐series glycolipids (Platt, Neises, Dwek, & Butters, 1994). The ability of Miglustat to cross the blood–brain barrier blocking glycolipid storage synthesis has opened new interesting options for the treatment of multiple lysosomal storage disorders, especially those with CNS involvement, such as Gaucher and Niemann Pick type C diseases (Cox et al., 2000; Ficicioglu, 2008; Patterson, Vecchio, Prady, Abel, & Wraith, 2007). Miglustat has also been proposed for treatment of other sphingolipidoses, such as GM1 gangliosidosis. Indeed, GM1 gangliosidosis mouse models demonstrated Miglustat effectiveness in reducing brain GM1 ganglioside content (Kasperzyk et al., 2004; Treiber, Morand, & Clozel, 2007). Data on Miglustat efficacy in patients with GM1 gangliosidosis are scarce but promising, as reported in a few pediatric and adult patients affected by type 1 and 2 forms (Deodato et al., 2017; Garzone et al., 2013; Tifft, Adams, & Morgan, 2007).\n\nHere, we describe the clinical course and adverse effects of Miglustat therapy in four pediatric patients with GM1 gangliosidosis type 2.\n\n2 MATERIALS AND METHODS\nAfter obtaining informed consent and approval from the local ethics committees, we reviewed the clinical and neuroradiological data of four patients with GM1 gangliosidosis treated in three different Italian pediatric hospitals specialized in metabolic diseases. The decision to initiate treatment was based on: (a) good safety profile of Miglustat, (b) good clinical results in other lysosomal storage diseases, and (c) promising preclinical data on GM1 mouse models. Miglustat was dosed according to guidelines for pediatric patients (younger than 12 years) affected by Niemann Pick type C disease. The drug was melted in water to facilitate the assumption and the dosage was progressively increased according to body surface area. Data on drug tolerance and compliance were collected from the mothers with follow‐up calls or during clinical assessment every 3 months. All patients were followed up at regular intervals by a multidisciplinary team and the development of side effects was monitored. Symptoms and signs and neurological evaluation of patients before and after Miglustat therapy are summarized in Table 1.\n\nTable 1 Symptoms and signs and neurological evaluation before and after Miglustat therapy\n\nPatient\tAge at onset of symptoms\tAge at Miglustat initiation\tAge at last follow‐up during Miglustat therapy\tSymptoms and signs\tNeurological evaluation\t\nBefore Miglustat therapy\tAfter Miglustat therapy\tBefore Miglustat therapy\tAfter Miglustat therapy\t\n1\t11 months\t20 months\t5 years\t\nThoracolumbar kyphosis and vertebral beaking (D11 to L4) at X‐ray\n\nAbdominal cystic lymphangioma\n\n\n\t\nSignificant improvement of the thoracic hyperkyphosis and stable appearance of the vertebral anomalies\n\n\n\t\nNormal neurological assessment\n\nNormal WPPSI‐III in verbal and performance IQ scores\n\n\n\tWPPSI‐III: mild worsening in fine motor skills and language\t\n2\t5 years\t10 years and 5 months\t16 years\t\nDevelopmental regression\n\nAttention deficit\n\nDysarthria\n\nExtrapyramidal symptoms\n\nAtypical absences\n\nDiffuse platyspondyly with mild anterior wedging of the lumbar vertebrae at Spinal MRI and X‐ray\n\n\n\tStable\t\nSevere dysarthria\n\nAttention deficit\n\nMild hypotonia\n\nBrisk reflex with mild bilateral clonus\n\nAwkwardness\n\nBradykinesia with freezing\n\nGait ataxia\n\nSevere cognitive impairment (IQ of 34 at WISC‐III Scale) and EDSS score of 7.5\n\n\n\tStable motor and cognitive impairment\t\n3\t5 years\t3 years and 8 months\t10 years and 5 months\tAsymptomatic\t\nDysarthria\n\nAttention deficit\n\nDiffuse platyspondyly with anterior wedging of the lumbar vertebrae at X‐ray\n\nEpileptic alterations at EEG during sleep\n\n\n\tNormal\t\nModerate intellectual disability\n\nClumsiness\n\nDysarthria\n\nSignificative hyperkinesia\n\nAttention deficit\n\nBehavioral problems with heteroaggressivity\n\nPsychomotor agitation outbursts\n\nEDSS score of 5.\n\n\n\t\n4\t18 months\t2 years and 9 months\t6 years and 7 months\t\nHypotonia\n\nDelayed psychomotor development\n\nSteppage gait\n\nSlightly coarse facies (downturned corners of the mouth, convergent strabismus of the left eye, and open bite with sialorrhea)\n\n\n\t\nTotal regression of language\n\nPyramidal and extrapyramidal signs\n\nSeizures\n\nSevere intellectual disability\n\nTotal gross and fine motor regression\n\n\n\t\nHypotonia\n\nDelayed psychomotor development\n\nSteppage gait\n\n\n\t\nTotal regression of language\n\nPyramidal and extrapyramidal signs\n\nSevere intellectual disability\n\nTotal gross and fine motor regression\n\n\n\t\nJohn Wiley & Sons, Ltd2.1 Patient 1\nPatient #1 was born at term after an uneventful pregnancy by spontaneous delivery. He was the first child of a healthy nonconsanguineous couple, with no contributory family history. Normal growth and neurodevelopmental milestones were referred until the age of 11 months. At this time, he was referred to the orthopedist for thoracolumbar kyphosis that was treated with a corset. The first clinical evaluation did not reveal any dysmorphological signs. Spine X‐Ray showed anterior vertebral beaking from D11 to L4, more evident in L1 and L2, associated with marked thoracic kyphosis. Electrocardiogram, echocardiogram, Boel test, fundus oculi and slit lamp examination, neurological assessment, abdomen echography, and hand X‐ray were normal. Routine blood tests, aminoacidemia/uria, acylcarnitines, urinary glycosaminoglycans screening test, and organic acids were normal. At 18 months of age, the patient was operated of an abdominal cystic lymphangioma.\n\nIncreased levels of urinary oligosaccharides were found using thin‐layer chromatographic (TLC) method, while fluorimetric enzyme assay in leucocytes revealed that β‐galactosidase (GLB1) enzyme activity was below normal range (6.9 nM mg−1 h−1; normal values 100–600 nM mg−1 h−1). GLB1 gene analysis was performed, revealing compound heterozygous mutations in c.602G>A p.(Arg201His) (inherited from the mother) and c.841C>T p.(His 281Tyr) (inherited from the father).\n\nBrain MRI and MR spectroscopy performed at 21 months of age were normal (Figure 2A,B). Cognitive assessment was performed with \"Wechsler Preschool And Primary Scale Of Intelligence\" (WPPSI‐III) resulting normal in both verbal and performance IQ scores.\n\nAt 20 months of age, after 2 months of preliminary dietary treatment (lactose‐free aliments), Miglustat therapy was started at a dose of 100 mg/day (subdivided into two doses) and progressively increased to 240 mg/day. At 4 years of age, the total drug amount was fractioned in three doses a day, while at 5 years, in four doses a day. Daily assumption of a probiotic product (Saccharomyces Boulardii) was also started. In the following years, height, weight, and head circumference growth curves were stable, between the 25th and 50th centiles. Orthopedic evaluations revealed a significant improvement of kyphosis with a nonstop use of the corset until the age of 4 years. Spine X‐Rays confirmed a significant improvement of the thoracic hyperkyphosis and a stable appearance of the vertebral anomalies. Follow‐up brain MRI scans at 4 and 5 years of age did not reveal any abnormality. Cognitive assessment using WPPSI‐III performed at 5 years of age showed mild worsening in fine motor skills and language. Routine blood tests were normal, except for mild and transient increase in alanine amino transpherase (ALT) levels.\n\n2.2 Patient 2\nPatient #2 is the first child of healthy nonconsanguineous parents with negative family history. She was born at term after an uneventful pregnancy. She showed a normal psychomotor development until the age of 5 years when she presented with developmental regression associated with attention deficit, dysarthria, and extrapyramidal symptoms. She came to our attention at the age of 9 years when she developed atypical absences with generalized sharp waves (3 Hz) followed by slow waves lasting 20‐12′ at EEG, and she started antiepileptic therapy with lamotrigine. Neurological examination showed severe dysarthria, mild hypotonia, brisk reflex with mild bilateral clonus, awkwardness, bradykinesia with freezing, and gait ataxia; she could not walk without assistance. Neuropsychological evaluation showed severe cognitive impairment (IQ of 34 at WISC‐III Scale) and EDSS score of 7.5. Brain MRI performed at 8 years of age revealed mild cerebral and cerebellar atrophy, white matter signal alterations consistent with lack of myelin, dysmyelination, and reduced thalamic volume (Figure 2D–F). Brain MR spectroscopy was normal. Spinal MRI and X‐ray showed diffuse platyspondyly with mild anterior wedging of the lumbar vertebrae (Figure 1b,c). Routine blood tests were normal, as well as genetic exams including cytogenetic studies, Array – Comparative Genomic Hybridization (Array – CGH), and analysis of subtelomeric regions and MECP2 gene.\n\nFigure 1 Spinal X‐ray and MRI features of the patients. (a) Spinal X‐ray, lateral view, of patient #1 performed at 6 years showing platyspondyly with anterior vertebral beaking from D11 to L4, more evident in L1 and L2 (arrows). (b) Spinal MRI, T2‐weighted sagittal image, and (c) Spinal X‐ray, lateral view, of patient #2 performed at 15 years of age demonstrates diffuse platyspondyly with mild anterior wedging of the lumbar vertebrae. (d) Spinal X‐ray, lateral view, of patient #3 performed at 9 years of age reveals diffuse platyspondyly with mild anterior wedging of the lumbar vertebrae, more evident in L3 (arrow)\n\nMetabolic exams, including blood chromatography of the amino acids, organic acidurias, mucopolysaccharidosis (MPS) urinary screening, plasma chitotriosidase, and fucosidase, mannosidase, were normal while the activity of β‐galactosidase was reduced in lymphocytes (16.2 nM mg−1 h−1; normal values 100–600 nM mg−1 h−1) as well as in cultured skin fibroblasts, leading to the diagnosis of GM1 gangliosidosis. The genetic analysis revealed compound heterozygous mutations in GLB1 in c.602G>A p.(Arg201His) and the novel c.247dup1 p.(Tyr83Leu fsx8).\n\nAt the age of 10 years and 5 months, the clinical picture and neurological examination were stable. Brain MRI showed mild progression of cerebral atrophy with enlargement of the lateral ventricles (Figure 2D′–F′). Therapy with Miglustat was started (age 10 years and 5 months) at the dosage of 100 mg three times a day, gradually increased to 200 mg three times a day. She initially presented occasional diarrhea and mild abdominal pain, spontaneously improving in the following weeks. In the first 4 months of therapy, her body weight decreased from 42.6 to 38.9 kg (BMI from 24.8 to 21.9). Subsequently, in the following 6 years, the BMI was quite stable between 21.1 and 22.3. She has now been on a stable dosage of 600 mg/day for 1 year with good compliance and without relevant adverse events. At last follow‐up, at the age of 16 years, neurological examination showed stable motor and cognitive impairment. Brain MRI revealed further progression of mild cortical atrophy and T2 hypointensity at the level of the globi pallidi, substantia nigra, red nuclei, and cerebellar dentate nuclei, associated with thickening of the skull bones (Figure 2D″–F″).\n\nFigure 2 Brain MRI features of the patients. (A–C) Axial T2‐weighted images of patient #1 performed at 21 months of age reveal normal brain anatomy and signal intensity. (D–F) Axial T2‐weighted images of patient #2 performed at 8 years of age show diffuse white matter hyperintensity, more evident at the level of posterior limbs of internal capsules (arrows), associated with small thalami (asterisks) and mild enlargement of the cerebral and cerebellar subarachnoid spaces. (D′–F′) Corresponding axial T2‐weighted images of the same patient performed at 10 years and 5 months reveal progressive enlargement of the cerebral and cerebellar subarachnoid spaces (thick arrows) and enlargement of the lateral ventricles (asterisks). (D″–F″) Follow‐up axial T2‐weighted images at 16 years reveal further progression of the cerebral atrophy, with thickening of the skull bones (empty arrows) and hypointensity of the globipallidi (arrowheads). (G–I) Axial T2‐weighted images of patient #3 performed at 6 years and 2 months of age reveal normal brain anatomy and signal intensity. (J–L) Axial T2‐weighted images of patient #4 performed at 2 years of age demonstrate mild hyperintensity of the white matter of the centri semiovali (empty arrows) and posterior limbs of internal capsules (arrows). There is also mild enlargement of the cerebral and cerebellar subarachnoid spaces. Note the small thalami (asterisks)\n\n2.3 Patient 3\nPatient #3 is the younger brother of Patient #2. He was born at term after an uneventful pregnancy. He was asymptomatic when GM1 gangliosidosis were diagnosed at the age of 3 years, and he harbored the same compound mutations of his sister. Treatment with Miglustat was started at the age of 3 years and 8 months but was stopped after a week for the appearance of severe hyporexia. Four months later, the treatment was reinitiated at the dosage of 70 mg/twice daily and gradually increased up to 300 mg/day (subdivided into 3 doses). Up to date, he has been on a stable dosage for 3 years with good compliance and insignificant side effects such as occasional abdominal pain with diarrhea. At the age of 5 years, he started to develop dysarthria and attention deficit.\n\nBrain MRI with MR spectroscopy performed at 6 years and 2 months was normal (Figure 2G–I). Spinal X‐ray revealed diffuse platyspondyly with anterior wedging of the lumbar vertebrae, especially of L3 (Figure 1d). At 10 years of age, he presented epileptic alterations at EEG during sleep, without evident clinical seizures and was treated with therapy with topiramate. Neurological examination revealed moderate intellectual disability, clumsiness, dysarthria, significative hyperkinesia, attention deficit, behavioral problems with heteroaggressivity, and psychomotor agitation outbursts. His EDSS score was 5. At last follow‐up, performed at 10 years and 5 months of age, neurological examination revealed a stable clinical course.\n\n2.4 Patient 4\nPatient #4 was born at term after an uneventful pregnancy by spontaneous delivery. At the age of 18 months, he presented with hypotonia, delayed psychomotor development, and a steppage gait characterized by widened base of support and retropulsion of the pelvis. He had slightly coarse facies with downturned corners of the mouth, convergent strabismus of the left eye, and open bite with sialorrhea. Abdominal ultrasound and metabolic screening tests were normal. Brain MRI performed at 2 years of age revealed white matter signal alterations consistent with lack of myelin and dysmyelination in the posterior limbs of internal capsules and pons, mild subarachnoid spaces enlargement, and reduced thalamic volume (Figure 2J–L). At the age of 2 years and 4 months, GM1 gangliosidosis was diagnosed by the β‐galactosidase enzymatic assay and GLB1 gene molecular analysis, which highlighted the presence in heterozygosis of the c.572G>A (p. Ser191Asn) and c.1445G>A (p. Arg482Hys) mutations. The boy started therapy with Miglustat at the age of 2 years and 9 months, at the dosage of 200 mg (subdivided into two doses).\n\nAt the age of 3 years and 2 months, the patient was again hospitalized for night cry, asthenia, and pain. The abdomen ultrasound was normal, while a barium X‐ray examination showed gastroesophageal reflux and therapy was initiated with esomeprazole. The neurological exam showed total regression of language, associated with pyramidal and extrapyramidal signs.\n\nAt the age of 3 years and 7 months, frequent daily seizures appeared, lasting few seconds and characterized by pathological eyes rolling and staring. An EEG showed high‐voltage slow waves and spike waves complexes on the right derivations. He began therapy with levetiracetam at the dosage of 400 mg/die with clinical improvement.\n\nWhen he was 6 years old, he was hospitalized because of significant weight loss, dehydration, sickness, and vomiting. Oral feeding was strongly compromised. A percutaneous gastrostomy was placed. Seven months later, therapy with Miglustat was also suspended. Last clinical follow‐up at 7 years of age revealed severe intellectual disability and total gross and fine motor regression. He depended on his parents for daily survival.\n\n3 DISCUSSION\nWe present our experience of Miglustat administration in four children affected by GM1 gangliosidosis type 2. In GM1 gangliosidosis type 2, the accumulation of GM1 ganglioside in the CNS begins in the early stages of development. Therefore, it has been hypothesized that the progression of the disease could only be avoided with early diagnosis and intervention (Del Vecchio et al., 2008; Jarnes Utz et al., 2017). Some therapeutic strategies have been implemented in animal models, such as bone marrow transplantation (Sano, Tessitore, Ingrassia, & d'Azzo, 2005), intracranial transplant of neuronal stem cells (Sawada et al., 2009), SRT (Elliot‐Smith et al., 2008; Kasperzyk et al., 2004; Suzuki et al., 2007), gene therapies (Baek et al., 2010), and enzyme replacement therapy (Condori et al., 2016). Additionally, a recent study demonstrated that the intracerebroventricular administration of recombinant human β‐galactosidase in a mouse model of GM1 gangliosidosis reduced brain levels of ganglioside and oligosaccharide substrates (Chen et al., 2019).\n\nIn human patients, several interventions have been undertaken to mitigate the relentless progression of disease (Regier et al., 2016). However, the failure to access glycolipid storage products in CNS during critical developmental periods and the absence of clinical markers to evaluate treatment efficacy have hindered progress in developing effective therapies (Jarnes Utz et al., 2017).\n\nSubstrate reduction therapy with oral administration of the iminosugar NB‐DNJ has been demonstrated to be effective in crossing the blood–brain barrier and blocking glycolipid storage synthesis (Kasperzyk et al., 2004; Treiber et al., 2007), thus revealing a potential therapeutic role in lysosomal storage disorders with neurological involvement (Platt et al., 1994). In particular, Miglustat has been approved in Europe and the United States for the treatment of patients with type 1 Gaucher disease with mild‐to‐moderate clinical manifestations for whom intravenous enzyme replacement therapy is not an option (Cox et al., 2000; Ficicioglu, 2008). Subsequently, Miglustat has also been approved for treating progressive neurologic manifestations in children and adults with Niemann Pick disease type C (Patterson et al., 2007).\n\nThe mechanism of Miglustat action has not been completely clarified yet. The efficacy of NB‐DNJ is related to its ability to cross the blood–brain barrier, inhibit the synthesis of storage products, and stabilize the enzyme with an enhancement of the catalytic residual activity (Alfonso et al., 2005; Kuter et al., 2013). Furthermore, several studies have proved the potential role of Miglustat administration in the regulation of the abnormal CNS inflammatory response observed in GM1 gangliosidosis (Jeyakumar et al., 2003), reducing levels of proinflammatory cytokines such as tumor necrosis factor‐α (TNF‐α) and interleukin‐1 beta (IL1‐β) (Jeyakumar et al., 2001; Masciullo et al., 2010; Santoro et al., 2013).\n\nDespite the demonstrated effectiveness of Miglustat in other storage disorders, its use in GM 1 gangliosidosis type 2 has been reported only in a few patients. In 2007, Tifft et al. (2007) reported that Miglustat administration improved neurological functions in two patients with juvenile GM1 gangliosidosis. Recently, Deodato et al. (2017) described similar neurological improvement in the juvenile form of the disease. In our patients, we observed stabilization and/or slowing down of the neurological progression in three of four patients. Of note, the administration of Miglustat was started few months after the genetic confirmation. In particular, patients #1 and #3 received an early diagnosis of GM1 gangliosidosis type 2 and the treatment was started within the fourth year of age, before the onset of neurological symptoms. In patient #1, early treatment limited the disease progression until 5 years of age, when minor motor problems were noticed. Moreover, the improvement of the kyphosis without other novel skeletal manifestations and the absence of neuroimaging abnormalities were indicative of substantial stabilization of the clinical course due to the treatment. In patient #3, who was asymptomatic at the beginning of therapy, we noted a very slow progression of symptomatology, appeared at the age of 5 years and evident since the age of 8 years, thus suggesting a possible role of Miglustat in slowing down the neurological deterioration.\n\nPatient #2 started the therapy rather late in the course of the disease, at the age of 10 years, when neurological symptoms and MRI alterations were already present. Surprisingly, in this case, we observed a stable motor and cognitive impairment for the following 5 years, while brain MRI showed only a minimal progression of the cerebral atrophy. On the other hand, Miglustat therapy was insufficient to avoid worsening of the clinical course in patient #4, who presented with a severe neurological phenotype since the first months of life.\n\nConsensus guidelines for clinical management of children with Niemann Pick type C recommend close clinical monitoring after the initiation of Miglustat therapy (NP‐C Guidelines Working Group, 2009). However, several studies have proved that Miglustat is safe and generally well tolerated, with minor and often transient adverse effects, such as tremor and gastrointestinal disturbances (Belmatoug et al., 2011). In particular, gastrointestinal problems, including diarrhea, abdominal pain, nausea, and weight loss, are mainly dose‐related and limited to the initial phase of the treatment. The mechanism is most likely the inhibition of intestinal disaccharidases leading to reduced absorption of dietary disaccharides and increase in undigested intraluminal oligosaccharides creating an osmotic gradient with the influx of water and electrolytes in the gastrointestinal tract. Subsequent colonic bacterial fermentation reduces caloric supply and triggers flatulence, abdominal distension, pain, and nausea. Of note, these symptoms generally disappear or decrease with dose escalation or discontinued administrations in association with a low‐carbohydrate/lactose diet and probiotic administration (Cox, 2015; Patterson et al., 2007). In this series, two patients presented minor gastrointestinal problems. In particular, patient #2 developed transient diarrhea and abdominal pain, while patient #3 presented severe hyporexia that subsided after brief treatment suspension and did not reappear after Miglustat reintroduction at lower and fractionated doses while occasional abdominal pain with diarrhea persisted. Interestingly, in patient #1, Miglustat therapy was started after 2 months of a preliminary diet based on lactose‐free products and daily assumption of probiotic Saccharomyces Boulardii, thus avoiding gastroenteric symptoms (carbohydrates were preserved in order to maintain an adequate nutrition).\n\nIn conclusion, our findings suggest that Miglustat is relatively well tolerated in children with GM1 type 2 gangliosidosis and seems more effective if used to slow down, rather than treat, both visceral and neurological manifestation, as in Niemann Pick type C pediatric patients (Di Rocco, Dardis, Madeo, Barone, & Fiumara, 2012). The rarity of GM1 gangliosidosis type 2 disease, fast clinical progression, and short lifespan make studies on clinical surveillance and therapeutic efficacy tough, as effective interventions are only possible before irreversible damage occurs. Since definitive conclusions cannot be drawn from small case series, further studies on larger number of patients and with longer follow‐up duration are needed to evaluate of the long‐term therapeutic effects of Miglustat in GM1 type II gangliosidosis.\n\nCONFLICT OF INTEREST\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nAUTHOR CONTRIBUTIONS\nAll authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.\n\nACKNOWLEDGMENTS\nAll authors contributed equally to the study design and performance.\n\nDATA AVAILABILITY STATEMENT\nThe data supporting the findings of the article can be requested to the authors at the following.\n==== Refs\nREFERENCES\n\n\nAlfonso , P. \n, \nPampín , S. \n, \nEstrada , J. \n, \nRodríguez‐Rey , J. C. \n, \nGiraldo , P. \n, \nSancho , J. \n, & \nPocoví , M. \n (2005 ). 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Xenobiotica , 37 , 298 –314\n. 10.1080/00498250601094543 \n17624027 \n\n\nYamamoto , Y. \n, \nHake , C. A. \n, \nMartin , B. M. \n, \nKretz , K. A. \n, \nAhern‐Rindell , A. J. \n, \nNaylor , S. L. \n, … \nO’Brien , J. S. \n (1990 ). Isolation, characterization, and mapping of a human acid beta‐galactosidase cDNA\n. DNA and Cell Biology , 9 , 119 –127\n. 10.1089/dna.1990.9.119 \n2111707\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2324-9269", "issue": "8(10)", "journal": "Molecular genetics & genomic medicine", "keywords": "GM1 gangliosidosis; Miglustat; pediatric", "medline_ta": "Mol Genet Genomic Med", "mesh_terms": "D017485:1-Deoxynojirimycin; D000293:Adolescent; D002490:Central Nervous System; D002648:Child; D002675:Child, Preschool; D004361:Drug Tolerance; D005260:Female; D016537:Gangliosidosis, GM1; D005964:Glucosyltransferases; D065089:Glycoside Hydrolase Inhibitors; D006801:Humans; D007223:Infant; D008297:Male", "nlm_unique_id": "101603758", "other_id": null, "pages": "e1371", "pmc": null, "pmid": "32779865", "pubdate": "2020-10", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016448:Multicenter Study", "references": "20976108;23619106;18387328;32779865;25881001;2111707;24820227;16138252;12615653;20821051;10801168;19647672;8500799;28577204;19279282;26766614;31481471;23683771;19118961;99363;16039881;23785136;25987179;8132559;21779792;22704015;17689147;18524657;15791924;17624027;9802482;15941905;17994547;17052929;15086521;18176072;12366816;28476546;27491214;18728838;11133779", "title": "Substrate reduction therapy with Miglustat in pediatric patients with GM1 type 2 gangliosidosis delays neurological involvement: A multicenter experience.", "title_normalized": "substrate reduction therapy with miglustat in pediatric patients with gm1 type 2 gangliosidosis delays neurological involvement a multicenter experience" }

[ { "companynumb": "IT-ACTELION-A-CH2020-208550", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "MIGLUSTAT" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "021348", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "200 MG, TID", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ZAVESCA" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LAMOTRIGINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMOTRIGINE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "MIGLUSTAT" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "021348", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "100 MG, TID", "drugenddate": null, "drugenddateformat": null, "drugindication": "GALACTOSIALIDOSIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ZAVESCA" } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": "42.6", "reaction": [ { "reactionmeddrapt": "Bone hypertrophy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Abdominal pain", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Concomitant disease progression", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cerebral atrophy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Weight decreased", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "FISCHETTO R, PALLADINO V, MANCARDI M, GIACOMINI T, PALLADINO S, ET AL. SUBSTRATE REDUCTION THERAPY WITH MIGLUSTAT IN PEDIATRIC PATIENTS WITH GM1 TYPE 2 GANGLIOSIDOSIS DELAYS NEUROLOGICAL INVOLVEMENT: A MULTICENTER EXPERIENCE. MOLECULAR GENETICS + GENOMIC MEDICINE. 2020?E1371", "literaturereference_normalized": "substrate reduction therapy with miglustat in pediatric patients with gm1 type 2 gangliosidosis delays neurological involvement a multicenter experience", "qualification": "1", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20200821", "receivedate": "20200821", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18180587, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "IT-JNJFOC-A-CH2020-208554", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "MIGLUSTAT" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "021348", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "100 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "GALACTOSIALIDOSIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ZAVESCA" } ], "patientagegroup": "3", "patientonsetage": "3", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Asthenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dehydration", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Psychomotor disadaptation syndrome", "reactionmeddraversionpt": "23.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Feeding disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Gastrostomy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Eye movement disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Loss of personal independence in daily activities", "reactionmeddraversionpt": "23.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Intentional product use issue", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Weight decreased", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Speech disorder developmental", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Illness", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Staring", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Crying", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pain", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Extrapyramidal disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intellectual disability", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Upper motor neurone lesion", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrooesophageal reflux disease", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PALLADINO V, PALLADINO S, GIACOMINI T, MANCARDI M, FISCHETTO R. 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SUBSTRATE REDUCTION THERAPY WITH MIGLUSTAT IN PEDIATRIC PATIENTS WITH GM1 TYPE 2 GANGLIOSIDOSIS DELAYS NEUROLOGICAL INVOLVEMENT: A MULTICENTER EXPERIENCE. 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SUBSTRATE REDUCTION THERAPY WITH MIGLUSTAT IN PEDIATRIC PATIENTS WITH GM1 TYPE 2 GANGLIOSIDOSIS DELAYS NEUROLOGICAL INVOLVEMENT: A MULTICENTER EXPERIENCE. MOLECULAR GENETICS + GENOMIC MEDICINE. 2020?E1371", "literaturereference_normalized": "substrate reduction therapy with miglustat in pediatric patients with gm1 type 2 gangliosidosis delays neurological involvement a multicenter experience", "qualification": "1", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20200824", "receivedate": "20200824", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18187921, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" } ]

{ "abstract": "An 83-year-old Japanese man with Alzheimer's disease was admitted to our hospital for treatment of hyponatremia resulting from water intoxication. During hospitalization, the patient developed focal impaired awareness seizures, focal to bilateral tonic-clonic seizures, and subsequent status epilepticus. Electroencephalogram during focal impaired awareness seizures showed rhythmic 5-9 Hz theta activity in the right frontotemporal region. Electroencephalogram during focal to bilateral tonic-clonic seizures showed bilateral polyspikes. Electroencephalogram during an interseizure period revealed sharp waves in the right frontal region. Continuous intravenous administration of midazolam was the only effective treatment for status epilepticus. The patient died of aspiration pneumonia on day 58. Hyponatremia-associated status epilepticus is rare; in the present case, multifocal epileptogenicity resulting from Alzheimer's disease and hyponatremia-associated elevation of glutamate levels in the synaptic cleft may have contributed to the onset of focal to bilateral tonic-clonic seizures with subsequent status epilepticus.", "affiliations": "Department of General Medicine, National Hospital Organization Shibukawa Medical Center, Shibukawa, Japan.;Department of General Medicine, National Hospital Organization Shibukawa Medical Center, Shibukawa, Japan.;Division of Neurosurgery, National Hospital Organization Shibukawa Medical Center, Shibukawa, Japan.", "authors": "Ichioka|Ken|K|;Akuzawa|Nobuhiro|N|https://orcid.org/0000-0002-1204-1294;Takahashi|Akio|A|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1177/2050313X20915416", "fulltext": "\n==== Front\nSAGE Open Med Case Rep\nSAGE Open Med Case Rep\nSCO\nspsco\nSAGE Open Medical Case Reports\n2050-313X SAGE Publications Sage UK: London, England \n\n10.1177/2050313X20915416\n10.1177_2050313X20915416\nCase Report\nStatus epilepticus during correction of hyponatremia in a patient\nwith Alzheimer’s disease: A case report\nIchioka Ken 1 https://orcid.org/0000-0002-1204-1294Akuzawa Nobuhiro 1 Takahashi Akio 2 1 Department of General Medicine, National\nHospital Organization Shibukawa Medical Center, Shibukawa, Japan\n2 Division of Neurosurgery, National\nHospital Organization Shibukawa Medical Center, Shibukawa, Japan\nNobuhiro Akuzawa, Department of General\nMedicine, National Hospital Organization Shibukawa Medical Center, 383 Shiroi,\nShibukawa 377-0280, Japan. Email:\[email protected]\n15 4 2020 \n2020 \n8 2050313X2091541620 8 2019 23 2 2020 © The Author(s) 20202020SAGE PublicationsThis article is distributed under the terms of the Creative Commons\nAttribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which\npermits non-commercial use, reproduction and distribution of the work\nwithout further permission provided the original work is attributed as\nspecified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).An 83-year-old Japanese man with Alzheimer’s disease was admitted to our hospital\nfor treatment of hyponatremia resulting from water intoxication. During\nhospitalization, the patient developed focal impaired awareness seizures, focal\nto bilateral tonic-clonic seizures, and subsequent status epilepticus.\nElectroencephalogram during focal impaired awareness seizures showed rhythmic\n5–9 Hz theta activity in the right frontotemporal region. Electroencephalogram\nduring focal to bilateral tonic-clonic seizures showed bilateral polyspikes.\nElectroencephalogram during an interseizure period revealed sharp waves in the\nright frontal region. Continuous intravenous administration of midazolam was the\nonly effective treatment for status epilepticus. The patient died of aspiration\npneumonia on day 58. Hyponatremia-associated status epilepticus is rare; in the\npresent case, multifocal epileptogenicity resulting from Alzheimer’s disease and\nhyponatremia-associated elevation of glutamate levels in the synaptic cleft may\nhave contributed to the onset of focal to bilateral tonic-clonic seizures with\nsubsequent status epilepticus.\n\nAlzheimer’s diseasefocal impaired awareness seizuresfocal to generalized tonic-clonic seizureshyponatremiastatus epilepticuscover-dateJanuary-December 2020typesetterts1\n==== Body\nIntroduction\nThe incidence of new-onset epilepsy in the elderly population is increasing; nearly\n25% of new-onset seizures occur in patients aged over 65 years and the incidence in\nthis population is twice as high as that in children.1 According to a previous study, 1% of elderly individuals have epilepsy.2 Regardless of the presence of precipitating factors, elderly people are more\nprone to develop seizures than younger people and elderly patients with epilepsy\nhave two to three times higher mortality than the general population.2 Moreover, 30% of acute seizures in elderly people may present as status\nepilepticus (SE), with a mortality rate of nearly 40%.2 Most cases of new-onset epilepsy in elderly individuals are secondary to\ncerebrovascular disease, metabolic disturbances, dementia, traumatic brain injury,\ntumor, or pharmacotherapy. Seizures occur in approximately 10% of patients with\nAlzheimer’s disease (AD); two major seizure subtypes observed in this population are\nfocal to bilateral tonic-clonic seizures (FTBTCS) and focal impaired awareness\nseizures (FIAS).2,3\nHowever, FIAS in patients with AD can occur without physical movement, presenting\ninstead as transient increased confusion. Therefore, the incidence of FIAS without\nphysical movement may be underestimated.2–4\n\nWe herein present a case of refractory SE that began with epileptic seizures during\ncorrection of hyponatremia in a patient diagnosed with AD 2 years before\nadmission.\n\nCase presentation\nAn 83-year-old man was admitted to our hospital for evaluation of general malaise. He\nhad a 10-year history of chronic atrial fibrillation and hypertension and had been\ntreated with candesartan (8 mg/day) and warfarin (2 mg/day). Two weeks before\npresentation, the patient had visited a urologist because of transient urinary tract\nhemorrhage. Detailed examination had shown no abnormalities of the urinary tract. He\nhad been advised to drink enough water to prevent urinary obstruction by blood clots\nfor 1–2 weeks. In response, the patient started drinking about 4 L of water per day.\nOne week later, he became aware of fatigability and gait disturbance but continued\ndrinking extra water. His symptoms gradually worsened until he was admitted to the\ngeneral medicine department of our hospital. The patient had no relevant medical or\nfamily history. He was a non-smoker and non-drinker.\n\nOn admission, the patient’s weight was 58 kg and his blood pressure was 102/72 mmHg.\nHe was alert and afebrile. The patient complained of gait disturbance, but physical\nand neurological examination showed no abnormalities. Electrocardiography showed\natrial fibrillation. Plain computed tomography of the neck, chest, and abdomen\nshowed no significant abnormalities. Notably, laboratory tests showed a markedly\ndecreased serum sodium level (105 mEq/L, normal: 138–145 mEq/L). Plasma and urine\nosmolality were 225 and 140 mOsm, respectively. Urine sodium level was undetectable.\nLevels of plasma adrenocorticotropic hormone, cortisol, and antidiuretic hormone\nwere normal, suggesting the possibility of water intoxication. The patient received\n0.5 L of normal saline solution in the emergency department and was transferred to a\ngeneral medicine bed 4 h after emergency department presentation. His serum sodium\nlevel increased by 4 mEq/L over 4 h. Administration of 5% glucose solution was\nstarted at a rate matching urine output to prevent a further increase in serum\nsodium level. On day 2, the patient’s serum sodium level rose to 113 mEq/L. His\nserum sodium level on day 3 was 121 mEq/L. Thereafter his serum sodium level\nincreased by 5 mEq/L per day.\n\nOn day 5, the patient’s serum sodium level was 130 mEq/L. He was alert and was\nimproving. However, he suddenly developed twitching of the left arm lasting for\n30 s, consistent with FIAS, followed by FTBTCS lasting for about 40 min. Assisted\nventilation was started; intravenous diazepam (10 mg) was administered twice but was\nineffective. Therefore, intravenous fosphenytoin sodium (1300 mg) was subsequently\nadministered. FTBTCS stopped after administration of the first dose of fosphenytoin.\nHowever, intermittent twitching of the left arm with impaired awareness resulting\nfrom FIAS continued several times per hour, with each episode lasting more than\n5 min. Moreover, the patient had five episodes of recurrent FTBTCS lasting for about\n30 min each in the first 24 h with prolonged impaired awareness, despite the\naddition of continuous intravenous fosphenytoin (400 mg/day). Ictal\nelectroencephalogram (EEG) during FTBTCS showed bilateral polyspikes but was\nobscured by artifact; ictal EEG during FIAS showed rhythmic 5–9 Hz theta activity in\nthe right frontotemporal region (data not shown). EEG recorded during an\ninterseizure period revealed irregular right frontal sharp waves with theta and\ndelta activities (Figure 1).\nMagnetic resonance imaging (MRI) of the brain showed no obvious signs suggesting\nosmotic demyelination syndrome (ODS); however, marked atrophy of the hippocampus and\ntemporal lobe was seen (Figure\n2). Further questioning of the patient’s family revealed that he had been\ndiagnosed with AD 2 years before admission. Although atrophy of the hippocampus and\ntemporal lobe has been associated with seizures in patients with AD,2–4 no symptomatic epileptic\nseizures had been recognized before hospitalization. On day 6, the frequency of\nFTBTCS decreased, but intermittent FIAS and FTBTCS did not completely disappear.\nCorrection of hyponatremia was suspended to lower serum sodium to 125 mEq/L.\nFosphenytoin administration was discontinued and was replaced with intravenous\nlevetiracetam (1000 mg/day); however, FTBTCS continued intermittently. The addition\nof perampanel (4 mg/day) and clonazepam (3 mg/day) to levetiracetam was ineffective\nat controlling seizures. Administration of lamotrigine (200 mg/day), carbamazepine\n(600 mg/day), and levetiracetam (1000 mg/day) on day 7 was also ineffective.\nContinuous intravenous infusion of midazolam (5 mg/h) was introduced to treat SE on\nday 8. Thereafter, both FIAS and FTBTCS subsided. Repeat MRI of the brain on days 7,\n14, and 28 revealed no obvious lesions suggesting ODS on diffusion-weighted,\nT2-weighted, or fluid attenuation inversion recovery imaging. Reduction of the\nmidazolam dose was not possible because of relapsing seizures. The patient’s general\nstatus gradually deteriorated; he died of aspiration pneumonia on day 58.\n\nFigure 1. Electroencephalogram recorded during interseizure period on day 5. Sharp\nwaves were recorded in the right frontal region (red box). These waveforms\nalso showed disruption of background activity and subsequent emergence of\nslow waves. Low resolution and clipping traces are due to malfunction of the\nrecording device.\n\nFigure 2. Coronal fluid attenuation inversion recovery magnetic resonance imaging of\nthe brain on day 5. Bilateral atrophy of the hippocampus is observed (white\narrows). No other clear abnormal findings, including ischemic\nleukoencephalopathy, were found. Diffusion-weighted imaging of the brain\nshowed no significant abnormalities.\n\nDiscussion\nIn the present case, refractory FIAS and FTBTCS with subsequent SE occurred during\ncorrection of hyponatremia resulting from polydipsia. Hyponatremia may lead to acute\nsymptomatic seizures, which are usually generalized tonic-clonic.5 In addition, acute epileptic seizures and focal neurological deficits are\nidentified concomitantly in 5% of patients with severe hyponatremia (<125 mEq/L).5 When correcting hyponatremia, ODS may also cause seizures,6 but no lesions suggesting ODS were found in the present case. Okazaki et al.7 reported the effects of polydipsia-induced hyponatremia on pre-existing FIAS\nin five patients. In that report, the frequency of symptomatic FIAS increased when\nserum sodium fell below 127 mEq/L; four of the five patients had hippocampal atrophy\nor sclerosis and developed FIAS or FTBTCS. This finding suggests that hyponatremia\nmay aggravate both FIAS and FTBTCS in patients with hippocampal atrophy or\nsclerosis.\n\nIt should be noted that hyponatremic seizures per se are not rare events and are\noften observed in children and women of childbearing age;5 however, SE associated with hyponatremia is rare. To the best of our\nknowledge, only nine patients with SE associated with hyponatremia have been\nreported in the PubMed database in the past 30 years.8–15 Characteristics of the nine\nreported patients and our patient are shown in Table 1. Among these 10 patients, six were\nmale and four were female. Patient age ranged from 10 to 83 years; serum sodium\nlevels ranged from 90 to 126 mEq/L. The causes of hyponatremia were, in the order of\ndescending prevalence, polydipsia (four cases), syndrome of inappropriate secretion\nof antidiuretic hormone (SIADH, three cases), cerebral salt wasting (two cases), and\nadrenal insufficiency (one case). Hence, polydipsia and SIADH may be leading causes\nof hyponatremia-associated SE. Regarding seizure types, generalized tonic-clonic\nseizures were most common (four cases); complex partial seizures (two cases) and\nnon-convulsive SE (two cases) were also observed. Eight patients had no past history\nof epileptic seizures. No patients developed ODS during the treatment of\nhyponatremia. In the nine previously reported cases, antiepileptic drugs effectively\nstopped SE; these patients all recovered without sequelae. Our patient was the only\none with AD and whose outcome was death.\n\nTable 1. Patients with status epilepticus secondary to hyponatremic seizures.\n\nAuthor\tPatient age (years)\tSex\tComorbidities\tHistory of epilepsy\tType of seizures\tCause of hyponatremia\tSerum sodium level (mEq/L)\tAEDs given\tPresence of ODS\tOutcome\t\nPrimavera8\t53\tF\tBorderline personality disorder\t(−)\tNCSE\tPolydipsia\t90\tPB\t(−)\tSurvival\t\nBartolomei9\t68\tM\tDepression, BPH\t(−)\tCPS\tAdrenal insufficiency\t117\tCZP\t(−)\tSurvival\t\nKawaguchi10\t45\tF\tLymphoblastic leukemia, post-BMT\t(−)\tGTC\tSIADH resulting from HHV-6-associated acute limbic\nencephalitis\t109\tUnknown\t(−)\tSurvival\t\nÇelik11\t12\tM\tEpilepsy, cognitive and motor impairment\t(+)\tUnknown\tCerebral salt wasting\t122\tMDZ\t(−)\tSurvival\t\nÇelik11\t10\tM\tRefractory epilepsy, severe intellectual disability\t(+)\tUnknown\tCerebral salt wasting\t120\tUnknown\t(−)\tSurvival\t\nDe Souza Franceschi12\t59\tM\tCLL, post-umbilical cord blood transplantation\t(−)\tNCSE\tSIADH resulting from HHV-6-associated encephalitis\t126\tPHT\nLEV\t(−)\tSurvival\t\nPatel13\t8\tM\tADHD\t(−)\tGTC\tPolydipsia resulting from MPH overdose\t118\tfosPHT\t(−)\tSurvival\t\nHashimoto14\t75\tF\tLeft lung tuberculosis\t(−)\tGTC\tSIADH resulting from lung tuberculosis\t120\tfosPHT\t(−)\tSurvival\t\nKurauchi15\t67\tF\tDepression\t(−)\tNCSE\tPolydipsia\t115\tDZP\nLEV\t(−)\tSurvival\t\nAkuzawa\t83\tM\tPolydipsia, hematuria, Alzheimer’s disease\t(−)\tCPS\nGTC\tPolydipsia\t105\tCZP\nDZP\nfosPHT\nLEV\nLTG\nMDZ\nPER\t(−)\tDeath\t\nADHD: attention-deficit/hyperactivity disorder; AED: antiepileptic drug;\nBMT: bone marrow transplantation; BPH: benign prostate hypertrophy; CLL:\nchronic lymphocytic leukemia; CPS: complex partial seizure; CZP:\nclonazepam; F: female; fosPHT: fosphenytoin; DZP: diazepam; GTC:\ngeneralized tonic-clonic seizure; HHV-6: human herpesvirus-6; LEV:\nlevetiracetam; LTG: lamotrigine; M: male; MDZ: midazolam; MPH:\nmethylphenidate; NCSE: non–convulsive status epilepticus; ODS: osmotic\ndemyelination syndrome; PB: phenobarbital; PER: perampanel; PHT:\nphenytoin; SIADH: syndrome of inappropriate secretion of antidiuretic\nhormone.\n\nInterestingly, our patient showed rhythmic 5–9 Hz theta activity in the right\nfrontotemporal region during FIAS. This finding is similar to the typical ictal EEG\nof temporal lobe epilepsy and is specific for hippocampal seizures.16 In contrast, EEG during a seemingly interseizure period showed irregular\nsharp waves with theta and delta activities in the right frontotemporal region; this\npattern resembles the ictal pattern of temporal lobe epilepsy associated with\nneocortical seizures.16 These observed EEG patterns may also indicate multiple epileptogenic foci.\nAccording to previous studies, hippocampal sclerosis and multifocal spikes on EEG\nmay be associated with FTBTCS in patients with temporal or frontal lobe\nepilepsy.17,18 Moreover, AD is a leading cause of frontal or temporal epilepsy\nin the aged population. AD can cause SE, but SE in our patient was unresponsive to\nfirst-, second-, and third-line therapies and recurred for ⩾24 h.19–22 These characteristics meet the\ncriteria of super-refractory SE, which has a distinctively high mortality (about\n40%).23–25 To our knowledge, no similar\nsuper-refractory SE cases have been reported among AD patients. Factors related to\nthe onset of super-refractory SE in our patient are unclear, but hyponatremia might\nhave accelerated neuronal hyperexcitability resulting from AD-related presynaptic\nglutamate release, leading to SE.4,4,26\n\nThe limitations of our report include the lack of EEG information before\nhospitalization. Regarding EEG data during hospitalization, a mechanical breakdown\nof recording devices prevented capture of complete data and therefore we could not\nshow ictal EEG data during FIAS and FTBTCS. In addition, although this patient was\ndiagnosed with AD 2 years before admission, the precise time of AD onset was\nunclear. Regarding imaging, follow-up MRI of the brain was not performed after day\n28 because of deterioration of the patient’s general status. However, this case\nhighlights interesting mechanisms of FIAS proceeding to FTBTCS or SE and may also\nalert physicians to the potential risk of triggering SE under hyponatremic\nconditions.\n\nIn conclusion, we have presented a case of super-refractory SE during correction of\nchronic hyponatremia. Physicians should be aware of the potential risk of triggering\nSE when correcting hyponatremia in patients with AD.\n\nWe thank Rebecca Tollefson, DVM, from Edanz Group (www.edanzediting.com/ac)\nfor editing a draft of this manuscript.\n\nDeclaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the\nresearch, authorship, and/or publication of this article.\n\nEthical approval: Our institution does not require ethical approval for reporting individual cases\nor case series.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or\npublication of this article.\n\nInformed consent: Written informed consent was obtained from the patient and legally authorized\nrepresentatives including the patient’s wife and son for anonymized patient\ninformation to be published in this article. A copy of this written consent is\navailable for review by the Editor-in-Chief of this journal.\n\nORCID iD: Nobuhiro Akuzawa \nhttps://orcid.org/0000-0002-1204-1294\n==== Refs\nReferences\n1. \nGhosh S Jehi LE. \nNew-onset epilepsy in the elderly: challenges for the\ninternist\n. Cleve Clin J Med \n2014 ; 81 (8 ):\n490 –498\n.25085987 \n2. \nBrodie MJ Kwan P. \nEpilepsy in elderly people\n. BMJ \n2005 ; 331 :\n1317 –1322\n.16322020 \n3. \nPandis D Scarmeas N. \nSeizures in Alzheimer disease: clinical and epidemiological\ndata\n. Epilepsy Curr \n2012 ; 12 (5 ):\n184 –187\n.23118603 \n4. \nVossel KA Tartaglia MC Nygaard HB , et al\nEpileptic activity in\nAlzheimer’s disease: cause and clinical relevance\n.\nLancet Neurol \n2017 ; 16 :\n311 –322\n.28327340 \n5. \nNardone R Brigo F Trinka E. \nAcute symptomatic seizures caused by electrolyte\ndisturbances\n. 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Lancet Neurol \n2011 ; 10 (10 ):\n922 –930\n.21939901 \n22. \nFernandez A Lantigua H Lesch C , et al\nHigh-dose midazolam infusion\nfor refractory status epilepticus\n.\nNeurology \n2014 ; 82 :\n359 –365\n.24363133 \n23. \nShorvon S Ferlisi M. \nThe treatment of super-refractory status epilepticus: a critical\nreview of available therapies and a clinical treatment\nprotocol\n. Brain \n2011 ; 134 (Pt. 10):\n2802 –2818\n.21914716 \n24. \nShorvon S Ferlisi M. \nThe outcome of therapies in refractory and super-refractory\nconclusive status epilepticus and recommendations for\ntherapy\n. Brain \n2012 ; 135 :\n2314 –2328\n.22577217 \n25. \nStrzelczyk A Ansorge S Hapfelmeier J , et al\nCosts, length of stay, and\nmortality of super-refractory status epilepticus: a population-based study\nfrom Germany\n. Epilepsia \n2017 ; 58 (9 ):\n1533 –1541\n.28681418 \n26. \nGiuliani C Peri A. \nEffects of hyponatremia on the brain\n. J\nClin Med \n2014 ; 3 :\n1163 –1177\n.26237597\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "2050-313X", "issue": "8()", "journal": "SAGE open medical case reports", "keywords": "Alzheimer’s disease; focal impaired awareness seizures; focal to generalized tonic-clonic seizures; hyponatremia; status epilepticus", "medline_ta": "SAGE Open Med Case Rep", "mesh_terms": null, "nlm_unique_id": "101638686", "other_id": null, "pages": "2050313X20915416", "pmc": null, "pmid": "32313652", "pubdate": "2020", "publication_types": "D002363:Case Reports", "references": "21914716;23173742;17472605;26900382;28850553;16322020;24791089;16102515;21939901;26237597;22577217;24363133;28681418;28424403;26212707;7578663;25085987;27115479;24485931;26754778;25285115;28202866;22429112;9729113;23118603;28327340", "title": "Status epilepticus during correction of hyponatremia in a patient with Alzheimer's disease: A case report.", "title_normalized": "status epilepticus during correction of hyponatremia in a patient with alzheimer s disease a case report" }

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"FOSPHENYTOIN SODIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CANDESARTAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "8", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CANDESARTAN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVETIRACETAM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": 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null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PERAMPANEL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "3", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARBAMAZEPINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBAMAZEPINE." } ], "patientagegroup": null, "patientonsetage": "83", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "58", "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ICHIOKA K, AKUZAWA N, TAKAHASHI A. STATUS EPILEPTICUS DURING CORRECTION OF HYPONATREMIA IN A PATIENT WITH ALZHEIMER^S DISEASE: A CASE REPORT.. SAGE OPEN MEDICAL CASE REPORTS. 2021?8:1?5.", "literaturereference_normalized": "status epilepticus during correction of hyponatremia in a patient with alzheimer s disease a case report", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20210429", "receivedate": "20210429", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19194964, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" } ]

{ "abstract": "A 26-year-old girl with a longstanding colonization by Pandoraea nosoerga underwent liver-lung transplantation for cystic fibrosis (CF) in 2018. Her brother also suffering from CF was also colonized by P. nosoerga. Despite appropriate perioperative antibiotic therapy, she had post-transplant bacteremic pneumonia caused by extensively drug-resistant P. nosoerga. Drug repurposing was used to optimize treatment options. The cause of post-transplant contamination was studied by comparative whole-genome sequencing including pre- and post-transplant strains and her brother's strains. Post-transplant contamination appeared to be due to her own pre-transplant strain, emphasizing the urgent need to study and implement effective decontamination protocols before transplantation.", "affiliations": "IRD, APHM, MEPHI, IHU-Méditerranée Infection, Aix Marseille Univ, 19-21 boulevard Jean Moulin, 13385, Marseille CEDEX 05, France.;IRD, APHM, MEPHI, IHU-Méditerranée Infection, Aix Marseille Univ, 19-21 boulevard Jean Moulin, 13385, Marseille CEDEX 05, France.;IRD, APHM, MEPHI, IHU-Méditerranée Infection, Aix Marseille Univ, 19-21 boulevard Jean Moulin, 13385, Marseille CEDEX 05, France.;IRD, APHM, MEPHI, IHU-Méditerranée Infection, Aix Marseille Univ, 19-21 boulevard Jean Moulin, 13385, Marseille CEDEX 05, France.;IRD, APHM, MEPHI, IHU-Méditerranée Infection, Aix Marseille Univ, 19-21 boulevard Jean Moulin, 13385, Marseille CEDEX 05, France. [email protected].", "authors": "Peyclit|Lucie|L|;Baron|Sophie Alexandra|SA|;Reynaud-Gaubert|Martine|M|;Cassir|Nadim|N|;Rolain|Jean-Marc|JM|", "chemical_list": null, "country": "Germany", "delete": false, "doi": "10.1007/s10096-021-04235-0", "fulltext": null, "fulltext_license": null, "issn_linking": "0934-9723", "issue": "40(11)", "journal": "European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology", "keywords": "Comparative genomic; Cystic fibrosis; Drug repurposing; Extensively drug-resistant bacteria; Pandoraea", "medline_ta": "Eur J Clin Microbiol Infect Dis", "mesh_terms": null, "nlm_unique_id": "8804297", "other_id": null, "pages": "2403-2406", "pmc": null, "pmid": "33830365", "pubdate": "2021-11", "publication_types": "D016428:Journal Article", "references": "25826590;28711221;28858970;11208624;30069386;32349719;27620956;32389488;30895843;31781066;31245302;31762328;30316849;29056926;27050666", "title": "Fatal Pandoraea nosoerga infection after combined liver-lung transplantation for cystic fibrosis: a recontamination by the pre-transplantation strain.", "title_normalized": "fatal pandoraea nosoerga infection after combined liver lung transplantation for cystic fibrosis a recontamination by the pre transplantation strain" }

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"activesubstancename": "DOXYCYCLINE" }, "drugadditional": "4", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Bacterial infection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXYCYCLINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "RISPERIDONE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": "078452", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Bacterial infection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RISPERIDONE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CHLORHEXIDINE GLUCONATE" }, "drugadditional": "4", "drugadministrationroute": "003", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, DAILY BATHING", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CHLORHEXIDINE GLUCONATE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Bacterial infection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPIN" } ], "patientagegroup": null, "patientonsetage": "26", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Septic shock", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Disease recurrence", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bacteraemia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Peyclit L, Baron SA, Reynaud-Gaubert M, Cassir N, Rolain JM.. Fatal Pandoraea nosoerga infection after combined liver-lung transplantation for cystic fibrosis: a recontamination by the pre-transplantation strain.. European Journal of Clinical Microbiology + Infectious Diseases.. 2021;40(11):2403-2406", "literaturereference_normalized": "fatal pandoraea nosoerga infection after combined liver lung transplantation for cystic fibrosis a recontamination by the pre transplantation strain", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20220308", "receivedate": "20220308", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20563324, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 1, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220424" }, { "companynumb": "FR-PFM-2022-01303", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOXYCYCLINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "091406", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Bacterial infection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXYCYCLINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RISPERIDONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076288", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Bacterial infection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RISPERIDONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CHLORHEXIDINE GLUCONATE" }, "drugadditional": "3", "drugadministrationroute": "003", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, DAILY BATHING", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CHLORHEXIDINE GLUCONATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Bacterial infection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPIN" } ], "patientagegroup": null, "patientonsetage": "26", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Septic shock", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Disease recurrence", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bacteraemia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Peyclit L, Baron SA, Reynaud-Gaubert M, Cassir N, Rolain JM. Fatal Pandoraea nosoerga infection after combined liver-lung transplantation for cystic fibrosis: a recontamination by the pre-transplantation strain. European Journal of Clinical Microbiology + Infectious Diseases. 2021;40(11):2403-2406", "literaturereference_normalized": "fatal pandoraea nosoerga infection after combined liver lung transplantation for cystic fibrosis a recontamination by the pre transplantation strain", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20220330", "receivedate": "20220330", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20654232, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 1, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220424" } ]

{ "abstract": "The prevalence of fungal otitis externa, or otomycosis, has been increasing in recent decades. Fungi may act as primary pathogens in this condition, or they may occur as secondary infections after prolonged ototopical treatment with antibiotics, which alters the flora of the external auditory canal (EAC) and enables overgrowth of its fungal inhabitants. We report here a case of otomycosis by Candida parapsilosis, Malassezia obtusa, and Malassezia furfur as a secondary infection following prolonged otic ofloxacin treatment. To the best of our knowledge, although isolation of C. parapsilosis and M. furfur from the EAC is not uncommon, the recovery of M. obtusa has not yet been reported. We also conducted a literature review of the searchable data on PubMed concerning the isolation of Malassezia species from the human EAC.", "affiliations": "Laboratory of Medical Mycology and Space Environmental Medicine, School of Medicine, Graduate School of Medicine, Teikyo University, 2-11-1 Kaga, Itabashi, Tokyo, 173-8605, Japan.;Teikyo University Institute of Medical Mycology, Tokyo, Japan.;Department of Sports and Medical Science, Faculty of Medical Technology, Teikyo University, Itabashi, Tokyo, Japan.;Teikyo University Institute of Medical Mycology, Tokyo, Japan.;Department of Otolaryngology, Teikyo University Hospital, Itabashi, Tokyo, Japan.;Teikyo University Institute of Medical Mycology, Tokyo, Japan.;Laboratory of Medical Mycology and Space Environmental Medicine, School of Medicine, Graduate School of Medicine, Teikyo University, 2-11-1 Kaga, Itabashi, Tokyo, 173-8605, Japan. [email protected].", "authors": "Alshahni|Mohamed Mahdi|MM|;Alshahni|Rima Zakzuk|RZ|;Fujisaki|Ryuichi|R|;Tamura|Takashi|T|;Shimizu|Yuya|Y|;Yamanishi|Chiaki|C|;Makimura|Koichi|K|http://orcid.org/0000-0003-1645-3445", "chemical_list": "D015242:Ofloxacin", "country": "Netherlands", "delete": false, "doi": "10.1007/s11046-021-00581-x", "fulltext": null, "fulltext_license": null, "issn_linking": "0301-486X", "issue": "186(6)", "journal": "Mycopathologia", "keywords": "Candida; Malassezia; Ofloxacin; Otitis externa; Otomycosis", "medline_ta": "Mycopathologia", "mesh_terms": "D005658:Fungi; D006801:Humans; D008290:Malassezia; D015242:Ofloxacin; D010032:Otitis Externa; D059249:Otomycosis", "nlm_unique_id": "7505689", "other_id": null, "pages": "871-876", "pmc": null, "pmid": "34410567", "pubdate": "2021-12", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": "11261868;9433684", "title": "A Case of Topical Ofloxacin-Induced Otomycosis and Literature Review.", "title_normalized": "a case of topical ofloxacin induced otomycosis and literature review" }

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A Case of Topical Ofloxacin-Induced Otomycosis and Literature Review. 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{ "abstract": "We report a case of rapid eradication of melanoma brain metastases and simultaneous near-fatal encephalomyelitis following double immune checkpoint blockade. Brain damage marker S-100B and C reactive protein increased before symptoms or signs of encephalomyelitis and peaked when the patient fell into a coma. At that point, additional brain damage markers and peripheral T cell phenotype was analyzed. The analyses were repeated four times during the patient's recovery. Axonal damage marker neurofilament light polypeptide (NFL) and astrocytic damage marker glial fibrillar acidic protein (GFAP) were very high in blood and cerebrospinal fluid and gradually normalized after immunosuppression and intensive care. The costimulatory receptor inducible T cell costimulatory receptor (ICOS) was expressed on a high proportion of CD4+ and CD8+T cells as encephalomyelitis symptoms peaked and then gradually decreased in parallel with clinical improvement. Both single and double immune checkpoint inhibitor-treated melanoma patients with other serious immune-related adverse events (irAE) (n=9) also expressed ICOS on a significantly higher proportion of CD4+ and CD8+T cells compared with controls without irAE (n=12). In conclusion, our results suggest a potential role for ICOS on CD4+ and CD8+T cells in mediating encephalomyelitis and other serious irAE. In addition, brain damage markers in blood could facilitate early diagnosis of encephalitis.", "affiliations": "Department of Oncology, Institute of Clinical Sciences, University of Gothenburg Sahlgrenska Academy, Goteborg, Sweden.;Department of Oncology, Institute of Clinical Sciences, University of Gothenburg Sahlgrenska Academy, Goteborg, Sweden.;Department of Oncology, Institute of Clinical Sciences, University of Gothenburg Sahlgrenska Academy, Goteborg, Sweden.;Department of Oncology, Sahlgrenska University Hospital, Goteborg, Sweden.;Department of Oncology, Institute of Clinical Sciences, University of Gothenburg Sahlgrenska Academy, Goteborg, Sweden.;Department of Neuroradiology, Sahlgrenska University Hospital, Goteborg, Sweden.;Department of Anesthesiology and Intensive Care, Sahlgrenska University Hospital, Goteborg, Sweden.;Department of Oncology, Institute of Clinical Sciences, University of Gothenburg Sahlgrenska Academy, Goteborg, Sweden.;Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, University of Gothenburg Sahlgrenska Academy, Goteborg, Sweden.;Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, University of Gothenburg Sahlgrenska Academy, Goteborg, Sweden.;Department of Psychiatry and Neurochemistry, University of Gothenburg Institute of Neuroscience and Physiology, Goteborg, Sweden.;Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg Sahlgrenska Academy, Goteborg, Sweden.;Department of Oncology, Institute of Clinical Sciences, University of Gothenburg Sahlgrenska Academy, Goteborg, Sweden [email protected].", "authors": "Bjursten|Sara|S|;Pandita|Ankur|A|;Zhao|Zhiyuan|Z|;Fröjd|Charlotta|C|;Ny|Lars|L|;Jensen|Christer|C|;Ullerstam|Tobias|T|;Jespersen|Henrik|H|;Borén|Jan|J|;Levin|Malin|M|;Zetterberg|Henrik|H|;Rudin|Anna|A|;Levin|Max|M|0000-0001-9676-5582", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1136/jitc-2021-002732", "fulltext": "\n==== Front\nJ Immunother Cancer\nJ Immunother Cancer\njitc\njitc\nJournal for Immunotherapy of Cancer\n2051-1426\nBMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR\n\n34215689\njitc-2021-002732\n10.1136/jitc-2021-002732\nCase Report\n1506\n2518 1619\nEarly rise in brain damage markers and high ICOS expression in CD4+ and CD8+ T cells during checkpoint inhibitor-induced encephalomyelitis\nBjursten Sara 12\nPandita Ankur 123\nZhao Zhiyuan 12\nFröjd Charlotta 2\nNy Lars 12\nJensen Christer 4\nUllerstam Tobias 5\nJespersen Henrik 126\nBorén Jan 3\nLevin Malin 3\nZetterberg Henrik 78910\nRudin Anna 11\nhttp://orcid.org/0000-0001-9676-5582\nLevin Max 123\n1 Department of Oncology, Institute of Clinical Sciences, University of Gothenburg Sahlgrenska Academy, Goteborg, Sweden\n2 Department of Oncology, Sahlgrenska University Hospital, Goteborg, Sweden\n3 Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, University of Gothenburg Sahlgrenska Academy, Goteborg, Sweden\n4 Department of Neuroradiology, Sahlgrenska University Hospital, Goteborg, Sweden\n5 Department of Anesthesiology and Intensive Care, Sahlgrenska University Hospital, Goteborg, Sweden\n6 Department of Oncology, Akershus University Hospital, Lorenskog, Norway\n7 Department of Psychiatry and Neurochemistry, University of Gothenburg Institute of Neuroscience and Physiology, Goteborg, Sweden\n8 Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Goteborg, Sweden\n9 Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK\n10 UK Dementia Research Institute, UCL, London, UK\n11 Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg Sahlgrenska Academy, Goteborg, Sweden\nCorrespondence to Dr Max Levin; [email protected]\n2021\n2 7 2021\n9 7 e00273210 6 2021\n© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See https://creativecommons.org/licenses/by/4.0/.\n\nWe report a case of rapid eradication of melanoma brain metastases and simultaneous near-fatal encephalomyelitis following double immune checkpoint blockade. Brain damage marker S-100B and C reactive protein increased before symptoms or signs of encephalomyelitis and peaked when the patient fell into a coma. At that point, additional brain damage markers and peripheral T cell phenotype was analyzed. The analyses were repeated four times during the patient’s recovery. Axonal damage marker neurofilament light polypeptide (NFL) and astrocytic damage marker glial fibrillar acidic protein (GFAP) were very high in blood and cerebrospinal fluid and gradually normalized after immunosuppression and intensive care. The costimulatory receptor inducible T cell costimulatory receptor (ICOS) was expressed on a high proportion of CD4+ and CD8+T cells as encephalomyelitis symptoms peaked and then gradually decreased in parallel with clinical improvement. Both single and double immune checkpoint inhibitor-treated melanoma patients with other serious immune-related adverse events (irAE) (n=9) also expressed ICOS on a significantly higher proportion of CD4+ and CD8+T cells compared with controls without irAE (n=12). In conclusion, our results suggest a potential role for ICOS on CD4+ and CD8+T cells in mediating encephalomyelitis and other serious irAE. In addition, brain damage markers in blood could facilitate early diagnosis of encephalitis.\n\nimmunotherapy\nmelanoma\nautoimmunity\nCD4-Positive T-Lymphocytes\nCD8-Positive T-Lymphocytes\nSwedish state under the agreement between the Swedish government and the county councils, the ALF-agreement ALFGBG-717541 ALFGBG-828121 ALFGBG-870351 ALFGBG-933754 http://dx.doi.org/10.13039/501100010223 Stiftelsen Jubileumsklinikens Forskningsfond mot Cancer 2020-313 http://dx.doi.org/10.13039/501100005009 Stiftelsen Assar Gabrielssons Fond special-featureunlocked\n==== Body\nImmune checkpoint blockade increases survival in patients with metastatic malignant melanoma, renal cell carcinoma, and lung cancer.1–4 Double immune checkpoint blockade activates T cells by blocking the inhibitory receptors programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) simultaneously, thereby promoting T cells to kill cancer cells. However, it increases the risk of autoimmune reactions in healthy tissue, immune-related adverse events (irAE).5 Any organ system can be affected by irAE and among the most feared is engagement of the brain, encephalitis.6–8 With the growing use of immune checkpoint blockade in cancer patients, encephalitis cases are expected to increase. A clinical challenge is to quickly and accurately diagnose encephalitis, which is difficult to distinguish from conditions such as progression of brain metastasis or infection that give rise similar symptoms. Also, little is known about the T cell mediated mechanisms promoting encephalitis and other serious irAE.\n\nEncephalomyelitis case and controls\n\nEncephalomyelitis case\n\nA 67-year-old man with metastases of melanoma in the brain, adrenal glands, lung, subcutis, and lymph nodes started double immune checkpoint blockade; PD1-inhibitor nivolumab (1 mg/kg) and the CTLA-4 inhibitor ipilimumab (3 mg/kg) given four times at 3-week intervals (figure 1A). After two treatments, MRI scans (MRI) showed regression of the brain metastases (figure 1B). The day after the fourth treatment, he developed a fever (39.1°C), elevation of C reactive protein (CRP) (45 mg/L), and dizziness. He was admitted to the oncology ward at Sahlgrenska University Hospital and was given IV antibiotics. After 2 days, he developed paraparesis in his lower limbs, decreased consciousness, and respiratory failure. His CRP level increased to 130 mg/L.\n\nFigure 1 Regression of encephalomyelitis induced by double immune checkpoint blockade. (A) shows a clinical overview. (B) shows regression of brain metastases and progression of encephalitis on MRI scans. At baseline, the patient had a 25 mm metastasis in the left portion of the splenium corpus callosum and an 18 mm metastasis in the right cerebellar hemisphere (red arrows). After two treatments (34 days), both metastases had partially regressed. After four treatments (68 days), regression was complete but new diffuse lesions were seen in the posterior horns of the lateral ventricles indicating encephalitis (red arrows). MRI scans were unchanged at day 71 and showed gradual decrease of the lesions in the brain at 78 and 85 days and complete resolution at 112 days. (C) shows serum levels of S-100B and C reactive protein (CRP), starting at baseline. The highest measurements coincided with the most severe symptoms of encephalitis. However, the first peak in S-100B and CRP levels occurred before the patient had any symptoms or radiological findings of encephalitis, suggesting a potential biomarker for early detection. IPI, ipilimumab; IVIG, intravenous immunoglobulin; MMF, mycophenolate mofetil; nivo, nivolumab.\n\nHe was admitted to the intensive care unit (ICU), intubated, and put on mechanical ventilation. On ICU day 1, MRI showed complete regression of his brain metastases but new diffuse lesions in the brain, brainstem, and cerebellum with a bilateral and asymmetric pattern (figure 1B), indicating acute disseminated encephalomyelitis.9 Analyses of cerebrospinal fluid (CSF) suggested autoimmune encephalitis (online supplemental table S1). Immunosuppression with methylprednisolone (1 g daily intravenously) was started. The next day he was alert during sedation stops but required respiratory support, reflecting brain stem damage. MRI on ICU day 3 revealed unchanged brain lesions and lesions in the spinal cord. Cyclophosphamide was administered (1.5 g intravenously as a single dose), but his condition did not improve. On ICU day 6, mycophenolate mofetil (1 g two times per day intravenously) was started to inhibit T and B cell proliferation.10 The next day, he had improved and could be extubated and transferred back to the oncology ward. He had flaccid paraparesis in his lower limbs with minor residual sensation and urine and fecal incontinence. High-dose cortisone and mycophenolate mofetil were continued, and intravenous immunoglobulins were given (35 g daily for 5 days). MRI 10 and 17 days after ICU admission revealed gradual decrease in lesions in the brain and spinal cord (figure 1B).\n\n10.1136/jitc-2021-002732.supp1 Supplementary data\n\nAfter 6 weeks, the patient was discharged from hospital care. Now, he had regained most sensory functions, and he could sit up and operate a wheelchair. After 10 weeks, the inflammatory lesions had resolved on MRI. The immunosuppressant treatment was tapered and permanently discontinued after 14 months. More than 2 years after the first dose of double immune checkpoint blockade, the patient no longer suffers from fecal incontinence and he can walk more than 100 steps with assistive devices. By becoming more independent, the patient’s quality of life has improved significantly and he remains tumor-free.\n\nControl patients with or without irAE\n\nIn addition to the encephalomyelitis patient, we also analyzed T cell characteristics in checkpoint inhibitor-treated patients with (n=9) or without other irAE (n=12) (table 1). The irAE were moderate to severe and occurred during double (n=2, including the encephalomyelitis patient) or single (PD-1) inhibition (n=8). Similarly, samples were obtained from patients without irAE during double (n=2) or single (PD-1) checkpoint inhibition (n=10). In addition, we performed repeated analysis of cytokines and soluble checkpoint proteins in CSF from the encephalomyelitis patient. As controls for this analysis, we used CSF from patients with autoimmune systemic lupus erythematosus without encephalitis (n=4).\n\nTable 1 Patient characteristics\n\nAge\tSex\tBRAF\tTumor stage*\tTreatment\tTime to irAE/test†\tAffected organ(s)\tGrade\n(CTCAE 5)‡\tTreatment of irAE\t\n68\tM\tV600K\tIV\tIpi+Nivo\t2 months\tBrain and spinal cord§\t4\tCORT, MMF, IVIG, CP\t\n52\tF\tWt\tIV\tIpi+Nivo\t2 months\tLiver\t4\tCORT, MMF\t\n72\tF\tNot known\tIV\tPembro\t3 months\tBlood (neutropenia)\t4\tCORT, filgrastim\t\n72\tM\tV600\tIV\tPembro\t13 months\tColon\t3\tCORT, infliximab\t\n55\tF\tV600\tIV\tNivo\t14 months\tJoints and muscles\t3\tCORT, MTX\t\n38\tF\tWt\tIV\tNivo¶\t5 months\tJoints and muscles\t3\tCORT\t\n83\tF\tV600E\tIV\tNivo\t1 month\tColon\t3\tCORT, infliximab\t\n53\tM\tV600K\tIV\tNivo\t11 months\tLungs\t2\tCORT\t\n80\tF\tWt\tIV\tNivo\t10 months\tLungs\t2\tCORT\t\n74\tM\tV600K\tIV\tNivo±Relatlimab\t2 months\tJoints and muscles\t2\tCORT\t\n\t \t \t \t \t\t \t\t \t\n71\tM\tWt\tIV\tIpi+Nivo\t9 months\tNo irAE\t0\tnone\t\n80\tM\tWt\tIV\tIpi+Nivo\t2 months\tNo irAE\t0\tnone\t\n80\tM\tV600K\tIV\tPembro\t5 months\tNo irAE\t0\tnone\t\n77\tF\tWt\tIV\tPembro\t4 months\tNo irAE\t0\tnone\t\n82\tF\tWt\tIV\tPembro\t3 months\tNo irAE\t0\tnone\t\n76\tM\tV600E\tIV\tPembro\t3 months\tNo irAE\t0\tnone\t\n67\tM\tV600\tIV\tPembro\t2 months\tNo irAE\t0\tnone\t\n68\tM\tV600E\tIV\tNivo\t4 months\tNo irAE\t0\tnone\t\n62\tF\tV600E\tIV\tNivo\t3 months\tNo irAE\t0\tnone\t\n57\tM\tV600E\tIV\tNivo\t2 months\tNo irAE\t0\tnone\t\n68\tM\tWt\tIII\tNivo\t1 month\tNo irAE\t0\tnone\t\n93\tM\tWt\tIII\tNivo\t1 month\tNo irAE\t0\tnone\t\n*Stage III: locally advanced disease. Stage IV: metastatic disease.\n\n†Time from treatment start until adverse event (and sample) or time from treatment start until sample in controls without irAE.\n\n‡CTCAE are a set of criteria for the standardized classification of adverse effects of cancer drugs. The scale ranges from grade 0 to grade 5. Grade 0 is no adverse event. Grade one adverse events have no or mild symptoms with or without laboratory abnormalities whereas grade five events are lethal.\n\n§Encephalomyelitis patient.\n\n¶irAE during Nivolumab monotherapy. Ipi/Nivo treatment previously without any side effects.\n\nCORT, corticosteroids; CP, cyclophosphamide; CTCAE, Common Terminology Criteria for Adverse Events; Ipi, ipilimumab; irAE, immune related adverse event; IVIG, intravenous immunoglobuline; MMF, mycophenolate mofetil; MTX, methotrexate; Nivo, nivolumab; Pembro, pembrolizumab; wt, wild type.\n\nMethods\n\nT cell characteristics, brain damage markers, and soluble checkpoint proteins were analyzed as described in online supplemental appendix.\n\nResults\n\nIncidence of encephalitis\n\nThe number of reported cases of encephalitis following both single and double immune checkpoint blockade is increasing and the fatality rate is high (WHO global database VigiBase, online supplemental figure S2).\n\nBrain damage markers and inflammation\n\nRetrospective analysis of blood tests unexpectedly revealed a distinct pattern that was not evident during the patient’s stay. The brain damage marker S-100B and the inflammatory marker CRP covaried strikingly over time (figure 1C), and levels of both were elevated after two treatments with ipilimumab/nivolumab. At that point, the patient had no symptoms, and MRI showed regression of the brain metastases and no signs of encephalitis. After the fourth and final treatment, S-100B and CRP peaked, indicating combined inflammation and brain damage. The patient rapidly deteriorated, and MRI showed acute disseminated encephalomyelitis. These results suggest that brain damage markers in blood may indicate encephalitis before the appearance of typical signs on MRI or clinical neurological symptoms.\n\nExtensive analysis of blood and CSF confirmed brain damage and inflammation (online supplemental figure S3, tables S1 and S4) but showed no signs of infection or autoantibodies (online supplemental tables S1 and S4). The brain damage markers neurofilament light polypeptide (NFL) and glial fibrillar acidic protein (GFAP) were extremely high in both CSF and plasma as symptoms peaked and gradually normalized during immunosuppression (online supplemental figure S3, tables S1 and S3). Tau and S-100B levels were moderately increased (online supplemental table S3). Collectively, these findings suggest severe axonal damage (NFL) and astrocyte injury (GFAP).11 Interferon-γ, tumor necrosis factor-α, and interleukin-6 levels were increased in CSF when symptoms peaked and normalized during recovery (online supplemental figure S3). The checkpoint proteins PD1, PD-L1, and Tim-3 showed a similar pattern (online supplemental figure S4). CTLA-4 and LAG-3 were not elevated.\n\nT cell characteristics\n\nFlow cytometry of peripheral T cells was done on ICU day 2 and repeated four times. The analysis included T cell subtypes, activation markers, costimulatory receptors, inhibitory immune checkpoints, transcription factors, and attack enzymes (online supplemental table S2). In addition to our encephalomyelitis patient, T cell phenotype was also analyzed in patients with other irAE as well as in patients without irAE (table 1). The most striking observation in the encephalomyelitis patient was high expression of inducible T cell costimulatory receptor (ICOS) on all subtypes of CD4 +T helper cells (figure 2A) (online supplemental figure S5) and on CD8+ cytotoxic T cells. ICOS expression on T cells gradually normalized during immunosuppression and in parallel with clinical improvement (figure 2B–D) (online supplemental figure S5B, C). Similarly, high ICOS on CD4+ and CD8+T cells was detected also in patients with other irAE (figure 2A) and decreased when irAEs had resolved (figure 2B). One patient developed grade 4 hepatitis during treatment with double checkpoint inhibition. In this patient, one sample was analyzed before irAE, when liver enzymes were normal. Interestingly ICOS on CD4+ and CD8+T cells increased in parallel with liver enzymes and decreased again after immunosuppression, and subsequent normalization of liver enzymes (figure 3). Collectively, our data indicate that ICOS may promote development of irAE. High ICOS expression could not be explained by longer duration of checkpoint inhibition because the difference was significant also if patients with late irAE (>6 months, 4 patients) were excluded from the analysis (irAE vs non-irAE; ICOS on CD8+ T cells, p<0.010; ICOS on CD4 +T cells, p<0.027). In addition, the difference in ICOS expression was significant also when only patients treated with single PD-1 inhibition was compared (irAE vs non-irAE; ICOS on CD8 +T cells, p<0.0085; ICOS on CD4+T cells, p<0.0062). This indicates that the difference in ICOS was not specific for anti-CTLA-4 treatment. Full data on T cell characteristics is shown in online supplemental figure S6. In addition to ICOS, TIM-3 (an inhibitory checkpoint protein and activation marker) was significantly higher on CD8 +T cells in patients with irAE and normalized when irAE were resolved. Also, PD-1 expression on CD4+ T cells was significantly higher in patients with irAE. The patients with irAE had similar proportion of immunosuppressive regulatory T cells as checkpoint inhibitor-treated controls (online supplemental figure S7). There was no difference in total number of CD8+ cytotoxic T cells, CD4+T helper cells, B cells, or natural killer cells, between our patient and checkpoint inhibitor-treated controls (online supplemental figure S8).\n\nFigure 2 High proportion of ICOS-expressing CD4+ and CD8+T cells during active encephalomyelitis. Panel (A) shows higher proportion of T cells expressing the costimulatory receptor ICOS at the peak of symptoms in checkpoint inhibitor-treated patients with immune-related adverse events (irAE; pink dots and the big red dot which indicates the encephalitis patient) than in patients without irAE (no irAE; green dots) (large dots—double inhibition; small dots—single PD-1-inhibition) (Mann-Whitney U test). The encephalitis patient had the highest proportion of ICOS positive CD4+T cells and the second highest proportion of ICOS-expression on CD8+ cells. (B) shows that immunosuppression decreased the proportion of ICOS expressing CD8+ and CD4+T cells in the encephalitis patient as well as in patients with other irAE (Wilcoxon matched-pairs signed rank test). (C) shows that the proportion of ICOS expressing CD8 (dotted red line) and CD4 (solid red line) T cells decreased in parallel with clinical improvement (box) and with decrease in brain damage marker GFAP in blood. GFAP, glial fibrillar acidic protein; ICOS, inducible T cell costimulatory receptor; PD-1, programmed cell death 1.\n\nFigure 3 High proportion of ICOS-expressing CD4+T cells during severe checkpoint inhibitor-induced hepatitis The figure shows covariation of liver enzymes—aspartate transaminase (AST; solid green line) and alanine aminotransferase (ALT; dotted green line)—and ICOS expression on CD4+T cells (solid red line) before, at the peak of, and after severe checkpoint inhibitor–induced hepatitis (grade 4). ICOS on CD8+T cells (dotted red line) showed a similar, but less pronounced, covariation with liver enzymes. The black triangles indicate time points for double checkpoint inhibition with ipilimumab and nivolumab. ICOS, inducible T cell costimulatory receptor.\n\nDiscussion and conclusion\n\nIn this study, we demonstrate a specific T cell phenotype in a patient with encephalomyelitis as well as in patients with other severe irAE. The most striking feature is high expression of costimulatory receptor ICOS on CD4+ and CD8+T cells. In addition, our study shows that brain damage markers in blood can help in early diagnosis of encephalitis.\n\nirAE are a diverse set of checkpoint inhibitor-induced autoimmune reactions but little is known about the mechanisms promoting irAE.5 Here, we identify high ICOS expression, on both CD4+ and CD8+ cells, during encephalomyelitis and other serious irAE. ICOS decreased when the irAE resolved suggesting that ICOS may promote irAE. In agreement, ICOS has been linked to the development of different autoimmune diseases.12 The association between T cell expression of ICOS and the clinical course of irAE is clear but it is important to clarify if the ICOS molecule promotes irAE. If this is the case, targeting ICOS with antagonists may constitute a therapeutic approach to dampen severe irAE; such as the near-fatal encephalomyelitis described here. However, it is possible that such an intervention, as well as the immunosuppressive treatments used in our patients, may increase the risk of tumor progression or recurrence because ICOS has also been identified as a mediator of response.13 14\n\nDouble immune checkpoint blockade is often more effective than PD-1 inhibition alone, as targeting CTLA-4 also activates CD4 +T cells.15 In mice, the absence of CTLA-4 promotes the expansion of ICOS-positive CD4+ effector T cells, which are important in mediating the response to CTLA-4 inhibition.14–17 Interestingly, high ICOS expression on CD4 +cells also promotes the development of neuromyelitis optica spectrum disorder,18 an autoimmune demyelinating disease of the central nervous system. The high levels of ICOS expression on CD4+ effector cells in our patient could help explain both the efficient eradication of tumor cells and the collateral damage to normal brain cells. Consistent with our data, activated CD4+ memory cells accumulated in inflamed brain tissue from a patient who died from checkpoint inhibitor-induced encephalitis.7 At autopsy, no signs of remaining melanoma brain metastases were found. In combination with previous clinical and experimental data, the findings in our case support a role for ICOS expression on CD4+ cells in mediating an aggressive immune reaction.\n\nThe current case shows that brain damage biomarkers in blood can help to diagnose encephalitis. Our patient had increased levels of the brain damage marker S-100B and CRP after two treatments, when he was asymptomatic and MRI showed no signs of encephalitis. S-100B and CRP peaked after the fourth and final treatment, when his encephalitis rapidly progressed. S-100B was analyzed because it is a melanoma marker. However, it was negative before treatment, and therefore the elevated level reflected treatment-induced brain damage and not progression of melanoma. Additional biomarkers were analyzed in the ICU and repeatedly during recovery. Most notably, the axonal damage marker NFL and the marker of astrocytic injury GFAP were extremely high in both blood and CSF and normalized during improvement. To facilitate diagnosis of encephalitis, we suggest that a set of brain damage markers in blood be included in laboratory panels taken during double-checkpoint inhibition. Our patient developed very severe encephalomyelitis and it needs to be investigated if brain damage markers in blood also indicate less severe cases of encephalitis.\n\nCheckpoint inhibitor-induced encephalitis is a diagnostic challenge. Given our patient’s serious cancer diagnosis, oncologists and intensivists discussed whether he should be admitted to the ICU. The decision to do so was based on the argument that the clinical and radiologic findings were consistent with causes other than cancer progression, such as infection or neurotoxicity. At admission, the patient was unconscious and had central respiratory depression. He would have died without ICU treatment.\n\nIn conclusion, this study suggests a potential role for ICOS on CD4+ and CD8+T cells in mediating encephalitis and other serious irAE. In addition, our case suggests that brain damage markers in blood should be analyzed to facilitate early diagnosis of encephalitis.\n\nWe thank Elisabeth Kapocs for coordinating patient samples, the Department of clinical immunology at Sahlgrenska University Hospital for performing flow cytometry, and Kerstin Andersson for flow cytometry gating. Ellen Nohle is acknowledged for discussing early drafts of the manuscript. We thank Stephen Ordway for editing the manuscript.\n\nEthics statements\n\nPatient consent for publication\n\nNot required.\n\nContributors: Acquisition of data: ML, SB, AP, ZZ, CJ, TU, HJ, HZ, AR. Analysis and interpretation of data: All authors. Writing the manuscript: SB and ML. Review, and/or revision of the manuscript: All authors.\n\nFunding: Supported by funding from the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (ALFGBG-828121 and 870 351 to ML; ALFGBG-717541 to AR; ALFGBG-933754 to SB), Jubileumsklinikens cancerfond (to ML) and Stiftelsen Assar Gabrielssons Fond (to SB).\n\nCompeting interests: None declared.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n\nSupplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.\n==== Refs\nReferences\n\n1 Tawbi HA, Forsyth PA, Algazi A, et al . Combined nivolumab and ipilimumab in melanoma metastatic to the brain. N Engl J Med 2018;379 :722–30. 10.1056/NEJMoa1805453 30134131\n2 Hellmann MD, Paz-Ares L, Bernabe Caro R, et al . Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N Engl J Med 2019;381 :2020–31. 10.1056/NEJMoa1910231 31562796\n3 Larkin J, Chiarion-Sileni V, Gonzalez R, et al . Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med 2019;381 :1535–46. 10.1056/NEJMoa1910836 31562797\n4 Motzer RJ, Rini BI, McDermott DF, et al . 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Sci Rep 2019;9 :14130. 10.1038/s41598-019-50479-4 31575949\n\n", "fulltext_license": "CC BY", "issn_linking": "2051-1426", "issue": "9(7)", "journal": "Journal for immunotherapy of cancer", "keywords": "CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; autoimmunity; immunotherapy; melanoma", "medline_ta": "J Immunother Cancer", "mesh_terms": null, "nlm_unique_id": "101620585", "other_id": null, "pages": null, "pmc": null, "pmid": "34215689", "pubdate": "2021-07", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": "27572859;32939077;31332390;32086972;30242316;31575949;31562797;29320654;30926234;30134131;31925406;28803728;21708958;30171200;31562796;31466995;31427204;32055040", "title": "Early rise in brain damage markers and high ICOS expression in CD4+ and CD8+ T cells during checkpoint inhibitor-induced encephalomyelitis.", "title_normalized": "early rise in brain damage markers and high icos expression in cd4 and cd8 t cells during checkpoint inhibitor induced encephalomyelitis" }

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JOURNAL FOR IMMUNOTHERAPY OF CANCER. 2021?9(7):1?7", "literaturereference_normalized": "early rise in brain damage markers and high icos expression in cd4 and cd8 t cells during checkpoint inhibitor induced encephalomyelitis", "qualification": "3", "reportercountry": "SE" }, "primarysourcecountry": "SE", "receiptdate": "20210726", "receivedate": "20210726", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19609392, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "SE-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-072105", "fulfillexpeditecriteria": "1", "occurcountry": "SE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "NIVOLUMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "125554", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTATIC MALIGNANT MELANOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NIVOLUMAB" } ], "patientagegroup": null, "patientonsetage": "83", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Gastrointestinal disorder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BJURSTEN S, PANDITA A, ZHAO Z, FROJD C, NY L, JENSEN C, ET AL. EARLY RISE IN BRAIN DAMAGE MARKERS AND HIGH ICOS EXPRESSION IN CD4+ AND CD8+ T CELLS DURING CHECKPOINT INHIBITOR?INDUCED ENCEPHALOMYELITIS. JOURNAL FOR IMMUNOTHERAPY OF CANCER. 2021?9(7):1?7", "literaturereference_normalized": "early rise in brain damage markers and high icos expression in cd4 and cd8 t cells during checkpoint inhibitor induced encephalomyelitis", "qualification": "3", "reportercountry": "SE" }, "primarysourcecountry": "SE", "receiptdate": "20210727", "receivedate": "20210727", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19617882, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "SE-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-072104", "fulfillexpeditecriteria": "1", "occurcountry": "SE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "NIVOLUMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "125554", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTATIC MALIGNANT MELANOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NIVOLUMAB" } ], "patientagegroup": null, "patientonsetage": "38", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Muscle disorder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Arthropathy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BJURSTEN S, PANDITA A, ZHAO Z, FROJD C, NY L, JENSEN C, ET AL. EARLY RISE IN BRAIN DAMAGE MARKERS AND HIGH ICOS EXPRESSION IN CD4+ AND CD8+ T CELLS DURING CHECKPOINT INHIBITOR?INDUCED ENCEPHALOMYELITIS. JOURNAL FOR IMMUNOTHERAPY OF CANCER. 2021?9(7):1?7", "literaturereference_normalized": "early rise in brain damage markers and high icos expression in cd4 and cd8 t cells during checkpoint inhibitor induced encephalomyelitis", "qualification": "3", "reportercountry": "SE" }, "primarysourcecountry": "SE", "receiptdate": "20210726", "receivedate": "20210726", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19609291, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" } ]

{ "abstract": "Heparin-induced thrombocytopenia (HIT) can occur following exposure to heparin and is characterized by thrombocytopenia with increased risk for thrombosis. This condition is mediated by formation of immunoglobulin G antibodies against platelet factor 4/heparin complexes that can subsequently lead to platelet activation. Herein, we detail the clinical and laboratory findings, treatments, and outcomes of two patients who developed HIT and thrombosis after undergoing collection of hematopoietic progenitor cells by apheresis (HPC-A) for autologous HPC transplant. Given that heparin may be used during HPC-A collections, these cases emphasize the importance of prompt consideration of HIT in patients that develop thrombocytopenia and thrombosis following HPC-A collection with heparin anticoagulation.", "affiliations": "Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina.;Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina.;Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina.;Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina.;Department of Medicine, University of North Carolina, Chapel Hill, North Carolina.;Department of Medicine, University of North Carolina, Chapel Hill, North Carolina.;Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina.", "authors": "Raval|Jay S|JS|https://orcid.org/0000-0001-9835-957X;Park|Yara A|YA|;Perjar|Irina|I|;Mazepa|Marshall A|MA|https://orcid.org/0000-0003-4294-3069;Vincent|Benjamin G|BG|;Ma|Alice D|AD|;Rollins-Raval|Marian A|MA|", "chemical_list": "D000418:Albumins; D000906:Antibodies; D000925:Anticoagulants; D007074:Immunoglobulin G; C000629325:PF4 protein, human; D010978:Platelet Factor 4; D006493:Heparin", "country": "United States", "delete": false, "doi": "10.1002/jca.21757", "fulltext": null, "fulltext_license": null, "issn_linking": "0733-2459", "issue": "35(1)", "journal": "Journal of clinical apheresis", "keywords": "HIT; apheresis; stem cell collection; thrombocytopenia; thrombosis", "medline_ta": "J Clin Apher", "mesh_terms": "D000368:Aged; D000418:Albumins; D000906:Antibodies; D000925:Anticoagulants; D001781:Blood Component Removal; D057286:Electronic Health Records; D005260:Female; D006412:Hematopoietic Stem Cells; D006493:Heparin; D006801:Humans; D007074:Immunoglobulin G; D008297:Male; D008875:Middle Aged; D015539:Platelet Activation; D010978:Platelet Factor 4; D012189:Retrospective Studies; D012306:Risk; D013921:Thrombocytopenia; D013927:Thrombosis", "nlm_unique_id": "8216305", "other_id": null, "pages": "59-61", "pmc": null, "pmid": "31696530", "pubdate": "2020-01", "publication_types": "D016428:Journal Article", "references": null, "title": "Heparin-induced thrombocytopenia associated with collection of hematopoietic progenitor cells by apheresis.", "title_normalized": "heparin induced thrombocytopenia associated with collection of hematopoietic progenitor cells by apheresis" }

[ { "companynumb": "US-DRREDDYS-USA/USA/19/0116604", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "HEPARIN SODIUM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "017064", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNFRACTIONATED HEPARIN", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "9780", "drugstructuredosageunit": "025", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HEPARIN SODIUM." } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Jugular vein thrombosis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "RAVAL JS, PARK YA, PERJAR I, MAZEPA MA, VINCENT BG, MA AD ET AL. HEPARIN-INDUCED THROMBOCYTOPENIA ASSOCIATED WITH COLLECTION OF HEMATOPOIETIC PROGENITOR CELLS BY APHERESIS. JOURNAL OF CLINICAL APHERESIS. 2019?1-3. DOI: 10.1002/JCA.21757.", "literaturereference_normalized": "heparin induced thrombocytopenia associated with collection of hematopoietic progenitor cells by apheresis", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200127", "receivedate": "20191202", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17097544, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "US-DRREDDYS-USA/USA/19/0116677", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "HEPARIN SODIUM" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "017064", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNFRACTIONATED HEPARIN", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "18378", "drugstructuredosageunit": "025", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HEPARIN SODIUM." } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pulmonary embolism", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Deep vein thrombosis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Heparin-induced thrombocytopenia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "RAVAL JS, PARK YA, PERJAR I, MAZEPA MA, VINCENT BG, MA AD ET AL. HEPARIN-INDUCED THROMBOCYTOPENIA ASSOCIATED WITH COLLECTION OF HEMATOPOIETIC PROGENITOR CELLS BY APHERESIS. JOURNAL OF CLINICAL APHERESIS. 2019?1-3. DOI: 10.1002/JCA.21757.", "literaturereference_normalized": "heparin induced thrombocytopenia associated with collection of hematopoietic progenitor cells by apheresis", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200127", "receivedate": "20191203", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17104927, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" } ]

{ "abstract": "BACKGROUND\nXeroderma pigmentosum is a rare genetic disorder of DNA repair, defined by extreme sensitivity to sunlight, leading to sunburn, skin pigmentation and increased incidence of skin cancers. Cisplatin acts by interfering with DNA repair mechanisms to cause DNA damage and apoptosis. It has indications in many malignancies including bladder, head and neck and lung cancers. Acute kidney injury is a well-known complication of cisplatin.\n\n\nMETHODS\nWe report a 42-year-old male with a long history of Xeroderma pigmentosum treated with adjuvant cisplatin (40 mg/m2) in combination with radiotherapy for cutaneous squamous cell carcinoma of the neck. He presented to clinic prior to his second weekly dose of cisplatin with a severe acute kidney injury and a creatine level of 813 mmol/L and eGFR of 7 mL/min. No myelosuppression was present.\nTreatment consisted of aggressive electrolyte and fluid management. Creatinine levels slowly improved with conservative management without the need for dialysis. Radiation was completed without further cisplatin.\n\n\nCONCLUSIONS\nThree cases of severe adverse effects from cisplatin administration in patients with Xeroderma pigmentosum have been reported, with all fatal. Xeroderma pigmentosum complementation group C plays an important role in the DNA repair process with the recognition and repair of damage to normal cells following cisplatin. Patients with Xeroderma pigmentosum can be carriers of defective Xeroderma pigmentosum complementation group C and if the degree of Xeroderma pigmentosum complementation group C inactivity is significant, fatalities could occur. Physicians should be aware of this rare but potentially lethal toxicity when considering systemic therapy for squamous cell carcinoma in patients diagnosed with Xeroderma pigmentosum.", "affiliations": "Cancer Care Services, Toowoomba Hospital, Australia.;Cancer Care Services, Toowoomba Hospital, Australia.", "authors": "Gilbar|Peter J|PJ|https://orcid.org/0000-0001-7748-1891;Pokharel|Khageshwor|K|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1177/10781552211038246", "fulltext": null, "fulltext_license": null, "issn_linking": "1078-1552", "issue": null, "journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners", "keywords": "Xeroderma pigmentosum; acute renal failure; cisplatin; nephrotoxicity", "medline_ta": "J Oncol Pharm Pract", "mesh_terms": null, "nlm_unique_id": "9511372", "other_id": null, "pages": "10781552211038246", "pmc": null, "pmid": "34647821", "pubdate": "2021-10-14", "publication_types": "D016428:Journal Article", "references": null, "title": "Severe cisplatin-induced renal toxicity in a patient with xeroderma pigmentosum.", "title_normalized": "severe cisplatin induced renal toxicity in a patient with xeroderma pigmentosum" }

[ { "companynumb": "AU-MYLANLABS-2021M1082092", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": "091062", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Injection", "drugdosagetext": "40 MILLIGRAM/SQ. METER, QW FOR 7 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "Squamous cell carcinoma of skin", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "20200830", "drugstartdateformat": "102", "drugstructuredosagenumb": "40", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Injection", "drugdosagetext": "12 MILLIGRAM BEFORE THE TREATMENT", "drugenddate": null, "drugenddateformat": null, "drugindication": "Prophylaxis of nausea and vomiting", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "12", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "8 MILLIGRAM, QD FOR 3 DAYS AFTER TREATMENT", "drugenddate": null, "drugenddateformat": null, "drugindication": "Prophylaxis of nausea and vomiting", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "8", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "NETUPITANT\\PALONOSETRON HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Prophylaxis of nausea and vomiting", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NETUPITANT\\PALONOSETRON HYDROCHLORIDE" } ], "patientagegroup": null, "patientonsetage": "42", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Gilbar PJ, Pokharel K. Severe cisplatin-induced renal toxicity in a patient with xeroderma pigmentosum. J-Oncol-Pharm-Pract 2021;null:null.", "literaturereference_normalized": "severe cisplatin induced renal toxicity in a patient with xeroderma pigmentosum", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20211110", "receivedate": "20211110", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20052796, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220303" } ]

{ "abstract": "Prosthetic joint infection (PJI) is a potentially limb-threatening complication of total knee arthroplasty. Phage therapy is a promising strategy to manage such infections including those involving antibiotic-resistant microbes, and to target microbial biofilms. Experience with phage therapy for infections associated with retained hardware is limited. A 62-year-old diabetic man with a history of right total knee arthroplasty 11 years prior who had suffered multiple episodes of prosthetic knee infection despite numerous surgeries and prolonged courses of antibiotics, with progressive clinical worsening and development of severe allergies to antibiotics, had been offered limb amputation for persistent right prosthetic knee infection due to Klebsiella pneumoniae complex. Intravenous phage therapy was initiated as a limb-salvaging intervention.\n\n\n\nThe patient received 40 intravenous doses of a single phage (KpJH46Φ2) targeting his bacterial isolate, alongside continued minocycline (which he had been receiving when he developed increasing pain, swelling, and erythema prior to initiation of phage therapy). Serial cytokine and biomarker measurements were performed before, during, and after treatment. The in vitro anti-biofilm activity of KpJH46Φ2, minocycline and the combination thereof was evaluated against a preformed biofilm of the patient's isolate and determined by safranin staining.\n\n\n\nPhage therapy resulted in resolution of local symptoms and signs of infection and recovery of function. The patient did not experience treatment-related adverse effects and remained asymptomatic 34 weeks after completing treatment while still receiving minocycline. A trend in biofilm biomass reduction was noted 22 hours after exposure to KpJH46Φ2 (P = .063). The addition of phage was associated with a satisfactory outcome in this case of intractable biofilm-associated prosthetic knee infection. Pending further studies to assess its efficacy and safety, phage therapy holds promise for treatment of device-associated infections.", "affiliations": "Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota, USA.;Infectious Diseases Research Laboratory, Mayo Clinic, Rochester, Minnesota, USA.;Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.;Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.;Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota, USA.;Adaptive Phage Therapeutics, Gaithersburg, Maryland, USA.;Adaptive Phage Therapeutics, Gaithersburg, Maryland, USA.;Adaptive Phage Therapeutics, Gaithersburg, Maryland, USA.;Genomics and Bioinformatics Department, Biological Defense Research Directorate, Naval Medical Research Center-Frederick, Fort Detrick, Maryland, USA.;Genomics and Bioinformatics Department, Biological Defense Research Directorate, Naval Medical Research Center-Frederick, Fort Detrick, Maryland, USA.;Genomics and Bioinformatics Department, Biological Defense Research Directorate, Naval Medical Research Center-Frederick, Fort Detrick, Maryland, USA.;Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota, USA.;Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota, USA.", "authors": "Cano|Edison J|EJ|;Caflisch|Katherine M|KM|;Bollyky|Paul L|PL|;Van Belleghem|Jonas D|JD|;Patel|Robin|R|;Fackler|Joseph|J|;Brownstein|Michael J|MJ|;Horne|Bri'Anna|B|;Biswas|Biswajit|B|;Henry|Matthew|M|;Malagon|Francisco|F|;Lewallen|David G|DG|;Suh|Gina A|GA|", "chemical_list": "D000900:Anti-Bacterial Agents", "country": "United States", "delete": false, "doi": "10.1093/cid/ciaa705", "fulltext": null, "fulltext_license": null, "issn_linking": "1058-4838", "issue": "73(1)", "journal": "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America", "keywords": "arthroplasty; bacteriophage therapy; biofilm; phage therapy; prosthetic joint infection", "medline_ta": "Clin Infect Dis", "mesh_terms": "D000900:Anti-Bacterial Agents; D019645:Arthroplasty, Replacement, Knee; D018441:Biofilms; D006801:Humans; D007711:Klebsiella pneumoniae; D008297:Male; D008875:Middle Aged; D000071059:Phage Therapy; D016459:Prosthesis-Related Infections", "nlm_unique_id": "9203213", "other_id": null, "pages": "e144-e151", "pmc": null, "pmid": "32699879", "pubdate": "2021-07-01", "publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't; D013486:Research Support, U.S. Gov't, Non-P.H.S.", "references": "25586931;30157981;31527029;24893003;27822205;27643529;28451862;30597868;17538551;30406049;29588855;30474047;32397354;30180053;30763536;30207891;25662974;29363518;21905786;30395179;24696437;31548497;29294147;27099694;26347362", "title": "Phage Therapy for Limb-threatening Prosthetic Knee Klebsiella pneumoniae Infection: Case Report and In Vitro Characterization of Anti-biofilm Activity.", "title_normalized": "phage therapy for limb threatening prosthetic knee klebsiella pneumoniae infection case report and in vitro characterization of anti biofilm activity" }

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"drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PENICILLIN V POTASSIUM" } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Stevens-Johnson syndrome", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Suicidal ideation", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20080101" } }, "primarysource": { "literaturereference": "Cano EJ, Caflisch KM, Bollyky PL, Van Belleghem JD, Patel R, Fackler J, et al. Phage Therapy for Limb-threatening Prosthetic Knee Klebsiella pneumoniae Infection: Case Report and In Vitro Characterization of Anti-biofilm Activity. 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PHAGE THERAPY FOR LIMB?THREATENING PROSTHETIC KNEE KLEBSIELLA PNEUMONIAE INFECTION: CASE REPORT AND IN VITRO CHARACTERIZATION OF ANTI?BIOFILM ACTIVITY. 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{ "abstract": "BACKGROUND\nClostridium difficile infection (CDI) is the leading infectious cause of nosocomial diarrhea. Hospitalized patients are at increased risk of developing CDI because they are exposed to C. difficile spores through contact with the hospital environment and often receive antibiotics and other medications that can disrupt the integrity of the indigenous intestinal microbiota and impair colonization resistance. Using whole metagenome shotgun sequencing, we examined the diversity and composition of the fecal microbiota in a prospective cohort study of 98 hospitalized patients.\n\n\nRESULTS\nFour patients had asymptomatic C. difficile colonization, and four patients developed CDI. We observed dramatic shifts in the structure of the gut microbiota during hospitalization. In contrast to CDI cases, asymptomatic patients exhibited elevated relative abundance of potentially protective bacterial taxa in their gut at the onset of C. difficile colonization. Use of laxatives was associated with significant reductions in the relative abundance of Clostridium and Eubacterium; species within these genera have previously been shown to enhance resistance to CDI via the production of secondary bile acids. Cephalosporin and fluoroquinolone exposure decreased the frequency of Clostridiales Family XI Incertae Sedis, a bacterial family that has been previously associated with decreased CDI risk.\n\n\nCONCLUSIONS\nThis study underscores the detrimental impact of antibiotics as well as other medications, particularly laxatives, on the intestinal microbiota and suggests that co-colonization with key bacterial taxa may prevent C. difficile overgrowth or the transition from asymptomatic C. difficile colonization to CDI.", "affiliations": "Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada.;Jewish General Hospital, Montréal, Québec, Canada.;Devil's Staircase Consulting, North Vancouver, British Columbia, Canada.;New York Genome Center, New York, NY, USA.;Génome Québec Innovation Centre, McGill University, Montréal, Québec, Canada.;School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada. [email protected].", "authors": "Vincent|Caroline|C|;Miller|Mark A|MA|;Edens|Thaddeus J|TJ|;Mehrotra|Sudeep|S|;Dewar|Ken|K|;Manges|Amee R|AR|", "chemical_list": "D000900:Anti-Bacterial Agents; D001647:Bile Acids and Salts; D002511:Cephalosporins; D024841:Fluoroquinolones; D054368:Laxatives", "country": "England", "delete": false, "doi": "10.1186/s40168-016-0156-3", "fulltext": "\n==== Front\nMicrobiomeMicrobiomeMicrobiome2049-2618BioMed Central London 15610.1186/s40168-016-0156-3ResearchBloom and bust: intestinal microbiota dynamics in response to hospital exposures and Clostridium difficile colonization or infection Vincent Caroline [email protected] Miller Mark A. [email protected] Edens Thaddeus J. [email protected] Mehrotra Sudeep [email protected] Dewar Ken [email protected] Manges Amee R. [email protected] Department of Microbiology and Immunology, McGill University, Montréal, Québec Canada Génome Québec Innovation Centre, McGill University, Montréal, Québec Canada Jewish General Hospital, Montréal, Québec Canada Devil’s Staircase Consulting, North Vancouver, British Columbia Canada New York Genome Center, New York, NY USA Department of Human Genetics, McGill University, Montréal, Québec Canada School of Population and Public Health, University of British Columbia, Vancouver, British Columbia Canada 14 3 2016 14 3 2016 2016 4 124 9 2015 14 2 2016 © Vincent et al. 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nClostridium difficile infection (CDI) is the leading infectious cause of nosocomial diarrhea. Hospitalized patients are at increased risk of developing CDI because they are exposed to C. difficile spores through contact with the hospital environment and often receive antibiotics and other medications that can disrupt the integrity of the indigenous intestinal microbiota and impair colonization resistance. Using whole metagenome shotgun sequencing, we examined the diversity and composition of the fecal microbiota in a prospective cohort study of 98 hospitalized patients.\n\nResults\nFour patients had asymptomatic C. difficile colonization, and four patients developed CDI. We observed dramatic shifts in the structure of the gut microbiota during hospitalization. In contrast to CDI cases, asymptomatic patients exhibited elevated relative abundance of potentially protective bacterial taxa in their gut at the onset of C. difficile colonization. Use of laxatives was associated with significant reductions in the relative abundance of Clostridium and Eubacterium; species within these genera have previously been shown to enhance resistance to CDI via the production of secondary bile acids. Cephalosporin and fluoroquinolone exposure decreased the frequency of Clostridiales Family XI Incertae Sedis, a bacterial family that has been previously associated with decreased CDI risk.\n\nConclusions\nThis study underscores the detrimental impact of antibiotics as well as other medications, particularly laxatives, on the intestinal microbiota and suggests that co-colonization with key bacterial taxa may prevent C. difficile overgrowth or the transition from asymptomatic C. difficile colonization to CDI.\n\nElectronic supplementary material\nThe online version of this article (doi:10.1186/s40168-016-0156-3) contains supplementary material, which is available to authorized users.\n\nKeywords\nClostridium difficile infectionWhole metagenome shotgun sequencingIntestinal microbiotaAntimicrobialsMedicationshttp://dx.doi.org/10.13039/501100000024Canadian Institutes of Health Research (CA)GSD-113375Vincent Caroline http://dx.doi.org/10.13039/100004319Pfizer (US)WS1954106Manges Amee R. issue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nClostridium difficile infection (CDI) is the leading cause of infectious diarrhea in hospitalized patients. In the USA alone, there are an estimated 453,000 cases and 29,300 deaths from CDI each year [1]. CDI is associated with a wide range of syndromes, from asymptomatic colonization to mild diarrhea or more severe pseudomembranous colitis that may progress to toxic megacolon, intestinal perforation, sepsis, and death [2]. Despite advances in infection control practices and the development of new treatment options, there has been a steady increase in the incidence and severity of CDI in the last decade and outbreaks continue to occur in hospitals and health-care institutions worldwide [3, 4].\n\nHospitalized patients are at increased risk of developing CDI because they are exposed to C. difficile spores through contact with the hospital environment and often receive broad-spectrum antimicrobials that disrupt the integrity of the indigenous intestinal microbiota and impair colonization resistance (i.e., the ability of the microbiota to prevent the establishment of enteropathogens like C. difficile in the gut). Nearly all classes of antibiotics have been associated with CDI, but clindamycin, penicillins, cephalosporins, and fluoroquinolones seem to pose the greatest risk [5–7]. Additional risk factors for CDI include advanced age, underlying diseases, gastrointestinal surgery, nasogastric tube feeding, and use of proton pump inhibitors (PPIs, a class of medications that inhibit the production of gastric acid in the stomach) [2, 8].\n\nAmong patients who acquire C. difficile in their gut, some will remain asymptomatically colonized while others may go on to develop diarrhea or more severe forms of CDI. Differences in pathogen or host factors like the immune status or the integrity of the intestinal microbiota may affect the clinical presentation of CDI. In hospitals and health-care facilities, asymptomatic carriers often outnumber symptomatic patients and may represent a considerable reservoir of C. difficile that contributes to environmental contamination and disease transmission among patients [9, 10]. It has been suggested that patients with asymptomatic C. difficile colonization are at decreased risk of developing CDI, but a recent meta-analysis has suggested this may not be the case [11, 12]. Previously, we showed that patients who have higher levels of Clostridiales Family XI Incertae Sedis were at a decreased risk of developing CDI [13], and others have demonstrated that the presence of secondary bile acid-producing bacteria such as Clostridium scindens was associated with resistance to CDI [14].\n\nDespite the strong relationship between the intestinal microbiota and CDI susceptibility, the impact of non-antimicrobial medications on the microbiota has not been examined in detail.\n\nIn this study, we prospectively examined the intestinal microbiota of hospitalized patients at-risk for CDI. Using whole metagenome shotgun (WMGS) DNA sequencing, we specifically assessed (i) the changes in the relative abundance of microbial taxa in patients who were identified as colonized or infected with C. difficile and (ii) the impact of antibiotics and other medications on the diversity and composition of the intestinal microbiota among patients who were neither colonized nor infected with C. difficile. We postulated that protective microbiota members which are thought to mediate competitive inhibition against C. difficile (such as Clostridiales Family XI Incertae Sedis and non-toxigenic C. difficile) [13, 15] or limit the germination and growth of C. difficile via the production of secondary bile acids (Clostridium and Eubacterium genera) [14, 16] are present in colonized but not in infected patients. We also hypothesized that not only antibiotics but also other medications such as PPIs will decrease the overall diversity of the intestinal microbiota and increase the relative abundance of opportunistic microorganisms such as enterococci and yeasts [17–20]. We report that the relative abundance of Clostridiales Family XI Incertae Sedis, Clostridium, and Eubacterium is higher in asymptomatically colonized patients than in CDI cases. Moreover, antibiotics and other medications such as laxatives have substantial effects on the intestinal microbiota of hospitalized patients and reduce the relative abundance of these potentially protective bacterial taxa. Even though the term “infected” is sometimes used to designate people who are asymptomatically colonized with C. difficile, in this report, we will use the term “infected” (or CDI) to describe patients who are symptomatic and “colonized” to describe patients who are asymptomatically colonized with C. difficile.\n\nResults\nSubject characteristics\nA total of 104 patients were enrolled in the study. Four patients did not provide any stool sample, and six stool samples were excluded because of poor library quality or sequencing results; this left a total of 98 patients and 229 fecal samples in the study. We analyzed a median of two fecal samples per patient (range, 1–15). Patient characteristics are shown in Table 1. The majority of patients (63 %) suffered from osteoarthritis and were admitted for orthopedic surgery; most of them (89 %) received cefazolin (a first-generation cephalosporin) as perioperative antimicrobial prophylaxis. One patient (1.0 %) had asymptomatic C. difficile colonization on admission, three patients (3.1 %) became asymptomatically colonized during hospitalization, and four patients (4.1 %) developed hospital-acquired CDI. All of the CDI cases had diarrhea during their initial episode but none of them developed recurrent CDI.Table 1 Characteristics of the study patients\n\nVariable\tNeither C. difficile infection nor colonization (n = 90)\t\nC. difficile infection (n = 4)\t\nC. difficile colonization (n = 4)\t\nAge, mean years (range)\t74 (61–91)\t71 (66–80)\t74 (71–78)\t\nMale sex\t44 (49)\t2 (50)\t2 (50)\t\nHorn’s indexa, median (range)\t1 (1–2)\t1 (1–1)\t1 (1–2)\t\nDuration of hospitalizationb, median days (range)\t5 (1–69)\t21 (2–61)\t5 (1–15)\t\nHospitalization in past 12 monthsc\n\t11 (12)\t0\t0\t\nFecal specimens analyzed, median (range)\t2 (1–12)\t4 (1–15)\t2 (1–4)\t\nReason for hospital admission\t\t\t\t\n Osteoarthritis/Rheumatoid arthritis\t62 (69)\t0\t1 (25)\t\n Pneumonia\t8 (9)\t1 (25)\t1 (25)\t\n Cellulitis\t4 (4)\t1 (25)\t1 (25)\t\n Fever\t2 (2)\t0\t0\t\n Chronic obstructive pulmonary disease\t3 (3)\t0\t0\t\n Othersd\n\t11 (12)\t2 (50)\t1 (25)\t\nMedication useb\n\t\t\t\t\n Non-steroidal anti-inflammatory drugs\t33 (37)\t4 (100)\t2 (50)\t\n Proton pump inhibitors\t26 (29)\t2 (50)\t2 (50)\t\n Glucocorticoids\t12 (13)\t2 (50)\t1 (25)\t\n Opioids\t25 (28)\t3 (75)\t1 (25)\t\n Laxatives\t16 (18)\t3 (75)\t0\t\n Propulsive agents\t3 (3)\t0\t0\t\n Antipropulsive agents\t1 (1)\t1 (25)\t0\t\n Chemotherapeutic agents\t0\t0\t1 (25)\t\n Any antibiotic\t80 (89)\t4 (100)\t4 (100)\t\n Cephalosporins\t60 (67)\t1 (25)\t1 (25)\t\n Fluoroquinolones\t13 (14)\t2 (50)\t0\t\n Penicillin with β-lactamase inhibitors\t12 (13)\t3 (75)\t1 (25)\t\n Vancomycin (intravenous)\t7 (8)\t2 (50)\t0\t\n Carbapenems\t6 (7)\t2 (50)\t2 (50)\t\n Penicillins\t5 (6)\t0\t0\t\n Azithromycin\t4 (4)\t1 (25)\t0\t\n Metronidazole\t3 (3)\t1 (25)\t0\t\n Cotrimoxazole\t2 (2)\t0\t0\t\n Otherse\n\t2 (2)\t3 (75)\t0\t\nData are number (%) of subjects unless otherwise specified\n\n\naEvaluated at study enrollment\n\n\nbFrom admission until diagnosis of C. difficile infection or colonization (for infected and colonized patients, respectively) or until discharge (for patients with neither infection nor colonization)\n\n\ncInformation about prior hospitalization was unknown for one of the 90 patients with neither C. difficile infection nor colonization\n\n\ndOther reasons include bladder/kidney/urinary tract infection, closed fracture, urosepsis, cholecystitis, chronic stasis dermatitis, perinephric infection, diverticulitis, abdominal pain, abdominal hernia, ureteral stone, gangrene, and hip pain\n\n\neOther antimicrobial agents include oral vancomycin, clindamycin, daptomycin, gentamicin, Tigecycline, antivirals, and antifungals\n\n\n\nWMGS sequencing\nFecal samples were evaluated by WMGS sequencing to assess the diversity and composition of the intestinal microbiota. We obtained a median of 6.1 million high-quality reads per sample (range, 0.6–41.9 million). The proportion of human DNA reads was highly variable (range, 0.1–94.9 %) but half of the samples contained <20 % of human reads. After removing the host DNA, we computed the frequency of 16S ribosomal RNA (rRNA) genes in each sample as a measure of bacterial DNA content. The mean frequency of 16S rRNA genes per megabase (Mb) of sequence data was 0.39 (standard deviation 0.18). Across all samples, we obtained a median of 2.1 % of reads (range, 0.1–4.8 %) with a hit to MetaPhlAn2’s taxonomic marker database, with at least 2700 hits per sample. Bacteroides (99.0 %), Prevotella (98.0 %), and Subdoligranulum (98.0 %) were the most common genera, and Porphyromonadaceae (100 %), Bacteroidaceae (99.0 %), Enterobacteriaceae (98.0 %), Prevotellaceae (98.0 %), and Ruminococcaceae (98.0 %) were the most common families detected across patients (percentage of patients in which the corresponding taxa was detected).\n\nC. difficile detection\nResults from the detection of C. difficile or its toxins in eight patients who developed C. difficile colonization (n = 4) or infection (n = 4) are provided in Table 2. Out of these eight patients, six had a positive C. difficile culture result (two of the four CDI cases did not have C. difficile detected by toxigenic culture but rather with an enzyme immunoassay). All patients with a positive C. difficile culture result had a single isolate recovered and characterized. Two of the four asymptomatic carriers were colonized with a toxigenic strain. C. difficile was also detected by WMGS sequencing in two of the four asymptomatically colonized patients as well as in two CDI patients with a positive C. difficile culture result. No other patients had C. difficile detected by culture or sequencing.Table 2 Detection of C. difficile and its toxins in four asymptomatically colonized and four CDI patients\n\nPatient ID\tSample type\tToxigenic culturea\n\tEnzyme immunoassayc\n\tWMGS sequencing\t\nCulture\tToxinb\n\tNo. of reads\tRelative abundance of C. difficile (%)\t\nAsymptomatically colonized\t\t\t\t\t\t\t\n 30\tRectal swab\tPositive\tNegative\tND\t8,487,324\t0.000\t\n 63\tRectal swab\tPositive\tPositive\tND\t10,366,360\t0.000\t\n 87\tRectal swab\tPositive\tNegative\tND\t4,489,956\t0.363\t\n 99\tStool\tPositive\tPositive\tND\t14,952,432\t0.064\t\nCDI\t\t\t\t\t\t\t\n 35\tStoold\n\tNegative\tND\tPositive\t5,926,081\t0.000\t\n 36\tStoold\n\tPositive\tPositive\tND\t7,068,998\t0.017\t\n 55\tStool\tPositive\tPositive\tPositive\t9,950,687\t0.003\t\n 98\tStool\tNegative\tND\tPositive\t4,337,018\t0.000\t\n\nWMGS whole-metagenome shotgun, ND not done\n\n\naPerformed by Dale N. Gerding’s laboratory\n\n\nbDetected by restriction endonuclease analysis or cytotoxicity assay\n\n\ncPerformed on a stool sample at the Jewish General Hospital\n\n\ndA rectal swab was used for WMGS sequencing\n\n\n\nIntestinal microbiota dynamics in patients with C. difficile colonization or infection\nFigure 1 shows variations in the relative abundance of microbial taxa, overall microbial diversity, as well as bacterial and human DNA proportions in relation to hospital exposures and length of stay for patients who became colonized (Fig. 1a–d) or infected (Fig. 1e–h) with C. difficile. The human DNA content and the composition and diversity of the intestinal microbiota were highly variable during patient hospitalization. In contrast, the proportion of bacterial DNA (measured after the exclusion of human DNA) was more stable.Fig. 1 Intestinal microbiota dynamics in patients with C. difficile colonization or infection. The figure shows changes in intestinal microbiota composition (area charts or bar charts for patients with a single measurement), Shannon diversity (dash-dotted line), bacterial DNA content (dotted line), and human DNA content (solid line) during hospitalization for patients who developed C. difficile colonization (a–d) or infection (e–h). Only those microbial taxa with a relative abundance of ≥10 % in at least one sample are depicted. The y-axis on the left shows the relative abundance of microbial taxa or human DNA proportions, while the y-axis on the right shows the Shannon diversity index or bacterial DNA content (expressed as number of 16S rRNA genes per Mb). The x-axis shows the number of days after hospital admission (day 0). The figures only display information for the period from hospital admission until the last stool collection. The bars underneath the graphs indicate hospital exposures: Azithro azithromycin, Ceph cephalosporin, Chemo chemotherapeutic agent, Metro metronidazole, NSAID nonsteroidal anti-inflammatory drug, Penicillin combination penicillin with β-lactamase inhibitor, PPI proton pump inhibitor, Steroid, glucocorticoid, Vanco IV intravenous vancomycin, Vanco PO oral vancomycin. The day on which a patient had a positive C. difficile culture (Culture+), the presence of C. difficile infection symptoms, but a negative C. difficile enzyme immunoassay (CDI symptoms) or a diagnosis of C. difficile infection (CDI diagnosis) is also indicated\n\n\n\nWe specifically looked at the relative abundance of potentially protective bacterial taxa, including Clostridiales Family XI Incertae Sedis, Clostridium, and Eubacterium. A few days prior to or at the time of C. difficile colonization, three out of four asymptomatic patients exhibited high relative abundance of these taxa in their intestinal microbiota: the relative abundance of Eubacterium was 24.3 % in patient 30 on the day C. difficile colonization was detected, the relative abundance of Anaerococcus (a Clostridiales Family XI Incertae Sedis member) was 31.3 % in patient 87 on the day C. difficile colonization was detected, and the relative abundance of Clostridium spp. other than C. difficile (mainly Clostridium bolteae) was 22.2 % in patient 99 4 days prior to C. difficile colonization. We also observed transient increases in the relative abundance of Clostridium spp. other than C. difficile (31.0 % [mainly C. bolteae and Clostridium hathewayi] 13 days prior to CDI diagnosis, patient 55) or Clostridiales Family XI Incertae Sedis (17.4 % 37 days prior to CDI diagnosis, patient 98; data not shown) in two of the four patients who developed CDI. However, these increases occurred several days prior to CDI onset and the corresponding bacterial taxa had a relative abundance of less than 5 % upon CDI diagnosis. In the fecal samples (n = 196) from the 90 patients who were neither colonized nor infected with C. difficile, the median abundance (range) of Clostridiales Family XI Incertae Sedis, Clostridium, and Eubacterium was 3.1 (0.0–62.3 %), 0.4 (0.0–67.6 %), and 0.2 % (0.0–37.0 %), respectively.\n\nWe observed transient but large increases of Microvirus (reaching a relative abundance of ≥50 % in patients 30, 98, and 99), Candida (reaching a relative abundance of >30 % in patients 98 and 99), and Leuconostoc (reaching a relative abundance of >15 % in patients 98 and 99). In patients 98 and 99, the increase in the relative abundance of Microvirus was concomitant with an increase of human read proportions and a decrease of microbial diversity. In patient 98, striking blooms of Enterococcus occurred on days 16 (98.0 %), 31 (60.8 %), and 47–62 (64.8–97.5 %) after admission and appeared to follow the administration of intravenous vancomycin. In the fecal samples (n = 196) from the 90 patients who were neither colonized nor infected with C. difficile, the median abundance (range) of Microvirus, Candida, Leuconostoc, and Enterococcus was 0.0 (0.0–95.6 %), 0.0 (0.0–3.5 %), 0.0 (0.0–51.0 %), and 0.1 % (0.0–91.7 %), respectively.\n\nMedication use and intestinal microbiota diversity and composition\nWe examined the effect of antibiotics as well as other medications on the diversity and composition of the gut microbiota. To avoid confounding the results, we excluded patients who were colonized or infected with C. difficile (n = 8) from these analyses; therefore, the Clostridium genera does not include C. difficile. Utilization of fluoroquinolone was moderately correlated with the use of metronidazole (ρ = 0.45), as were use of penicillin with use of gentamicin (ρ = 0.57), and use of opioids with use of laxatives (ρ = 0.41).\n\nAmong patients who were neither infected nor colonized with C. difficile, we obtained a mean Shannon diversity index of 2.0 (standard deviation 0.6). Exposure to fluoroquinolones and intravenous vancomycin was associated with a significant decrease in intestinal microbiota diversity, while use of opioids was associated with an increase in diversity (Table 3).Table 3 Associations between medication use and intestinal microbiota diversity\n\nMedicationa\n\tNo. of patients exposed\tNo. of samples exposed\tEstimateb\n\tStandard error\t\nP valuec\n\t\nAntibiotics\t\t\t\t\t\t\n Cephalosporins\t57\t81\t−0.06\t0.07\t0.3764\t\n Fluoroquinolones\t8\t15\t−0.20\t0.10\t\n0.0367\n\t\n Penicillin with β-lactamase inhibitors\t7\t12\t−0.17\t0.19\t0.3805\t\n Carbapenems\t5\t11\t−0.30\t0.26\t0.2417\t\n Intravenous vancomycin\t6\t12\t−0.41\t0.15\t\n0.0080\n\t\nOther medications\t\t\t\t\t\t\n Glucocorticoids\t7\t13\t−0.02\t0.17\t0.8977\t\n Laxatives\t13\t24\t−0.05\t0.09\t0.5976\t\n Non-steroidal anti-inflammatory drugs\t30\t57\t0.08\t0.08\t0.3264\t\n Opioids\t23\t38\t0.13\t0.06\t\n0.0202\n\t\n Proton pump inhibitors\t21\t54\t−0.11\t0.10\t0.2738\t\nAmong patients who were neither colonized nor infected with C. difficile\n\n\n\naReceived within 3 days prior to stool collection\n\n\nbA positive value indicates that intestinal microbiota diversity was higher among patients exposed to the medication, while a negative value indicates that intestinal microbiota diversity was lower\n\n\nc\nP values were determined by using the GEE-derived robust z scores\n\n\n\nA large number of microbial taxa were affected by common hospital exposures; out of a total of 125 genera and 59 families identified in at least 5 % of the patients, 88 genera (70.4 %) and 42 families (71.2 %) were associated with a statistically significant increase or decrease in relative abundance in univariable analyses (Additional file 1: Table S1 and Additional file 2: Table S2). With the exception of non-steroidal anti-inflammatory drugs (NSAIDs) and opioids, most medications tended to decrease, rather than increase, the relative abundance of affected microbial taxa. Carbapenems (33 genera and 13 families) and intravenous vancomycin (34 genera and 15 families) influenced the largest number of microbial taxa.\n\nIn multivariable analyses, we specifically looked at the impact of medications on the relative abundance of microbial taxa that are thought to be protective against CDI (Clostridiales Family XI Incertae Sedis, Clostridium, and Eubacterium) as well as opportunistic microorganisms that can overgrow as a result of antimicrobial use (Enterococcus and Candida) (Table 4). Use of laxatives was associated with significant reductions in the relative abundance of Clostridium and Eubacterium. Administration of cephalosporins, fluoroquinolones, or penicillin with β-lactamase inhibitor was associated with significant reductions in the frequency of Clostridiales Family XI Incertae Sedis. Exposure to fluoroquinolones significantly increased the relative abundance of Enterococcus, while intravenous vancomycin was of borderline significance. None of the medications were associated with significant variations in the relative abundance of Candida in multivariable analyses.Table 4 Multivariable analysis of medications associated with selected microbial taxa\n\nTaxa (outcome)\tMedicationa\n\tEstimateb\n\tStandard error\t\nP valuec\n\t\n\nClostridium\n\tGlucocorticoids\t3.72\t1.65\t0.0239\t\nLaxatives\t−2.46\t0.99\t0.0126\t\nNon-steroidal anti-inflammatory drugs\t−2.11\t0.90\t0.0197\t\n\nEubacterium\n\tFluoroquinolones\t−0.99\t0.44\t0.0237\t\nLaxatives\t−1.21\t0.48\t0.0115\t\nClostridiales Family XI Incertae Sedis\tCephalosporins\t−5.78\t2.08\t0.0055\t\nFluoroquinolones\t−5.95\t2.21\t0.0071\t\nNon-steroidal anti-inflammatory drugs\t3.76\t1.99\t0.0580\t\nPenicillin with β-lactamase inhibitors\t−5.70\t2.54\t0.0248\t\n\nEnterococcus\n\tFluoroquinolones\t215.43\t102.34\t0.0353\t\nIntravenous vancomycin\t181.32\t95.02\t0.0564\t\nAmong patients who were neither colonized nor infected with C. difficile. All of the multivariable models were adjusted for age, sex, and duration of hospitalization\n\n\naReceived within 3 days prior to stool collection\n\n\nbA positive value indicates that the relative abundance of the corresponding taxa was higher among patients exposed to the medication, while a negative value indicates that the relative abundance was lower\n\n\nc\nP values were determined by using the GEE-derived robust z scores\n\n\n\nDiscussion\nWe previously demonstrated that a reduction in Clostridiales Family XI Incertae Sedis is significantly and independently associated with the risk of CDI in a distinct patient population [13]. Certain species within the Eubacterium and Clostridium genera, notably C. scindens, have the ability to convert primary bile acids into secondary bile acids [16] and have been shown to strongly inhibit C. difficile in the intestinal microbiota of antibiotic-treated mice and humans [14]. In this study, asymptomatically colonized patients, but not CDI cases, exhibited elevated relative abundance of Clostridiales Family XI Incertae Sedis, Clostridium, or Eubacterium in their gut shortly prior to or when C. difficile colonization was detected. These observations are in agreement with our initial hypothesis and suggest that co-colonization with any of these potentially protective bacterial taxa might prevent C. difficile overgrowth in colonized subjects or the transition from asymptomatic colonization to a full-blown infection.\n\nPrevious studies have shown that in the absence of gross perturbation, the intestinal microbiota of healthy subjects is relatively stable over time [21, 22]. In contrast, we observed dramatic shifts in the composition and diversity of the intestinal microbiota in patients who developed C. difficile colonization or infection, as well as in other hospitalized patients (data not shown). These observations suggest that single measurements of the intestinal microbiota may be problematic when studying hospitalized patients, in particular, as their microbiota composition is strongly influenced by their illness and medical interventions. This offers one explanation why some studies examining the role of the intestinal microbiota on health outcomes may yield conflicting results.\n\nIn a previous study, we showed that fecal excretion of human DNA was significantly increased in patients with CDI or having other gastrointestinal problems and appeared to be an outcome of intestinal inflammation [23]. In this study, the proportion of human DNA was highly variable over time but was observed to be higher prior to CDI development in two of the four cases. In some of our patients, increases in the proportion of human DNA were concomitant with a reduction of microbial diversity and increases in the relative abundance of Microvirus. Microviruses are single-stranded DNA bacteriophages that infect enterobacteria and are commonly found in human gut samples [24]. High levels of human DNA excretion have been associated with a reduction of intestinal microbiota diversity [23].\n\nOne of the patients who developed CDI (patient 98) exhibited striking blooms of Enterococcus (with frequencies reaching 98 %) on multiple occasions during his hospitalization. These blooms appeared to follow the administration of intravenous vancomycin and may represent an overgrowth of vancomycin-resistant Enterococcus (VRE). Studies have shown that the use of intravenous vancomycin is significantly associated with VRE colonization or infection [25]. Although we do not know whether this patient actually carried VRE or developed sepsis, Ubeda et al. have previously shown that intestinal domination by VRE typically precedes bloodstream infection in hospitalized patients [26]. In the cohort of patients who were neither colonized nor infected with C. difficile, we confirm that the use of intravenous vancomycin is associated with increases in the relative abundance of Enterococcus.\n\nReceipt of opioids was associated with significant increases in microbial diversity. This medication typically delays gastrointestinal transit time and may facilitate microbial growth in the colon, thereby increasing diversity. Significant reductions in intestinal microbiota diversity were only associated with the use of fluoroquinolones and intravenous vancomycin. Surprisingly, exposure to other antibiotics and PPIs did not reduce overall microbiota diversity in our cohort but did influence the relative abundance of numerous microbial taxa. The association between PPIs and CDI development is still a controversial issue [27]. The notion of reduced microbiota diversity may suggest that the number and relative abundance of microbial taxa are both declining. However, our study suggests that microbiota dynamics are much more complex; many taxa are being depleted while others are blooming. Therefore, measurement of the overall diversity is masking important distortions in the composition of the microbial community.\n\nIn multivariable analyses, we showed that the use of laxatives is associated with significant reductions in the relative abundance of Clostridium and Eubacterium; certain species among these genera may confer protection against CDI via the production of secondary bile acids. However, in a post hoc analysis, the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway corresponding to secondary bile acid biosynthesis (ko00121) was not detected in any our metagenomic samples. Laxatives accelerate gastrointestinal transit time and may have detrimental effects on the intestinal microbiota. van der Wulp et al. previously showed that treatment with polyethylene glycol (an osmotic laxative) changes the composition of the intestinal microbiota and decreases the production of secondary bile acids in rats [28]. We also demonstrated that the use of cephalosporins, fluoroquinolones, and penicillin with β-lactamase inhibitors is significantly and independently associated with reductions in the relative abundance of Clostridiales Family XI Incertae Sedis representatives. Since cephalosporin and fluoroquinolone exposure, as well as depletions of Clostridiales Family XI Incertae Sedis, have been associated with CDI risk [13], this provides a potential explanation for why these antibiotics increase the susceptibility to CDI in hospitalized patients.\n\nWe observed discrepancies in the detection of C. difficile or its toxins by culture, WMGS sequencing, and enzyme immunoassay. In two of the four asymptomatically colonized patients, C. difficile was detected by culture but not by WMGS sequencing. In two of the four CDI cases, C. difficile could not be detected, either by culture or sequencing (their CDI diagnosis was based on a positive enzyme immunoassay performed at the hospital). This may be due to a low organism load, the lack of biomass collected with the rectal swabs, or insufficient sequencing depth. One patient (patient 98) received vancomycin and metronidazole treatment for presumptive CDI prior to the actual diagnosis by enzyme immunoassay, which may have reduced the quantity of C. difficile organisms available for detection.\n\nThe number of patients who developed C. difficile colonization or infection was limited in our study; therefore, we could not perform statistical analyses to assess the role of hospital exposures and microbial taxa for patients with these outcomes. In all of the four patients who developed asymptomatic colonization, C. difficile was detected by culture in the last stool collected prior to patient discharge. Therefore, we could not determine whether C. difficile colonization was transient (present in only one occasion) or not in these patients. In the full cohort, insufficient numbers of patients exposed to certain medications (e.g., metronidazole and cotrimoxazole) or colonized by specific microbial taxa (e.g., Aerococcus and Microbacteriaceae) precluded statistical analyses. Diet and other factors such as underlying disease state can affect the intestinal microbiota and could still confound the associations identified in our study.\n\nConclusions\nThe integrity of the intestinal microbiota is intricately related to the health of the host. In this study, we show that the diversity and composition of the intestinal microbiota in hospitalized patients is highly dynamic. Use of antibiotics, as well as other non-antimicrobial medications, particularly laxatives, has a profound and rapid effect on the structure of the intestinal microbiota and significantly decreased the relative abundance of key bacterial taxa that may be involved in CDI protection. Our results also support the hypothesis that co-colonization with key bacterial taxa such as Clostridiales Family XI Incertae Sedis, Clostridium, or Eubacterium may prevent C. difficile overgrowth or the transition from asymptomatic C. difficile colonization to CDI. A better understanding of CDI pathogenesis, including the medical exposures that undermine the effectiveness of colonization resistance and the specific microbiota alterations that allow C. difficile to infect the gut, will contribute to our ability to develop novel clinical strategies to prevent or treat this life-threatening infection.\n\nMethods\nPatient recruitment and follow-up\nResearch subjects were recruited as part of a prospective cohort study conducted at the Jewish General Hospital (JGH) in Montréal between October 2009 and April 2011. Patients ≥60 years of age, who were expected to stay more than 2 days in the hospital at the time of study enrolment, and who had received antimicrobials in the previous 48 h or were expected to receive some in the next 24 h were eligible to participate in the study. Patients admitted to the hospital for CDI were excluded. Subjects were enrolled in the study within 5 days after admission to selected medical wards or surgical units. Patients were followed for 60 days after study enrolment or 30 days after hospital discharge (whichever came first) to ascertain the development of CDI. CDI cases were followed for 60 days after successfully completing CDI treatment to monitor the development of recurrent CDI.\n\nEthics, consent, and permissions\nAll study participants provided informed written consent. The Research Ethics Boards of the JGH (08-118A) and the McGill University Health Centre (11-205 GEN) approved the research protocol.\n\nSample and epidemiologic data collection\nFecal specimens were obtained from each patient at study enrollment, every 3 days during hospitalization, at the onset of diarrhea (if applicable), and at discharge. The samples were collected as bulk stool or with the use of a rectal swab if the patient was not producing stool. Rectal swabs are a convenient means of sampling the human gut and give highly reproducible microbiota profiles that can closely resemble that of fecal samples [29]. Epidemiologic information was extracted from the patients’ medical charts and included patient demographics, previous hospitalizations, reason of admission, disease severity index, dates of admission and discharge, CDI diagnosis, and the use of antimicrobials and other medications during hospitalization (with corresponding start and stop dates).\n\nToxigenic C. difficile culture\nToxigenic culture test results were provided as a courtesy of Dr. Dale N. Gerding (Hines VA Hospital and Loyola University Chicago Stritch School of Medicine, IL). Briefly, stool or rectal swab specimens were streaked onto selective pre-reduced cefoxitin-cycloserine-fructose agar supplemented with taurocholate (TCCFA) and incubated anaerobically for 48 h. Presumptive identification of C. difficile was based on typical colony morphology. If colony morphologies suggested that a mixture of C. difficile strains were present, multiple colonies were picked and saved individually. All rectal swabs were also inoculated onto non-selective blood agar to detect the growth of intestinal microbiota and confirm proper sampling technique, thereby excluding the possibility of false-negative results on the TCCFA. Purified isolates were characterized by restriction endonuclease analysis (REA) to determine their toxin classification [30]. The Bartels Cytotoxicity Assay (Trinity Biotech) was performed to determine the presence of toxin B in C. difficile isolates with an undetermined REA group.\n\nStudy definitions\nCDI was defined as follows: (i) the presence of symptoms (diarrhea, fever, abdominal pain, or ileus) and a positive C. difficile enzyme immunoassay (ImmunoCard Toxins A&B, Meridian Bioscience, Inc.) or toxigenic culture, (ii) an endoscopic diagnosis of pseudomembranes, or (iii) a pathological/histological diagnosis of CDI. Diarrhea was defined as the passage of ≥3 new unformed stools within 24 h. Recurrent CDI was defined as a CDI diagnosis that occurs within 60 days after successfully completing the treatment for the initial episode of CDI. Asymptomatic C. difficile colonization was defined as a positive stool culture for C. difficile and the absence of a CDI diagnosis during follow-up. Colonization or infection was considered hospital-acquired if the diagnosis was made ≥48 h after hospital admission and during the study follow-up period.\n\nWMGS sequencing and data analysis\nTotal DNA was extracted from rectal swabs with use of the DNA IQ System (Promega) and from bulk stool aliquots with the use of the QIAamp DNA Stool Mini Kit (Qiagen). Multiplexed DNA libraries were prepared according to a previously described protocol that allows the generation of libraries from low amounts of input DNA [31]. WMGS sequencing was performed with 150-nucleotide read lengths on the Illumina HiSeq 2000 and 2500 platforms at the McGill University and Génome Québec Innovation Centre. Up to 14 samples were multiplexed in each sequencing lane. Reads derived from the human genome were identified and removed with BMTagger [32]. Additional quality filtering steps included the trimming of sequencing adapters and low-quality bases from the 3′ end of reads as well as the removal of short (<60 bases) and duplicate reads [33, 34]. We retrieved all reads containing the V1–V3 reverse primer sequence (which targets a segment of the 16S rRNA gene) [35] and their 3′ sequences in order to obtain 55-mers originating with the primer sequence. The frequency of 16S rRNA genes (55-mers) per Mb of sequence data was used as a measure of bacterial DNA content in each sample. High-quality reads were also analyzed by MetaPhlAn2 [36] in order to determine the family, genus, and species level relative abundances. Diversity was calculated at the genus level with the Shannon index. HUMAnN version 0.99 [37] was used in conjunction with RAPSearch2 [38] and the KEGG database [39] to evaluate the presence of the pathway for secondary bile acid biosynthesis (ko00121) in each metagenomic sample.\n\nStatistical analyses\nWe provide a descriptive analysis of microbiota composition for patients who were either colonized or infected by C. difficile; we specifically examined changes in the relative abundance of potential CDI-protecting microorganisms (i.e., Clostridiales Family XI Incertae Sedis, Clostridium, and Eubacterium). In order to assess the relationship between hospital exposures (e.g., antibiotics and other medications) and either overall microbiota diversity or relative abundance of microbiota members, we used generalized estimating equation (GEE) analyses with a Gaussian link. GEE takes into account the multiple samples per subject and the likelihood that the microbiota profiles are correlated over time within patients. Microbial diversity and relative abundances were modeled using a log transformation. In these analyses, we excluded patients who were colonized or infected with C. difficile and considered only those microbial taxa and medications that were present in or administered to at least 5 % of the patients (i.e., cephalosporins, fluoroquinolones, penicillin with β-lactamase inhibitors, carbapenems, intravenous vancomycin, glucocorticoids, laxatives, NSAIDs, opioids, and PPIs). Use of medication was treated as a binary variable with “1” indicating exposure within 1 to 3 days prior to stool collection and “0” indicating otherwise. We included exposure to intravenous vancomycin in our analyses, as evidence suggests that substantial amounts of the drug can be excreted in the bowel and may therefore affect the intestinal microbiota [40]. Multivariable analyses were used in order to take into account the correlation in the use of certain medications. In addition to the medications mentioned above, all multivariable models included adjustment for age, sex, and duration of hospitalization. Final multivariable models retained significant exposure variables at a p value of <0.05. A positive estimate value indicates that the corresponding exposure is associated with an increase in either overall microbiota diversity or relative abundance of the given microbial taxa. All statistical analyses were performed in R [41]; GEE was performed using the geepack package. P values were determined by using the GEE-derived robust z scores.\n\nAvailability of supporting data\nThe sequence data supporting the results of this article are available in the National Center for Biotechnology Information Sequence Read Archive under accession number SRP064400 (http://www.ncbi.nlm.nih.gov/sra/SRP064400).\n\nAdditional files\nAdditional file 1: \n Table S1. Significant associations between medication use and intestinal microbiota genera (univariable analysis). (XLSX 433 KB)\n\nAdditional file 2: \n Table S2. Significant associations between medication use and intestinal microbiota families (univariable analysis). (XLSX 385 KB)\n\n\n\nAbbreviations\nCDIClostridium difficile infection\n\nPPIproton pump inhibitors\n\nWMGSwhole metagenome shotgun\n\nTCCFAcefoxitin-cycloserine-fructose agar supplemented with taurocholate\n\nREArestriction endonuclease analysis\n\nGEEgeneralized estimating equations\n\nrRNAribosomal RNA\n\nVREvancomycin-resistant Enterococcus\n\nJGHJewish General Hospital\n\nNSAIDnon-steroidal anti-inflammatory drug\n\nCompeting interests\n\nMAM has been an employee of bioMerieux since October 2012. The other authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nCV prepared the sequencing libraries, performed the bioinformatic analyses, participated in data analysis and interpretation, and drafted the manuscript. MAM provided patient epidemiologic information and clinical samples and participated in data analysis and interpretation. TJE performed the statistical analyses. SM assisted with bioinformatic analyses. KD participated in data analysis and interpretation. ARM conceived and designed the study, participated in data analysis and interpretation, and helped to draft the manuscript. All authors read and approved the final manuscript.\n\nAcknowledgements\nThe authors would like to thank Dr. Dale N. Gerding for the toxigenic C. difficile culture, REA typing, and cytotoxicity assays done as part of a parallel study on the same patient cohort. They also thank the clinical research staff at the JGH, Jennifer Eastmond, Romina Gheorghe, and Sophie Florencio, for their valuable help with the collection of clinical samples and the chart reviews. This work was supported by a Pfizer ASPIRE Award in Antibacterial Research [WS1954106 to A.R.M.], a Studentship from the Research Institute of the McGill University Health Centre [C.V.], as well as a Frederick Banting and Charles Best Canada Graduate Scholarship (Doctoral Award) from the Canadian Institutes of Health Research [GSD-113375 to C.V.]. The funding bodies had no role in the study design, in the collection, analysis, and interpretation of data, in the writing of the manuscript, and in the decision to submit the manuscript for publication.\n==== Refs\nReferences\n1. Lessa FC Mu Y Bamberg WM Beldavs ZG Dumyati GK Dunn JR Burden of Clostridium difficile infection in the United States N Engl J Med 2015 372 9 825 34 10.1056/NEJMoa1408913 25714160 \n2. Surawicz CM Brandt LJ Binion DG Ananthakrishnan AN Curry SR Gilligan PH Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections Am J Gastroenterol 2013 108 4 478 98 10.1038/ajg.2013.4 23439232 \n3. 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Abubucker S Segata N Goll J Schubert AM Izard J Cantarel BL Metabolic reconstruction for metagenomic data and its application to the human microbiome PLoS Comput Biol 2012 8 6 e1002358 10.1371/journal.pcbi.1002358 22719234 \n38. Zhao Y Tang H Ye Y RAPSearch2: a fast and memory-efficient protein similarity search tool for next-generation sequencing data Bioinformatics 2012 28 1 125 6 10.1093/bioinformatics/btr595 22039206 \n39. Kanehisa M Goto S KEGG: kyoto encyclopedia of genes and genomes Nucleic Acids Res 2000 28 1 27 30 10.1093/nar/28.1.27 10592173 \n40. Currie BP Lemos-Filho L Evidence for biliary excretion of vancomycin into stool during intravenous therapy: potential implications for rectal colonization with vancomycin-resistant enterococci Antimicrob Agents Chemother 2004 48 11 4427 9 10.1128/AAC.48.11.4427-4429.2004 15504873 \n41. The R project for statistical computing. http://www.r-project.org/.\n\n", "fulltext_license": "CC BY", "issn_linking": "2049-2618", "issue": "4()", "journal": "Microbiome", "keywords": "Antimicrobials; Clostridium difficile infection; Intestinal microbiota; Medications; Whole metagenome shotgun sequencing", "medline_ta": "Microbiome", "mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D001647:Bile Acids and Salts; D002511:Cephalosporins; D016360:Clostridioides difficile; D003428:Cross Infection; D003967:Diarrhea; D004761:Enterocolitis, Pseudomembranous; D005051:Eubacterium; D005260:Female; D024841:Fluoroquinolones; D000069196:Gastrointestinal Microbiome; D006801:Humans; D054368:Laxatives; D008297:Male; D054892:Metagenome; D008875:Middle Aged; D011446:Prospective Studies", "nlm_unique_id": "101615147", "other_id": null, "pages": "12", "pmc": null, "pmid": "26975510", "pubdate": "2016-03-14", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": "16206099;11136263;10592173;23439232;20516186;25337874;8394378;25437605;26090486;22441775;21099116;23828941;23868407;17879913;16965399;15504873;18971494;9310680;24066741;25020051;22719234;9500319;24450844;25942722;22039206;18177218;11871461;26418763;25732416;25426290;21829582;20388221;25714160;21119612;26164495", "title": "Bloom and bust: intestinal microbiota dynamics in response to hospital exposures and Clostridium difficile colonization or infection.", "title_normalized": "bloom and bust intestinal microbiota dynamics in response to hospital exposures and clostridium difficile colonization or infection" }

[ { "companynumb": "CA-MYLANLABS-2016M1050742", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "VANCOMYCIN" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": "065397", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CLOSTRIDIUM DIFFICILE INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VANCOMYCIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Enterococcal infection", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VINCENT C, MILLER MA, EDENS TJ, MEHROTRA S, DEWAR K, MANGES AR. BLOOM AND BUST: INTESTINAL MICROBIOTA DYNAMICS IN RESPONSE TO HOSPITAL EXPOSURES AND CLOSTRIDIUM DIFFICILE COLONIZATION OR INFECTION. MICROBIOME 2016;4:12.", "literaturereference_normalized": "bloom and bust intestinal microbiota dynamics in response to hospital exposures and clostridium difficile colonization or infection", "qualification": "3", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20161128", "receivedate": "20161128", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 12979098, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" } ]

{ "abstract": "METHODS\nTo present a case of photopsia resulting from digoxin intoxication brought about by dehydration in a 72-year-old woman.\n\n\nCONCLUSIONS\nOphthalmologists may be the first clinicians to notice the symptoms of digitalis intoxication, which is potentially a life-threatening condition.", "affiliations": "Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Japan. [email protected]", "authors": "Oishi|Akio|A|;Miyamoto|Kazuaki|K|;Kashii|Satoshi|S|;Yoshimura|Nagahisa|N|", "chemical_list": "D002316:Cardiotonic Agents; D004077:Digoxin", "country": "England", "delete": false, "doi": "10.1016/S0008-4182(06)80031-1", "fulltext": null, "fulltext_license": null, "issn_linking": "0008-4182", "issue": "41(5)", "journal": "Canadian journal of ophthalmology. Journal canadien d'ophtalmologie", "keywords": null, "medline_ta": "Can J Ophthalmol", "mesh_terms": "D000368:Aged; D002316:Cardiotonic Agents; D003681:Dehydration; D004077:Digoxin; D005260:Female; D005440:Fluid Therapy; D006212:Hallucinations; D006801:Humans; D010719:Phosphenes", "nlm_unique_id": "0045312", "other_id": null, "pages": "603-4", "pmc": null, "pmid": "17016533", "pubdate": "2006-10", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Photopsia as a manifestation of digitalis toxicity.", "title_normalized": "photopsia as a manifestation of digitalis toxicity" }

[ { "companynumb": "JP-CONCORDIA PHARMACEUTICALS INC.-GSH201706-003336", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DIGOXIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "020405", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".125", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIGOXIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "FUROSEMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FUROSEMIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "SPIRONOLACTONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SPIRONOLACTONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CARVEDILOL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARVEDILOL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LOSARTAN POTASSIUM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOSARTAN POTASSIUM." } ], "patientagegroup": null, "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "52", "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Photopsia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "OISHI A,MIYAMOTO K,KASHII S,YOSHIMURA N. PHOTOPSIA AS A MANIFESTATION OF DIGITALIS TOXICITY.. CAN J OPHTHALMOL. 2006 OCT;41(5):603-604.", "literaturereference_normalized": "photopsia as a manifestation of digitalis toxicity", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "CH", "receiptdate": "20170621", "receivedate": "20170606", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13615183, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20170830" } ]

{ "abstract": "This report describes a case of lung cancer with sarcoid reaction following chemoradiotherapy, showing false-positive accumulation of (18)F-fluorodeoxyglucose on positron-emission tomography in a 55-year-old man. Treatment-related sarcoid reaction should be considered when the accumulation of (18)F-fluorodeoxyglucose shows rapid extension in the course of treatment.", "affiliations": "Department of General Thoracic Surgery, Kawasaki Medical School, Okayama, Japan.", "authors": "Yukawa|Takuro|T|;Shimizu|Katsuhiko|K|;Hirami|Yuji|Y|;Maeda|Ai|A|;Yasuda|Koichiro|K|;Nakata|Masao|M|", "chemical_list": "D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D000077146:Irinotecan; D002945:Cisplatin; D002166:Camptothecin", "country": "England", "delete": false, "doi": "10.1177/0218492312468592", "fulltext": null, "fulltext_license": null, "issn_linking": "0218-4923", "issue": "21(6)", "journal": "Asian cardiovascular & thoracic annals", "keywords": "Adenocarcinoma; Lung neoplasms; Lymphatic metastasis; Positron-emission tomography; Sarcoidosis", "medline_ta": "Asian Cardiovasc Thorac Ann", "mesh_terms": "D000230:Adenocarcinoma; D000077192:Adenocarcinoma of Lung; D000971:Antineoplastic Combined Chemotherapy Protocols; D002166:Camptothecin; D059248:Chemoradiotherapy; D002945:Cisplatin; D005189:False Positive Reactions; D019788:Fluorodeoxyglucose F18; D006801:Humans; D000077146:Irinotecan; D008175:Lung Neoplasms; D008198:Lymph Nodes; D008297:Male; D008875:Middle Aged; D049268:Positron-Emission Tomography; D011237:Predictive Value of Tests; D011829:Radiation Dosage; D019275:Radiopharmaceuticals; D012507:Sarcoidosis; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D047368:Tumor Burden", "nlm_unique_id": "9503417", "other_id": null, "pages": "732-4", "pmc": null, "pmid": "24569337", "pubdate": "2013-12", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Lung cancer with sarcoid reaction in the lymph nodes following chemoradiotherapy.", "title_normalized": "lung cancer with sarcoid reaction in the lymph nodes following chemoradiotherapy" }

[ { "companynumb": "JP-PFIZER INC-2014306160", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "IRINOTECAN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "020571", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG/M2, ON DAYS 1 AND 8", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG ADENOCARCINOMA STAGE III", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IRINOTECAN HCL" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "60 MG/M2, ON DAY 1", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG ADENOCARCINOMA STAGE III", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN." } ], "patientagegroup": null, "patientonsetage": "55", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Sarcoidosis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "YUKAWA, T.. LUNG CANCER WITH SARCOID REACTION IN THE LYMPH NODES FOLLOWING CHEMORADIOTHERAPY. ASIAN CARDIOVASCULAR + THORACIC ANNALS. 2013;21(6):732-734", "literaturereference_normalized": "lung cancer with sarcoid reaction in the lymph nodes following chemoradiotherapy", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20141205", "receivedate": "20141112", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10578976, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150529" }, { "companynumb": "PHHY2014JP153882", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "IRINOTECAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090137", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG/M2, QD (DAYS 1 AND 8)", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG ADENOCARCINOMA STAGE III", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IRINOTECAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "60 MG/M2, QD (DAY 1)", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG ADENOCARCINOMA STAGE III", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN." } ], "patientagegroup": null, "patientonsetage": "55", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Sarcoidosis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "YUKAWA T, SHIMIZU K, HIRAMI Y, MAEDA A, YASUDA K, NAKATA M.. LUNG CANCER WITH SARCOID REACTION IN THE LYMPH NODES FOLLOWING CHEMORADIOTHERAPY... 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LUNG CANCER WITH SARCOID REACTION IN THE LYMPH NODES FOLLOWING CHEMORADIOTHERAPY. 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LUNG CANCER WITH SARCOID REACTION IN THE LYMPH NODES FOLLOWING CHEMORADIOTHERAPY. 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{ "abstract": "Background - Pre-existing pathology, the development of acute new one strictly dependent of the pregnancy or an independent acute or chronic medical problems generate a highly complex disease that requires a nuanced interpretation of the pregnant women in an attempt to identify the most favorable solutions for evaluation and treatment. Case report - 26-28 weeks pregnant women, 23 years old, known epilepsy, HIV encephalitis and pulmonary TB in inconsistent treatment with prolonged seizure status. Emergency air evacuation from a third degree medical center to regional center ( first level) under general anesthesia. After 24 hours, conscious, without focal signs. Favorable ongoing pregnancy. Conclusions - Considering the medical history, we analyzed several possibly triggering and maintenance of the crisis elements so that clarification of them constituted the main challenges. Finding an imaging examination solution with minimal harming effect on the fetus was a key decision points. Tocography and excluding eclampsia as the etiology were the main reasons to refrain from practicing cesarean section and magnesium sulphate administration. Paralytic agents use, in particular succinylcholine was a decisional key point, considering the variation in serum cholynesterase activity in peripartum period. The phenytoin administration was also a difficult choice because of the risk of bradycardia to the fetus. No any adverse event as effects of the crisis and medical intervention on the mother reported to the newborn during the first 8 months of life, but cerebral palsy continues to concern before 24 months.", "affiliations": "Emergency & First Aid Department, University of Medicine and Pharmacy of Craiova, Emergency Department - SMURD, University County Hospital Craiova.;University of Medicine and Pharmacy of Craiova.;University of Medicine and Pharmacy of Târgu - Mureș, Emergency Department - SMURD, University County Hospital Târgu - Mureș.", "authors": "Rotaru|L T|LT|;Popescu|R M|RM|;Boeriu|C|C|", "chemical_list": null, "country": "Romania", "delete": false, "doi": "10.12865/CHSJ.41.01.09", "fulltext": "\n==== Front\nCurr Health Sci JCurr Health Sci JCHSJCurrent Health Sciences Journal2067-06562069-4032Medical University Publishing House Craiova 2015.01.0910.12865/CHSJ.41.01.09Case Report Plurietiologyc Possibilities and Difficulties of Seizures Management in Pregnancy\n ROTARU L.T. 1POPESCU R.M. 2BOERIU C 31 Emergency & First Aid Department, University of Medicine and Pharmacy of Craiova, Emergency Department – SMURD, University County Hospital Craiova2 University of Medicine and Pharmacy of Craiova3 University of Medicine and Pharmacy of Târgu – Mureș, Emergency Department – SMURD, University County Hospital Târgu – MureșCorresponding Author: Dr. Luciana Rotaru\nAssociate Professor Emergency & First Aid DepartmentUniversity of Medicine and Pharmacy Craiova, Medical Director Emergency Department – SMURD, University County Hospital Craiova\nTabaci St. No. 1Craiova [email protected] Jan-Mar 2015 15 3 2015 41 1 67 69 27 2 2015 15 3 2015 Copyright © 2015, Medical University Publishing\nHouse Craiova2015This is an open-access article distributed under the terms of a\nCreative Commons Attribution-NonCommercial-ShareAlike 4.0 International\nPublic License, which permits unrestricted use, adaptation, distribution and\nreproduction in any medium, non-commercially, provided the new creations are\nlicensed under identical terms as the original work and the original work is\nproperly cited.Background - Pre-existing pathology, the development of acute new one strictly dependent of the pregnancy or an independent acute or chronic medical problems generate a highly complex disease that requires a nuanced interpretation of the pregnant women in an attempt to identify the most favorable solutions for evaluation and treatment. Case report - 26-28 weeks pregnant women, 23 years old, known epilepsy, HIV encephalitis and pulmonary TB in inconsistent treatment with prolonged seizure status. Emergency air evacuation from a third degree medical center to regional center ( first level) under general anesthesia. After 24 hours, conscious, without focal signs. Favorable ongoing pregnancy. Conclusions - Considering the medical history, we analyzed several possibly triggering and maintenance of the crisis elements so that clarification of them constituted the main challenges. Finding an imaging examination solution with minimal harming effect on the fetus was a key decision points. Tocography and excluding eclampsia as the etiology were the main reasons to refrain from practicing cesarean section and magnesium sulphate administration. Paralytic agents use, in particular succinylcholine was a decisional key point, considering the variation in serum cholynesterase activity in peripartum period. The phenytoin administration was also a difficult choice because of the risk of bradycardia to the fetus. No any adverse event as effects of the crisis and medical intervention on the mother reported to the newborn during the first 8 months of life, but cerebral palsy continues to concern before 24 months.\n\nseizurespregnancytocographycesarean sectioneclampsia\n==== Body\nIntroduction\nEmergency management of pregnancy is always a challenge because of the risk of fetal damage induced by generating condition, medications, procedures and physiological changes that pregnancy induces to the maternal body. \n\nPre-existing pathology, the development of acute new one strictly dependent of the pregnancy or an independent acute or chronic medical problems generate a highly complex disease that requires a nuanced interpretation in an attempt to identify the most favorable solutions for evaluation and treatment [1].\n\nCase report\nWe present a 23 years old woman case known epilepsy treated with carbamazepine and phenobarbitalum, 26-28 weeks pregnant brought by the ordinary ambulance to a level III medical center in epileptic status since 1 hour. The patient was out with HIV encephalitis and pulmonary TB in inconsistent treatment. BP 96/68mmHg. HR - 134/min. Normal blood glucose level and ECG, negative toxicological report. Fetal HR 100-115/min. Normal uterine tone. \n\nAfter repeated diazepam administration with no significant response in crisis suppression, the patient was air evacuated (HEMS resuscitation team) to the regional medical center (general anesthesia, endotracheal intubation, mechanical ventilation / volume IPPV cycled) with IV. benzodiazepine dose supplementation and IV. Phenytoin administration - 15mg/kg. \n\nFig. 1a and 2b Air evacuation to County University Hospital Craiova\n\nFig.1a Fig.1b Initial crush induction sequence (succinylcholine) sustained by deep sedation (fentanyl, etomidate, diazepam). Under general anesthesia (maintained over 6 hours by the anesthesiologist) has cupped seizures but maintained tachycardia. At 7 hours, she has been extubated without further medical events.\n\n At 24 hours conscious, without focal signs or subsequent seizures. Favorable ongoing pregnancy. \n\nAfter 5 weeks – natural delivery of a 1936 grams, male newborn. No any signs of abnormal brain electrical activity or seizures to the baby related to the mother medical problems during the first 8 months of life, but considering the severe event and therapy cerebral palsy remains under suspicion until 24 months. \n\nDiscussions\nThe main key decision points were the etiology of seizure status, differentiation eclampsia, brain imaging investigation options, anticonvulsant and anesthetics medications, and the decision to perform caesarean section. Each of these assumptions could have an impact on subsequent management decisions regarding caesarean section of necessity, type and level of anesthesia, child monitoring:\n\nThe etiology of seizure status. We have considered several possibilities possibly triggering and maintenance of the crisis: eclampsia, epilepsy, HIV encephalitis outbreak, septic or other opportunist, or any intracranial process (including posttraumatic related to previous seizures), hypoglycemia, intoxication, overdose or withdrawal of anticonvulsant medication. Since toxicological examination was negative, with high probability one of the causes triggering or at least favoring, was constituted by suppressing their medication. \n\nDifferentiation eclampsia. Under normal uterine tone, normal blood count (platelet count 211x106.l), no proteinuria confirmed, normal liver and renal function, LDH and creatinine and coagulation status, no haemolysis, normal and D dimmers level, BP progress and tocography s - decided that determinism is conceivable excluding eclampsia[2].That was the reason of do not attempt magnesium sulphate administration even if, a probability of eclamptic development assumed, very low gestational age and possible delivery needs considered in short horizon of time. In worst-case scenario of imposed hurry delivery, the fetal cerebral risks in this situation were appreciated as very high but the probability of this development of the situation was appreciated as being low. In the same time the cumulative effect of bradycardia induced by magnesium sulphate on the fetus would be reasonable to refrain of that and keep it as a backup solution in eventuality of repeated seizures [3].\n\nBrain imaging investigation. The options were related to performing brain CT (abdominal protection) or MRI (more acceptable to the fetus), considered mandatory to exclude certain items that require special intervention (as brain hemorrhagic event). S - Decided and performed MRI even if CT perhaps more reliant in view of acute minor bleeding. No acute pathological elements showed.\n\nAnticonvulsant and anesthetics medications. Concern was generated by using of succinylcholine, followed by rocuronium (serum cholinesterase activity decreases 30% during pregnancy and remains depressed postpartum [4] and subsequently the need of phenytoin administration. However, is not evidenced prolonged recovery in term-pregnant patients related succinylcholine [5] but cardiac effects on the fetus are not well known. There were no reported any disrhythmias or bradycardia to the fetus following conjugate administration of this drug to the mother.\n\nFigure 2 Abdominal echography - ED Craiova - normal ongoing pregnancy\n\nThe decision to perform caesarean section was related to potential fetal distress caused by prolonged hypoxia, induction and maintenance of long term general anesthesia and phenytoin administration [2] Being small gestational age, management to ensure acceptable adaptation and aggression already exercised on the fetus - considered that keeping it into the ,,natural incubator”, army expectative, tocography and mother observation is more profitable to improve prognosis.\n\nGiven to the patient history is never easy to determine the cause of the current crisis and decide further management, it may be necessary invasive investigations, over which the decision must be nuanced and custom. In the same time, the age of the pregnancy could induce confusion with eclampsia, and the specific management was sensible different. Using antihypertensive therapy administration and volume replacement in attempt of pressure and under perfusion of the placental bed control (which determine uterine ischemia and worsening of the fetus outcome) could induce interstitial pulmonary oedema [6] or rising intracranial pressure especially if preexisting damages, but eclampsia is an acute life-threatening complication of pregnancy and rapid identification and therapeutic decision (including assuming cesarean section) is crucial.\n\nThe existence of brain damage and a previous seizure induced background assumption as at least maintenance factors of the crisis but the imaging examination decision was a difficult one, in attempt to choose the minimal harming effect on the fetus and an acceptable sensitivity and accuracy of the result. \n\nConcerns about the cumulative effects of phenytoin on succinylcholine on fetal heart rate and rhythm - no confirmed, no any bradycardia or other cardiac dysrhythmia was reported and waiting on decision of cesarean section was beneficial.\n\nConclusion\nAlthough it supported increasing the frequency and duration of epilepsy seizures during pregnancy, treatment neglect condition requires exclusion documented as another cerebral etiology (HIV, trauma, toxic context, acute hemorrhagic event) and particularly eclampsia. \n\nCrush induction decision imposed in the context of a very prolonged, severe seizures, air evacuation and anticipating an extended brain imaging investigation. Mivacurium could be an alternative to succinylcholine, but succiniycholine was an option that has not generated any adverse elements from mother to fetus. \n\nPhenytoin administration was mandatory to stop seizures and has not caused either bradycardia or other cumulative adverse effects to the fetus\n\nRefrain from opening delivery was a favorable decision to the fetus, allowing growth to continue, although it may be controversial given mother's medication type and dosage administered [7]. \n\nSevere flightiness could rather be a trigger-to-trigger brain suffering (and hence to seizures in children) than the continuation of anticonvulsant treatment with maximum load.\n\nComplex pathologic and evolutionary context imposes upon the practitioner in emergency medicine at the systematic evaluation of both the mother and fetus to systematic approach and maximal emergency management providing to ensure and improvement vital functions, to prevent of secondary brain injury and several systemic side effects problems (induced by hypoxia, agitation, hyperthermia) and a multidisciplinary decision for the benefit of well weighed both, even if the risk of maternal plurimedicalisation apparaently exhibits risky on the fetus.\n==== Refs\nReferences\n1 Schachter SC Management of epilepsy and pregnancy 2014 \nAvailable from: http://www.uptodate.com/home/index.html \n2 Harden CL Management issues for women with epilepsy - Focus on pregnancy (an evidence-based review): I. Obstetrical complications and change in seizure frequency: Report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the American Epilepsy Society Epilepsia 2009 50 1229 1229 19496807 \n3 Altman D Carroli G Duley L Farrell B Moodley J Nelson J Do women with preeclampsia and their babies benefit from magnesium sulphate? The MAGPLE trial: a randomized placebo - controlled trial Lancet 2002 359 1877 1890 12057549 \n4 Leighton BL Cheek TG Gross JB Apfelbaum JL Shantz BB Gutsche BB Rosenberg H Succinylcholine pharmacodynamics in peripartum patients Anesthesiology 1986 2 64 202 205 3946807 \n5 Mohd Asim Rasheed Urmila Palaria Umesh K Bhadani Abdul Quadir Determination of optimal dose of succinylcholine to facilitate endotracheal intubation in pregnant females undergoing elective cesarean section Journal of Obstetric Anaesthesia and Critical Care 2012 2 2 86 91 \n6 Engelhardt T MacLennan FM Fluid management in pre-eclampsia International Journal of Obstetric Anesthesia 1999 8 253 259 15321120 \n7 Haddad B Deis S Goffnet F Paniel BJ Cabrol D Siba BM Maternal and perinatal outcomes during expectant management of 239 severe preeclamptic women between 24 and 33 weeks gestation Am. J. Obstet. Gynecol. 2004 190 1590 1597 15284743\n\n", "fulltext_license": "CC BY-NC-SA", "issn_linking": null, "issue": "41(1)", "journal": "Current health sciences journal", "keywords": "cesarean section; eclampsia; pregnancy; seizures; tocography", "medline_ta": "Curr Health Sci J", "mesh_terms": null, "nlm_unique_id": "101597164", "other_id": null, "pages": "67-69", "pmc": null, "pmid": "30151252", "pubdate": "2015", "publication_types": "D016428:Journal Article", "references": "12057549;15284743;3946807;19496807;15321120", "title": "Plurietiologyc Possibilities and Difficulties of Seizures Management in Pregnancy.", "title_normalized": "plurietiologyc possibilities and difficulties of seizures management in pregnancy" }

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{ "abstract": "Background Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) are two rare headache syndromes classified broadly as Trigeminal Autonomic Cephalalgias (TACs). Methods Here, 65 SUNCT (37 males) and 37 SUNA (18 males) patients were studied to describe their clinical manifestations and responses to treatment. Results Pain was almost always unilateral and side-locked. There were three types of attack: Single stabs, stab groups, and a saw-tooth pattern, with some patients experiencing a mixture of two types. As to cranial autonomic symptoms, SUNA patients mainly had lacrimation (41%) and ptosis (40%). Most cases of the two syndromes had attack triggers, and the most common triggers were touching, chewing, or eating for SUNCT, and chewing/eating and touching for SUNA. More than half of each group had a personal or family history of migraine that resulted in more likely photophobia, phonophobia and persistent pain between attacks. For short-term prevention, both syndromes were highly responsive to intravenous lidocaine by infusion; for long-term prevention, lamotrigine and topiramate were effective for SUNCT, and lamotrigine and gabapentin were efficacious in preventing SUNA attacks. A randomized placebo-controlled cross-over trial of topiramate in SUNCT using an N-of-1 design demonstrated it to be an effective treatment in line with clinical experience. Conclusions SUNCT and SUNA are rare primary headache disorders that are distinct and very often tractable to medical therapy.", "affiliations": "1 Department of Neurology, Wan Fang Hospital, Taipei Medical University, and Department of Neurology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.;3 Clinical Neurosciences, Royal Free Hospital, London, UK.;2 University of California, San Francisco, San Francisco, San Francisco CA, USA.;2 University of California, San Francisco, San Francisco, San Francisco CA, USA.", "authors": "Weng|Hsing-Yu|HY|;Cohen|Anna S|AS|;Schankin|Christoph|C|;Goadsby|Peter J|PJ|", "chemical_list": "D000700:Analgesics; D000927:Anticonvulsants; D000077236:Topiramate; D000077206:Gabapentin; D000077213:Lamotrigine", "country": "England", "delete": false, "doi": "10.1177/0333102417739304", "fulltext": "\n==== Front\nCephalalgiaCephalalgiaCEPspcepCephalalgia0333-10241468-2982SAGE Publications Sage UK: London, England 10.1177/033310241773930410.1177_0333102417739304Original ArticlesPhenotypic and treatment outcome data on SUNCT and SUNA, including a randomised placebo-controlled trial Weng Hsing-Yu 12Cohen Anna S 3Schankin Christoph 24Goadsby Peter J 251 Department of Neurology, Wan Fang Hospital, Taipei Medical University, and Department of Neurology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan2 University of California, San Francisco, San Francisco, San Francisco CA, USA3 Clinical Neurosciences, Royal Free Hospital, London, UK4 Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland5 NIHR-Wellcome Trust King’s Clinical Research Facility, King’s College London, UKPeter J Goadsby, Wellcome Foundation Building, King’s College Hospital, London SE5 9PJ, UK. Email: [email protected] 11 2017 8 2018 38 9 1554 1563 27 12 2016 24 8 2017 2 10 2017 6 10 2017 © International Headache Society 20172017International Headache SocietyThis article is distributed under the terms of the Creative Commons Attribution 4.0 License (http://www.creativecommons.org/licenses/by/4.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Background\nShort-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) are two rare headache syndromes classified broadly as Trigeminal Autonomic Cephalalgias (TACs).\n\nMethods\nHere, 65 SUNCT (37 males) and 37 SUNA (18 males) patients were studied to describe their clinical manifestations and responses to treatment.\n\nResults\nPain was almost always unilateral and side-locked. There were three types of attack: Single stabs, stab groups, and a saw-tooth pattern, with some patients experiencing a mixture of two types. As to cranial autonomic symptoms, SUNA patients mainly had lacrimation (41%) and ptosis (40%). Most cases of the two syndromes had attack triggers, and the most common triggers were touching, chewing, or eating for SUNCT, and chewing/eating and touching for SUNA. More than half of each group had a personal or family history of migraine that resulted in more likely photophobia, phonophobia and persistent pain between attacks. For short-term prevention, both syndromes were highly responsive to intravenous lidocaine by infusion; for long-term prevention, lamotrigine and topiramate were effective for SUNCT, and lamotrigine and gabapentin were efficacious in preventing SUNA attacks. A randomized placebo-controlled cross-over trial of topiramate in SUNCT using an N-of-1 design demonstrated it to be an effective treatment in line with clinical experience.\n\nConclusions\nSUNCT and SUNA are rare primary headache disorders that are distinct and very often tractable to medical therapy.\n\nSUNCTSUNAtrigeminal autonomic cephalalgiacranial autonomic symptomstriggerslidocainelamotriginetopiramategabapentin\n==== Body\nIntroduction\nShort-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) is a rare form of primary headache (1,2). It is clear in tertiary headache practice that many patients do not manifest both conjunctival injection and tearing (3). The current terminology has evolved to respect the initial description and acronym, and acknowledge the underlying physiological principle of co-existent cranial autonomic activation (4). SUNCT syndrome was initially included in the second edition of the International Headache Classification and SUNA in the appendix (5). In the latest version, ICHD-3 beta (6), SUNCT and SUNA are included in the main body.\n\nAt least two unresolved issues arise in these syndromes. First, should they be collapsed under an umbrella or left distinct? Given their rarity, substantial series have not been available to explore the phenotypes. Previously, we reported on 43 SUNCT and nine SUNA patients (3); in the following decade, we have seen more patients with these syndromes and sought here to examine whether the syndromes are sufficiently distinct to maintain their separation. Moreover, we had noted in previous work that migraine features in the phenotype appeared to be associated with an underlying migrainous biology (3); we, therefore, wished to test the question as to whether having underlying migrainous biology influenced the phenotypic expression of these syndromes with our expanded cohort. Secondly, while there are treatment guidelines (7), the body of evidence for the guidance is minimal. We have been able to collect substantial treatment response data, and uniquely have conducted a randomized placebo-controlled trial of SUNCT to test whether topiramate is an effective treatment. We therefore set out to provide experience as an evidence base (8) for treatment recommendations.\n\nMaterial and methods\nClinical material\nAll patients attended outpatient clinics at either the National Hospital for Neurology and Neurosurgery (NHNN), London, UK, between 2002 and 2007; the Headache Center, University of California, San Francisco (UCSF), San Francisco, CA, USA, from 2007 to 2013, or as outpatients at King’s College Hospital, London, UK from 2013 to 2015. Patients were diagnosed as having SUNCT or SUNA as defined by the International Classification of Headache Disorders, Second Edition (ICHD-2) (5) and were consistent with proposed ICHD-3 beta criteria (6). Every patient was seen by at least one of us (PJG). The cohort represents those previously reported (3) whose clinical data were re-reviewed, and additional cases. The study was approved by the NHNN Institute of Neurology Joint Research Ethics Committee (reference 00/N072), by the UCSF Committee for Human Research, and is presented as an audit of practice at King’s College Hospital, London.\n\nIn every patient, detailed and standardised history-taking was carried out, including the side, location, frequency, duration, and character of their headaches, types of attacks, accompanying symptoms, triggering factors, personal and family histories, and their responses to medicines or other treatments. The study focuses on lateralization and type of attacks, cranial autonomic symptoms, and treatment outcomes.\n\nClinical data analysis\nAll data were recorded using Microsoft Excel. All descriptive calculations were performed in Excel. Summary measures are reported for the cohort as n’s with percentages. To test whether the SUNCT and SUNA are different based on phenotype as a surrogate for biology, apart from the cranial autonomic symptom distinction, we used a multinomial logistic model, with a logit link function, and diagnosis as the dependent variable (IBM SPSS Statistics v 22). To test the relationship of background migrainous biology, defined as a personal or family history of migraine, to the presence of a clinical phenotype, we used a binary logistic model, with a logit link function, and the presence of migrainous biology as a binary dependent variable. To test single phenotype questions, a chi squared test was employed. For all analyses, significance was set as p < 0.05. The clinical effect from preventives is recorded as patients subjectively reported their effects, and as it was recorded in the documentation.\n\nClinical trial\nFive male patients (aged 51–72, mean 59 years) with SUNCT were recruited from the Outpatient department at the National Hospital for Neurology and Neurosurgery (NHNN), London, between 2003 and 2004 (Figure 1). They were initially diagnosed with SUNCT using operational criteria later incorporated into ICHD-2 (5). Inclusion criteria were: Diagnosis of SUNCT; willingness to stop any current treatments; and willingness to comply with a diary of attacks as they occurred. Exclusion criteria were: Previous exposure to topiramate; being pregnant or lactating; having a history of renal calculi; and any contraindications to the use of topiramate according to the Summary of Product Characteristics (Medicines and Healthcare products Regulatory Agency- MHRA, UK). The subjects gave their informed consent and were free to withdraw from the study at any time. The study was conducted before trial registration became commonplace (9).\nFigure 1. CONSORT flow diagram.\n\n\n\nDesign\nThe design of the study was a randomised, double-blind, placebo-controlled crossover trial of topiramate. The treatments were topiramate tablets and matching placebo, supplied by Janssen UK; and labelled Treatment 1 and Treatment 2, to be taken in the first and second arm of the study, respectively. The order of active treatment and placebo was randomised by NHNN pharmacy, and each participant was assigned a randomisation number. The code was held by the pharmacy until study completion and database locking.\n\nConduct\nPatients were required to withdraw from preventive medications prior to commencement of the study. After an initial washout drug-free period of 10 days, treatment was started at topiramate 12.5 mg at night and increased every five days to a maximum of 50 mg twice daily for 10 days, after which the dose was reduced over the next 10 days, or the same regimen with matched placebo. A 10-day washout drug-free period followed, after which the patients commenced the second arm of the study in the same paradigm. The patients with episodic SUNCT started the 10-day washout period at the start of their bout.\n\nThe patients were instructed to keep a diary for the duration of the study, which documented the date, time, severity, and duration of each attack.\n\nClinical trial data analysis\nThe primary endpoint was the reduction of attack frequency, as measured by the mean daily number of attacks during the 10 days at maximum dose compared to the 10 drug free days pre-treatment, comparing active and placebo treatment arms. A secondary endpoint, ‘attack load’, was calculated as the number of minutes of pain per day for each patient, to take account of longer attacks, such as saw-tooth patterns (3). The results are presented on an N-of-1 basis. A positive result was declared for the endpoint in each patient, if the outcome was reduced by 50% or more compared to placebo. Given SUNCT attack frequency can vary considerably from week to week, we converted changes to percentages and calculated:%therapeutic effect = (topiramate change) minus (placebo change).\n\n\n\nResults\nClinical data\nSubjects\nOne hundred and two cases were identified: 65 with SUNCT, and 37 with SUNA. There were 37 male and 28 female SUNCT patients, and 18 male and 19 female SUNA patients. The mean age of onset of SUNCT patients was 46 ± 13 (mean ± SD; range: 13–75) years, and that of SUNA was 45 ± 16 (range 15–92).\n\nLaterality of attacks\nOf all the SUNCT and SUNA patients, 48 (47%) cases had only left-side attacks, and 52 (51%) cases had attacks exclusively on the right side; 12 (12%) cases had unilateral attacks with side variance; one case had a unilateral attack with nearly equal possibility of left or right side; only one case had experienced bilateral attacks.\n\nCranial autonomic symptoms\nBy definition, every SUNCT patient had attacks with both an ipsilateral conjunctival injection and lacrimation, while less than half of SUNA patients had either. SUNCT is generally more feature-full in terms of cranial autonomic symptoms than is SUNA. SUNA is dominated by lacrimation, nasal symptoms, and ptosis (Table 1).\nTable 1. Cranial autonomic features.\n\nFeature\tSUNCT n (%)\tSUNA n (%)\t\nConjunctival injection\t65 (100)\t7 (24)\t\nLacrimation\t65 (100)\t14 (48)\t\nNasal: Blocking or rhinorrhea\t44 (67)\t12 (36)\t\nAural fullness\t12 (50)\t5 (17)\t\nPeriorbital oedema\t25 (41)\t8 (29)\t\nForehead/facial:\t\t\t\n Sweating\t4 (7)\t1 (3)\t\n Flushing\t11 (18)\t5 (17)\t\nSympathetic:\t\t\t\n Ptosis\t31 (51)\t11 (38)\t\n Miosis\t1 (2)\t0\t\n\n\nComparing the phenotypes\nTriggering\nAmong SUNCT patients, one patient had only triggered attacks, with no spontaneous ones. Eight (12%) SUNCT patients had only spontaneous attacks with no triggered ones. All the other patients had both spontaneous and triggered attacks. In SUNA patients, 10 (27%) patients had only spontaneous attacks with no triggers, and the remainder had more triggered attacks than spontaneous ones. Of all SUNCT patients, 56 (86%) cases had pain attacks with a cutaneous trigger. The most common triggers included touch (39 cases, 60%), chewing or eating (35 cases, 54%), the wind (24 cases, 37%) and brushing the teeth (23 cases, 35%). Among SUNA patients, 32 (86%) cases had pain with triggers. The most frequent triggers of SUNA cases were chewing or eating (12 cases) and touch (10 cases).\n\nRefractory period\nOf SUNCT cases for whom we had data, 1/52 had a refractory period to cutaneous triggering. Of SUNA cases, 4/32 had a refractory period after cutaneous triggering.\n\nTypes of attacks\nAttacks of SUNCT and SUNA take one or more of three forms: Single stabs, a group of stabs, or a saw-tooth pattern of stabs. In this cohort, SUNCT patients had more single stabs, while SUNA had more groups of stabs (χ2 = 23.4, p < 0.0001). The saw-tooth pattern was comparable in both conditions (Table 2).\nTable 2. Pattern of attacks.\n\n\tSUNCT n (%)\tSUNA n (%)\t\nSingle stabs\t41 (64)\t8 (37)*\t\nGroups of stabs\t23 (36)\t23 (62)*\t\nSaw-tooth pattern\t22 (34)\t9 (24)\t\nSingle stabs + groups of stabs\t10 (18)\t2 (9)\t\nSingle stabs + saw-tooth pattern\t5 (9)\t1 (5)\t\nGroups of stabs + saw-tooth pattern\t1 (2)\t1 (5)\t\nSingle stabs + groups of stabs + saw-tooth pattern\t3 (5)\t0\t\n* p < 0.0001\n\n\n\nMigrainous background\nBoth SUNCT and SUNA patients had a background migrainous biology in 57 % of cases for which we had data. In a model examining the pain features, a migrainous background was strongly associated with background pain between attacks (Wald χ2 = 6.5, p = 0.01) and worsening of pain during the attack (Wald χ2 = 8.2, p = 0.004). In a model examining the canonical migraine features, the presence of nausea was not associated with migrainous biology (Wald χ2 = 1.04, p = 0.307), whereas the presence of either photophobia or phonophobia was associated (Wald χ2 = 6.8, p = 0.009). Worsening of background pain with movement was seen in 26% (n = 55) of SUNCT cases and in 46% (n = 28) of SUNA cases. Nausea was seen in 27% (n = 64) of SUNCT cases and 29% (n = 35) of SUNA cases. Similarly, for photophobia or phonophobia, 61% (n = 64) of SUNCT and 58% (n = 36) of SUNA cases had one, or both, symptoms.\n\nTreatment effects\nShort-term prevention\nSumatriptan was used in 14 SUNCT and nine SUNA patients, and the attacks lessened in only one of each. High-flow oxygen was tried, but neither SUNCT nor SUNA cases were responsive. Placebo-controlled indomethacin injections (10) had no effect on either SUNCT or SUNA. Intravenous lidocaine had a very good effect in reducing attacks of SUNCT (100%) and SUNA (88%), when it could be tolerated. Dihydroergotamine (11) and corticosteroids seem generally unhelpful in both SUNCT and SUNA. Greater occipital nerve (GON) injections (12) were beneficial in 50% (6 of 12 cases) of SUNCT patients, but had no reliable effect in SUNA cases (Table 3).\nTable 3. Effect of acute treatments of TACs on SUNCT and SUNA.\n\n\tSUNCT\tSUNA\t\nTotal n\tEffective n\tTotal n\tEffective n\t\nSumatriptan 6 mg sc\t14\t1\t9\t1\t\nOxygen 12–15 L/min 100%\t14\t0\t7\t0\t\nIndomethacin 100 mg imi*\t13\t0\t6\t0\t\nLidocaine (iv)\t15\t15\t9\t8\t\nDihydroergotamine, iv over 5 days**\t5\t0\t5\t0\t\nCorticosteroids – oral high dose\t20\t2\t6\t0\t\nGreater occipital nerve injection***\t12\t6\t4\t3\t\n* Placebo controlled (10); **over five days (11); ***with lidocaine and depomethylprednisolone ipsilateral to pain (12).\n\n\n\nLong-term prevention\nLamotrigine had a good effect in reducing the frequency or severity of the attacks in 62% of SUNCT and 31% of SUNA patients at doses of about 100 to 600 mg/day (Table 4).\nTable 4. Effectiveness* of preventive.\n\n\tSUNCT\tSUNA\t\n\tTotal n\tEffectiveness n (%)\tTotal n\tEffectiveness n (%)\t\nLamotrigine\t29\t18 (62)\t16\t5 (31)\t\nTopiramate\t27\t13 (48)\t9\t1\t\nGabapentin\t29\t11 (38)\t18\t7 (39)\t\nCarbamazepine\t43\t16 (36)\t20\t4 (20)\t\nOxcarbazepine\t7\t1 (14)\t6\t0\t\nPregabalin\t7\t1 (14)\t16\t1\t\nVerapamil\t16\t2 (13)\t5\t0\t\nValproate\t13\t0\t4\t0\t\nBeta-blocker\t7\t0\t4\t0\t\nTricylic\t36\t3\t17\t3\t\n* Effectiveness: Reported to be useful in reducing frequency or severity of attacks by the patient.\n\n\n\nTopiramate had a good effect in 48% of SUNCT patients at doses of 50–500 mg/day. However, no SUNA case had a good or better response to topiramate.\n\nGabapentin was used in 18 SUNA patients at a dose of 1800–2400 mg/day; seven cases had good to moderate improvement (39%). In addition, gabapentin was also beneficial in 11 of 29 SUNCT cases.\n\nCarbamazepine also had a good to moderate effect in 36% of SUNCT patients at doses of 100–1200 mg/day. Carbamazepine was effective in 20% of SUNA cases.\n\nBrain imaging\nThere were 55 SUNCT (85%) and 33 SUNA (89%) patients with brain imaging, which were almost all magnetic resonance (MR). No abnormal findings on brain images were identified in 42 SUNCT (76%) and 31 SUNA (94%) cases, and apart from pituitary changes, none were SUNCT or SUNA related. There were four SUNCT patients with pituitary lesions. Two of them had macroadenomas, which resolved after treatment of the tumors. The other two had microadenomas, and one of them became pain-free for eight months after resection of the tumor. Vascular loops were found in the brain MR of five SUNCT (10%) and two SUNA (8%) patients. Among them, three SUNCT and two SUNA cases had vascular loops compressing the trigeminal nerves, one was ipsilateral to the pain, one had bilateral loops but unilateral pain only, and one had a vessel loop at one side but had bilateral pain. One SUNCT and two SUNA cases received microvascular decompression: One SUNA case was pain-free for only three months after the surgery, and the operation had no effect in improving the attacks of the SUNCT and the other SUNA cases.\n\nClinical trial\nAll five patients completed the trial (Figure; Table 5).\nTable 5. Clinical trial: Demographics and outcomes.\n\n\tPatient\t\n\t#1\t#2\t#3\t#4\t#5\t\nAge (years)\t72\t54\t60\t59\t51\t\nDuration of SUNCT attacks\t120–1800 s\t1 s stabs, 3600 s groups\t5 s\t1 s stabs, 300 s groups\t60 s\t\nDaily frequency of attacks pre-placebo\t7\t13\t140\t13\t10\t\n% change in frequency on placebo\t−100\t+52\t−15\t+22\t−10\t\nDaily frequency of attacks pre-topiramate\t2\t23\t138\t10\t6\t\n% effect – frequency topiramate\t+2063\t−19\t−100\t+27\t−18\t\nPrimary endpoint %gain Topiramate − placebo\t+2163\t−71\t−85\t+5\t−8\t\nDaily attack load (minutes) pre-placebo\t3\t5\tNA\t93\t11\t\n% change in attack load on placebo\t−100\t+178\tNA\t+192\t+45\t\nDaily attack load pre-topiramate\t57\t33\tNA\t197\t3\t\n% change in attack load on topiramate\t+920\t−71\tNA\t−17\t+160\t\nSecondary endpoint %effect Topiramate − placebo\t+1020\t−249\tNA\t−209\t+115\t\n\n\nPatient #1 had a good effect whilst on placebo, with complete cessation of his attacks. On topiramate, there was an increase of both attack frequency and attack load. He was classified as a topiramate failure; indeed, it appeared to worsen his problem.\n\nPatient #2 had a reduced frequency of attacks by 71% compared to placebo; he was classified a success. He also had a substantial reduction in attack load compared to the placebo period.\n\nPatient #3 had complete cessation of his attacks on topiramate, and a milder 15% reduction on placebo. He was classified as a success. He did not provide attack length data.\n\nPatient #4 had a 5% difference between placebo and topiramate arms in terms of frequency, and was classified as a topiramate failure. On the secondary measure, there was a greater than 200% reduction in attack load.\n\nPatient #5 had an 8% reduction in frequency on the placebo arm when compared to the topiramate arm. He was classified as a failure. On the secondary endpoint of attack load, he worsened by 115 %.\n\nOverall, on the primary endpoint, two patients had improvement, two patients had no change and one worsened.\n\nClinical trial – adverse events\nOne patient (#4) reported peripheral paraesthesiae on topiramate. One patient (#5) reported peripheral paraesthesiae on both treatments and also had dull headache attacks whilst on both treatments, which were not related to his SUNCT or migraine, and not recorded as such. He had one episode of diplopia lasting an hour on placebo, and reported indigestion whilst on topiramate.\n\nDiscussion\nIn this substantial cohort of patients with SUNCT and SUNA, we have been able to explore similarities and differences between the conditions, and explore treatment outcomes. The data suggest sufficient differences in core phenotypes to maintain the current classification. Cranial autonomic symptoms are distributed differently, even allowing for the definitional constraint in SUNCT. Attack pain features show SUNCT being more likely to have single stabs and SUNA more likely to have groups of stabs. In terms of preventive treatments, SUNA is generally less responsive, being most likely to be improved by gabapentin or lamotrigine, while SUNCT is more likely to be improved by lamotrigine and topiramate. Our small randomised placebo-controlled trial of topiramate in SUNCT supports the clinical data and, since SUNA seems much less likely to respond, provides another hint that the conditions have some difference. While the data certainly do not settle the issue of whether SUNCT is on a continuum with SUNA, they do suggest it is reasonable from both a clinical and research perspective to maintain the distinction until more data can be collected.\n\nThe outcome of treatments is instructive as to the biology of SUNCT/SUNA. The conditions respond very well, almost invariably, to intravenous lidocaine, if it is tolerated. There is no effect of oxygen, which although open label, was administered in a dose effective for cluster headache (13). Similarly, while cluster headache is very likely to respond to sumatriptan by injection (14), one only in each group responded here. Again corticosteroids, which can certainly be helpful in the short term in many patients with cluster headache (15), were not useful in most patients with SUNCT or SUNA. In contrast to paroxysmal hemicrania, where an indomethacin effect is diagnostic (16), no such effect is seen in SUNCT or SUNA. One outcome shared with all the TACs, indeed with migraine (12), is a useful effect of greater occipital nerve injection (GONi) with local anesthetic and corticosteroid. The distinction between that effect and the lack of effect of high dose corticosteroids alone suggests the GONi has more than an effect of corticosteroid dose.\n\nAn interesting issue that has arisen in the literature is the relationship between SUNCT/SUNA and trigeminal neuralgia (17). The distribution of pain seems clearly different: SUNCT/SUNA much more often involves the ophthalmic division of the trigeminal nerve, in more than two-thirds of cases (3), while trigeminal neuralgia only involves this division in 4% of cases (18). Cranial autonomic symptoms are the rule in SUNCT/SUNA, with more than 99% of SUNCT/SUNA we have reviewed having one or more, and all SUNCT patients having at least two, while, depending on what cases are accepted, the rate is considerably less in trigeminal neuralgia (18). Less than 5% of SUNCT/SUNA patients presented in our cohort had a refractory period to re-triggering, while almost all trigeminal neuralgia patients have a refractory period. The pain of trigeminal neuralgia is classically described as short electric-shock like pains, whereas up to one-third of our SUNCT/SUNA cohort had the saw-tooth pattern, which is invariably longer than a less than one second stab. Interestingly, both conditions have background pain in about half of patients (19); this would fit well to a common basis for that pain, i.e. associated migrainous biology rather than a common mechanism for trigeminal neuralgia and SUNCT/SUNA. The treatment recommendations for SUNCT/SUNA, and our data, differ considerably to those for trigeminal neuralgia. Carbamazepine and oxcarbazepine are preferred treatments for trigeminal neuralgia, with lamotrigine and gabapentin having insufficient evidence for recommendation (20). In contrast, lamotrigine emerges as the most useful treatment for SUNCT, next topiramate, which now has randomised placebo-controlled trial data, while gabapentin emerges as the most useful treatment of SUNA. Remarkably, topiramate is not listed in the top tier treatments of trigeminal neuralgia (20). The finding of an abnormal vascular loop is common in classical trigeminal neuralgia (21,22). We report these loops in 10% of cases. An important limitation of our data is that they were not collected with this question in mind, scanners used were not uniform, and we only had clinically noted reporting. We remain impressed by the indifferent effects of surgery beyond what would be expected after manipulation in this region and anaesthetic. Lastly, functional imaging studies have established changes in the posterior hypothalamic region in SUNCT (23,24), whereas no such changes have been reported in trigeminal neuralgia. Taken together, the evidence to differentiate between SUNCT/SUNA and trigeminal neuralgia is strong. One possible issue is under-diagnosis of SUNA in what is, in our experience, often called atypical trigeminal neuralgia (25). This issue certainly deserves further attention.\n\nA family history in SUNCT is reported in only one cohort (26). Regarding other trigeminal autonomic cephalalgias, there are reports of familial cluster headache (27–30), familial paroxysmal hemicrania (31) and familial hemicrania continua (32), as well as twins with cluster headache (33–35). Whether the rarity of familial cases reflects a non-genetic basis to the condition or simply the rarity of the problem remains an important unresolved issue.\n\nThe majority of SUNCT and SUNA cases were idiopathic in previous reports. SUNCT syndrome was delineated in patients with microprolactinomas (36) and macroprolactinomas (37,38), with attacks appearing on the same side as the tumors. A further five SUNCT cases were reported with pituitary adenomas, all with attacks ipsilateral to the side of the tumor (39); among the five patients, two of them did not improve after surgical removal of the tumor, one case was pain-free after surgery, one case was pain-free for 1 year then the pain relapsed with tumor recurrence, and one patient had a major reduction in headaches. In our cohort, there were four SUNCT and no SUNA cases with pituitary lesions (two macroadenomas and two microadenomas). When one considers TAC presentations and pituitary tumours (40) in the context of population-based pituitary tumour presentations (41), and the subsequent concordant course of the disorders, there does seem to be a relationship between TACs and acromegaly/prolactinoma not accounted for by chance.\n\nIn the literature, SUNCT patients were reported to be responsive to topiramate at doses of between 75 and 300 mg/day (42,43). The data from our reported cohort suggest about half of SUNCT patients find topiramate useful whereas few patients with SUNA find it useful. The open label SUNCT data are now supported by the placebo-controlled data that we report. SUNCT is rare, and doing large controlled trials in SUNCT prevention is challenging. The N-of-1 crossover approach is appropriate for this patient group. The finding that two of the five patients clearly benefitted on the primary endpoint and one on an important secondary endpoint of reducing time spent in pain, supports the open label experience and offers a clear mandate to continue to offer topiramate to SUNCT patients.\n\nThe issue of inter-paroxysmal pain in SUNCT/SUNA, and more broadly in trigeminal autonomic cephalalgias, is an important pathophysiological issue. It can confuse clinicians and certainly can be an important part of the disability of these conditions. In these patients, a little more than half had some identified migrainous biology, which we defined operationally as a personal or family history of migraine. While this seems considerable, if one reviews the cumulative lifetime migraine incidence for episodic migraine, it is 43% in females (44). If one adds in patients with probable migraine and chronic migraine, it could be easily seen that the gene pool for migraine in females is about 50%. It could be argued that the rates we see here are a combination of that gene pool and the diagnostic bias of seeing a physician. Interestingly, inter-paroxysmal background pain was strongly associated with migrainous biology, as was a worsening of pain with movement, and the presence of photophobia and phonophobia. It may be argued that SUNCT and SUNA facilitate the expression of migrainousness, which expresses itself in these other features. Interestingly, nausea did not seem to be associated, which may be because it is relatively less common or because the SUNCT/SUNA effect on migraine pathways is not universal.\n\nIn summary, a very substantial cohort of patients with SUNCT and SUNA is presented. Based on the phenotypic presentation of the pain features and the distribution of cranial autonomic symptoms, the two seem different. This is supported by differences in response to preventive therapies, particularly topiramate, for which we supply data from a randomised placebo-controlled trial. An analysis of the clinical, therapeutic, and pathophysiological findings in SUNCT/SUNA supports their differentiation from classical trigeminal neuralgia. The findings of associations between background migrainous biology and features such as inter-paroxysmal pain and aggravation of pain with movement, suggest SUNCT and SUNA can trigger the expression of an underlying migrainous process that colours the clinical presentation. SUNCT and SUNA seem well placed as trigeminal autonomic cephalalgias (TACs), and our clinical data offer both directions for new work and consolidate what is known about these rare and highly disabling conditions.\n\nClinical implications\n\nShort-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) are two rare headache syndromes classified broadly as trigeminal autonomic cephalalgias (TACs).\n\nRegarding cranial autonomic features, SUNA patients were most likely to have lacrimation and ptosis.\n\nPatients with SUNCT and SUNA who had had a personal or family history of migraine were more likely to have photophobia, phonophobia and persistent pain between attacks.\n\nA randomized placebo-controlled cross-over trial of topiramate in SUNCT using an N-of-1 design supports offering this therapy to patients with SUNCT.\n\n\n\n\nAuthor contributions\nHsing-Yu Weng: Saw patients and compiled the data into a summary sheet, and did the analyses.\n\nAnna S Cohen: Saw patients, compiled data from the patients into the results spreadsheet and conducted the randomised controlled trial.\n\nChristophe Schankin: Saw patients and helped compile the data summary sheet.\n\nPeter J Goadsby: Saw all the patients, checked the spreadsheet and the trial calculations and edited the final manuscript.\n\nDeclaration of conflicting interests\nThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Hsing-Yu Weng reports no conflicts of interest.\n\nAnna S Cohen reports no conflicts of interest.\n\nChristoph Schankin reports no conflicts of interest.\n\nPeter J Goadsby reports no conflicts of interest in this paper.\n\nFor completeness, in the three years prior to submission, Dr Goadsby also reports grants and personal fees from Allergan, Amgen, Eli-Lilly and Company, and eNeura Inc., and personal fees from Akita Biomedical, Alder Biopharmaceuticals, Autonomic Technologies Inc, Avanir Pharma, Cipla Ltd, Colucid Pharmaceuticals, Ltd, Dr Reddy’s Laboratories, Electrocore LLC, Novartis, Pfizer Inc, Scion, Teva Pharmaceuticals, Trigemina Inc., MedicoLegal work, Journal Watch, Up-to-Date and Oxford University Press outside the submitted work. In addition, Dr Goadsby had a patent magnetic stimulation for headache pending to eNeura.\n\nFunding\nThe authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Dr Weng was funded by Wan Fang Hospital, Taipei Medical University, Taiwan. Dr Cohen was funded by a Wellcome Trust Training fellowship. Topiramate and matching placebo were provided by Janssen, UK, without charge and without any input into the design, execution, analysis, or manuscript.\n==== Refs\nReferences\n1 Sjaastad O, Russell D, Horven I, et al (editors). Multiple neuralgiform unilateral headache attacks associated with conjunctival injection and appearing in clusters. A nosological problem. In Proceedings of the Scandinavian Migraine Society, 1978; Arhus .\n2 Sjaastad O Saunte C Salvesen R et al. \nShortlasting unilateral neuralgiform headache attacks with conjunctival injection, tearing, sweating, and rhinorrhea . 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Curr Pain Headache Rep \n2015 ; 19 : 473 –473 .25501956 \n18 Maarbjerg S Gozalov A Olesen J et al. \nTrigeminal neuralgia – a prospective systematic study of clinical characteristics in 158 patients . Headache \n2014 ; 54 : 1574 –1582 .25231219 \n19 Maarbjerg S Gozalov A Olesen J et al. \nConcomitant persistent pain in classical trigeminal neuralgia – evidence for different subtypes . Headache \n2014 ; 54 : 1173 –1183 .24842632 \n20 Zakrzewska JM Linskey ME \nTrigeminal neuralgia . BMJ \n2015 ; 350 : h1238 –h1238 .25767102 \n21 Love S Coakham HB \nTrigeminal neuralgia: Pathology and pathogenesis . Brain \n2001 ; 124 : 2347 –2360 .11701590 \n22 Maarbjerg S Wolfram F Gozalov A et al. \nSignificance of neurovascular contact in classical trigeminal neuralgia . Brain \n2015 ; 138 : 311 –319 .25541189 \n23 May A Bahra A Buchel C et al. \nFunctional MRI in spontaneous attacks of SUNCT: Short-lasting neuralgiform headache with conjunctival injection and tearing . Ann Neurol \n1999 ; 46 : 791 –793 .10554000 \n24 Cohen AS Matharu MS Kalisch R et al. \nFunctional MRI in SUNCT (Short-lasting Unilateral Neuralgiform headache attacks with Conjunctival injection and Tearing) and SUNA (Short-lasting Unilateral Neuralgiform headache attacks with cranial Autonomic symptoms) shows differential hypothalamic activation with increasing pain . Cephalalgia \n2006 ; 26 : 1402 –1403 .\n25 May A Goadsby PJ \nThe enigma of the interconnection of trigeminal pain and cranial autonomic symptoms . Cephalalgia \n2016 ; 36 : 727 –729 .26453658 \n26 Gantenbein A Goadsby PJ \nFamilial SUNCT . Cephalalgia \n2005 ; 25 : 457 –459 .15910571 \n27 Spierings EL Vincent AJ \nFamilial cluster headache . Neurology \n1992 ; 42 : 1399 –1400 .1620353 \n28 D’Amico D Leone M Moschiano F et al. \nFamilial cluster headache: Report of three families . Headache \n1996 ; 36 : 41 –43 .8666537 \n29 Leone M Russell MB Rigamonti A et al. \nIncreased familial risk of cluster headache . Neurology \n2001 ; 56 : 1233 –1236 .11342697 \n30 El Amrani M Ducros A Boulan P et al. \nFamilial cluster headache: A series of 186 index patients . Headache \n2002 ; 42 : 974 –977 .12453028 \n31 Cohen AS Matharu MS Goadsby PJ \nFamilial paroxysmal hemicrania . Cephalalgia \n2004 ; 24 : 1099 –1099 .\n32 Weatherall MW Bahra A \nFamilial hemicrania continua . Cephalalgia \n2011 ; 31 : 245 –249 .20956404 \n33 Couturier EG Hering R Steiner TJ \nThe first report of cluster headache in identical twins . Neurology \n1991 ; 41 : 761 –761 .\n34 Roberge C Bouchard JP Simard D et al. \nCluster headache in twins . Neurology \n1992 ; 42 : 1255 –1256 .\n35 Sjaastad O Shen JM Stovner LJ et al. \nCluster headache in identical twins . Headache \n1993 ; 33 : 214 –217 .8496062 \n36 Levy MJ Matharu MS Goadsby PJ \nProlactinomas, dopamine agonist and headache: Two case reports . Eur J Neurol \n2003 ; 10 : 169 –174 .12603293 \n37 Massiou H Launay JM Levy C et al. \nSUNCT syndrome in two patients with prolactinomas and bromocriptine-induced attacks . Neurology \n2002 ; 58 : 1698 –1699 .12058109 \n38 Matharu MS Levy MJ Merry RT et al. \nSUNCT syndrome secondary to prolactinoma . J Neurol Neurosurg Psychiatry \n2003 ; 74 : 1590 –1592 .14617728 \n39 Chitsantikul P Becker WJ \nSUNCT, SUNA and pituitary tumors: Clinical characteristics and treatment . Cephalalgia \n2013 ; 33 : 160 –170 .23197348 \n40 Levy M Matharu MS Meeran K et al. \nThe clinical characteristics of headache in patients with pituitary tumours . Brain \n2005 ; 128 : 1921 –1930 .15888539 \n41 Agustsson TT Baldvinsdottir T Jonasson JG et al. \nThe epidemiology of pituitary adenomas in Iceland, 1955–2012: A nationwide population-based study . Eur J Endocrinol \n2015 ; 173 : 655 –664 .26423473 \n42 Matharu MS Boes CJ Goadsby PJ \nSUNCT syndrome: Prolonged attacks, refractoriness and response to topiramate . Neurology \n2002 ; 58 : 1307 –1307 .11971110 \n43 Rossi P Cesarino F Faroni J et al. \nSUNCT syndrome successfully treated with topiramate: Case reports . Cephalalgia \n2003 ; 23 : 998 –1000 .14984234 \n44 Stewart WF Wood C Reed ML et al. \nCumulative lifetime migraine incidence in women and men . Cephalalgia \n2008 ; 28 : 1170 –1178 .18644028\n\n", "fulltext_license": "CC BY", "issn_linking": "0333-1024", "issue": "38(9)", "journal": "Cephalalgia : an international journal of headache", "keywords": "SUNA; SUNCT; cranial autonomic symptoms; gabapentin; lamotrigine; lidocaine; topiramate; trigeminal autonomic cephalalgia; triggers", "medline_ta": "Cephalalgia", "mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000700:Analgesics; D000927:Anticonvulsants; D018592:Cross-Over Studies; D005260:Female; D005500:Follow-Up Studies; D000077206:Gabapentin; D006261:Headache; D006801:Humans; D000077213:Lamotrigine; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D050798:SUNCT Syndrome; D000077236:Topiramate; D016896:Treatment Outcome; D055815:Young Adult", "nlm_unique_id": "8200710", "other_id": null, "pages": "1554-1563", "pmc": null, "pmid": "29096522", "pubdate": "2018-08", "publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't", "references": "26453658;25501956;10027765;15888539;20558416;16905753;1647496;12058109;18644028;24842632;15356289;2743414;10554000;2027500;25767102;18252775;1097222;12453028;16527404;20956404;15910571;25231219;8666537;1603361;23771276;16987158;11971110;1620353;22049203;11342697;14984234;11701590;23197348;8496062;12603293;19996400;26423473;25541189;14617728", "title": "Phenotypic and treatment outcome data on SUNCT and SUNA, including a randomised placebo-controlled trial.", "title_normalized": "phenotypic and treatment outcome data on sunct and suna including a randomised placebo controlled trial" }

[ { "companynumb": "TW-MYLANLABS-2018M1069661", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TOPIRAMATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "076314", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "12.5 MG/AT NIGHT; THE DOSE WAS INCREMENTED EVERY FIVE DAYS", "drugenddate": null, "drugenddateformat": null, "drugindication": "SUNCT SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "12.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOPIRAMATE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TOPIRAMATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "076314", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG/MAXIMUM DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOPIRAMATE." } ], "patientagegroup": null, "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "SUNCT syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WENG H-Y, COHEN AS, SCHANKIN C, GOADSBY PJ. PHENOTYPIC AND TREATMENT OUTCOME DATA ON SUNCT AND SUNA, INCLUDING A RANDOMISED PLACEBO-CONTROLLED TRIAL. CEPHALALGIA 2018?38(9):1554-1563.", "literaturereference_normalized": "phenotypic and treatment outcome data on sunct and suna including a randomised placebo controlled trial", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "TW", "receiptdate": "20181001", "receivedate": "20181001", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15451308, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190204" } ]

{ "abstract": "Therapy-related myelodysplasticsyndrome(t-MDS)has been reported to occur after treatment with cytotoxic agents and radiation. Here, we report a case of t-MDS following oxaliplatin(L-OHP)exposure, which was successfully treated with azacitidine(AZA). A 71-year-old man was referred to our department because of pancytopenia. He had been diagnosed with rectal cancer(cT4aNXM0, stage II B-III C, RAS gene status wild-type)3 years ago and had received 8 courses of capecitabine(CAP)and L-OHP(XELOX regimen), followed by 48 courses of CAP and bevacizumab. Before referral, recurrence of rectal cancer was detected using CT after the last course of chemotherapy. A bone marrow examination revealed multilineage dysplasia and 9.0%myeloblasts. Cytogenetic analysis disclosed a chromosome 7 abnormality. The diagnosis of t- MDS was made and treatment with AZA was initiated. Subsequently, temporary but significant hematological improvements were observed, which enabled the patient to receive additional palliative radiation therapy against the locally relapsed rectal cancer. AZA might be useful in t-MDS because of its efficacy and low toxicity.", "affiliations": "Dept. of Oncology, Japan Labour Health and Welfare Organization Kanto Rosai Hospital.", "authors": "Matsui|Tomoharu|T|;Sakamoto|Nami|N|;Doi|Ayako|A|;Fujii|Tomoki|T|;Ohno|Nobuhiro|N|;Sahara|Naohi|N|;Irie|Seiji|S|", "chemical_list": "D000964:Antimetabolites, Antineoplastic; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D001374:Azacitidine; D002955:Leucovorin", "country": "Japan", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0385-0684", "issue": "45(8)", "journal": "Gan to kagaku ryoho. Cancer & chemotherapy", "keywords": null, "medline_ta": "Gan To Kagaku Ryoho", "mesh_terms": "D000368:Aged; D000964:Antimetabolites, Antineoplastic; D001374:Azacitidine; D003131:Combined Modality Therapy; D017809:Fatal Outcome; D006801:Humans; D002955:Leucovorin; D008297:Male; D009190:Myelodysplastic Syndromes; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D012004:Rectal Neoplasms", "nlm_unique_id": "7810034", "other_id": null, "pages": "1201-1203", "pmc": null, "pmid": "30158420", "pubdate": "2018-08", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Azacitidine for Therapy-Related Myelodysplastic Syndrome Following Oxaliplatin (L-OHP)Therapy for Metastatic Rectal Cancer.", "title_normalized": "azacitidine for therapy related myelodysplastic syndrome following oxaliplatin l ohp therapy for metastatic rectal cancer" }

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METER,DAYS 1-4; EVERY FOUR WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE MYELOID LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACLARUBICIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "AZACITIDINE" }, "drugadditional": "2", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "D75 MILLIGRAM(S)/SQ. METER ,DAY 1-7 OF EVERY 4 WEEKS CYCLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYELODYSPLASTIC SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZACITIDINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": "2", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM(S)/SQ. METER,DAYS 1-13", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE MYELOID LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." } ], "patientagegroup": null, "patientonsetage": "71", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bone marrow failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Acute myeloid leukaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "MATSUI T, SAKAMOTO N, DOI A, FUJII T, OHNO N, SAHARA N, ET AL.. AZACITIDINE FOR THERAPY-RELATED MYELODYSPLASTIC SYNDROME FOLLOWING OXALIPLATIN (L-OHP)THERAPY FOR METASTATIC RECTAL CANCER.. GAN-TO-KAGAKU-RYOHO. 2018?45(8):1201-1203.", "literaturereference_normalized": "azacitidine for therapy related myelodysplastic syndrome following oxaliplatin l ohp therapy for metastatic rectal cancer", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20181204", "receivedate": "20181128", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15666077, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "JP-SA-2018SA259049", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021759", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTASES TO ADRENALS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021759", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "COLORECTAL CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN." } ], "patientagegroup": "6", "patientonsetage": "71", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Acute myeloid leukaemia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Bone marrow failure", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "MATSUI T., SAKAMOTO N., DOI A., FUJII T., OHNO N., SAHARA N. ET AL.. AZACITIDINE FOR THERAPY?RELATED MYELODYSPLASTIC SYNDROME FOLLOWING OXALIPLATIN (L?OHP)THERAPY FOR METASTATIC RECTAL CANCER. GAN TO KAGAKU RYOHO. 2018?45(8):1201?1203", "literaturereference_normalized": "azacitidine for therapy related myelodysplastic syndrome following oxaliplatin l ohp therapy for metastatic rectal cancer", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20180919", "receivedate": "20180919", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15404269, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20181010" }, { "companynumb": "JP-TEVA-2018-JP-980154", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "CAPECITABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "8 COURSES; TREATMENT COMPLETED; XELOX REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "RECTAL CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CAPECITABINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "022160", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "8 COURSES; TREATMENT COMPLETED; XELOX REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "RECTAL CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN (L-OHP)" } ], "patientagegroup": null, "patientonsetage": "71", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Myeloid leukaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Bone marrow failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "MATSUI T, SAKAMOTO N, DOI A, FUJII T, OHNO N, SAHARA N, ET AL. AZACITIDINE FOR THERAPY-RELATED MYELODYSPLASTIC SYNDROME FOLLOWING OXALIPLATIN (L-OHP)THERAPY FOR METASTATIC RECTAL CANCER. GAN-TO-KAGAKU-RYOHO 2018?45(8):1201-1203.", "literaturereference_normalized": "azacitidine for therapy related myelodysplastic syndrome following oxaliplatin l ohp therapy for metastatic rectal cancer", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190115", "receivedate": "20181129", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15668852, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "PHHY2018JP157914", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CAPECITABINE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "RECTAL CANCER METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CAPECITABINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "78817", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "RECTAL CANCER METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "BEVACIZUMAB" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "RECTAL CANCER METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BEVACIZUMAB." } ], "patientagegroup": null, "patientonsetage": "71", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Metastases to adrenals", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dysplasia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Metastases to peritoneum", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rectal cancer metastatic", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Malignant neoplasm progression", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pancytopenia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MATSUI T, SAKAMOTO N, DOI A,FUJII T, OHNO N, SAHARA N ET AL.. AZACITIDINE FOR THERAPY-RELATED MYELODYSPLASTIC SYNDROME FOLLOWING OXALIPLATIN (L-OHP) THERAPY FOR METASTATIC RECTAL CANCER. JAPANESE JOURNAL OF CANCER AND CHEMOTHERAPY. 201/?45(8):1201-3", "literaturereference_normalized": "azacitidine for therapy related myelodysplastic syndrome following oxaliplatin l ohp therapy for metastatic rectal cancer", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20181121", "receivedate": "20181121", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15645755, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2018RR-192151", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "202922", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "COLORECTAL CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN." } ], "patientagegroup": null, "patientonsetage": "71", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MATSUI T, SAKAMOTO N, DOI A, FUJII T, OHNO N, SAHARA N, ET AL. AZACITIDINE FOR THERAPY-RELATED MYELODYSPLASTIC SYNDROME FOLLOWING OXALIPLATIN (L-OHP) THERAPY FOR METASTATIC RECTAL CANCER. JPN J CANCER CHEMOTHER. 2018?AUG? 45(8):1201-1203", "literaturereference_normalized": "azacitidine for therapy related myelodysplastic syndrome following oxaliplatin l ohp therapy for metastatic rectal cancer", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20181128", "receivedate": "20181128", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15663585, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "JP-PFIZER INC-2018356459", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "CAPECITABINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK (48 COURSES)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CAPECITABINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BEVACIZUMAB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK (48 COURSES)", "drugenddate": null, "drugenddateformat": null, "drugindication": "RECTAL CANCER STAGE II", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BEVACIZUMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "078813", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK (8 COURSES)", "drugenddate": null, "drugenddateformat": null, "drugindication": "RECTAL CANCER STAGE II", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CAPECITABINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK (8 COURSES)", "drugenddate": null, "drugenddateformat": null, "drugindication": "RECTAL CANCER STAGE II", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CAPECITABINE." } ], "patientagegroup": null, "patientonsetage": "71", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Second primary malignancy", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "MATSUI, T.. AZACITIDINE FOR THERAPY?RELATED MYELODYSPLASTIC SYNDROME FOLLOWING OXALIPLATIN (L?OHP) THERAPY FOR METASTATIC RECTAL CANCER. GAN TO KAGAKU RYOHO [JAPANESE JOURNAL OF CANCER + CHEMOTHERAPY]. 2018?45 (8):1201?1203", "literaturereference_normalized": "azacitidine for therapy related myelodysplastic syndrome following oxaliplatin l ohp therapy for metastatic rectal cancer", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20180920", "receivedate": "20180906", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15357681, "safetyreportversion": 4, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" } ]

{ "abstract": "BACKGROUND\nStandard-of-care antiretroviral therapy (ART) uses a combination of drugs deemed essential to minimise treatment failure and drug resistance. Protease inhibitors are potent, with a high genetic barrier to resistance, and have potential use as monotherapy after viral load suppression is achieved with combination treatment. We aimed to assess clinical risks and benefits of protease inhibitor monotherapy in long-term clinical use: in particular, the effect on drug resistance and future treatment options.\n\n\nMETHODS\nIn this pragmatic, parallel-group, randomised, controlled, open-label, non-inferiority trial, we enrolled adults (≥18 years of age) positive for HIV attending 43 public sector treatment centres in the UK who had suppressed viral load (<50 copies per mL) for at least 24 weeks on combination ART with no change in the previous 12 weeks and a CD4 count of more than 100 cells per μL. Participants were randomly allocated (1:1) to maintain ongoing triple therapy (OT) or to switch to a strategy of physician-selected ritonavir-boosted protease inhibitor monotherapy (PI-mono); we recommended ritonavir (100 mg)-boosted darunavir (800 mg) once daily or ritonavir (100 mg)-boosted lopinavir (400 mg) twice daily, with prompt return to combination treatment if viral load rebounded. All treatments were oral. Randomisation was with permuted blocks of varying size and stratified by centre and baseline ART; we used a computer-generated, sequentially numbered randomisation list. The primary outcome was loss of future drug options, defined as new intermediate-level or high-level resistance to one or more drugs to which the patient's virus was deemed sensitive at trial entry (assessed at 3 years; non-inferiority margin of 10%). We estimated probability of rebound and resistance with Kaplan-Meier analysis. Analyses were by intention to treat. This trial is registered with the International Standard Randomised Controlled Trial Number registry, number ISRCTN04857074.\n\n\nRESULTS\nBetween Nov 4, 2008, and July 28, 2010, we randomly allocated 587 participants to OT (291) or PI-mono (296). At 3 years, one or more future drug options had been lost in two participants (Kaplan-Meier estimate 0·7%) in the OT group and six (2·1%) in the PI-mono group: difference 1·4% (-0·4 to 3·4); non-inferiority shown. 49 (16·8%) participants in the OT group and 65 (22·0%) in the PI-mono group had grade 3 or 4 clinical adverse events (difference 5·1% [95% CI -1·3 to 11·5]; p=0·12); 45 (six treatment related) and 56 (three treatment related) had serious adverse events.\n\n\nCONCLUSIONS\nProtease inhibitor monotherapy, with regular viral load monitoring and prompt reintroduction of combination treatment for rebound, preserved future treatment options and did not change overall clinical outcomes or frequency of toxic effects. Protease inhibitor monotherapy is an acceptable alternative for long-term clinical management of HIV infection.\n\n\nBACKGROUND\nNational Institute for Health Research.", "affiliations": "Medical Research Council Clinical Trials Unit at University College London, London, UK; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Electronic address: [email protected].;Medical Research Council Clinical Trials Unit at University College London, London, UK.;Medical Research Council Clinical Trials Unit at University College London, London, UK.;Brighton and Sussex University Hospitals NHS Trust, Brighton, UK.;Research Department of Infection and Population Health, University College London, London, UK.;Royal Free Hospital, London, UK.;Barts and the Royal London Hospital NHS Trust, London, UK.;Royal Berkshire Hospital, Reading, UK.;Manchester Royal Infirmary, Manchester, UK.;St Mary's Hospital, London, UK.;Southmead Hospital, Bristol, UK.;Guy's and St Thomas' Hospital, London, UK.;Medical Research Council Clinical Trials Unit at University College London, London, UK.;Medical Research Council Clinical Trials Unit at University College London, London, UK.", "authors": "Paton|Nicholas I|NI|;Stöhr|Wolfgang|W|;Arenas-Pinto|Alejandro|A|;Fisher|Martin|M|;Williams|Ian|I|;Johnson|Margaret|M|;Orkin|Chloe|C|;Chen|Fabian|F|;Lee|Vincent|V|;Winston|Alan|A|;Gompels|Mark|M|;Fox|Julie|J|;Scott|Karen|K|;Dunn|David T|DT|;|||", "chemical_list": "D017320:HIV Protease Inhibitors", "country": "Netherlands", "delete": false, "doi": null, "fulltext": "\n==== Front\nLancet HIVLancet HIVThe Lancet. HIV2352-3018Elsevier B.V S2352-3018(15)00176-910.1016/S2352-3018(15)00176-9ArticlesProtease inhibitor monotherapy for long-term management of HIV infection: a randomised, controlled, open-label, non-inferiority trial Paton Nicholas I [email protected]*Stöhr Wolfgang PhDaArenas-Pinto Alejandro PhDaFisher Martin ProfMBBScWilliams Ian FRCPdJohnson Margaret ProfFRCPeOrkin Chloe MBBChfChen Fabian FRCPgLee Vincent MBChBhWinston Alan MDiGompels Mark MBBSjFox Julie MDkScott Karen BAaDunn David T ProfPhDafor the Protease Inhibitor Monotherapy Versus Ongoing Triple Therapy (PIVOT) Trial Team†a Medical Research Council Clinical Trials Unit at University College London, London, UKb Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singaporec Brighton and Sussex University Hospitals NHS Trust, Brighton, UKd Research Department of Infection and Population Health, University College London, London, UKe Royal Free Hospital, London, UKf Barts and the Royal London Hospital NHS Trust, London, UKg Royal Berkshire Hospital, Reading, UKh Manchester Royal Infirmary, Manchester, UKi St Mary's Hospital, London, UKj Southmead Hospital, Bristol, UKk Guy's and St Thomas' Hospital, London, UK* Correspondence to: Prof Nicholas I Paton, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228Correspondence to: Prof Nicholas I PatonDepartment of MedicineYong Loo Lin School of MedicineNational University of SingaporeSingapore119228 [email protected]† Members listed at end of paper\n\n14 9 2015 10 2015 14 9 2015 2 10 e417 e426 © 2015 Paton et al. Open Access article published under the terms of CC BY2015This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Summary\nBackground\nStandard-of-care antiretroviral therapy (ART) uses a combination of drugs deemed essential to minimise treatment failure and drug resistance. Protease inhibitors are potent, with a high genetic barrier to resistance, and have potential use as monotherapy after viral load suppression is achieved with combination treatment. We aimed to assess clinical risks and benefits of protease inhibitor monotherapy in long-term clinical use: in particular, the effect on drug resistance and future treatment options.\n\nMethods\nIn this pragmatic, parallel-group, randomised, controlled, open-label, non-inferiority trial, we enrolled adults (≥18 years of age) positive for HIV attending 43 public sector treatment centres in the UK who had suppressed viral load (<50 copies per mL) for at least 24 weeks on combination ART with no change in the previous 12 weeks and a CD4 count of more than 100 cells per μL. Participants were randomly allocated (1:1) to maintain ongoing triple therapy (OT) or to switch to a strategy of physician-selected ritonavir-boosted protease inhibitor monotherapy (PI-mono); we recommended ritonavir (100 mg)-boosted darunavir (800 mg) once daily or ritonavir (100 mg)-boosted lopinavir (400 mg) twice daily, with prompt return to combination treatment if viral load rebounded. All treatments were oral. Randomisation was with permuted blocks of varying size and stratified by centre and baseline ART; we used a computer-generated, sequentially numbered randomisation list. The primary outcome was loss of future drug options, defined as new intermediate-level or high-level resistance to one or more drugs to which the patient's virus was deemed sensitive at trial entry (assessed at 3 years; non-inferiority margin of 10%). We estimated probability of rebound and resistance with Kaplan-Meier analysis. Analyses were by intention to treat. This trial is registered with the International Standard Randomised Controlled Trial Number registry, number ISRCTN04857074.\n\nFindings\nBetween Nov 4, 2008, and July 28, 2010, we randomly allocated 587 participants to OT (291) or PI-mono (296). At 3 years, one or more future drug options had been lost in two participants (Kaplan-Meier estimate 0·7%) in the OT group and six (2·1%) in the PI-mono group: difference 1·4% (−0·4 to 3·4); non-inferiority shown. 49 (16·8%) participants in the OT group and 65 (22·0%) in the PI-mono group had grade 3 or 4 clinical adverse events (difference 5·1% [95% CI −1·3 to 11·5]; p=0·12); 45 (six treatment related) and 56 (three treatment related) had serious adverse events.\n\nInterpretation\nProtease inhibitor monotherapy, with regular viral load monitoring and prompt reintroduction of combination treatment for rebound, preserved future treatment options and did not change overall clinical outcomes or frequency of toxic effects. Protease inhibitor monotherapy is an acceptable alternative for long-term clinical management of HIV infection.\n\nFunding\nNational Institute for Health Research.\n==== Body\nIntroduction\nCurrent HIV treatment guidelines recommend a combination of two drug classes for initiation and maintenance of antiretroviral therapy (ART).1, 2 The principle of combining drugs with different mechanisms of action to increase potency and reduce selection of drug-resistant mutants is common to the treatment of many infectious diseases. However, in HIV, the need for combination treatment might decrease once viral load has been suppressed.\n\nProtease inhibitors are potent, with a high genetic barrier to resistance, and are the only drugs that act at many steps of the HIV lifecycle, thus having potential for use alone as monotherapy.3 Protease inhibitor monotherapy could be an attractive therapeutic option because of its potential to reduce renal, CNS, and other toxic effects associated with drugs widely used in standard ART combinations. The high genetic barrier to resistance might reduce the risk of resistance during periods of suboptimum treatment adherence. Furthermore, use of a single drug might decrease treatment costs. Although inadequate for initial treatment,4 findings from previous randomised trials of maintenance protease inhibitor monotherapy5, 6, 7, 8, 9 have shown high levels of short-term viral load suppression. However, these trials have not been of sufficient size and duration to address definitively the effects on long-term drug resistance, clinical disease progression, and drug toxic effects in clinical practice.5, 6, 7, 8, 9 Furthermore, investigators have mostly restricted the standard-of-care treatment to a specific protease inhibitor regimen and mandated use of a particular protease inhibitor for monotherapy, neither of which takes account of the diversity of regimen selection in routine clinical practice.\n\nResearch in context\nEvidence before this study\n\nWe searched PubMed for reports published between Jan 1, 1998, and Jan 1, 2008, with no language restrictions, using terms including “protease inhibitors”, “monotherapy”, and the individual drug names, and reviewed relevant HIV conference abstracts to identify randomised controlled trials that compared protease inhibitor monotherapy with triple antiretroviral therapy (ART) in patients who had previously achieved viral load suppression. We identified three trials, all investigating lopinavir monotherapy, and, overall, these trials supported the hypothesis of virological non-inferiority of monotherapy to triple therapy. Since then, authors of a meta-analysis of ten trials noted an overall risk ratio of 0·94 for viral load suppression at 48 weeks with protease inhibitor monotherapy compared with triple ART, with, at most, a 13% increase in the absolute risk of virological failure with protease inhibitor monotherapy.\n\nAdded value of this study\n\nTo our knowledge, this trial is the largest and longest-duration protease inhibitor monotherapy trial done so far, with more than three times the randomly allocated person follow-up time of previous trials, and thus it provides more precise estimates of important but uncommon efficacy and safety outcomes than did previous trials. By contrast with previous studies that restricted the choice of drugs in both the monotherapy (single specified protease inhibitor) and combination ART (usually to a protease-inhibitor-containing combination, and with the same protease inhibitor as specified for monotherapy) groups, this trial used a pragmatic design representative of routine clinical care, with flexibility of drug selection in both treatment groups. Also, whereas previous trials compared predefined regimens with short-term viral load endpoints, this trial compared treatment strategies with a primary efficacy endpoint (preservation of drug options) relevant to long-term clinical management. In this trial we noted an increase of about 32% in absolute risk of virological failure with protease inhibitor monotherapy (much greater than that previously reported), but all patients with rebound resuppressed spontaneously or with reintroduction of combination ART. Findings from this trial showed that the protease inhibitor monotherapy strategy was non-inferior to triple ART in preservation of future treatment options and did not change overall clinical outcomes or frequency of toxic effects.\n\nImplications of all the available evidence\n\nProtease inhibitor monotherapy does not increase the risk of drug resistance and is an acceptable alternative for long-term clinical management of HIV infection. Clinical benefits, if any, seem slight, and some patients might need to switch back to combination ART. Nevertheless, this approach could appeal to patients who are stable on treatment but who wish to minimise their exposure to specific drugs or more than one drug class.\n\n\n\nWe did a pragmatic randomised controlled trial comparing a protease inhibitor monotherapy treatment strategy with clinician-selected standard combination treatment, aiming to assess effects on drug resistance, future treatment options, and other, long-term, clinically relevant outcomes.\n\nMethods\nStudy design and patients\nIn this pragmatic, parallel-group, randomised, controlled, open-label, non-inferiority trial, we enrolled participants attending 43 public sector hospital-based HIV treatment centres in the UK. Eligible participants were adults aged 18 years or older who were HIV positive, had been on ART consisting of two nucleoside reverse transcriptase inhibitors (NRTIs) and one non-NRTI (NNRTI) or protease inhibitor for at least 24 weeks with no change in the previous 12 weeks, had a viral load of less than 50 copies per mL at screening and for at least 24 weeks before screening (one blip to less than 200 copies per mL allowed during this period if followed by at least two results less than 50 copies per mL), had a CD4 count of more than 100 cells per μL at screening, and who were willing to continue current ART or change according to the randomised allocation. Exclusion criteria were known major protease inhibitor resistance mutations at previous resistance testing (if done; not mandated), previous ART change for unsatisfactory virological response (ie, slow initial virological suppression, incomplete suppression, or rebound; change for convenience or toxic effect prevention or management allowed), protease inhibitor allergy, concomitant drugs with protease inhibitor interactions, present or anticipated need for radiotherapy or cytotoxic chemotherapy, treatment for acute opportunistic infection within the previous 3 months, present or planned pregnancy, active substance misuse or psychiatric illness, history of HIV encephalopathy with a present deficit of more than 1 in any domain of the Neuropsychiatric AIDS Rating Scale,10, 11 history of cardiovascular disease or a 10 year absolute coronary heart disease risk of more than 30% or more than 20% with diabetes or a family history of premature ischaemic heart disease or stroke,12 insulin-dependent diabetes mellitus, active or planned hepatitis C virus treatment, hepatitis B surface antigen positive at screening or since HIV diagnosis (unless hepatitis B DNA of less than 1000 copies per mL taken while off drugs active against hepatitis B), or a fasting plasma glucose of more than 7·0 mmol/L at screening.\n\nThe protocol was approved by the Cambridgeshire 4 Research Ethics Committee and Medicines and Healthcare Products Regulatory Agency. All participants provided written informed consent.\n\nRandomisation and masking\nParticipants were randomly assigned (1:1) to maintain ongoing triple therapy (OT) or switch to a protease inhibitor monotherapy strategy (PI-mono). Randomisation was stratified by centre (nine groups, based on the eight largest sites and one group for the remaining sites) and baseline ART regimen (protease inhibitor or NNRTI). The computer-generated, sequentially numbered randomisation list (random permuted blocks of varying size) was preprepared by WS. Sites faxed screening forms to the trial coordinating centre, where trial staff confirmed eligibility and did the randomisation (they could access the next number on the list, but not the whole list). Treatment allocation was open label.\n\nProcedures\nIn the OT group, we managed patients using triple combination treatment. In the PI-mono group, we switched patients to a single ritonavir-boosted protease inhibitor selected by the physician: we recommended darunavir (800 mg) boosted with ritonavir (100 mg) once daily or lopinavir (400 mg) boosted with ritonavir (100 mg) twice daily. Drugs were taken orally. Patients switching from NNRTI-based regimens continued NRTIs for the first 2 weeks. Protease inhibitor substitution was allowed in the event of toxic effects or for convenience. The strategy required prompt reintroduction of NRTIs (switch of protease inhibitor to NNRTI optional) for protocol-defined confirmed viral load rebound and management with combination treatment for the remainder of the trial (subsequent switches for toxic effects, convenience, and viral load failure allowed, as in OT group).\n\nStudy visits at baseline, weeks 4 and 8 (PI-mono group only), week 12, and every 12 weeks thereafter included assessment of clinical status, drug adherence (standardised questions), viral load, CD4 cell count, and safety blood tests (measured at site laboratory). Visits at baseline, week 12, week 48, and every 48 weeks thereafter included additional assessments of cardiovascular disease risk (Framingham equation),13 neurocognitive function (standard five-test battery),14, 15 symptomatic peripheral neuropathy (Brief Peripheral Neuropathy Screen),16 and quality of life (self-completed Medical Outcomes Study HIV Health Survey questionnaire17, 18). We classified clinical and laboratory events with protocol-defined diagnostic criteria (on the basis of Centers for Disease Control and Prevention criteria for AIDS,19 INSIGHT criteria for serious non-AIDS events,20 and Division of AIDS criteria for adverse events21), and an independent physician at the coordinating centre reviewed them. We calculated estimated glomerular filtration rate (eGFR) with the Chronic Kidney Disease Epidemiology Collaboration equation.22\n\nIf viral load was detectable at 50 copies per mL or higher at any visit, we repeated the test (on the same sample if available or a fresh sample draw if not). If viral load was less than 50 copies per mL on the repeat test, we continued routine follow-up, but if higher, we did adherence counselling and patients returned for a confirmatory test at least 4 weeks from the date that the first sample was taken. If viral load was less than 50 copies per mL with the confirmatory test, we resumed routine follow-up, but if higher (ie, on the third consecutive test), this result met the protocol definition of confirmed rebound and so the patient was required to change treatment, and we did a repeat test 4 weeks later.\n\nWe did genotypic resistance testing on all viral load rebound samples that were confirmed or preceded treatment switch. We did genotypic testing at site laboratories, repeated at the central laboratory if local sequencing was unsuccessful. We used the Stanford algorithm for drug susceptibility prediction. If we identified resistance mutations, we compared them with any genotypic testing reports from before the trial.\n\nOutcomes\nThe primary outcome was loss of future drug options, defined as new intermediate-level or high-level resistance to one or more drugs in contemporary use to which we deemed patient's virus to be sensitive at trial entry (assessed at 3 years). We defined contemporary use on the basis of inclusion in present UK treatment guidelines,1 with saquinavir added because this drug was taken by some participants during the trial.\n\nSecondary outcomes were occurrence of serious drug-related or disease-related complications, including death or serious AIDS-defining (excluding oesophageal candidiasis or chronic mucocutaneous herpes simplex virus infection) or non-AIDS-defining illness; total number of grade 3 and 4 adverse events; confirmed virological rebound; CD4 cell count change from baseline; neurocognitive function change from baseline; cardiovascular risk change from baseline; and health-related quality of life change from baseline (mental and physical health summary scores). Additional specified safety outcomes were facial lipoatrophy, abdominal fat accumulation, peripheral neuropathy, and estimated glomerular filtration rate.\n\nStatistical analysis\nWe defined non-inferiority of the PI-mono group by the upper limit of the two-sided 95% CI for the difference in proportions of patients who maintain all future drug options during 3 years (OT group minus the PI-mono group) being less than 10%. We chose the 10% non-inferiority margin on the basis of US Food and Drug Administration guidance 23, 24 and with reference to other protease inhibitor monotherapy trials.9 Using a survival analysis approach (on a hazard ratio scale) to allow inclusion of all follow-up data for estimation of the primary endpoint, and assuming that 97% of patients in the OT group would meet the primary endpoint,7, 25, 26 with an 85% power and a 10% loss to follow-up, we estimated that about 280 patients per group would be needed to show non-inferiority. This approach gives a conservative estimate of the sample size, which has the additional advantage of allowing precise estimates of important secondary safety outcomes. On the basis of a conventional analysis of proportions, the power of the study to show non-inferiority for the primary endpoint with use of the same parameters would be more than 99%.\n\nAll comparisons were as randomised (intention to treat). We deemed a per-protocol analysis not relevant for this pragmatic trial in view of the fact that a switch back to combination treatment in the PI-mono group was an intrinsic element of the clinical strategy being assessed. Statistical tests are two-sided and test the hypotheses of no difference between randomised groups. We estimated the absolute difference between groups in reduction of future drug options using Kaplan-Meier analysis, with the 95% CI (two-sided) derived with bootstrap methods. In this analysis and other time-to-event analyses, we censored participants at the time of death, loss to follow-up, or withdrawal. The primary analysis included all new resistance mutations noted that conferred intermediate-level or high-level drug resistance. We predefined a sensitivity analysis in which we restricted loss of drug options to classes to which the patient was exposed during the trial, thus excluding mutations that were probably archived (ie, acquired at transmission or during treatment before enrolment, but unknown at trial entry).\n\nFor secondary endpoints, we compared binary outcome variables between groups using χ2 or Fisher's exact tests, with conventional or Agresti-Caffo 95% CIs for the risk difference and logistic regression models for adjusted analyses. For continuous variables, we compared groups by use of mean change from baseline and t tests or linear regression; we estimated change from baseline to the last available visit at which a measurement was done at or after week 144 (we did not include patients without such data). We estimated the proportion of patients who had viral load rebound with Kaplan-Meier analysis and compared groups by use of a log-rank test. We compared incidence rates with Poisson regression. We compared adherence during the entire follow-up period between groups with generalised estimating equations (independent correlation structure; binomial distribution).\n\nWe used Stata version 12.1 for all analyses. A data monitoring committee reviewed interim data annually. This trial is registered with the International Standard Randomised Controlled Trial Number registry, number ISRCTN04857074.\n\nRole of the funding source\nThe funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.\n\nResults\nBetween Nov 4, 2008, and July 28, 2010, we randomly allocated 587 participants to OT (291) or PI-mono (296; figure 1). One (<1%) died and 11 (4%) withdrew or were lost to follow-up in the OT group, whereas six (2%) died and five (2%) withdrew or were lost to follow-up in the PI-mono group. Study visits ended on Nov 1, 2013. The median duration of trial follow-up was 44 months (maximum 59 months). Participant characteristics were similar between groups (table 1).\n\nIn the PI-mono group, initial drug choices were darunavir in 233 (80%) of patients, lopinavir in 40 (14%), atazanavir in 16 (6%), and saquinavir in 1 (<1%); 58% were still taking monotherapy at trial end. Combination treatment was reintroduced for the following reasons: 69 (23%) for protocol-defined confirmed viral rebound (appendix p 8), 11 (4%) for viral rebound not meeting protocol criteria, 16 (5%) for toxic effects, and 22 (7%) for other or unknown reasons; 6 (2%) never started monotherapy. Overall, 72% of follow-up time was spent on monotherapy. Self-reported adherence to study drugs was high: participants reported not missing any ART doses in the past 2 weeks at 4301 (93%) of 4635 visits in the OT group and 4376 (92%) of 4748 visits in the PI-mono group (p=0·52).\n\nThe number of patients with loss of future drug options at 3 years (the primary outcome) was two patients (Kaplan-Meier estimate 0·7%) in the OT group and six (2·1%) in the PI-mono group (difference 1·4% [95% CI −0·4 to 3·4]), therefore meeting the non-inferiority criterion. PI-mono was also non-inferior with prespecified analyses of loss of future drug options during the full trial follow-up period (OT 1·8%; PI-mono 2·1%; difference 0·2% [–2·5% to 2·6]) and loss of future drug options during the full trial period but excluding mutations that were probably archived (OT 1·5%; PI-mono 1·0%; difference −0·4% [–2·9% to 1·4%]). One (<1%) participant on atazanavir monotherapy developed the Ile50Leu mutation (as a mixture with wild-type), conferring predicted high-level atazanavir resistance. We detected an isolated Leu90Met mutation in two (<1%) patients on darunavir monotherapy; both resuppressed with reintroduction of NRTIs. This mutation, possibly archived, does not affect darunavir sensitivity, but confers resistance to saquinavir and thus meets the endpoint definition. Three (1%) patients in the PI-mono group had NRTI or NNRTI mutations detected, probably archived from previous treatment. In the OT group, three (1%) patients had loss of future drug options to drug classes that they were taking and one (<1%) taking a protease-inhibitor-based regimen had NNRTI mutations that were probably archived (table 2; appendix p 2–3).\n\nWe noted one or more episodes of confirmed viral load rebound in eight (Kaplan-Meier estimate 3·2%) patients in the OT group and 95 (35·0%) in the PI-mono group during all follow-up: absolute risk difference 31·8% (95% CI 24·6–39·0; p<0·0001). Rebound while actually on monotherapy (occurred in 93 patients) was more common in the first year (24 per 100 person-years) than in subsequent years (six per 100 person-years; figure 2). Findings were similar with use of an extended definition of viral load rebound (appendix, p 9) and across the different protease inhibitors used as monotherapy. The median peak viral load at first episode of rebound on monotherapy was 526 copies per mL (peak was less than 400 copies per mL in 39 [42%] of 93 patients); of the 91 (98%) patients with subsequent tests available, 22 (24%) had resuppressed spontaneously and 69 (76%) resuppressed after changing ART: 47 (68%) by adding NRTIs only, 18 (26%) by adding NRTIs and changing the protease inhibitor to an NNRTI, two (3%) by changing the protease inhibitor monotherapy drug, and two (3%) other changes (appendix p 8). Viral load was resuppressed to less than 50 copies per mL after a median of 3·5 weeks (figure 2).\n\nWe noted no differences in serious drug-related or disease-related complications (death, AIDS, or serious non-AIDS) between groups (table 3). Causes of the one death in the OT group and six in the PI-mono group were diverse, and we did not deem any to be related to treatment strategy (appendix p 4). CD4 cell count increased similarly in both groups (table 3). Serious adverse events and clinical grade 3 and 4 adverse events did not differ between groups (table 3, appendix p 5–7). Fewer patients in the PI-mono group had a serum phosphate concentration of less than 0·65 mmol/L (p<0·0001, appendix p 6) and an eGFR of less than 60 mL/min per 1·73 m2 during follow-up (table 3). However, mean change in eGFR did not differ between groups (table 3), and only one case of end-stage renal failure occurred: a patient in the PI-mono group with pre-existing chronic renal impairment. Proportions of patients with symptomatic peripheral neuropathy, facial lipoatrophy, or abdominal fat accumulation during follow-up, and changes in neurocognitive function summary, cardiovascular disease risk, or quality of life summary scores did not differ between groups (table 3).\n\nDiscussion\nIn patients who have achieved viral load suppression with combination treatment, a maintenance strategy of protease inhibitor monotherapy, with reintroduction of combination treatment in the event of viral load rebound, was non-inferior to continuous combination treatment for preservation of future treatment options during 3–5 years. Furthermore, and perhaps more relevant than is non-inferiority for understanding of the clinical implications of this approach, the findings showed that the absolute number of patients who lost future drug options with protease inhibitor monotherapy was very low. Only one patient developed clinically significant resistance to a protease inhibitor taken as monotherapy, an Ile50Leu mutation with atazanavir monotherapy; clinical negative effects are mitigated by an increase in sensitivity to other protease inhibitors conferred by this mutation.27 None of the 277 patients taking darunavir or lopinavir (the recommended options for monotherapy in this trial, taken by almost all patients) developed resistance affecting their efficacy. The very low amount of resistance concurs with previous trials of monotherapy (and trials with protease-inhibitor-based combinations),5, 6, 7, 8, 9 but extend findings from these trials to provide the crucial long-term randomised outcome data from a large pragmatic trial needed to provide confidence in use of protease inhibitor monotherapy in clinical practice.\n\nWe sought resistance fastidiously, testing confirmed viral rebound samples irrespective of level of viraemia with standard population sequence genotypic testing. Although protease inhibitor resistance could occur in other regions of the virus, such as gag or env genes, or in minority species that are not detected by population assays,3 previous minority species sequencing in patients with viral rebound on monotherapy has shown only a small excess of resistance compared with that detected by population sequencing.28, 29 Furthermore, our finding that patients with viral load rebound in the PI-mono group, without exception, achieved full viral load suppression when switched to combination treatment (usually by reintroduction of NRTIs) provides an important assurance that any mutations that were not detected by population sequencing did not affect subsequent treatment efficacy. The follow-up period of 3–5 years, long for an HIV treatment trial, is sufficient to have confidence that preservation of treatment options is likely to be durable in the long term.\n\nA higher proportion of patients in the PI-mono group had viral rebound, as expected, although the difference was much greater than the 10–13% noted in a previous systematic review.9 Viral suppression is the traditional outcome variable for comparison of treatment regimens in clinical trials, but is less informative in long-term strategy trials such as this one, especially in view of the different effect of viral rebound on risk of drug resistance for different drug classes. Aside from risk of resistance (shown to be negligible in this study), these brief episodes of low-level viraemia, rapidly reversed by reintroduction of combination treatment, are unlikely to have adverse long-term clinical effects: much higher levels of viraemia are needed than those noted in this study to drive HIV disease progression,30 and CD4 cell count increases and total HIV disease-related clinical events were similar between the two groups. Risk of transmission to others arising from such short episodes of low-level viraemia is also likely to be negligible in view of the fact that transmission is exceedingly rare in patients with a low viral load, whether on or off ART.31, 32 Although more deaths occurred in the PI-mono group, the difference was not statistically significant and the causes were diverse, without a plausible link to the drugs taken or HIV disease progression. This finding is probably a chance imbalance, and follow-up of the cohort continues. Further analyses of predictive factors are planned that might enable identification of patients at low risk of rebound. However, selection factors are unlikely to be able to remove the excess risk entirely, and rebound and resuppression should be viewed as an integral part of the strategy for some patients. After the first year of suppression on monotherapy, the risk of rebound is much reduced, and this factor might increase acceptability for patients.\n\nWe noted fewer episodes of renal impairment in the PI-mono group as expected in view of the well-recognised renal toxic effects of NRTIs (especially tenofovir). However, the risk of serious drug toxic effects can be minimised by close laboratory monitoring and pre-emptive treatment changes, and no patients in the OT group developed end-stage renal disease.33 This pragmatic trial in which clinicians were allowed to switch drugs at clinical discretion (rather than being restricted to single-protocol-mandated regimens) provides a realistic estimate of the effect of protease inhibitor monotherapy in routine clinical practice, suggesting that benefits in terms of renal toxic effects would be small. We did not find any other clinical advantages of the monotherapy strategy. Treatment costs might be reduced, partly offset by increased monitoring costs, but considerations are complex, and detailed cost-effectiveness analyses will be reported in a separate paper.\n\nA concern with protease inhibitor monotherapy is that suboptimum drug penetration into the CNS might lead to harm.34, 35 However, we noted no difference in neurocognitive function between groups, nor any significant excess of neurological events in the PI-mono group. We used a small battery of neurocognitive tests (for feasibility in view of the large numbers of patients and repeated assessments), possibly less sensitive than a comprehensive neurocognitive assessment would be. Although we cannot rule out delayed effects on neurocognitive function or neurological events after longer periods on monotherapy than those in this study, the size and duration of our trial nevertheless provides reassurance that even if monotherapy were to have less brain penetration, this factor is unlikely to have important clinical negative effects.\n\nThe strengths of this trial are its size and duration (more than three times the randomly allocated person follow-up time of previous studies, allowing precise estimates of important but uncommon efficacy and safety outcomes); low withdrawal and loss-to-follow-up; pragmatic design set in routine clinical care, with flexibility in drug selection in both treatment groups; and use of a primary efficacy endpoint relevant to long-term management. The open-label design, a possible limitation, is unlikely to have affected detection of viral rebound or resistance (and hence the primary endpoint) because the protocol-mandated frequency of viral load testing was identical in the two groups (apart from two extra tests at weeks 4 and 8 in the monotherapy group), and we did resistance testing in everyone with viral rebound. Likewise, the open-label design is unlikely to have affected adverse event detection because the frequency of laboratory safety monitoring was standardised and adverse events were graded with standardised diagnostic criteria. Another possible limitation is the absence of before-treatment resistance tests that would help rule out resistance acquired before the trial. Although entry criteria were broad, patients entering this trial were established for years on a stable effective regimen, yet needed to be willing to change to an alternative regimen (in some cases adding new drugs with risk of side-effects or increased pill burden) if randomly allocated to do so. In view of the absence of any certainty of benefit, only a few eligible patients would therefore have been likely to be prepared to participate. Such motivated patients might have better outcomes (perhaps mediated by adherence) than the general clinic population would have, and this notion is consistent with the very low amount of rebound and resistance noted in the OT group. The main study finding that, despite high levels of viral load rebound, protease inhibitor monotherapy does not jeopardise future treatment options is likely to be generalisable internationally to settings where treatment is individualised and regular viral load monitoring done. However, protease inhibitor monotherapy is not appropriate for resource-limited settings delivering treatment without regular viral load monitoring.36\n\nProtease inhibitor monotherapy is an acceptable alternative to standard combination ART for long-term HIV management, with a slight benefit in terms of a reduction of renal toxic effects. The need for regular viral load monitoring and a possible switch back to combination treatment might be perceived as drawbacks, but this approach could nevertheless appeal to patients who are stable on treatment but wish to minimise their exposure to specific drugs or more than one drug class. Broadly, the trial challenges the notion that combination treatment is essential for management of chronic HIV infection.\n\nSupplementary Material\nSupplementary appendix\n \n\nAcknowledgments\nThis study was funded by the National Institute for Health Research Health Technology Assessment programme (project number 06/403/90). The views and opinions expressed herein are those of the authors and do not necessarily reflect those of the Health Technology Assessment programme, National Institute for Health Research, National Health Service, or the Department of Health. We thank all patients and staff from all the centres participating in the Protease Inhibitor Monotherapy Versus Ongoing Triple Therapy trial, and the UK Community Advisory Board and African Eye for community support.\n\nContributors\nNIP and DTD designed the study. AA-P, MF, IW, MJ, CO, FC, VL, AW, MG, and JF enrolled participants into the study. NIP, WS, AA-P, KS, and DTD coordinated and oversaw the study. WS and DTD did the statistical analysis. All authors interpreted data. NIP, WS, AA-P, and DTD drafted the report. All authors provided input into the report and approved the final version of the report.\n\nProtease Inhibitor Monotherapy Versus Ongoing Triple Therapy (PIVOT) Trial Team\nParticipating UK sites: M Fisher, A Clarke, W Hadley, D Stacey (Elton John Centre, Brighton). M Johnson, P Byrne (Royal Free Hospital, London). I Williams, N De Esteban, P Pellegrino, L Haddow, A Arenas-Pinto (Mortimer Market Centre, London). C Orkin, J Hand, C De Souza, L Murthen, A Crawford-Jones (Barts & the London Hospital, London). F Chen, R Wilson, E Green, J Masterson (Royal Berkshire Hospital, Reading). V Lee, K Patel, R Howe (Manchester Royal Infirmary, Manchester). A Winston, S Mullaney (St Mary's Hospital, London). M Gompels, L Jennings (Southmead Hospital, Bristol). N Beeching, R Tamaklo (Royal Liverpool University Hospital, Liverpool). J Fox, A Teague, I Jendrulek, J Tiraboschi (Guy's and St Thomas' Hospital, London). E Wilkins, Y Clowes, A Thompson (North Manchester General Hospital, Manchester). G Brook, M Trivedi (Central Middlesex Hospital, London). K Aderogba, M Jones (Avenue House Clinic, Eastbourne). A DeBurgh-Thomas, L Jones (Gloucester Royal Hospital, Gloucester). I Reeves, S Mguni (Homerton University Hospital, London). D Chadwick, P Spence, N Nkhoma (James Cook University Hospital, Middlesbrough). Z Warwick, S Price, S Read (Derriford Hospital, Plymouth). E Herieka, J Walker, R Woodward (Royal Bournemouth Hospital, Bournemouth). J Day, L Hilton (Southend University Hospital, Westcliff-on-Sea). V Harinda, H Blackman (St Mary's Hospital, Portsmouth). P Hay, W Mejewska, O Okolo (St George's Hospital, London). E Ong, K Martin, L Munro (Royal Victoria Infirmary, Newcastle). D Dockrell, L Smart (Royal Hallamshire Hospital, Sheffield). J Ainsworth, A Waters (North Middlesex University Hospital, London). S Kegg, S McNamara (Queen Elizabeth Hospital, Woolwich). S Taylor, G Gilleran (Birmingham Heartlands Hospital, Birmingham). B Gazzard, J Rowlands (Chelsea and Westminster Hospital, London). S Allan, R Sandhu (University Hospital of Coventry, Coventry). N O'Farrell, S Quaid (Ealing Hospital, London). F Martin, C Bennett (Harrogate District Hospital, Harrogate). M Kapembwa (Northwick Park Hospital, Harrow). J Minton, J Calderwood (St James' Hospital, Leeds). F Post, L Campbell, E Wandolo (King's College Hospital, London). A Palfreeman, L Mashonganyika (Leicester Royal Infirmary, Leicester). T Balachandran, M Kakowa (Luton and Dunstable Hospital, Luton). R O'Connell, C Tanawa (Newham University Hospital, London). S Jebakumar, L Hagger (Edith Cavell Hospital, Peterborough). S Quah, S McKernan (Royal Victoria Hospital, Belfast). C Lacey, S Douglas, S Russell-Sharpe, C Brewer (York Teaching Hospital, York). C Leen, S Morris (Western General Hospital, Edinburgh). S Obeyesekera, S Williams (Barking Hospital, London). N David (Norfolk and Norwich University Hospital, Norwich). M Roberts, J Wollaston (Worcester Royal Hospital, Worcester).\n\nMedical Research Council Clinical Trials Unit at University College London: N Paton, W Stöhr, A Arenas-Pinto, K Scott, D Dunn, E Beaumont, S Fleck, M Hall, S Hennings, I Kummeling, S Martins, E Owen-Powell, K Sanders, F van Hooff, L Vivas, E White.\n\nIndependent event reviewer: B Angus.\n\nTrial Steering Committee: A Freedman (chair), B Cromarty, D Mercey, S Fidler, E Torok, A Babiker, B Gazzard, C Orkin, N Paton.\n\nData Monitoring Committee: T Peto (chair), D Lalloo, A Phillips, R James.\n\nDeclaration of interests\nNIP, WS, KS, and DTD report grants from the National Institute of Health Research Health Technology Assessment programme during the conduct of this study. AA-P, MF, IW, MJ, CO, FC, VL, AW, MG, and JF report non-financial support from the UK Clinical Research Network during the conduct of this study. NIP reports grants, personal fees, and non-financial support from AbbVie and Janssen; personal fees and non-financial support from Merck and Roche; grants and non-financial support from GlaxoSmithKline; and non-financial support from Gilead Sciences, all outside the submitted work. AA-P reports grants from Janssen and ViiV Healthcare outside the submitted work. MF reports personal fees from AbbVie, Bristol-Myers Squibb, and Janssen; and grants and personal fees from Gilead Sciences, all outside the submitted work. IW reports grants and personal fees from Gilead Sciences; and grants from Pfizer, Merck Sharp & Dohme, and Bristol-Myers Squibb, all outside the submitted work. CO reports grants, personal fees, and non-financial support from Gilead Sciences, Janssen, ViiV Healthcare, and Bristol-Myers Squibb; and grants from Abbvie and Boehringer Ingelheim, all outside the submitted work. VL reports grants from Gilead Sciences, Merck Sharp & Dohme, ViiV Healthcare, Abbvie, Boehringer Ingelheim, and Janssen, all during the conduct of this study. AW reports honoraria or research grants from or engagement as a consultant or investigator in clinical trials sponsored by Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Janssen-Cilag, Roche, Pfizer, and ViiV Healthcare. MG reports speakers fees, meeting sponsorship, and educational grants from Bristol-Myers Squibb, Boehringer Ingelheim, and Janssen.\n\nFigure 1 Trial profile\n\nART=antiretroviral therapy. PI=protease inhibitor. NNRTI=non-nucleoside reverse transcriptase inhibitor. NRTI=nucleoside reverse transcriptase inhibitor. VL=viral load. *Six patients had more than one reason for ineligibility.\n\nFigure 2 Viral load rebound and resuppression\n\n(A) Time to viral rebound. (B) Time to viral resuppression after change of ART in the PI-mono group. The time to first viral load of less than 50 copies per mL (midpoint between last test 50 copies per mL or more and first test of less than 50 copies per mL) for patients at the time of first rebound who were taking protease inhibitor monotherapy (excluding two patients in the PI-mono group who rebounded while not on monotherapy) is shown. Outcomes by type of treatment switch are shown in the appendix (p 8). ART=antiretroviral therapy. HR=hazard ratio. OT=ongoing triple therapy. PI-mono=protease inhibitor monotherapy. VL=viral load.\n\nTable 1 Baseline characteristics\n\n\t\tOT (n=291)\tPI-mono (n=296)\tTotal (n=587)\t\nDemographic and clinical characteristics\t\nAge (years)\t43 (37–49, 23–75)\t45 (39–50, 23–67)\t44 (38–49, 23–75)\t\nRoute of infection\t\n\tHomosexual\t175 (60%)\t176 (59%)\t351 (60%)\t\n\tHeterosexual\t108 (37%)\t108 (36%)\t216 (37%)\t\n\tOther\t8 (3%)\t12 (4%)\t20 (3%)\t\nFemale\t64 (22%)\t73 (25%)\t137 (23%)\t\nEthnic origin\t\n\tWhite\t206 (71%)\t195 (66%)\t401 (68%)\t\n\tBlack\t73 (25%)\t90 (30%)\t163 (28%)\t\n\tOther\t12 (4%)\t11 (4%)\t23 (4%)\t\nHepatitis C virus antibody positive\t7 (2%)\t14 (5%)\t21 (4%)\t\nHIV disease status\t\nPrevious AIDS-defining illness\t59 (20%)\t57 (19%)\t116 (20%)\t\nNadir CD4 count (cells per μL)\t181 (90–258)\t170 (80–239)\t178 (86–250)\t\nBaseline CD4 count (cells per μL)\t512 (386–658)\t516 (402–713)\t513 (392–682)\t\nUndetectable baseline HIV viral load\t276 (95%)\t279 (94%)\t555 (95%)\t\nDuration of undetectable viral load (months)\t36 (17–62)\t38 (22–66)\t37 (20–63)\t\nART history\t\nYears since ART started\t3·9 (2·0–6·4)\t4·2 (2·4–6·9)\t4·0 (2·2–6·7)\t\nOn first ART combination\t91 (31%)\t96 (32%)\t187 (32%)\t\nNumber of drugs ever received\t5 (3–6)\t4 (3–6)\t4 (3–6)\t\nNNRTI at entry\t\n\tAny\t157 (54%)\t157 (53%)\t314 (53%)\t\n\tEfavirenz\t115 (40%)\t115 (39%)\t230 (39%)\t\n\tNevirapine\t42 (14%)\t39 (13%)\t81 (14%)\t\n\tEtravirine\t0\t3 (1%)\t3 (1%)\t\nProtease inhibitor at entry\t\n\tAny\t134 (46%)\t139 (47%)\t273 (47%)\t\n\tAtazanavir\t59 (20%)\t59 (20%)\t118 (20%)\t\n\tLopinavir\t28 (10%)\t49 (17%)\t77 (13%)\t\n\tDarunavir\t24 (8%)\t13 (4%)\t37 (6%)\t\n\tSaquinavir\t16 (5%)\t15 (5%)\t31 (5%)\t\n\tFosamprenavir\t7 (2%)\t3 (1%)\t10 (2%)\t\nNRTIs at entry\t\n\tAny\t291 (100%)\t296 (100%)\t587 (100%)\t\n\tEmtricitabine and tenofovir\t190 (65%)\t180 (61%)\t370 (63%)\t\n\tLamivudine and abacavir\t80 (27%)\t82 (28%)\t162 (28%)\t\n\tOther\t21 (7%)\t34 (11%)\t55 (9%)\t\nResistance\t\nResistance test result available before trial\t181 (62%)\t165 (56%)\t346 (59%)\t\nIntermediate-level or high-level resistance to NRTI or NNRTI before trial*\t4 (2%)\t7 (4%)\t11 (3%)\t\nData are median (IQR, range), median (IQR), or n (%). OT=ongoing triple therapy. PI-mono=protease inhibitor monotherapy. ART=antiretroviral therapy. NNRTI=non-nucleoside reverse transcriptase inhibitor. NRTI=nucleoside reverse transcriptase inhibitor.\n\n* Percentages are of the numbers of patients with resistance test results available before the trial.\n\nTable 2 Individual patients with loss of future drug options by end of trial\n\n\tDrugs received during trial\tReverse transcriptase mutations\tProtease mutations\tLost drug options\t\nOT\t\n1*\tABC, 3TC, ATV\tVal118Ile, Val179Asp, Met184Val\tIle84Val\t3TC, FTC, ATV, SQV, FPV, TPV\t\n2\tTDF, FTC, RPV, DRV\tLeu100Ile, Lys103Asn, Met184Val\tAla71Val\t3TC, FTC, NVP, EFV, ETV, RPV\t\n3\tTDF, FTC, ETV, NVP, EFV, DRV\tLys65Arg, Glu138Ala, Tyr181Cys, Met184Val/Ile, His221Tyr, Met230Leu\t..\t3TC, FTC, ABC, TDF, NVP, EFV, ETV, RPV\t\n4*\tTDF, FTC, DRV\tVal106Ala\t..\tNVP,‡ EFV‡\t\nPI-mono\t\n5*\tATV\t..\tLys20Thr, Ile50Leu/Ile, Ala71Thr\tATV\t\n6*\tDRV\t..\tLeu90Met\tSQV†\t\n7*\tDRV\t..\tAla71Thr, Leu90Met\tSQV†\t\n8*\tDRV\tLys103Asn\t..\tNVP,‡ EFV‡\t\n9*\tDRV\tLys103Asn\t..\tNVP,‡ EFV‡\t\n10*\tDRV\tMet41Leu, Thr215Asp\t..\tZDV‡\t\nOT=ongoing triple therapy. ABC=abacavir. 3TC=lamivudine. ATV=atazanavir. FTC=emtricitabine. SQV=saquinavir. FPV=fosamprenavir. TPV=tipranavir. TDF=tenofovir. RPV=rilpivirine. NVP=nevirapine. EFV= efavirenz. ETV=etravirine. DRV=darunavir. PI-mono=protease inhibitor monotherapy. ZDV=zidovudine.\n\n* Met primary outcome at 3 years.\n\n† Possibly archived resistance.\n\n‡ Probably archived resistance (excluded in sensitivity analysis).\n\nTable 3 Secondary outcomes\n\n\t\tOT (n=291)\tPI-mono (n=296)\tDifference (95% CI)*\tp value\t\nSerious drug-related or disease-related complications\t\n\tTotal\t8 (2·7%)\t15 (5·1%)\t2·3% (−0·8 to 5·4)\t0·15\t\n\tDeath†\t1 (0·3%)\t6 (2·0%)\t1·7% (−0·3 to 3·6)\t0·12\t\n\tAIDS-defining event\t1 (0·3%)\t1 (0·3%)\t0·0% (−1·3 to 1·3)\t1·00\t\n\tSerious non-AIDS event\t7 (2·4%)\t12 (4·1%)\t1·6% (−1·2 to 4·5)\t0·26\t\nCD4 change (cells per mm3)\t93 (10)\t109 (9)\t16 (−11 to 42)\t0·30\t\nSerious adverse event\t45 (15·5%)\t56 (18·9%)\t3·5% (−2·6 to 9·6)\t0·27\t\nTotal grade 3 or 4 adverse event\t159 (54·6%)\t137 (46·3%)\t−8·4% (−16·4 to −0·3)\t0·043\t\nClinical grade 3 or 4 adverse event\t49 (16·8%)\t65 (22·0%)\t5·1% (−1·3 to 11·5)\t0·12\t\nEGFR\t\n\t<60 mL/min per 1·73 m2‡\t28/290 (9·7%)\t15/296 (5·1%)\t−4·6% (−8·8 to −0·4)\t0·033\t\n\tChange (mL/min per 1·73 m2)\t−5·13 (0·67)\t−3·83 (0·66)\t1·30% (−0·55 to 3·15)\t0·092\t\nSymptomatic peripheral neuropathy§\t44/283 (15·5%)\t46/289 (15·9%)\t0·4% (−5·6 to 6·3)\t0·90\t\nFacial lipoatrophy¶\t23/282 (8·2%)\t35/289 (12·1%)\t4·0% (−1·0 to 8·9)\t0·12\t\nAbdominal fat accumulation¶\t47/274 (17·2%)\t57/277 (20·6%)\t3·4% (−3·1 to 10·0)\t0·30\t\n10 year cardiovascular disease risk change\t1·32 (0·31)\t1·59 (0·31)\t0·27 (−0·58 to 1·12)\t0·52\t\nNeurocognitive function change (NPZ-5 score)\t0·53 (0·04)\t0·52 (0·04)\t−0·01 (−0·11 to 0·09)\t0·94\t\nQuality of life change\t\n\tMental health score\t−0·75 (0·57)\t−1·82 (0·54)\t−1·07 (−2·61 to 0·47)\t0·17\t\n\tPhysical health score\t−0·76 (0·53)\t−1·17 (0·46)\t−0·41 (−1·79 to 0·98)\t0·56\t\nData are n (%), n/N (%), or mean (SE). Means are predicted means adjusted for baseline values. The numbers of patients are the numbers of patients having the specified event during the entire trial follow-up period. OT=ongoing triple therapy. PI-mono=protease inhibitor monotherapy. EGFR=estimated glomerular filtration rate.\n\n* Difference between PI-mono and OT. Absolute differences for binary outcomes or mean differences for continuous outcomes shown.\n\n† Causes of death were metastatic adenocarcinoma in the OT group and suicide, pulmonary embolism, breast carcinoma (recurrent), small-cell lung carcinoma, glioblastoma, and anal carcinoma in the PI-mono group (details in appendix p 4).\n\n‡ New episodes after baseline.\n\n§ Symptomatic peripheral neuropathy at one or more of the post-baseline-scheduled follow-up assessments (irrespective of status at baseline).\n\n¶ Facial lipoatrophy present at one or more of the post-baseline-scheduled follow-up assessments (irrespective of status at baseline), assessed by a doctor or nurse; abdominal fat accumulation at last available assessment compared with baseline (irrespective of status at baseline), self-assessed by the patient.\n==== Refs\nReferences\n1 Williams I Churchill D Anderson J British HIV Association guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy 2012 HIV Med 13 suppl 2 2012 1 85 \n2 Thompson MA Aberg JA Hoy JF Antiretroviral treatment of adult HIV infection: 2012 recommendations of the International Antiviral Society-USA panel JAMA 308 2012 387 402 22820792 \n3 Rabi SA Laird GM Durand CM Multi-step inhibition explains HIV-1 protease inhibitor pharmacodynamics and resistance J Clin Invest 123 2013 3848 3860 23979165 \n4 Ghosn J Flandre P Cohen-Codar I Long-term (96-week) follow-up of antiretroviral-naïve HIV-infected patients treated with first-line lopinavir/ritonavir monotherapy in the MONARK trial HIV Med 11 2010 137 142 19682100 \n5 Arribas JR Delgado R Arranz A Lopinavir-ritonavir monotherapy versus lopinavir-ritonavir and 2 nucleosides for maintenance therapy of HIV: 96-week analysis J Acquir Immune Defic Syndr 51 2009 147 152 19349870 \n6 Cameron DW da Silva BA Arribas JR A 96-week comparison of lopinavir-ritonavir combination therapy followed by lopinavir-ritonavir monotherapy versus efavirenz combination therapy J Infect Dis 198 2008 234 240 18540803 \n7 Katlama C Valantin MA Algarte-Genin M Efficacy of darunavir/ritonavir maintenance monotherapy in patients with HIV-1 viral suppression: a randomized open-label, noninferiority trial, MONOI-ANRS 136 AIDS 24 2010 2365 2374 20802297 \n8 Arribas JR Clumeck N Nelson M Hill A van Delft Y Moecklinghoff C The MONET trial: week 144 analysis of the efficacy of darunavir/ritonavir (DRV/r) monotherapy versus DRV/r plus two nucleoside reverse transcriptase inhibitors, for patients with viral load <50 HIV-1 RNA copies/mL at baseline HIV Med 13 2012 398 405 22413874 \n9 Mathis S Khanlari B Pulido F Effectiveness of protease inhibitor monotherapy versus combination antiretroviral maintenance therapy: a meta-analysis PLoS One 6 2011 e22003 21811554 \n10 Hughes CP Berg L Danziger WL Coben LA Martin RL A new clinical scale for the staging of dementia Br J Psychiatry 140 1982 566 572 7104545 \n11 Price RW Brew BJ The AIDS dementia complex J Infect Dis 158 1988 1079 1083 3053922 \n12 Wilson PW D'Agostino RB Levy D Belanger AM Silbershatz H Kannel WB Prediction of coronary heart disease using risk factor categories Circulation 97 1998 1837 1847 9603539 \n13 D'Agostino RB Sr Vasan RS Pencina MJ General cardiovascular risk profile for use in primary care: the Framingham Heart Study Circulation 117 2008 743 753 18212285 \n14 Winston A Arenas-Pinto A Stohr W Neurocognitive function in HIV infected patients on antiretroviral therapy PLoS One 8 2013 e61949 23646111 \n15 Arenas-Pinto A Winston A Stohr W Neurocognitive function in HIV-infected patients: comparison of two methods to define impairment PLoS One 9 2014 e103498 25078406 \n16 Evans SR Ellis RJ Chen H Peripheral neuropathy in HIV: prevalence and risk factors AIDS 25 2011 919 928 21330902 \n17 Wu AW Rubin HR Mathews WC A health status questionnaire using 30 items from the Medical Outcomes Study. Preliminary validation in persons with early HIV infection Med Care 29 1991 786 798 1875745 \n18 Wu AW Hanson KA Harding G Responsiveness of the MOS-HIV and EQ-5D in HIV-infected adults receiving antiretroviral therapies Health Qual Life Outcomes 11 2013 42 23497257 \n19 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults MMWR Recomm Rep 41 1992 1 19 \n20 Lifson AR Belloso WH Davey RT Development of diagnostic criteria for serious non-AIDS events in HIV clinical trials HIV Clin Trials 11 2010 205 219 20974576 \n21 National Institutes of Health Division of AIDS Division of AIDS table for grading the severity of adult and pediatric adverse events http://rsc.tech-res.com/document/safetyandpharmacovigilance/table_for_grading_severity_of_adult_pediatric_adverse_events.pdf (accessed Jan 1, 2008). \n22 Levey AS Stevens LA Schmid CH A new equation to estimate glomerular filtration rate Ann Intern Med 150 2009 604 612 19414839 \n23 US Department of Health and Human Services Guidance for industry. 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Human Immunodeficiency Virus-1 infection: developing antiretroviral drugs for treatment 2013 US Department of Health and Human Services Washington, DC \n25 Pulido F Arribas JR Noninferiority and lopinavir/ritonavir monotherapy trials AIDS 22 2008 1696 1697 18670240 \n26 Arribas JR Horban A Gerstoft J The MONET trial: darunavir/ritonavir with or without nucleoside analogues, for patients with HIV RNA below 50 copies/ml AIDS 24 2010 223 230 20010070 \n27 Sista P Wasikowski B Lecocq P Pattery T Bacheler L The HIV-1 protease resistance mutation I50L is associated with resistance to atazanavir and susceptibility to other protease inhibitors in multiple mutational contexts J Clin Virol 42 2008 405 408 18472298 \n28 McKinnon JE Delgado R Pulido F Shao W Arribas JR Mellors JW Single genome sequencing of HIV-1 gag and protease resistance mutations at virologic failure during the OK04 trial of simplified versus standard maintenance therapy Antivir Ther 16 2011 725 732 21817194 \n29 Lambert-Niclot S Flandre P Valantin MA Resistant minority species are rarely observed in patients on darunavir/ritonavir monotherapy J Antimicrob Chemother 67 2012 1470 1474 22396434 \n30 Raffanti SP Fusco JS Sherrill BH Effect of persistent moderate viremia on disease progression during HIV therapy J Acquir Immune Defic Syndr 37 2004 1147 1154 15319674 \n31 Quinn TC Wawer MJ Sewankambo N Viral load and heterosexual transmission of human immunodeficiency virus type 1. Rakai Project Study Group N Engl J Med 342 2000 921 929 10738050 \n32 Supervie V Viard JP Costagliola D Breban R Heterosexual risk of HIV transmission per sexual act under combined antiretroviral therapy: systematic review and Bayesian modeling Clin Infect Dis 59 2014 115 122 24723286 \n33 Ryom L Mocroft A Kirk O Predictors of advanced chronic kidney disease and end-stage renal disease in HIV-positive persons AIDS 28 2014 187 199 24361680 \n34 Gutmann C Cusini A Gunthard HF Randomized controlled study demonstrating failure of LPV/r monotherapy in HIV: the role of compartment and CD4-nadir AIDS 24 2010 2347 2354 20802298 \n35 Paton NI Meynard JL Pulido F Arenas-Pinto A Girard PM Arribas J Inappropriate claim of ‘failure of ritonavir-boosted lopinavir monotherapy in HIV’ in the Monotherapy Switzerland/Thailand (MOST) trial AIDS 25 2011 393 394 21239897 \n36 Paton NI Kityo C Hoppe A Assessment of second-line antiretroviral regimens for HIV therapy in Africa N Engl J Med 371 2014 234 247 25014688\n\n", "fulltext_license": "CC BY", "issn_linking": "2352-3018", "issue": "2(10)", "journal": "The lancet. HIV", "keywords": null, "medline_ta": "Lancet HIV", "mesh_terms": "D000328:Adult; D000368:Aged; D018791:CD4 Lymphocyte Count; D024882:Drug Resistance, Viral; D005260:Female; D006678:HIV; D015658:HIV Infections; D017320:HIV Protease Inhibitors; D006801:Humans; D060046:Maintenance Chemotherapy; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D006113:United Kingdom; D019562:Viral Load; D055815:Young Adult", "nlm_unique_id": "101645355", "other_id": null, "pages": "e417-26", "pmc": null, "pmid": "26423649", "pubdate": "2015-10", "publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't", "references": "15319674;22396434;21817194;7104545;3053922;22830364;23497257;23646111;23979165;24361680;25014688;25078406;24723286;22820792;10738050;22413874;1875745;1361652;9603539;18212285;18540803;18472298;18670240;19414839;19349870;20010070;19682100;20802297;20802298;20974576;21239897;21330902;21811554", "title": "Protease inhibitor monotherapy for long-term management of HIV infection: a randomised, controlled, open-label, non-inferiority trial.", "title_normalized": "protease inhibitor monotherapy for long term management of hiv infection a randomised controlled open label non inferiority trial" }

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{ "abstract": "Pemetrexed is a multitargeted antifolate that has demonstrated antitumor activity in non-small cell lung cancer. A 70-year-old male presented with a stage IV non-small cell lung cancer. The patient was treated with pemetrexed as third-line chemotherapy. However, a pneumothorax occurred 16 days after the administration of the second cycle of pemetrexed. The pneumothorax was slight and the patient was observed without undergoing any additional treatment. Twenty-four days after its initial occurrence, the pneumothorax had improved. This is the first case of pneumothorax that has been observed during pemetrexed treatment. Pneumothorax during chemotherapy is rare; however, it is a life-threatening complication and should not be overlooked.", "affiliations": "Department of Respiratory Medicine, Kitasato University School of Medicine, Sagamihara, Japan.;Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.;Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.;Department of Respiratory Medicine, Kitasato University School of Medicine, Sagamihara, Japan.;Research and Development Center for New Medical Frontiers, Kitasato University School of Medicine, Sagamihara, Japan.;Department of Respiratory Medicine, Kitasato University School of Medicine, Sagamihara, Japan.", "authors": "Nakahara|Yoshiro|Y|;Mikura|Shinichiro|S|;Nagamata|Makoto|M|;Fukui|Tomoya|T|;Sasaki|Jiichiro|J|;Masuda|Noriyuki|N|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.1159/000471479", "fulltext": "\n==== Front\nCase Rep OncolCase Rep OncolCROCase Reports in Oncology1662-6575S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, [email protected] 10.1159/000471479cro-0010-0428Case ReportPneumothorax during Pemetrexed Treatment in a Patient with Non-Small Cell Lung Cancer: A Case Report and Literature Review Nakahara Yoshiro ab*Mikura Shinichiro bNagamata Makoto bFukui Tomoya aSasaki Jiichiro cMasuda Noriyuki aaDepartment of Respiratory Medicine, Kitasato University School of Medicine, Sagamihara, JapanbDepartment of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, JapancResearch and Development Center for New Medical Frontiers, Kitasato University School of Medicine, Sagamihara, Japan*Yoshiro Nakahara, Department of Respiratory Medicine, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-Ku, Sagamihara, Kanagawa 252-0374 (Japan), E-Mail [email protected] 2017 9 5 2017 9 5 2017 10 2 428 432 14 3 2017 15 3 2017 Copyright © 2017 by S. Karger AG, Basel2017This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Pemetrexed is a multitargeted antifolate that has demonstrated antitumor activity in non-small cell lung cancer. A 70-year-old male presented with a stage IV non-small cell lung cancer. The patient was treated with pemetrexed as third-line chemotherapy. However, a pneumothorax occurred 16 days after the administration of the second cycle of pemetrexed. The pneumothorax was slight and the patient was observed without undergoing any additional treatment. Twenty-four days after its initial occurrence, the pneumothorax had improved. This is the first case of pneumothorax that has been observed during pemetrexed treatment. Pneumothorax during chemotherapy is rare; however, it is a life-threatening complication and should not be overlooked.\n\nKeywords\nPemetrexedPneumothoraxNon-small cell lung cancer\n==== Body\nIntroduction\nPemetrexed is a multitargeted antifolate that has demonstrated antitumor activity in non-small cell lung cancer. It has several notable adverse effects including myelosuppression, nausea, vomiting, diarrhea, and skin toxicity. However, the occurrence of pneumothorax during pemetrexed chemotherapy has not been previously reported [1]. Herein, we present a case of pneumothorax that was observed during pemetrexed chemotherapy.\n\nCase Report\nAn asymptomatic 70-year-old man was referred to the Department of Respiratory Diseases because of abnormal shadows found during a chest computed tomography scan. The scan revealed bilateral infiltrative shadows in the lower lung lobes (Fig. 1). Transbronchial lung biopsy was performed and the patient was diagnosed with non-small cell lung cancer classified as stage IV (T3N3M1a). The patient was treated every 3 weeks with 3 cycles of first-line chemotherapy, including carboplatin (AUC 5) on day 1 and gemcitabine (1,000 mg/m2) on days 1 and 8. After 3 cycles of chemotherapy, the bilateral infiltrative shadows had progressed. Consequently, the patient was treated every 3 weeks with 3 cycles of docetaxel (60 mg/m2) monotherapy as second-line chemotherapy. However, after the third cycle, the infiltrative shadows had progressed again. Subsequently, the patient was treated with pemetrexed (500 mg/m2) as third-line chemotherapy, every 3 weeks. In the first cycle of the chemotherapy, there were no grade 3 or 4 adverse events. However, the patient experienced sudden onset of cough and dyspnea 16 days after the administration of the second cycle of pemetrexed. Physical examination showed decreased breathing sounds in the right chest, and a chest radiograph revealed a pneumothorax (Fig. 2, Fig. 3). Because the pneumothorax was slight, the patient was observed without any treatment, and pemetrexed therapy was stopped. The pneumothorax had improved 24 days after the occurrence of the pneumothorax (Fig. 4). However, the patient died 2 months after the occurrence of pneumothorax because of disease progression.\n\nDiscussion\nSecondary spontaneous pneumothorax after chemotherapy is rare; however, well-documented occurrence is associated with primary or metastatic lung lesions. Lai et al. [2] reported that pneumothorax appeared in 18 out of 5,567 (0.32%) lung cancer patients, and 2 out of 18 patients experienced pneumothorax during chemotherapy. Maniwa et al. [3] reported that pneumothorax associated with the treatment for pulmonary malignancy (primary and metastatic) tends to require chest tube drainage over a long period, and sometimes requires surgical treatment; this is associated with increased perioperative morbidity and mortality because of the dense adhesions or anatomical changes in the thoracic cavity caused by treatment or the progression of the tumors [3].\n\nRecently, molecular targeted therapies have also been linked with the occurrence of pneumothorax. Mori et al. [4] reported a case of simultaneous bilateral spontaneous pneumothorax that occurred during gefitinib treatment for lung adenocarcinoma with multiple lung metastases. A case of pneumothorax after bevacizumab-containing chemotherapy for colorectal cancer with lung metastases was reported by Yang et al. [5]. In addition, Gennatas et al. [6] reported a case of pneumothorax during crizotinib therapy in a patient with anaplastic lymphoma kinase-rearranged lung adenocarcinoma. In contrast, pneumothorax during cytotoxic chemotherapy treatment is rare, and secondary spontaneous pneumothorax during pemetrexed has not been previously reported in the available literature.\n\nThe mechanism of secondary pneumothorax from pulmonary malignancy is unclear, although several theories have been proposed. The proposed mechanisms are as follows: accidental rupture of the subpleural bulla or bleb during chemotherapy; the formation of a bronchopleural fistula as a result of direct tumor invasion or necrosis of the peripheral tumor after effective chemotherapy; a check-valve mechanism associated with airway compression by the tumor; and an air leak caused by pulmonary infarction from tumor emboli [7].\n\nIn the present case, there was no clinical response to pemetrexed treatment, and tumor necrosis was not observed. Furthermore, neither progression of airway compression or signs of pulmonary infarction were observed. In addition, there were no subpleural bullae or blebs on chest computed tomography before pemetrexed treatment. We believe that the pneumothorax was possibly caused by the formation of a bronchopleural fistula as a result of direct tumor invasion of the peripheral tumor.\n\nIn summary, ours is the first reported case of pneumothorax to have occurred during pemetrexed treatment. Pneumothorax during chemotherapy is rare; however, it is a life-threatening complication that should not be overlooked. It is important to observe the patients’ symptoms during chemotherapy treatment.\n\nStatement of Ethics\nThe authors have no ethical conflicts to disclose.\n\nDisclosure Statement\nThe authors state that they have no conflict of interest.\n\nFig. 1 Chest computed tomography demonstrating bilateral infiltrative shadows. These lesions were diagnosed as non-small cell lung cancer by transbronchial lung biopsy.\n\nFig. 2 Chest X-ray demonstrating right pneumothorax.\n\nFig. 3 Chest computed tomography demonstrating right pneumothorax, and bilateral infiltrative shadows had progressed.\n\nFig. 4 The pneumothorax had improved 24 days after the occurrence of the pneumothorax.\n==== Refs\nReferences\n1 Hanna N Shepherd FA Fossella FV Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy J Clin Oncol 2004 22 1589 1597 15117980 \n2 Lai RS Perng RP Chang SC Primary lung cancer complicated with pneumothorax Jpn J Clin Oncol 1992 22 194 197 1518168 \n3 Maniwa T Nakagawa K Isaka M Pneumothorax associated with treatment for pulmonary malignancy Interact Cardiovasc Thorac Surg 2011 13 257 261 21700592 \n4 Mori M Nakagawa M Fujikawa T Simultaneous bilateral spontaneous pneumothorax observed during the administration of gefitinib for lung adenocarcinoma with multiple lung metastases Intern Med 2005 44 862 864 16157988 \n5 Yang SH Lin JK Chen WS Pneumothorax after bevacizumab-containing chemotherapy: a case report Jpn J Clin Oncol 2011 41 269 271 21030401 \n6 Gennatas S Stanway SJ Thomas R Early pneumothorax as a feature of response to crizotinib therapy in a patient with ALK rearranged lung adenocarcinoma BMC Cancer 2013 13 207 23617826 \n7 Srinivas S Varadhachary G Spontaneous pneumothorax in malignancy: a case report and review of the literature Ann Oncol 2000 11 887 889 10997821\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1662-6575", "issue": "10(2)", "journal": "Case reports in oncology", "keywords": "Non-small cell lung cancer; Pemetrexed; Pneumothorax", "medline_ta": "Case Rep Oncol", "mesh_terms": null, "nlm_unique_id": "101517601", "other_id": null, "pages": "428-432", "pmc": null, "pmid": "28626401", "pubdate": "2017", "publication_types": "D002363:Case Reports", "references": "16157988;10997821;21030401;21700592;15117980;23617826;1518168", "title": "Pneumothorax during Pemetrexed Treatment in a Patient with Non-Small Cell Lung Cancer: A Case Report and Literature Review.", "title_normalized": "pneumothorax during pemetrexed treatment in a patient with non small cell lung cancer a case report and literature review" }

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{ "abstract": "Elizabethkingia anophelis, originally discovered from Anopheles mosquito gut, is an emerging pathogen, especially in immunocompromised patients. We isolated two strains of E. anophelis from two separate patients with multiple organ dysfunction syndrome and lower respiratory tract infection. In this paper, we reviewed the status of E. anophelis infection and its antibiotics resistance from reported cases.", "affiliations": "Yun Leung Laboratory for Molecular Diagnostics, School of Biomedical Sciences, Huaqiao University Xiamen, China.;Yun Leung Laboratory for Molecular Diagnostics, School of Biomedical Sciences, Huaqiao University Xiamen, China.;Department of Medical Laboratory, Institute of Nanomedicine Technology, Weifang Medical University Weifang, China.;Yun Leung Laboratory for Molecular Diagnostics, School of Biomedical Sciences, Huaqiao University Xiamen, China.;Department of Medical Laboratory, Institute of Nanomedicine Technology, Weifang Medical University Weifang, China.;Department of Information, Quanzhou First Hospital Affiliated to Fujian Medical University Fujian, China.;Department of Information, Quanzhou First Hospital Affiliated to Fujian Medical University Fujian, China.;Yun Leung Laboratory for Molecular Diagnostics, School of Biomedical Sciences, Huaqiao UniversityXiamen, China; Department of Medical Laboratory, Institute of Nanomedicine Technology, Weifang Medical UniversityWeifang, China.;Department of Clinical Laboratory, Quanzhou First Hospital Affiliated to Fujian Medical University Fujian, China.;Department of Microbiology and Molecular Genetics, Michigan State University East Lansing, MI, USA.", "authors": "Hu|Shaohua|S|;Jiang|Tao|T|;Zhang|Xia|X|;Zhou|Yajun|Y|;Yi|Zhengjun|Z|;Wang|Youxi|Y|;Zhao|Sishou|S|;Wang|Mingxi|M|;Ming|Desong|D|;Chen|Shicheng|S|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.3389/fmicb.2017.00382", "fulltext": "\n==== Front\nFront MicrobiolFront MicrobiolFront. Microbiol.Frontiers in Microbiology1664-302XFrontiers Media S.A. 10.3389/fmicb.2017.00382MicrobiologyCase ReportElizabethkingia anophelis Isolated from Patients with Multiple Organ Dysfunction Syndrome and Lower Respiratory Tract Infection: Report of Two Cases and Literature Review Hu Shaohua 1†Jiang Tao 1†Zhang Xia 2Zhou Yajun 1Yi Zhengjun 2Wang Youxi 3Zhao Sishou 3Wang Mingxi 12*Ming Desong 4*Chen Shicheng 5*1Yun Leung Laboratory for Molecular Diagnostics, School of Biomedical Sciences, Huaqiao UniversityXiamen, China2Department of Medical Laboratory, Institute of Nanomedicine Technology, Weifang Medical UniversityWeifang, China3Department of Information, Quanzhou First Hospital Affiliated to Fujian Medical UniversityFujian, China4Department of Clinical Laboratory, Quanzhou First Hospital Affiliated to Fujian Medical UniversityFujian, China5Department of Microbiology and Molecular Genetics, Michigan State UniversityEast Lansing, MI, USAEdited by: Leonard Peruski, US Centers for Disease Control and Prevention, USA\n\nReviewed by: Peter Bergman, Karolinska Institutet, Sweden; Marquita Vernescia Gittens-St.Hilaire, University of the West Indies, Barbados\n\n*Correspondence: Mingxi Wang [email protected] Ming [email protected] Chen [email protected] article was submitted to Infectious Diseases, a section of the journal Frontiers in Microbiology\n\n†These authors have contributed equally to this work.\n\n08 3 2017 2017 8 38220 11 2016 23 2 2017 Copyright © 2017 Hu, Jiang, Zhang, Zhou, Yi, Wang, Zhao, Wang, Ming and Chen.2017Hu, Jiang, Zhang, Zhou, Yi, Wang, Zhao, Wang, Ming and ChenThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Elizabethkingia anophelis, originally discovered from Anopheles mosquito gut, is an emerging pathogen, especially in immunocompromised patients. We isolated two strains of E. anophelis from two separate patients with multiple organ dysfunction syndrome and lower respiratory tract infection. In this paper, we reviewed the status of E. anophelis infection and its antibiotics resistance from reported cases.\n\nE. anophelisemerging pathogenmultiple organ dysfunction syndromelower respiratory tract infectionantibiotics resistance\n==== Body\nBackground\nElizabethkingia, a Gram-negative, aerobic, rod-shaped bacterium, belongs to the family Flavobacteriaceae within the phylum Bacteroidetes. Four species are assigned to this genus, including Elizabethkingia meningoseptica, E. anophelis, Elizabethkingia miricola, and Elizabethkingia endophytica, with the first three being considered to be medically important (Kukutla et al., 2013, 2014; Lau et al., 2015; Breurec et al., 2016). E. anophelis was initially isolated from the midgut of mosquito Anopheles gambiae in 2011 (Kämpfer et al., 2011). Later, it was found in the environment (water and soil) and health care settings (Balm et al., 2013; Teo et al., 2013). It rarely causes infections in healthy people while it is pathogenic to immunocompromised patients with a high mortality rate (Teo et al., 2013; Lau et al., 2016; https://www.cdc.gov/elizabethkingia/outbreaks/). The first reported case of E. anophelis infection was meningitis in an 8-day-old girl delivered by cesarean section in the Central African Republic in 2011 (Frank et al., 2013). It also caused nosocomial outbreak in two intensive-care units from a hospital in Singapore in 2012 (Teo et al., 2013). By conventional phenotypic test, an epidemiological survey of bacteremia from five regional hospitals in Hong Kong (from 2004 to 2013) identified 17 cases of E. anophelis bacteremia (Lau et al., 2016). E. anophelis was implicated in recent outbreaks of infections in the Midwest regions. In Wisconsin, 63 confirmed and 4 possible infections were reported between November 1, 2015 and January 11, 2017. Among these cases, a total of 19 deaths (estimated mortality rate, 28%) were found (https://www.dhs.wisconsin.gov/disease/elizabethkingia.htm). At least 10 E. anophelis infections were reported in Illinois (between January 2014 and April 2016) and one in Michigan in March 2016 (https://www.cdc.gov/elizabethkingia/outbreaks/). Most patients were over 65 years old with serious underlying diseases (https://www.cdc.gov/elizabethkingia/outbreaks/). We report here two cases of E. anophelis infection at Quanzhou First Hospital, Fujian, China.\n\nCase presentation\nCase 1\nAn 82-year-old male patient presenting with lethargy in consciousness, malnutrition, multiple bedsores [an 8 × 10 cm2 at level I (containing a 5 × 6 cm2 at level II) on the sacrococcygeal region, two 5 × 5 cm2 at level I on the both heel, two 2 × 2 cm2 at level I on both external malleolus] was admitted on December 14, 2009. He had a history of surgery for esophagus cancer at 73 years old, hypertension at level III, two hospitalizations due to lower respiratory tract infections (treated by azithromycin, cefoperazone/tazobactam, levofloxacin, meropenem, linezolid, piperacillin/tazobactam, and ciprofloxacin) 4 months before this final hospitalization. He demonstrated expectoration and shortness of breath for 7 days before admission. The blood gas analysis and blood biochemical test at admission showed respiratory acidosis (pCO2 97 mm Hg, pO2 122 mm Hg), metabolic alkalosis (pH 7.48, HCO3- > 60 mmol/L, CO2 36.8 mmol/L), very low blood K+ (2.1 mmol/L), renal dysfunction (BUN 23.9 mmol/L), and extremely low Cl− (68.6 mmol/L). He came into deep coma with BP 58/34 mmHg within 2 h after admission. Emergency salvage was given, including assisted ventilation, raising BP by dopamine and L-noradrenaline, supplement of potassium chloride, and anti-infection treatment with piperacillin/tazobactam and ciprofloxacin. In the subsequent 2 days, he recovered from coma gradually, but presented clear sign of lung infection (fever, moist rale sound in both sides of lower lung lobes, blood WBC 9.8 × 109/L, NEUT 94.61%, CRP 146 mg/L). Diagnoses of shock, multiple organ dysfunction syndrome (MODS), and lower respiratory tract infection were made. The infection and the respiratory acidosis combined with metabolic alkalosis lasted for nearly the whole 52 day-hospitalization. On the 45th day of hospitalization, a fistula between the esophagus and trachea was found through gastroscopy and further verified by bronchoscopy. It was treated with tracheal stenting 2 days later. However, 5 h after post-tracheal stenting, sudden cardiac arrest occurred, complicated with a loss of spontaneous breathing, then he went into coma (combined with dilated pupils and disappeared light reflex of both sides) again. BP and SpO2 could not be measured while his pulse and spontaneous breathing returned 5 min after salvage. BP, SpO2, and light reflex of both pupils returned to normal gradually within the subsequent 5 h. However, the patient was still in coma and was discharged after 7 days at his family's request to terminate treatment.\n\nDuring the hospitalization, the separately or jointed isolated pathogenic microbes for the lung infection included Acinetobacter calcoaceticus–Acinetobacter baumannii complex (7 times isolated from sputum, 7 TIFS), Acinetobacter baumannii (4 TIFS), Enterobacter cloacae (3 TIFS), Pseudomonas aeruginosa (2 TIFS), Serratia marcescens (2 TIFS), molds (2 TIFS), and E. anophelis (7 TIFS) (named as 12012 PRCM). E. anopheles 12012 PRCM was verified by 16S rRNA gene sequencing (GenBank accession no. KR349263) of the genomic DNA with the forward primer 27F (5′-AGAGTTTGATCCTGGCTCAG-3′) and the reverse primer 1492R (5′-GGTTACCTTGTTACGACTT-3′; Lane, 1991). It was resistant to all the 20 antibiotics in the antibiotic susceptibility tests (AST) panel, including β-lactams (ampicillin, piperacillin, ampicillin-sulbactam, piperacillin-tazobactam, ceftazidime, cefotaxime, cephazolin, cefepime, aztreonam, imipenem, and meropenem), aminoglycosides (amikacin, gentamicin), tetracycline, chloramphenicol, and polymyxin, quinolones (ciprofloxacin, levofloxacin, moxifloxacin), and sulfamethoxazole-trimethoprim. The strain was also resistant to another antibiotic amoxicillin-clavulanate tested. To investigate the resistance mechanisms, extended spectrum β-lactamase (ESBL) detection was performed on the E. anophelis 12012 PRCM using BD's PhoenixTM-100 Automated Microbiology System with the NMIC/ID-4 panel (Becton, Dickinson, and Company; Stefaniuk et al., 2003; Liu et al., 2005). The cephalosporin test was positive and the carbapenem-hydrolyzing β-lactamases and carbapenemases (CHBLs) were detected. In addition, we found this strain was co-positive between EDTA (Ethylenediaminetetraacetic acid) and imipenem. These laboratory findings indicated strain 12012 PRCM could produce metal-beta-lactamase, possibly conferring the β-lactamases resistance.\n\nCase 2\nA 47-year-old male with hypotension (BP 95/55 mmHg) was admitted to our hospital on August 21, 2015. He had history of exacerbated abdominal pain and abdominal distension for more than 10 days, shortness of breath for 3 days, complicated with stagnated exhaust and defecation. Before admission, his pressure was maintained by continuous pumping of L-noradrenaline and dopamine. Physical examination found weak breath sounds in both sides of lung lobes and severe subcutaneous edema on whole body. The arterial blood gas analysis displayed acidosis (pH 7.20, pCO2 11.1 mmHg, pO2 99 mmHg, HCO3- −8.6 mmol/L, BE −23.3 mmol/L). He had a low white blood cell count (WBC) (2.35 × 109/L). Blood biochemical test showed several abnormal results (glucose 8.86 mmol/L, BUN 18.93 mmol/L, creatinine 271 μmol/L, GFR 24.20 ml/min, AST 827 U/L, ALT 197 U/L, albumin 30.5 g/L, T-BIL 29.5 μmol/L, D-BIL 12.8 μmol/L, total osmotic pressure 280 mOsm/L). Ultrasound imaging demonstrated liver cirrhosis, echo enhancement in parenchyma of both kidneys and effusion around left renal. Computed tomography scanning revealed inflammatory changes within both sides of the lower lung lobes, severe effusion within bilateral pleural, abdominal, and pelvic cavity, edema within subcutaneous soft tissue of chest and abdominal wall. Diagnoses of shock, MODS, electrolyte imbalances (low sodium, low calcium), diabetes and pulmonary infection were made. Within 16 h after admission, the patient further presented oliguria and aggravated during the 12-day hospitalization. On the 3rd day, hepatic virus infection [with positive HBsAg, anti-HBe antibody, and anti-HBc antibody (IgG)], abnormal blood coagulation [prothrombin time (PT) 16.7 s, partial prothrombin time (APTT) 67.8 s, fibrinogen (FIB) 1.75 g/L, D-dimer 8.32 mg/L, international normalized ratio (INR) 1.43], and thrombocytopenia (84 × 109/L) were diagnosed, with the latter lasting for the remaining hospitalization. The treatment strategies included drainage of bilateral pleural effusion, maintaining blood pressure as previously, improving liver function, daily hemodialysis, management of electrolyte, insulin injection and improving nutrition. The empirical antimicrobial therapy was started with IV piperacillin and tazobactam during the first 3 days of hospitalization, then changed to IV imipenem and cilastatin sodium for 1 day and further combined with vancomycin; the latter lasted for the remaining 8 days of hospitalization. The patient died of sudden cardiac arrest.\n\nBy using BD's Phoenix™-100 Automated Microbiology System with the NMIC/ID-4 panel as Case 1, we repeatedly isolate E. meningoseptica (on the 7th and 9th day of hospitalization respectively) and Stenotrophomonas maltophilia (on the 8th and 9th day of hospitalization respectively) from sputum cultures. Later, E. meningoseptica was verified as E. anophels (named as N107618, GenBank accession No. KX775952) by 16S rRNA gene sequencing as Case 1. E. anophelis N107618 was resistant to 16 out of 20 antibiotics in the same AST panel used to test the E. anophelis 12012 PRCM, and was only susceptible to ciprofloxacin, levofloxacin, moxifloxacin, and sulfamethoxazole-trimethoprim.\n\nDiscussion\nE. anophelis was an opportunistic pathogen but it could result in a high mortality rate (Teo et al., 2013; Lau et al., 2016; https://www.cdc.gov/elizabethkingia/outbreaks/). The number of E. anophelis infections was possibly underestimated because E. anophelis were often misidentified as E. meningoseptica by conventional identification methods (Kämpfer et al., 2011; Teo et al., 2013, 2014; Nicholson et al., 2016). Identification of E. anophelis by the matrix assisted laser desorption-ionization time-of-flight (MALDI-TOF) mass spectrometry will be helpful if E. anophelis reference is added in the database (Teo et al., 2013; Lau et al., 2016). 16S rRNA gene sequencing should be performed as a routine bacterial identification tool in the medical laboratories without MALDI-TOF mass spectrometry (Teo et al., 2013; Lau et al., 2016).\n\nThe high mortality rate of E. anophelis infection was partly due to its property of multidrug-resistance. E. anophelis N107618 was resistant to 16 out of 20 antibiotics while strain 12012 PRCM was resistant to all the 20 antibiotics in the AST panel, indicating that our two clinical E. anophelis isolates were multidrug-resistant. Furthermore, our tests showed that the isolate E. anophelis 12012 PRCM produced metallo-beta-lactamase(s). β-lactams resistance has been shown in many clinical important Elizabethkingia isolates (Frank et al., 2013; Lau et al., 2015, 2016). Notably, all clinical E. anophelis isolates, except for our strain 12012 PRCM, were susceptible to one or more quinolones such as ciprofloxacin or moxifloxacin (Frank et al., 2013; Lau et al., 2015). Therefore, ciprofloxacin or moxifloxacin might be considered as empirical antibiotic therapy of E. anophelis infections. For example, Frank et al. reported that a clinical isolate was resistant to all β-lactams tested (amoxicillin, cefotaxime, ceftazidime, cefepime, and imipenem) except for piperacillin and aminoglycosides (amikacin, tobramycin, and gentamicin) while it was susceptible to moxifloxacin (Frank et al., 2013). Similarly, three clinical E. anophelis strains were resistant to β-lactams aminoglycosides, tetracycline, and chloramphenicol while they were susceptible to pipercillin, cefoperazone-sulbactam, trimethoprim-sulfamethoxazole, ciprofloxacin, moxifloxacin, and rifampin (Lau et al., 2015). Moreover, the survey of 17 E. anophelis bacteremia demonstrated that they were resistant or intermediate-resistant to imipenem, amikacin, gentamicin, and tobramycin, but they were susceptible to ceftazidime, piperacillin, and rifampicin (Lau et al., 2016).\n\nNext generation sequencing (NGS) techniques greatly contribute to our understanding of drug resistance and infectivity of E. anophelis. For example, 16 and 19 antibiotic resistance genes were found from the core and accessory genomes of E. anophelis, respectively (Teo et al., 2014). The genome of E. anophelis NUHP1 contained 14 antibiotic resistant genes that correlated to its multi-drug resistance (Li et al., 2015). Breurec et al. reported that at least 17 antimicrobial resistance genes in E. anophelis consisted of metallo-beta-lactamase genes blablaB and blaGOB (conferring β-lactams resistance), subclass B1 beta-lactamase gene, efflux systems, conserved chloramphenicol acetyltransferase (CAT and AAC3-I) gene, a tetX gene (encoding for a tetracycline inactivating enzyme) and LinF gene (encoding lincosamide resistance protein; Breurec et al., 2016). Genome sequencing analysis showed that E. anophelis processed virulence genes encoding cell wall hydrolase A, listeriolysin O (LLO), phospholipase (PlcA), virulence cluster protein B (VclB), and arylsulfatase (Lau et al., 2015; Breurec et al., 2016). These virulence factors possibly contribute to the invading of the host, escape from phagocytosis, surviving in the secondary vacuole of macrophages, and propagating in bloodstreams (Lau et al., 2015; Breurec et al., 2016).\n\nConclusion\nE. anophelis is an emerging opportunistic pathogen. It often leads to a high mortality rate because of its multiple antibiotic resistance. Therefore, E. anophelis infections should be considered clinically significant. Investigation of antibiotic resistance mechanisms are warranted.\n\nEthics statement\nThe written informed consents were obtained from the patients or their relatives/guardians. This work was already approved by the Ethics Committee of Quanzhou First Hospital.\n\nAuthor contributions\nSH and TJ contributed equally to this work. All of authors wrote the papers. SH conducted the test. MW, DM, and SC guided the testing and experiments.\n\nConflict of interest statement\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nThis work was supported by Huaqiao University Graduate Student Scientific Research Innovation Ability Cultivation Plan Projects, the Fong Shu Fook Tong and Fong Yun Wah Foundations (14X30127), the Xiamen Southern Oceanographic Center (14GYY008NF08), the Natural Science Fund Project of Fujian Province (2015J01514), the Technology Planning Projects of Quanzhou Social Development Fields (2014Z24), and the Major Support Research Project of National Key Colleges Construction of Quanzhou Medical College (2013A13).\n==== Refs\nReferences\nBalm M. N. Salmon S. Jureen R. Teo C. Mahdi R. Seetoh T. . (2013 ). Bad design, bad practices, bad bugs: frustrations in controlling an outbreak of Elizabethkingia meningoseptica in intensive care units . J. Hosp. Infect. \n85 , 134 –140 . 10.1016/j.jhin.2013.05.012 23958153 \nBreurec S. Criscuolo A. Diancourt L. Rendueles O. Vandenbogaert M. Passet V. . (2016 ). Genomic epidemiology and global diversity of the emerging bacterial pathogen Elizabethkingia anophelis . Sci. Rep. \n6 :30379 . 10.1038/srep30379 27461509 \nFrank T. Gody J. C. Nguyen L. B. Berthet N. Le Fleche-Mateos A. Bata P. . (2013 ). First case of Elizabethkingia anophelis meningitis in the Central African Republic . Lancet \n381 :1876 . 10.1016/S0140-6736(13)60318-9 23706804 \nKämpfer P. Matthews H. Glaeser S. P. Martin K. Lodders N. Faye I. (2011 ). Elizabethkingia anophelis sp. nov., isolated from the midgut of the mosquito Anopheles gambiae . Int. J. Syst. Evol. Microbiol. \n61 (Pt 11 ), 2670 –2675 . 10.1099/ijs.0.026393-0 21169462 \nKukutla P. Lindberg B. G. Pei D. Rayl M. Yu W. Steritz M. . (2013 ). Draft genome sequences of Elizabethkingia anophelis strains R26T and Ag1 from the midgut of the malaria mosquito Anopheles gambiae . Genome Announc. \n1 , e01030 –e01013 . 10.1128/genomeA.01030-13 24309745 \nKukutla P. Lindberg B. G. Pei D. Rayl M. Yu W. Steritz M. . (2014 ). Insights from the genome annotation of Elizabethkingia anophelis from the malaria vector Anopheles gambiae . PLoS ONE \n9 :e97715 . 10.1371/journal.pone.0097715 24842809 \nLane D. J. (1991 ). 16S/23S rRNA sequencing , in Nucleic Acid Techniques in Bacterial Systematics , eds Stackebrandt E. Goodfellow M. (Chichester : John Wiley & Sons ), 115 –175 .\nLau S. K. Chow W. N. Foo C. H. Curreem S. O. Lo G. C. Teng J. L. . (2016 ). Elizabethkingia anophelis bacteremia is associated with clinically significant infections and high mortality . Sci. Rep. \n6 :26045 . 10.1038/srep26045 27185741 \nLau S. K. Wu A. K. Teng J. L. Tse H. Curreem S. O. Tsui S. K. . (2015 ). Evidence for Elizabethkingia anophelis transmission from mother to infant, Hong Kong . Emerg. Infect. Dis. \n21 , 232 –241 . 10.3201/eid2102.140623 25625669 \nLi Y. Liu Y. Chew S. C. Tay M. Salido M. M. Teo J. . (2015 ). Complete genome sequence and transcriptomic analysis of the novel pathogen Elizabethkingia anophelis in response to oxidative stress . Genome Biol. Evol. \n7 , 1676 –1685 . 10.1093/gbe/evv101 26019164 \nLiu Z. K. Ling T. K. Cheng A. F. (2005 ). Evaluation of the BD phoenix automated microbiology system for identification and antimicrobial susceptibility testing of common clinical isolates . Med. Princ. Pract. \n14 , 250 –254 . 10.1159/000085744 15961935 \nNicholson A. C. Whitney A. M. Emery B. D. Bell M. E. Gartin J. T. Humrighouse B. W. . (2016 ). Complete genome sequences of four strains from the 2015-2016 Elizabethkingia anophelis outbreak . Genome Announc. \n4 , e00563 –00564 . 10.1128/genomeA.00563-16 27313304 \nStefaniuk E. Baraniak A. Gniadkowski M. Hryniewicz W. (2003 ). Evaluation of the BD Phoenix automated identification and susceptibility testing system in clinical microbiology laboratory practice . Eur. J. Clin. Microbiol. Infect. Dis. \n22 , 479 –485 . 10.1007/s10096-003-0962-y 12884060 \nTeo J. Tan S. Y. Liu Y. Tay M. Ding Y. Li Y. . (2014 ). Comparative genomic analysis of malaria mosquito vector-associated novel pathogen Elizabethkingia anophelis . Genome Biol. Evol. \n6 , 1158 –1165 . 10.1093/gbe/evu094 24803570 \nTeo J. Tan S. Y. Tay M. Ding W. Kjelleberg S. Givskov M. . (2013 ). First case of E. anophelis outbreak in an intensive-care unit . Lancet \n382 , 855 –856 . 10.1016/S0140-6736(13)61858-9 24012265\n\n", "fulltext_license": "CC BY", "issn_linking": "1664-302X", "issue": "8()", "journal": "Frontiers in microbiology", "keywords": "E. anophelis; antibiotics resistance; emerging pathogen; lower respiratory tract infection; multiple organ dysfunction syndrome", "medline_ta": "Front Microbiol", "mesh_terms": null, "nlm_unique_id": "101548977", "other_id": null, "pages": "382", "pmc": null, "pmid": "28337189", "pubdate": "2017", "publication_types": "D002363:Case Reports", "references": "12884060;24803570;24309745;15961935;23706804;24842809;23958153;27185741;21169462;24012265;25625669;27461509;27313304;26019164", "title": "Elizabethkingia anophelis Isolated from Patients with Multiple Organ Dysfunction Syndrome and Lower Respiratory Tract Infection: Report of Two Cases and Literature Review.", "title_normalized": "elizabethkingia anophelis isolated from patients with multiple organ dysfunction syndrome and lower respiratory tract infection report of two cases and literature review" }

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null, "reaction": [ { "reactionmeddrapt": "Multiple organ dysfunction syndrome", "reactionmeddraversionpt": "19.1", "reactionoutcome": null }, { "reactionmeddrapt": "Respiratory acidosis", "reactionmeddraversionpt": "19.1", "reactionoutcome": null }, { "reactionmeddrapt": "Metabolic alkalosis", "reactionmeddraversionpt": "19.1", "reactionoutcome": null }, { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Coma", "reactionmeddraversionpt": "19.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Tracheo-oesophageal fistula", "reactionmeddraversionpt": "19.1", "reactionoutcome": null }, { "reactionmeddrapt": "Pathogen resistance", "reactionmeddraversionpt": "19.1", "reactionoutcome": null }, { "reactionmeddrapt": "Respiratory tract infection", "reactionmeddraversionpt": "19.1", "reactionoutcome": null }, { "reactionmeddrapt": "Shock", "reactionmeddraversionpt": "19.1", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "HU S, JIANG T, ZHANG X, ZHOU Y, YI Z, WANG Y, ZHAO S, WANG M, MING D, CHEN S. ELIZABETHKINGIA ANOPHELIS ISOLATED FROM PATIENTS WITH MULTIPLE ORGAN DYSFUNCTION SYNDROME AND LOWER RESPIRATORY TRACT INFECTION: REPORT OF TWO CASES AND LITERATURE REVIEW. FRONTIERS IN MICROBIOLOGY. 2017;8:XX", "literaturereference_normalized": "elizabethkingia anophelis isolated from patients with multiple organ dysfunction syndrome and lower respiratory tract infection report of two cases and literature review", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20170321", "receivedate": "20170321", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13356174, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20170429" } ]

{ "abstract": "We describe our experience, gained over the past 3 years, in the treatment of gastroesophageal junction adenocarcinoma, whose incidence has been increasing in recent years. In our series, we present the results to a follow-up of about 2 years for a total of 18 patients, treated with a particularly intensive combination treatment. It consists of neoadjuvant induction chemotherapy with the protocol docetaxel-cisplatin-5-fluorouracil for four cycles, before a concomitant chemoradiotherapy treatment. During combined phase, patients received an intensity-modulated radiotherapy and a weekly cisplatin. We will present the data to a long follow-up time and we will discuss the literature, the integration with thoracoabdominal surgery and other specific issues of this pathology.", "affiliations": "UOC Radiodiagnostica e Radioterapia, AOU Policlinico-VE di Catania, 95125, Italy.;UOC Radiodiagnostica e Radioterapia, AOU Policlinico-VE di Catania, 95125, Italy.;UOC Radiodiagnostica e Radioterapia, AOU Policlinico-VE di Catania, 95125, Italy.;UOC Radiodiagnostica e Radioterapia, AOU Policlinico-VE di Catania, 95125, Italy.;UOC Radiodiagnostica e Radioterapia, AOU Policlinico-VE di Catania, 95125, Italy.;UOC Radiodiagnostica e Radioterapia, AOU Policlinico-VE di Catania, 95125, Italy.;UOC Radiodiagnostica e Radioterapia, AOU Policlinico-VE di Catania, 95125, Italy.;UOC Chirurgia Toracica, AOU Policlinico-VE Catania, Italy.;UOC Radiodiagnostica e Radioterapia, AOU Policlinico-VE di Catania, 95125, Italy.;UOC Chirurgia Digerente e colo-rettale, AOU Policlinico-VE Catania, Italy.;UOC Radioterapia AOE Cannizzaro Catania, Italy.;UOC Radiodiagnostica e Radioterapia, AOU Policlinico-VE di Catania, 95125, Italy.", "authors": "Spatola|Corrado|C|;Tocco|Alessandra|A|;Pagana|Antonio|A|;Milazzotto|Roberto|R|;Luigi|Raffaele|R|;Salamone|Vincenzo|V|;Militello|Carmelo|C|;Migliore|Marcello|M|;Foti|Pietro Valerio|PV|;Cataldo|Antonio Di|AD|;Acquaviva|Grazia|G|;Privitera|Giuseppe|G|", "chemical_list": "D043823:Taxoids", "country": "England", "delete": false, "doi": "10.2217/fon-2017-0342", "fulltext": null, "fulltext_license": null, "issn_linking": "1479-6694", "issue": "14(6s)", "journal": "Future oncology (London, England)", "keywords": "gastroesophageal junction adenocarcinoma; intensity-modulated radiotherapy; simultaneous integrated boost", "medline_ta": "Future Oncol", "mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D059248:Chemoradiotherapy; D018572:Disease-Free Survival; D004938:Esophageal Neoplasms; D004943:Esophagogastric Junction; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D011829:Radiation Dosage; D050397:Radiotherapy, Intensity-Modulated; D013274:Stomach Neoplasms; D043823:Taxoids; D014057:Tomography, X-Ray Computed", "nlm_unique_id": "101256629", "other_id": null, "pages": "47-51", "pmc": null, "pmid": "29664354", "pubdate": "2018-03", "publication_types": "D016428:Journal Article", "references": null, "title": "Combined taxane-based chemotherapy and intensity-modulated radiotherapy with simultaneous integrated boost for gastroesophageal junction adenocarcinoma.", "title_normalized": "combined taxane based chemotherapy and intensity modulated radiotherapy with simultaneous integrated boost for gastroesophageal junction adenocarcinoma" }

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COMBINED TAXANE-BASED CHEMOTHERAPY AND INTENSITY-MODULATED RADIOTHERAPY WITH SIMULTANEOUS INTEGRATED BOOST FOR GASTROESOPHAGEAL JUNCTION ADENOCARCINOMA. 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{ "abstract": "Lung is the most common site of distant metastasis for patients with head and neck squamous cell carcinoma (HNSCC). However, differentiating second primary lung cancers from metastasis may be difficult for p16 negative HNSCC.\n\n\n\nWe describe a case of oral cavity squamous cell carcinoma (SCC) who was found to have lung nodule and hilar lymphadenopathy (LAD) after surgery and radiation therapy. Hilar node was consistent with SCC however, it was difficult to differentiate second primary lung cancer and metastasis from oral cavity SCC. Next-generation sequencing was done for the primary oral cavity and the hilar node. Both samples had the same type of TP53 mutation and variants of unknown significance suggesting metastatic HNSCC. He was treated with a chemotherapy regimen for metastatic HNSCC.\n\n\n\nMolecular studies can help to differentiate metastasis from second primary lung cancers for p16 negative HNSCC.", "affiliations": "Department of Hematology and Medical Oncology, Cleveland Clinic, Cleveland, Ohio, USA.;Department of Radiation Oncology, University of Kansas Medical Center, Kansas City, Kansas, USA.;University of New Mexico Comprehensive Cancer Center, University of New Mexico, Albuquerque, New Mexico, USA.;University of New Mexico Comprehensive Cancer Center, University of New Mexico, Albuquerque, New Mexico, USA.;Department of Pathology, University of New Mexico, Albuquerque, New Mexico, USA.", "authors": "Yilmaz|Emrullah|E|0000-0003-2308-713X;Gan|Gregory N|GN|;Schroeder|Thomas M|TM|;Cowan|Andrew|A|;Joste|Nancy|N|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1002/cnr2.1363", "fulltext": "\n==== Front\nCancer Rep (Hoboken)\nCancer Rep (Hoboken)\n10.1002/(ISSN)2573-8348\nCNR2\nCancer Reports\n2573-8348\nJohn Wiley and Sons Inc. Hoboken\n\n34161676\n10.1002/cnr2.1363\nCNR21363\nCase Report\nCase Reports\nRole of molecular signature to differentiate second primary lung cancer from metastasis in a patient with squamous cell carcinoma of oral cavity\nYilmaz et al.\nYilmaz Emrullah https://orcid.org/0000-0003-2308-713X\n1 [email protected]\n\nGan Gregory N. 2\nSchroeder Thomas M. 3\nCowan Andrew 3\nJoste Nancy 4\n1 Department of Hematology and Medical Oncology Cleveland Clinic Cleveland Ohio USA\n2 Department of Radiation Oncology University of Kansas Medical Center Kansas City Kansas USA\n3 University of New Mexico Comprehensive Cancer Center University of New Mexico Albuquerque New Mexico USA\n4 Department of Pathology University of New Mexico Albuquerque New Mexico USA\n* Correspondence\nEmrullah Yilmaz, MD, PhD, Department of Hematology and Medical Oncologt, Cleveland Clinic, Cleveland, OH.\nEmail: [email protected]\n\n23 6 2021\n8 2021\n4 4 10.1002/cnr2.v4.4 e136331 1 2021\n09 10 2020\n22 2 2021\n© 2021 The Authors. Cancer Reports published by Wiley Periodicals LLC.\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.\n\nAbstract\n\nBackground\n\nLung is the most common site of distant metastasis for patients with head and neck squamous cell carcinoma (HNSCC). However, differentiating second primary lung cancers from metastasis may be difficult for p16 negative HNSCC.\n\nCase\n\nWe describe a case of oral cavity squamous cell carcinoma (SCC) who was found to have lung nodule and hilar lymphadenopathy (LAD) after surgery and radiation therapy. Hilar node was consistent with SCC however, it was difficult to differentiate second primary lung cancer and metastasis from oral cavity SCC.\n\nNext‐generation sequencing was done for the primary oral cavity and the hilar node. Both samples had the same type of TP53 mutation and variants of unknown significance suggesting metastatic HNSCC. He was treated with a chemotherapy regimen for metastatic HNSCC.\n\nConclusion\n\nMolecular studies can help to differentiate metastasis from second primary lung cancers for p16 negative HNSCC.\n\nhead and neck cancer\nlung cancer\nlung metastasis\nmolecular signature\nsource-schema-version-number2.0\ncover-dateAugust 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.6 mode:remove_FC converted:26.08.2021\nYilmazE, GanGN, SchroederTM, CowanA, JosteN. Role of molecular signature to differentiate second primary lung cancer from metastasis in a patient with squamous cell carcinoma of oral cavity. Cancer Reports. 2021;4 :e1363. 10.1002/cnr2.1363\n==== Body\n1 INTRODUCTION\n\nHead and neck squamous cell carcinoma (HNSCC) patients are at risk for developing both lung metastasis and second primary lung squamous cell carcinoma.1, 2 P16 immunohistochemistry (IHC) can help to differentiate the metastasis vs the second primary if the primary HNSCC is human papilloma virus (HPV) related.3 However, diagnosis is more challenging for HPV‐unrelated, p16 negative HNSCC. The role of the IHC is limited to distinguish second primary lung SCC. Thyroid transcription factor 1 (TTF‐1) can be positive in 7%‐10% of primary lung carcinoma, and not found in head and neck cancer.4 An algorithm using cytokeratin 19 (CK19), matrix metallopeptidase 3 (MMP3), and peptidase inhibitor 3 (PI3) IHC was suggested to help differentiate metastasis from second lung primary SCC.5 Loss of heterozygosity and TP53 mutations were found to be stable during tumor progression in HNSCC.6 Therefore LOH and TP53 status were suggested as markers to diagnose metastasis in retrospective studies.6, 7, 8 In the era of molecular studies, we suggest that molecular profiling can help to differentiate metastasis vs the second primary for HPV negative cancers for these cancers. Here, we present the use of comprehensive molecular profiling in a patient with squamous cell carcinoma (SCC) of the oral cavity.\n\n2 CASE REPORT\n\nA 67‐year‐old male presented with an ulcer in the right ventral tongue, approximately 2 cm in the greatest dimension. He was then found to have SCC of the tongue, which immunohistochemical staining showed to be p16 negative. (Figure 1) He underwent right partial glossectomy with skin graft reconstruction and selective neck dissection, pathology was pT1N2b with negative margins and no extranodal extension. He then received adjuvant radiotherapy. His post‐treatment positron emission tomography (PET) showed a metabolic response in the neck, but a new spiculated right lower lobe mass and hilar and subcarinal nodes were found. (Figure 2) Fine needle aspiration (FNA) from the hilar node showed malignant squamous cells. IHC demonstrated strong staining of the tumor with cytokeratin 5 and p40 and no staining with TTF‐1, napsin A, and p16, Therefore cytology was consistent squamous cell carcinoma, however unable to exclude a second primary right lung SCC with hilar node involvement. Next‐generation sequencing (NGS) with FoundationOne was performed for both primary tongue tumor and hilar lymph node.\n\nFIGURE 1 Invasive squamous cell carcinoma involving the tongue. A, infiltrating nests of squamous cell carcinoma (H&E, ×200); B, p16 immunostain with negative staining (×200)\n\nFIGURE 2 PET/CT showing right lung nodule A, and right hilar lymph node B. CT imaging of the spiculated lung nodule C\n\nBoth specimens had the same TP53 (R273H) and BRCA2 (W563*) mutations. The specimen from the hilar lymph node had FAT1 (Q1138*) and TERT promoter (−124C > T) mutations in addition to TP53 and BRCA2. BRCA2 allele frequency was 50% suggesting germline mutation. His family history of cancer included his mother with multiple myeloma and his father with lung cancer and melanoma. So, the patient was referred to genetics and a blood test confirmed germline BRCA2 mutation. The variants of unknown significance (VUS) were also identical in both specimens. (Table 1) Having the identical TP53 mutation and VUS in both specimens was consistent with metastatic disease from SCC of the tongue. The patient was treated with carboplatin/5‐Fluorouracil (5‐FU) and cetuximab with initial partial response in lung nodule and hilar lymph node however, he subsequently had progression with bone metastasis. He was briefly on olaparib, and then pembrolizumab without response so he transitioned to hospice.\n\nTABLE 1 Genomic alterations and variants of unknown significance found in primary tongue lesion and hilar lymph node\n\n\tTongue lesion\tHilar lymph node\t\nGenomic alteration\tTP53 R273H\n\nBRCA2 W563*\n\n\tTP53 R273H\n\nBRCA2 W563*\n\nFAT1 Q1138\n\nTERT promoter −124C > T\n\n\t\nVariants of unknown significance\tJUN T239I\n\nMYST3 I729L\n\nNOTCH3 C1222G\n\nRAF1 A237G\n\nSRC K106R\n\nSUFU R289Q\n\n\tJUN T239I\n\nMYST3 I1729L\n\nNOTCH3 C1222G\n\nRAF1 A237G\n\nSRC K106R\n\nSUFU R289Q\n\n\t\n\n3 DISCUSSION\n\nLung is the most common site of distant metastasis in HNSCC. Given the high incidence of second primary lung squamous cell carcinoma in patients with HNSCC, differentiating the second primary from metastasis helps to identify the next line of treatment. Clinical features can help to guide the treatment. Lung metastasis from HNSCC usually presents as smoothly defined multiple lesions whereas lung cancer is usually a single spiculated lung nodule.9 Our patient had a spiculated lung nodule with associated hilar LAD suspicious for second primary lung cancer. On the other hand, his lung finding was seen within 6 months of the initial surgery and he had no tobacco smoking or alcohol history. Recurrence risk in HNSCC is higher in the first year of the initial treatment.10 Tobacco smoking increases the risk of the second primary malignancies in HNSCC patients.11 However, a recent study using the TP53 mutation status to differentiate metastasis from second primary lung malignancies suggested that 55% of the patients received incorrect treatments based on clinical and immunohistochemical data.8 Molecular alterations in pathways affecting the cell cycle, cell death, DNA repair mechanism, and cell differentiation are common in HNSCC.12 Incorporation of molecular profiling of the HPV negative HNSCC can help to distinguish second primary lung cancer from metastasis. (Figure 3) Molecular signature with clinical presentation supporting the metastasis from HNSCC, our patient received systemic treatment for metastatic HNSCC.\n\nFIGURE 3 A suggested approach to biopsy from suspicious lung nodule or mediastinal lymph node biopsy in head and neck squamous cell carcinoma\n\nInterestingly, our patient had FAT1 and TERT promoter mutations in the metastatic tumor, while they were not observed in the primary tumor FAT1 mutation was observed in 21.7% of the HNSCC samples in The Cancer Genome Atlas (TCGA) database.12 FAT1 is known to have a role in cell migration and EMT.13, 14 TERT promoter mutations are common in solid tumors and associated with metastasis and poor survival.15, 16 Although the tumor heterogeneity could have played a role in the lack of FAT1 and TERT promoter mutations in the primary tumor; similar allele frequency with the TP53 mutation in both samples suggests the same clone with the primary tumor. As FAT1 and TERT are both known to be associated with cell migration and metastasis; the subclones with these two mutations could have been selected following radiation to drive the metastasis. Analysis of larger cohorts to differentiate the molecular characteristics of primary tumor and metastasis for HNSCC might help to identify mechanisms of metastasis.\n\nSomatic mutations of the BRCA2 gene can be seen in up to 9% of HNSCC.17 However, germline mutations can also be identified using NGS.18, 19 This also brings ethical considerations to share with patients incidental findings from NGS. Our patient knew about the risk of BRCA2 and hereditary cancer risk and since he had 50% BRCA2 allele frequency, he consented for genetics counseling which confirmed germline BRCA2 mutations. Germline BRCA2 mutation has been identified in SCC of the esophagus and lung.20, 21 Poly (ADP‐ribose) polymerase (PARP) inhibitors are used in ovarian, breast, and pancreatic cancer patients with germline BRCA mutations.22, 23, 24 However, the role of the PARP inhibitors in other solid tumors with uncommon germline BRCA mutations is not well known. Our patient was briefly on PARP inhibitor without response.\n\nTo summarize, the molecular signature of primary HNSCC tumor and hilar node led to three observations in our patient: (a) Molecular signature may help to identify metastasis from second primary lung cancer for p16 negative HNSCC, (b) Further studies needed to identify differences in molecular signatures of primary tumor and metastasis of HNSCC, which may help to better understanding and therapeutics strategies for metastasis, (c) Increased use of NGS may increase identification of germline mutations.\n\nCONFLICT OF INTEREST\n\nNone of the authors have a conflict of interest to declare.\n\nAUTHOR CONTRIBUTIONS\n\nGregory N Gan: Conceptualization; writing‐review and editing. Thomas M Schroeder: Conceptualization; writing‐review and editing. Andrew Cowan: Conceptualization; writing‐review and editing. Nancy Joste: Conceptualization; data curation; formal analysis; writing‐review and editing.\n\nETHICS STATEMENT\n\nThe patient was not alive at the time of the manuscript submission and he did not have contact information for next of kin documented in his medical records, therefore we were unable to obtain a written informed consent. This case study was reviewed by the University of New Mexico Human Research Review Committee (HRRC). The HRRC determined that the proposed activity is not research involving human subjects. HRRC review and approval is not required.\n\nDATA AVAILABILITY STATEMENT\n\nThe data that support the findings of this study are available from the corresponding author upon reasonable request.\n==== Refs\nREFERENCES\n\n1 BudnikJ, DeNunzioNJ, SinghDP, MilanoMT. Second primary non‐small‐cell lung cancer after head and neck cancer: a population‐based study of clinical and pathologic characteristics and survival outcomes in 3597 patients. 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Cancer Med. 2019;8 (12 ):5810‐5819.31400079\n11 DoKA, JohnsonMM, LeeJJ, et al. Longitudinal study of smoking patterns in relation to the development of smoking‐related secondary primary tumors in patients with upper aerodigestive tract malignancies. Cancer. 2004;101 (12 ):2837‐2842.15536619\n12 LawrenceMS, SougnezC, LichtensteinL, et al. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 2015;517 (7536 ):576‐582.25631445\n13 MorrisLG, KaufmanAM, GongY, et al. Recurrent somatic mutation of FAT1 in multiple human cancers leads to aberrant Wnt activation. Nat Genet. 2013;45 (3 ):253‐261.23354438\n14 NishikawaY, MiyazakiT, NakashiroK, et al. Human FAT1 cadherin controls cell migration and invasion of oral squamous cell carcinoma through the localization of β‐catenin. Oncol Rep. 2011;26 (3 ):587‐592.21617878\n15 HannenR, BartschJW. Essential roles of telomerase reverse transcriptase hTERT in cancer stemness and metastasis. FEBS Lett. 2018;592 (12 ):2023‐2031.29749098\n16 WangK, WangRL, LiuJJ, et al. The prognostic significance of hTERT overexpression in cancers: a systematic review and meta‐analysis. Medicine (Baltimore). 2018;97 (35 ):e11794.30170373\n17 FeldmanR, GatalicaZ, KnezeticJ, et al. Molecular profiling of head and neck squamous cell carcinoma. Head Neck. 2016;38 (Suppl 1 ):E1625‐E1638.26614708\n18 OngPY, PoonSL, TanKT, et al. Using next‐generation sequencing (NGS) platform to diagnose pathogenic germline BRCA1/2 mutations from archival tumor specimens. Gynecol Oncol. 2019;155 (2 ):275‐279.31481248\n19 StjepanovicN, BedardPL, OzaAM, et al. Incidental germline findings identified in a somatic genomic sequencing program for advanced cancer patients. J Clin Oncol. 2016;34 (15_suppl ):1532‐1532.\n20 AkbariMR, MalekzadehR, NasrollahzadehD, et al. Germline BRCA2 mutations and the risk of esophageal squamous cell carcinoma. Oncogene. 2008;27 (9 ):1290‐1296.17724471\n21 HuX, YangD, LiY, et al. Prevalence and clinical significance of pathogenic germline BRCA1/2 mutations in Chinese non‐small cell lung cancer patients. Cancer Biol Med. 2019;16 (3 ):556‐564.31565484\n22 RobsonM, ImSA, SenkusE, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017;377 (6 ):523‐533.28578601\n23 DomchekSM, AghajanianC, Shapira‐FrommerR, et al. Efficacy and safety of olaparib monotherapy in germline BRCA1/2 mutation carriers with advanced ovarian cancer and three or more lines of prior therapy. Gynecol Oncol. 2016;140 (2 ):199‐203.26723501\n24 GolanT, HammelP, ReniM, et al. Maintenance Olaparib for germline BRCA‐mutated metastatic pancreatic cancer. N Engl J Med. 2019;381 (4 ):317‐327.31157963\n\n", "fulltext_license": "CC BY", "issn_linking": "2573-8348", "issue": "4(4)", "journal": "Cancer reports (Hoboken, N.J.)", "keywords": "head and neck cancer; lung cancer; lung metastasis; molecular signature", "medline_ta": "Cancer Rep (Hoboken)", "mesh_terms": null, "nlm_unique_id": "101747728", "other_id": null, "pages": "e1363", "pmc": null, "pmid": "34161676", "pubdate": "2021-08", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "31400079;26614708;23354438;29749098;31481248;26723501;27597287;28578601;31565484;15536619;30914310;11793443;28949800;25631445;34161676;29522268;21617878;10679659;31157963;16847186;26350882;17724471;18318581;30170373", "title": "Role of molecular signature to differentiate second primary lung cancer from metastasis in a patient with squamous cell carcinoma of oral cavity.", "title_normalized": "role of molecular signature to differentiate second primary lung cancer from metastasis in a patient with squamous cell carcinoma of oral cavity" }

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Role of molecular signature to differentiate second primary lung cancer from metastasis in a patient with squamous cell carcinoma of oral cavity. 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{ "abstract": "A longer duration of untreated psychosis (DUP) has been linked with poor clinical outcomes and variation in resting-state striatal connectivity with central executive regions. However, the link between DUP and task-based activation of executive neurocognition has not previously been examined. This functional magnetic resonance imaging study examined the association between DUP and both activation and frontostriatal functional connectivity during a visual working memory (WM) paradigm in patients with first-episode psychosis.\n\n\n\nPatients with first-episode psychosis (n = 37) underwent functional magnetic resonance imaging scanning while performing a visual WM task. At the single-subject level, task conditions were modeled; at the group level, each condition was examined along with DUP. Activation was examined within the dorsolateral prefrontal cortex, a primary region supporting visual WM activation. Frontostriatal functional connectivity during the WM was examined via psychophysical interaction between the dorsal caudate and the dorsolateral prefrontal cortex. Results were compared with a reference range of connectivity values in a matched group of healthy volunteers (n = 25). Task performance was also examined in relation to neuroimaging findings.\n\n\n\nNo significant association was observed between DUP and WM activation. Longer DUP showed less functional frontostriatal connectivity with the maintenance of increasing WM load. Results were not related to task performance measures, consistent with previous work.\n\n\n\nOur data suggest that DUP may affect frontostriatal circuitry that supports executive functioning. Future work is necessary to examine if these findings contribute to the mechanism underlying the relationship between DUP and worsened clinical outcomes.", "affiliations": "Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania.;Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania.;Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania.;Department of Psychology, Temple University, Philadelphia, Pennsylvania.;Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania.;Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania.;Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Psychology, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania.;Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania. Electronic address: [email protected].", "authors": "Manivannan|Ashwinee|A|;Foran|William|W|;Jalbrzikowski|Maria|M|;Murty|Vishnu P|VP|;Haas|Gretchen L|GL|;Tarcijonas|Goda|G|;Luna|Beatriz|B|;Sarpal|Deepak K|DK|", "chemical_list": "D014150:Antipsychotic Agents", "country": "United States", "delete": false, "doi": "10.1016/j.bpsc.2019.01.007", "fulltext": null, "fulltext_license": null, "issn_linking": "2451-9022", "issue": "4(5)", "journal": "Biological psychiatry. Cognitive neuroscience and neuroimaging", "keywords": "Duration of untreated psychosis; Frontostriatal connectivity; Psychosis; Schizophrenia; Working memory; fMRI", "medline_ta": "Biol Psychiatry Cogn Neurosci Neuroimaging", "mesh_terms": "D000293:Adolescent; D000328:Adult; D014150:Antipsychotic Agents; D002648:Child; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008570:Memory, Short-Term; D009434:Neural Pathways; D017397:Prefrontal Cortex; D011618:Psychotic Disorders; D061665:Time-to-Treatment; D055815:Young Adult", "nlm_unique_id": "101671285", "other_id": null, "pages": "454-461", "pmc": null, "pmid": "30852127", "pubdate": "2019-05", "publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't", "references": "27386561;18971297;26315980;25300902;14992973;25471062;25651194;26873890;18400794;19042912;29137828;16448803;19675535;26831091;16343792;24559680;22378170;12271790;28320846;29748629;23337947;25649287;12505813;1503130;25251486;22569188;19042105;16199825;21596142;21914644;19897178;28294137;15231551;27056754;23034655;25588418;17306506;11581115;26558708;24067164;24657353;19652121;3387514;11231835;19196494;21706013;25372846;28634088;25252316", "title": "Association Between Duration of Untreated Psychosis and Frontostriatal Connectivity During Maintenance of Visuospatial Working Memory.", "title_normalized": "association between duration of untreated psychosis and frontostriatal connectivity during maintenance of visuospatial working memory" }

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{ "abstract": "Drug-induced immune hemolytic anemia (DIIHA) is an uncommon side effect of pharmacologic intervention. A rare mediator of DIIHA, carboplatin is an agent used to treat many pediatric cancers. We describe here, the first case of fatal carboplatin induced DIIHA in a pediatric patient and a brief review of the literature. Our patient developed acute onset of multi-organ failure with evidence of complement activation, secondary to a drug induced red cell antibody. Early recognition of the systemic insult associated with carboplatin induced hemolytic anemia may allow for future affected patients to receive plasmapheresis, a potentially effective therapy.", "affiliations": "Division of Pediatric Hematology/Oncology, Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA.;Division of Pediatric Hematology/Oncology, Department of Pediatrics, Wake Forest Baptist Health, Medical Center Blvd, Winston-Salem, NC, USA.;Departments of Pathology, Medicine and Pediatrics, Oregon Health and Science University, Portland, OR, USA.;American Red Cross Blood Services, Pomona, CA, USA.;American Red Cross Blood Services, Pomona, CA, USA.;Division of Pediatric Hematology/Oncology, Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA.;Division of Pediatric Hematology/Oncology, Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA.", "authors": "Haley|Kristina M|KM|;Russell|Thomas B|TB|;Boshkov|Lynn|L|;Leger|Regina M|RM|;Garratty|George|G|;Recht|Michael|M|;Nazemi|Kellie J|KJ|", "chemical_list": null, "country": "New Zealand", "delete": false, "doi": "10.2147/JBM.S59192", "fulltext": "\n==== Front\nJ Blood MedJ Blood MedJournal of Blood Medicine1179-2736Dove Medical Press 10.2147/JBM.S59192jbm-5-055Case ReportFatal carboplatin-induced immune hemolytic anemia in a child with a brain tumor Haley Kristina M 1Russell Thomas B 2Boshkov Lynn 3Leger Regina M 4Garratty George 4†Recht Michael 1Nazemi Kellie J 11 Division of Pediatric Hematology/Oncology, Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA2 Division of Pediatric Hematology/Oncology, Department of Pediatrics, Wake Forest Baptist Health, Medical Center Blvd, Winston-Salem, NC, USA3 Departments of Pathology, Medicine and Pediatrics, Oregon Health and Science University, Portland, OR, USA4 American Red Cross Blood Services, Pomona, CA, USACorrespondence: Kristina M Haley, Division of Pediatric Hematology/Oncology, Department of Pediatrics, Oregon Health & Science University, 3181 SW Gaines Street, Mail code: CDRCP, Portland, OR 97239, USA, Tel +1 503 494 0829, Fax +1 503 494 2721, Email [email protected]† George Garratty passed away March 2014\n\n2014 15 5 2014 5 55 58 © 2014 Haley et al. This work is published by Dove Medical Press Ltd, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License2014The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Ltd, provided the work is properly attributed.Drug-induced immune hemolytic anemia (DIIHA) is an uncommon side effect of pharmacologic intervention. A rare mediator of DIIHA, carboplatin is an agent used to treat many pediatric cancers. We describe here, the first case of fatal carboplatin induced DIIHA in a pediatric patient and a brief review of the literature. Our patient developed acute onset of multi-organ failure with evidence of complement activation, secondary to a drug induced red cell antibody. Early recognition of the systemic insult associated with carboplatin induced hemolytic anemia may allow for future affected patients to receive plasmapheresis, a potentially effective therapy.\n\nKeywords\nhemolytic anemiacarboplatingliomacomplement fixationdrug-induced hemolysis\n==== Body\nCase\nAn 11-year-old female was being treated for low-grade astrocytoma with carboplatin and vincristine. The patient was also receiving levothyroxine for central hypothyroidism, ondansetron for chemotherapy-induced nausea, omeprazole for gastrointestinal reflux, and trimethoprim-sulfamethoxazole for Pneumocystis jirovecii pneumonia prophylaxis. Notably, she was not receiving any steroids. On day 15 of cycle five (carboplatin dose number 22), the patient reported acute lower back pain prior to receiving chemotherapy. Her physical exam was unremarkable. She had a stable macrocytic anemia and normal platelet count (Table 1). Thought to be of musculoskeletal origin, the back pain resolved with hydromorphone and ibuprofen. Vincristine 2 mg (max dose) and carboplatin 294 mg (175 mg/m2) were administered. She developed abdominal pain, diarrhea, chills, and tachypnea within approximately 8 hours of chemotherapy administration. The following morning, upon arrival at the local emergency room, she was afebrile, tachycardic, hypertensive, tachypneic, and hypoxemic. She had diffuse abdominal tenderness, delayed capillary refill time, and a normal neurologic exam. She had worsening anemia (with rouleaux formation but without schistocytes) and had acute renal failure and hepatitis (Table 1). Transfusion support and broad-spectrum antibiotics were initiated. She was started on continuous positive airway pressure, and remained alert and interactive.\n\nPossible explanations of the patient’s acute presentation include; hemolytic uremic syndrome (HUS), atypical HUS, viral hepatitis, autoimmune hemolytic anemia, sepsis with disseminated intravascular coagulation (DIC), and toxic exposure. Concurrent with this patient’s presentation, there was an epidemic of HUS occurring in her community. She denied similar exposures to those reported by the affected patients. Review of the peripheral smear did not demonstrate the typical significant schistocytosis found in HUS. Furthermore, stool cultures were negative. While the patient presented acutely with multi-organ failure, she was not febrile and did not have the characteristic distributive shock associated with bacterial sepsis. Blood culture at the time of admission grew non-typable Haemophilis influenzae; repeat cultures after 24 hours of cefepime were negative. It seemed that her severe illness could not be primarily attributed to this positive culture because she was not neutropenic, non-typeable H. influenzae is not typically associated with severe infection, and the culture cleared quickly with appropriate antibiotics.\n\nComputed tomography (CT) of the chest, abdomen, and pelvis done on hospital day 2, demonstrated a small right pleural effusion, multi-focal nodular ground glass and tree-in-bud opacities in both lungs concerning for atypical infections or diffuse alveolar injury, hepatic steatosis versus edema, and edematous kidneys. An endotracheal aspirate culture grew Aspergillus. As she was not neutropenic and had not been on steroids previously, this appeared to be consistent with laboratory contaminant. Furthermore, her chest CT did not reveal the typical findings associated with invasive pulmonary aspergillosis. Serum viral studies were negative except for Epstein–Barr virus (EBV polymerase chain reaction: 320 copies/mL). Serum cortisol was normal at 46 μg/dL. Acetaminophen level was less than 10 μg/mL.\n\nWhile undergoing dialysis on hospital day 2 the patient complained of severe headache, became lethargic, and required intubation. Her pupils became fixed and dilated. Head CT demonstrated diffuse cerebral and cerebellar edema (Figure 1). An external ventricular drain was placed. Approximately 40 hours into the hospitalization, she had no brain or brainstem activity. She was pronounced dead 64 hours after initial presentation to our hospital.\n\nThe temporal relationship between the patient’s acute deterioration and the administration of carboplatin and vincristine suggested that one of these agents or the fluids accompanying them was the cause for multi-organ failure and death. The hospital’s carboplatin and vincristine stock concentrations and the patient’s doses were verified. The patient had received the only dose of carboplatin from a specific manufacturer on that day, while many patients had received vincristine from the same supplier. The stock of carboplatin was quarantined. Evaluation for organismal and toxic contamination was unrevealing. An US Food and Drug Administration (FDA) MedWatch alert was placed. No other reports of hemolytic anemia or multi-organ failure were reported in patients receiving carboplatin from this specific manufacturer.\n\nAn initial direct anti-globulin test (DAT) at our institution was negative. Evidence of intravascular hemolysis associated with acute renal failure, hepatitis, and coagulopathy, plus concern that the other findings did not fully explain her severe clinical presentation prompted repeat DAT and collection of multiple samples for investigation of carboplatin drug-induced immune hemolytic anemia (DIIHA), by the American Red Cross in Pomona, CA, USA. The repeat DAT was strongly positive for immunoglobulin (Ig) G (3+) and C3 (3+) as well as weakly positive (1+) for IgM. The patient’s serum was found to contain strongly reactive carboplatin-dependent IgG and IgM antibodies that agglutinated (titer =2) and sensitized (titer =32) carboplatin-treated red cells but not untreated red cells. The patient’s serum also agglutinated (titer =16) and sensitized (titer =128) untreated red cells in the presence of a solution of carboplatin; there was no reactivity in the control without drug added. A weak drug-independent antibody was also found in an acid eluate prepared from the patient’s red cells. This testing confirmed carboplatin-induced immune hemolytic anemia.\n\nA post-mortem exam was requested for the patient by our institution, but the family declined.\n\nDiscussion\nDIIHA is a rare cause of hemolytic anemia with an estimated incidence of one per million individuals.2 Over 125 drugs have been implicated in DIIHA, with additional drugs reported to be associated with hemolysis but not meeting the full criteria for DIIHA.2 The mechanism and severity of hemolysis varies among different drugs. Approximately 15% of the implicated drugs are anti-neoplastic agents.2,3\n\nThese drugs cause immune hemolysis through drug-dependent and drug-independent mechanisms. Drug-dependent antibodies can result in hemolytic anemia through two mechanisms.3 In the first, a drug binds covalently to proteins on the red cell membrane, then anti-drug antibodies bind to the drug-red blood cell (RBC) membrane complex, resulting in extravascular hemolysis. Two hypotheses have been proposed to explain the second mechanism.3 According to the immune complex hypothesis; anti-drug antibody combines with the drug to form an immune complex. This immune complex then attaches to the RBC membrane and activates complement. Alternatively, the neoantigen hypothesis suggests that the drug binds to the RBC membrane and changes the membrane forming a novel antigen that is part red cell membrane and part drug. Specific anti-drug antibodies then bind to the neoantigen, which may fix complement.\n\nThe mechanism of antibody formation in drug-independent hemolytic anemia is poorly understood but has been attributed to molecular mimicry, drug adsorption causing red cell membrane alteration, or immune dysregulation.3 The antibody reacts in vitro in the absence of drug. Laboratory and clinical findings are identical to RBC autoantibodies and autoimmune hemolytic anemia (AIHA). The treatment of choice for DIIHA is supportive care and immediate withdrawal of the causative agent. Steroids or intravenous IgG are not indicated for drug-dependent DIIHA. However, these therapies may provide some benefit in treatment of drug-independent DIIHA given the similarities to AIHA.3,4 Hence, DIIHA may result in life-threatening or fatal hemolytic anemia.2,3\n\nPlatinum-based chemotherapies result in cytopenias through marrow suppression but may also cause cytopenias through immune mediated mechanisms.5,6 IgE mediated hypersensitivity reactions occur with platinum-based chemotherapies as well, but likely through a separate mechanism from immune-mediated cytopenias.7 There have been several reports of oxaliplatin-induced immune cytopenias in the literature;5,6,8–10 however, only three case reports of carboplatin-induced immune hemolytic anemia exist. Marani et al12 described an 8-year-old boy, treated with a carboplatin-based chemotherapy regimen, who complained of low back pain during his 26th dose of carboplatin with subsequent overt intravascular hemolysis with his 27th dose. His anemia responded to blood transfusion, and the hemolysis ceased without further intervention.11,12 Maloisal et al13 reported a 44-year-old female developing hemolytic anemia following carboplatin administration. Interestingly, her hemolysis did not worsen with additional doses. Dacha et al14 described a 72-year-old female who developed acute onset intravascular hemolysis during infusion of carboplatin and subsequently died of multi-organ failure. In our patient, carboplatin-dependent antibodies were identified. The clinical picture and laboratory evidence support the pathophysiologic mechanism of drug-dependent immune hemolytic anemia resulting in complement fixation and intravascular hemolysis prompting a systemic inflammatory response, resulting in acute multi-organ failure and death.\n\nConclusion\nAlthough uncommon, DIIHA is often responsive to drug withdrawal and supportive care.3 Select drugs have been implicated in a more serious, often fatal form of DIIHA. Here we report the second case of fatal carboplatin-induced immune hemolytic anemia, the first in a pediatric patient. Despite its rarity, DIIHA must be included in the differential diagnosis of any patient receiving platinum-based chemotherapy that presents with overt hemolysis, sudden changes in serum chemistry values, or unexplained back pain. Along with supportive care, clearing the offending antibodies via plasma exchange may control the underlying cause and prevent the brisk and efficient complement fixation that characterizes this form of severe DIIHA.1 Due to the rapidity of clinical deterioration, plasma exchange was not performed in this case.\n\nAcknowledgments\nThe authors wish to acknowledge the contributions of our colleague, Dr George Garratty, to the fields of immunohematology, hematology, and transfusion medicine. Dr Garratty sadly passed away during the preparation of this manuscript. Dr Garratty’s work and research propelled the field of immunohematology to new fronts, and his persistent curiosity and pure appreciation for the complex nature of transfusion medicine and immune hemolytic anemia was infectious and inspiring. Always available to clinicians and scientists across the world, Dr Garratty was the consummate teacher –guiding us through the complex and sometimes confusing answers to our clinical problems. Dr Garratty was always just a phone call or email away and always willing to help us explain our particular clinical conundrum while simultaneously shedding light on how we could apply the information to the next scenario. He will surely be missed.\n\nDisclosure\n\nThe authors have no conflicts of interest to disclose.\n\nFigure 1 An axial, non-contrast enhanced view of the brain shows severe diffuse cerebral and cerebellar edema.\n\nNotes: The normal definition between gray and white matter tissue is poor because of the edema. The quadrigeminal and ambient basal cisterns (white arrows) are no longer seen due to upward transtentorial herniation. The fourth ventricle (black circle) is not seen as edematous cerebellum displaces the CSF. The cystic (asterisk) and calcified suprasellar mass is seen.\n\nTable 1 Vital signs and laboratory values before acute decompensation, on the day of therapy, at the referring hospital, and at our institution\n\n\tClinic visit for chemotherapy 2 weeks prior to acute decompensation\tDay of clinic visit (1 day prior to acute decompensation)\tAt presentation to referring hospital\tAt presentation to our institution\t\nHeart rate (bpm)\t91\t109\t122\t125\t\nBlood pressure (mmHg)\t111/70\t149/90\t134/82\t156/91\t\nRespiratory rate (bpm)\t18\t22\t44\t45\t\nWhite blood cell count (μL)\t4.8\t7.2\t9.3\t8.4\t\nAbsolute neutrophil count (μL)\t2,300\t2,900\t4,950\t3,700\t\nHemoglobin (g/dL)\t12.2\t9.9\t7.2\t6.2\t\nMean corpuscular volume (fL)\t101.1\t98.1\t90.7\tInterfering substances\t\nPlatelet count (μL)\t224\t241\t181\t92\t\nBlood urea nitrogen (mg/dL)\t11\tNA\t47\t50\t\nCreatinine (mg/dL)\t0.49\tNA\t3.2\t4.23\t\nAspartate aminotransferase (U/L)\t23\tNA\t1,636\t3,977\t\nAlanine aminotransferase (U/L)\t27\tNA\t1,263\t3,029\t\nTotal bilirubin (mg/dL)\t0.4\tNA\t5.6\t7.7\t\nDirect bilirubin (mg/dL)\tNA\tNA\tNA\t3\t\nAbbreviations: NA, not available; bpm, beats or breaths per minute.\n==== Refs\nReferences\n1 Doratota S Recht M Garratty G Krupicka M Thomas GA Boshkov L Successful treatment of life-threatening ceftriaxone-induced hemolysis by plasmapheresis Transfusion 2009 49 S 13A abtr 18954397 \n2 Garratty G Arndt PA Review: drug-induced immune hemolytic anemia – the last decade Immunohematology 2004 20 3 138 146 15373645 \n3 Garratty G Immune hemolytic anemia associated with drug therapy Blood Rev 2010 24 4–5 143 150 20650555 \n4 Pierce A Nester T Pathology consultation on drug-induced hemolytic anemia Am J Pathol 2011 136 1 7 12 \n5 Cobo F De Celis G Pereira A Latorre X Pujadas J Albiol S Oxaliplatin-induced immune hemolytic anemia: a case report and review of the literature Anticancer Drugs 2007 18 8 973 976 17667605 \n6 Arndt PA Garratty G Isaak E Bolger M Lu Q Positive direct and indirect anti-globulin tests associated with oxaliplatin can be due to drug antibody and/or drug-induced nonimmunologic protein adsorption Transfusion 2009 49 4 711 718 19192254 \n7 Makrilia N Syrigou E Kaklamanos I Manolopoulos L Saif MW Hypersensitivity reactions associated with platinum antineoplastic agents: a systematic review Met Based Drugs Epub 9 20 2010 \n8 Hofheinz RD Nguyen XD Buchheidt D Kerowgan M Hehlmann R Hochhaus A Two potential mechanisms of oxaliplatin-induced haemolytic anemia in a single patient Cancer Chemother Pharmacol 2004 53 276 277 14676977 \n9 Sorbye H Bruserud O Dahl O Oxaliplatin-induced haematological emergency with an immediate severe thrombocytopenia and haemolysis Acta Oncol 2001 40 7 882 883 11859992 \n10 Teng CJ Hsieh YY Chen KW Chao TC Tzeng CH Wang WS Sudden-onset pancytopenia with intracranial hemorrhage after oxaliplatin treatment: a case report and literature review Jpn J Clin Oncol 2011 41 1 125 129 20826449 \n11 Marani T Leatherbarrow HB Armstrong KS Carboplatin-induced immune hemolytic anemia (CIHA) due to an antibody reaction with features of both the immune complex (IC) and drug-adsorption (DA) mechanisms [abstract] Transfusion 1994 34 20S \n12 Marani TM Trich MB Armstrong KS Carboplatin-induced immune hemolytic anemia Transfusion 1996 36 11–12 1016 1018 8937414 \n13 Maloisal F Kurtz JE Andres E Gorodetsky C Dufour P Oberling F Platin salts-induced hemolytic anemia: cisplatin- and the 2nd case of carboplatin-induced hemolysis Anticancer Drugs 1995 6 2 324 326 7795280 \n14 Dacha S Reddivan AK Latta S Devidi M Iroegbu N Carboplatin-induced fatal autoimmune hemolytic anemia: first reported case World J Oncol 2010 1 4 173 175\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1179-2736", "issue": "5()", "journal": "Journal of blood medicine", "keywords": "carboplatin; complement fixation; drug-induced hemolysis; glioma; hemolytic anemia", "medline_ta": "J Blood Med", "mesh_terms": null, "nlm_unique_id": "101550884", "other_id": null, "pages": "55-8", "pmc": null, "pmid": "24868179", "pubdate": "2014", "publication_types": "D002363:Case Reports", "references": "17667605;8937414;19192254;15373645;21685026;20826449;20650555;11859992;14676977;7795280;20886011;29147201", "title": "Fatal carboplatin-induced immune hemolytic anemia in a child with a brain tumor.", "title_normalized": "fatal carboplatin induced immune hemolytic anemia in a child with a brain tumor" }

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{ "abstract": "Concurrent chemoradiotherapy (CCRT) with three-weekly high-dose cisplatin (100 mg/m2) is a standard treatment for locally advanced head and neck squamous cell carcinoma (HNSCC), but compliance with cisplatin is often poor due to various adverse events. The aim of this prospective, observational study was to determine the predictors of achievement of full-dose cisplatin.\n\n\n\nA prospective, observational study was conducted involving 60 patients who received CCRT with three-weekly high-dose cisplatin (100 mg/m2) for locally advanced HNSCC. Possible predictors affecting compliance with cisplatin were subjected to univariate and multivariate logistic regression analyses. Age, sex, primary site, clinical stage, treatment intent, history of hypertension, diabetes mellitus, smoking and drinking habits, body mass index, creatinine clearance, serum albumin, controlling nutrition status, trace elements (Fe, Zn, Cu, Se), acute kidney injury, white blood cell count decrease, neutrophilia, and weight loss were the variables evaluated.\n\n\n\nTwenty-seven patients achieved full-dose cisplatin (300 mg/m2), and the other 33 patients did not. Multivariate logistic regression analysis showed that both mild renal dysfunction and selenium deficiency before treatment independently had negative impacts on achievement of full-dose cisplatin.\n\n\n\nAs well as renal function, selenium deficiency is a potential therapeutic target for CCRT with high-dose cisplatin in HNSCC patients.", "affiliations": "Department of Otorhinolaryngology, Head and Neck Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan. Electronic address: [email protected].;Department of Otorhinolaryngology, Head and Neck Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan.;Department of Otorhinolaryngology, Head and Neck Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan.;Department of Otorhinolaryngology, Head and Neck Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan.;Department of Otorhinolaryngology, Head and Neck Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan.;Department of Otorhinolaryngology, Head and Neck Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan.;Department of Otorhinolaryngology, Head and Neck Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan.;Department of Otolaryngology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu City 501-1193, Japan.;Department of Otorhinolaryngology, Head and Neck Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan.", "authors": "Ohkoshi|Akira|A|;Ishii|Ryo|R|;Wakamori|Shun|S|;Nakayama|Yuki|Y|;Yoshida|Takuya|T|;Higashi|Kenjiro|K|;Nakanome|Ayako|A|;Ogawa|Takenori|T|;Katori|Yukio|Y|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1016/j.oraloncology.2021.105475", "fulltext": null, "fulltext_license": null, "issn_linking": "1368-8375", "issue": "121()", "journal": "Oral oncology", "keywords": "Cisplatin; Concurrent chemoradiotherapy; Head and neck cancer; Renal insufficiency; Selenium; Trace elements", "medline_ta": "Oral Oncol", "mesh_terms": null, "nlm_unique_id": "9709118", "other_id": null, "pages": "105475", "pmc": null, "pmid": "34364132", "pubdate": "2021-10", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Serum selenium predicts achievement of full-dose cisplatin in concurrent chemoradiotherapy for locally advanced head and neck squamous cell carcinoma: A prospective, observational study.", "title_normalized": "serum selenium predicts achievement of full dose cisplatin in concurrent chemoradiotherapy for locally advanced head and neck squamous cell carcinoma a prospective observational study" }

[ { "companynumb": "JP-HQ SPECIALTY-JP-2021INT000236", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "018057", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG/M2, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Squamous cell carcinoma of head and neck", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RADIATION THERAPY" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Squamous cell carcinoma of head and neck", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RADIATION THERAPY" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Septic shock", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute respiratory distress syndrome", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Ohkoshi A., Ishii R., Wakamori S., Nakayama Y., Yoshida T., Higashi K., et al. Serum selenium predicts achievement of full-dose cisplatin in concurrent chemoradiotherapy for locally advanced head and neck squamous cell carcinoma: A prospective, observational study. 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Serum selenium predicts achievement of full-dose cisplatin in concurrent chemoradiotherapy for locally advanced head and neck squamous cell carcinoma: A prospective, observational study. 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{ "abstract": "OBJECTIVE\nMethotrexate (MTX) can cause significant clinical neurotoxicity and asymptomatic leukoencephalopathy. We sought to identify clinical, pharmacokinetic, and genetic risk factors for these MTX-related toxicities during childhood acute lymphoblastic leukemia (ALL) therapy and provide data on safety of intrathecal and high-dose MTX rechallenge in patients with neurotoxicity.\n\n\nMETHODS\nProspective brain magnetic resonance imaging was performed at four time points for 369 children with ALL treated in a contemporary study that included five courses of high-dose MTX and 13 to 25 doses of triple intrathecal therapy. Logistic regression modeling was used to evaluate clinical and pharmacokinetic factors, and a genome-wide association study (GWAS) was performed to identify germline polymorphisms for their association with neurotoxicities.\n\n\nRESULTS\nFourteen patients (3.8%) developed MTX-related clinical neurotoxicity. Of 13 patients rechallenged with intrathecal and/or high-dose MTX, 12 did not experience recurrence of neurotoxicity. Leukoencephalopathy was found in 73 (20.6%) of 355 asymptomatic patients and in all symptomatic patients and persisted in 74% of asymptomatic and 58% of symptomatic patients at the end of therapy. A high 42-hour plasma MTX to leucovorin ratio (measure of MTX exposure) was associated with increased risk of leukoencephalopathy in multivariable analysis (P = .038). GWAS revealed polymorphisms in genes enriched for neurodevelopmental pathways with plausible mechanistic roles in neurotoxicity.\n\n\nCONCLUSIONS\nMTX-related clinical neurotoxicity is transient, and most patients can receive subsequent MTX without recurrence of acute or subacute symptoms. All symptomatic patients and one in five asymptomatic patients develop leukoencephalopathy that can persist until the end of therapy. Polymorphisms in genes related to neurogenesis may contribute to susceptibility to MTX-related neurotoxicity.", "affiliations": "All authors: St Jude Children's Research Hospital; and Deepa Bhojwani, Jun J. Yang, Hiroto Inaba, Jeffrey E. Rubnitz, Monika L. Metzger, Scott C. Howard, Raul C. Ribeiro, Sima Jeha, John T. Sandlund, and Ching-Hon Pui, University of Tennessee Health Sciences Center, College of Medicine, Memphis, TN.", "authors": "Bhojwani|Deepa|D|;Sabin|Noah D|ND|;Pei|Deqing|D|;Yang|Jun J|JJ|;Khan|Raja B|RB|;Panetta|John C|JC|;Krull|Kevin R|KR|;Inaba|Hiroto|H|;Rubnitz|Jeffrey E|JE|;Metzger|Monika L|ML|;Howard|Scott C|SC|;Ribeiro|Raul C|RC|;Cheng|Cheng|C|;Reddick|Wilburn E|WE|;Jeha|Sima|S|;Sandlund|John T|JT|;Evans|William E|WE|;Pui|Ching-Hon|CH|;Relling|Mary V|MV|", "chemical_list": "D000964:Antimetabolites, Antineoplastic; D002955:Leucovorin; D008727:Methotrexate", "country": "United States", "delete": false, "doi": "10.1200/JCO.2013.53.0808", "fulltext": null, "fulltext_license": null, "issn_linking": "0732-183X", "issue": "32(9)", "journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", "keywords": null, "medline_ta": "J Clin Oncol", "mesh_terms": "D000293:Adolescent; D000964:Antimetabolites, Antineoplastic; D000971:Antineoplastic Combined Chemotherapy Protocols; D001921:Brain; D002648:Child; D002675:Child, Preschool; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D018095:Germ-Line Mutation; D006801:Humans; D002955:Leucovorin; D056784:Leukoencephalopathies; D016015:Logistic Models; D008279:Magnetic Resonance Imaging; D008297:Male; D008727:Methotrexate; D020258:Neurotoxicity Syndromes; D011110:Polymorphism, Genetic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011446:Prospective Studies; D012307:Risk Factors", "nlm_unique_id": "8309333", "other_id": null, "pages": "949-59", "pmc": null, "pmid": "24550419", "pubdate": "2014-03-20", "publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't", "references": "19404257;21646343;22683712;21091140;19553647;19068252;15569732;16568441;18285545;6693915;15527894;1734087;19006245;1525778;22927505;22586486;21545793;9697870;14576448;12714818;19193882;20182759;23650422;12915598;7776773;16219848;20732627;21832240;23049924;19901119;11070477;17170721;23760811;20573900;9586883;21148812;10835412;17264302;12761601;17947226;11493634;21064136;21444869;18367627;18056785;15891195", "title": "Methotrexate-induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia.", "title_normalized": "methotrexate induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia" }

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METHOTREXATE-INDUCED NEUROTOXICITY AND LEUKOENCEPHALOPATHY IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA.. JOURNAL OF CLINICAL ONCOLOGY. 2014?32(9):949-959", "literaturereference_normalized": "methotrexate induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190328", "receivedate": "20190328", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16130874, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "US-PFIZER INC-2009171003", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "3", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": 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"patientagegroup": null, "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Leukoencephalopathy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Cerebrovascular accident", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "BHOJWANI, D.. METHOTREXATE-INDUCED NEUROTOXICITY AND LEUKOENCEPHALOPATHY IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA. JOURNAL OF CLINICAL ONCOLOGY. 2014?32(9):949-959", "literaturereference_normalized": "methotrexate induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190207", "receivedate": "20190207", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15933784, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "US-PFIZER INC-2014090746", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "3", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, 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"drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCORTISONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG/M2, CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEUCOVORIN." }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": null, "drugadministrationroute": "041", "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "1 G/M2", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, 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"drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." } ], "patientagegroup": null, "patientonsetage": "11", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Generalised tonic-clonic seizure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukoencephalopathy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BHOJWANI, D.. METHOTREXATE-INDUCED NEUROTOXICITY AND LEUKOENCEPHALOPATHY IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA.. JOURNAL OF CLINICAL ONCOLOGY.. 2014?32(9):949-959", "literaturereference_normalized": "methotrexate induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190311", "receivedate": "20190311", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16056614, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "US-PFIZER INC-2373784", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "NOT REPORTED", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": "3", "drugadministrationroute": "041", "drugauthorizationnumb": "011719", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 G/M^2", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": "3", "drugadministrationroute": "041", "drugauthorizationnumb": "011719", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 G/M^2", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROCORTISONE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "NOT REPORTED", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCORTISONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG/M2, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEUCOVORIN /00566701/" } ], "patientagegroup": null, "patientonsetage": "5", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Leukoencephalopathy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Generalised tonic-clonic seizure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CHENG C., PUI C., BHOJWANI D., PEI D., INABA H., RUBNITZ JE., PANETTA J., SANDLUND JT., YANG JJ., KRULL KR., RELLING MV., METZGER ML., SABIN ND., KHAN RB., RIBEIRO RC., HOWARD SC., JEHA S., REDDICK. METHOTREXATE-INDUCED NEUROTOXICITY AND LEUKOENCEPHALOPATHY IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA. J CLIN ONCOL. 2014?32(9):949-959", "literaturereference_normalized": "methotrexate induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190314", "receivedate": "20190314", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16073067, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "US-PFIZER INC-2014090788", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG/M2, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEUCOVORIN [FOLINIC ACID]" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROCORTISONE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCORTISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 G/M2 OVER 24 HOURS, ADJUSTED TO 65 UMOL/L", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." } ], "patientagegroup": null, "patientonsetage": "18", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cerebrovascular accident", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Leukoencephalopathy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "BHOJWANI, D.. METHOTREXATE-INDUCED NEUROTOXICITY AND LEUKOENCEPHALOPATHY IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA.. JOURNAL OF CLINICAL ONCOLOGY.. 2014?32(9):949-959", "literaturereference_normalized": "methotrexate induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190208", "receivedate": "20190208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15937147, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "US-PFIZER INC-2373834", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "3", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": null, "drugadministrationroute": "041", "drugauthorizationnumb": "011719", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 G/M^2", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": null, "drugadministrationroute": "041", "drugauthorizationnumb": "011719", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 G/M^2", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "NOT REPORTED", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG/M2, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEUCOVORIN /00566701/" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROCORTISONE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "NOT REPORTED", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCORTISONE." } ], "patientagegroup": null, "patientonsetage": "18", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cerebrovascular accident", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukoencephalopathy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CHENG C., PUI CH., BHOJWANI D., PEI D., INABA H., RUBNITZ JE., PANETTAJC., SANDLUND JT., YANG JJ., KRULL KR., RELLING MV., METZGER ML., SABIN ND., KHAN RB., RIBEIRO RC., HOWARD SC., JEHA S., REDDICK W. METHOTREXATE-INDUCED NEUROTOXICITY AND LEUKOENCEPHALOPATHY IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA. J CLIN ONCOL. 2014?32(9):949-949", "literaturereference_normalized": "methotrexate induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190208", "receivedate": "20190208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15939187, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "US-PFIZER INC-2014090696", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "5 G/M2 OVER 24 HOURS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROCORTISONE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", 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null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEUCOVORIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": "3", "drugadministrationroute": "041", "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "1 G/M2", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." } ], "patientagegroup": null, "patientonsetage": "5", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Generalised tonic-clonic seizure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukoencephalopathy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BHOJWANI, D.. METHOTREXATE-INDUCED NEUROTOXICITY AND LEUKOENCEPHALOPATHY IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA. JOURNAL OF CLINICAL ONCOLOGY. 2014?32(9):949-959", "literaturereference_normalized": "methotrexate induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190314", "receivedate": "20190314", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16071988, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "US-PFIZER INC-2014090785", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, 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}, { "reactionmeddrapt": "Leukoencephalopathy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cerebrovascular accident", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BHOJWANI, D.. METHOTREXATE-INDUCED NEUROTOXICITY AND LEUKOENCEPHALOPATHY IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA.. JOURNAL OF CLINICAL ONCOLOGY.. 2014?32(9):949-959", "literaturereference_normalized": "methotrexate induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190304", "receivedate": "20190304", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16029646, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "US-PFIZER INC-2373799", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": 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null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCORTISONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG/M2", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEUCOVORIN /00566701/" } ], "patientagegroup": null, "patientonsetage": "10", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Focal dyscognitive seizures", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukoencephalopathy", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BHOJWANI, D.. METHOTREXATE-INDUCED NEUROTOXICITY AND LEUKOENCEPHALOPATHY IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA. JOURNAL OF CLINICAL ONCOLOGY.. 2014?32(9):949-959", "literaturereference_normalized": "methotrexate induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190408", "receivedate": "20190408", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16170836, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "US-PFIZER INC-2014090762", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "AMINOPHYLLINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMINOPHYLLINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROCORTISONE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCORTISONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG/M2, CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", 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"drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "5 G/M2 OVER 24 HOURS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." } ], "patientagegroup": null, "patientonsetage": "14", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukoencephalopathy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Headache", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cerebrovascular accident", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Confusional state", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BHOJWANI, D.. METHOTREXATE-INDUCED NEUROTOXICITY AND LEUKOENCEPHALOPATHY IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA.. JOURNAL OF CLINICAL ONCOLOGY.. 2014?32(9):949-959", "literaturereference_normalized": "methotrexate induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190329", "receivedate": "20190329", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16135196, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "US-PFIZER INC-2014090731", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG/M2, CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEUCOVORIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROCORTISONE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCORTISONE." }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "5 G/M2 OVER 24 HOURS, CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": null, "drugadministrationroute": "041", "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "1 G/M2", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": null, "drugadministrationroute": "041", "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "5 G/M2", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEUCOVORIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." } ], "patientagegroup": null, "patientonsetage": "4", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukoencephalopathy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ataxia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BHOJWANI, D.. METHOTREXATE-INDUCED NEUROTOXICITY AND LEUKOENCEPHALOPATHY IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA.. JOURNAL OF CLINICAL ONCOLOGY.. 2014?32(9):949-959", "literaturereference_normalized": "methotrexate induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190321", "receivedate": "20190321", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16100369, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": 1, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "US-PFIZER INC-2014090775", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "5 G/M2 OVER 24 HOURS, ADJUSTED TO 65 UMOL/L", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROCORTISONE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCORTISONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG/M2, CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEUCOVORIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." } ], "patientagegroup": null, "patientonsetage": "5", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Focal dyscognitive seizures", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukoencephalopathy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BHOJWANI, D.. METHOTREXATE-INDUCED NEUROTOXICITY AND LEUKOENCEPHALOPATHY IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA.. JOURNAL OF CLINICAL ONCOLOGY.. 2014?32(9):949-959", "literaturereference_normalized": "methotrexate induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190314", "receivedate": "20190314", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16071989, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "US-PFIZER INC-2373789", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROCORTISONE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "NOT REPORTED", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCORTISONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "NOT REPORTED", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG/M2, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEUCOVORIN /00566701/" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": "3", "drugadministrationroute": "041", "drugauthorizationnumb": "011719", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 G/M^2", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": "3", "drugadministrationroute": "041", "drugauthorizationnumb": "011719", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 G/M^2", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." } ], "patientagegroup": null, "patientonsetage": "15", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Leukoencephalopathy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cerebrovascular accident", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CHENG C., PUI C.H., BHOJWANI D., PEI D., INABA H., RUBNITZ JE., PANETTA JC., SANDLUND JT., YANG JJ., KRULL KR., RELLING MV., METZGER ML., SABIN ND., KHAN RB., RIBEIRO RC., HOWARD SC., JEHA S., REDDICK. METHOTREXATE-INDUCED NEUROTOXICITY AND LEUKOENCEPHALOPATHY IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA. J CLIN ONCOL. 2014?32(9):949-959", "literaturereference_normalized": "methotrexate induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190219", "receivedate": "20190215", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15967089, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "US-PFIZER INC-2014090718", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROCORTISONE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCORTISONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG/M2, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEUCOVORIN [FOLINIC ACID]" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "5 G/M2 OVER 24 HOURS, CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." } ], "patientagegroup": null, "patientonsetage": "15", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cerebrovascular accident", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukoencephalopathy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BHOJWANI, D.. METHOTREXATE-INDUCED NEUROTOXICITY AND LEUKOENCEPHALOPATHY IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA.. JOURNAL OF CLINICAL ONCOLOGY.. 2014?32(9):949-959", "literaturereference_normalized": "methotrexate induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190215", "receivedate": "20190215", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15966182, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "US-PFIZER INC-2014090819", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MG/M2, WEEKLY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROCORTISONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCORTISONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG/M2, CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEUCOVORIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK MG/M2, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEUCOVORIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MG/M2, WEEKLY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." } ], "patientagegroup": null, "patientonsetage": "17", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukoencephalopathy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CHENG C., PUI C., BHOJWANID., PEI D., INABA H., RUBNITZ J., PANETTA J., SANDLUND J., YANG J., KRULL K., RELLING M., METZGER M., SABIN N., KHAN R., RIBEIRO R., HOWARD S., JEHA S., REDDICK W., EVANS W.. METHOTREXATE-INDUCED NEUROTOXICITY AND LEUKOENCEPHALOPATHY IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA.. JOURNAL OF CLINICAL ONCOLOGY.. 2014?32(9):949-959", "literaturereference_normalized": "methotrexate induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190328", "receivedate": "20190328", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16127710, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "US-PFIZER INC-2014090660", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "3", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": null, "drugadministrationroute": "041", "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "2.5 G/M^2", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": null, "drugadministrationroute": "041", "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "1 G/M^2", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROCORTISONE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCORTISONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "2.5 G/M2 INFUSED OVER 24 HOURS FOR FOUR DOSES,ADJUSTED TO PLASMA CONCENTRATION OF 33 UMOL/L", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG/M2", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEUCOVORIN /00566701/" } ], "patientagegroup": null, "patientonsetage": "3", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Focal dyscognitive seizures", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Leukoencephalopathy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CHENG C.,PUI C.,BHOJWANI D.,PEI D.,INABA H.,RUBNITZ J.,PANETTA J.,SANDLUND J.,YANG J.,KRULL K.,RELLING M.,METZGER M.,SABIN N.,KHAN R.,RIBEIRO R.,HOWARD S.,JEHA S.,REDDICK W.,EVANS W.. METHOTREXATE-INDUCED NEUROTOXICITY AND LEUKOENCEPHALOPATHY IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA.. JOURNAL OF CLINICAL ONCOLOGY.. 2014?32(9):949-959", "literaturereference_normalized": "methotrexate induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190321", "receivedate": "20190321", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16100421, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "US-PFIZER INC-2014090647", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG/M2, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEUCOVORIN [FOLINIC ACID]" }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 G/M2 OVER 24 HOURS, ADJUSTED TO 65 UMOL/L", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROCORTISONE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, 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"drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." } ], "patientagegroup": null, "patientonsetage": "13", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Generalised tonic-clonic seizure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukoencephalopathy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BHOJWANI, D.. METHOTREXATE-INDUCED NEUROTOXICITY AND LEUKOENCEPHALOPATHY IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA.. JOURNAL OF CLINICAL ONCOLOGY.. 2014?32(9):949-959", "literaturereference_normalized": "methotrexate induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190304", "receivedate": "20190304", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16029133, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" } ]

{ "abstract": "BACKGROUND\nWe aimed to improve the outcomes for locoregionally advanced nasopharyngeal carcinoma by testing the feasibility and safety of the addition of bevacizumab to chemoradiotherapy.\n\n\nMETHODS\nWe enrolled patients older than 18 years with stage IIB-IVB nasopharyngeal carcinoma from 19 centres in North America and Hong Kong. Treatment consisted of three cycles of bevacizumab (15 mg/kg) and cisplatin (100 mg/m(2)) both given on days 1, 22, and 43 of radiation (70 Gy) with intensity-modulated radiation therapy delivered over 33 days on a daily basis, Monday through Friday. Patients then received three cycles of bevacizumab (15 mg/kg) and cisplatin (80 mg/m(2)), both given on days 64, 85, and 106 after radiation, and three cycles of fluorouracil (1000 mg/m(2) per day), given on days 64-67, 85-88, and 106-109 after radiation. The primary endpoint was the occurrence of treatment-related grade 4 haemorrhage or any grade 5 adverse event in the first year. Analyses were done with all eligible patients who started protocol treatment. The trial is registered at ClinicalTrials.gov, number NCT00408694.\n\n\nRESULTS\nFrom Dec 13, 2006, to Feb 5, 2009, we enrolled 46 patients, of whom 44 were eligible for analysis. We recorded no grade 3-4 haemorrhages or grade 5 adverse events; nine patients (20%) had a treatment-related grade 1-2 haemorrhage. Nine patients had one or more grade 4 blood or bone marrow-related complication (grade 4 leucopenia was noted in six patients, grade 4 lymphopenia in five, grade 4 neutrophils in five, and grade 4 anaemia in one). One patient had two grade 4 infections with grade 3-4 neutrophils. One patient reported grade 4 tinnitus, one patient reported grade 4 thrombosis, one reported grade 4 radiation mucositis, and two reported grade 4 pharyngolaryngeal pain. With a median follow-up of 2·5 years (IQR 2·1-2·9), the estimated 2 year locoregional progression-free interval was 83·7% (95% CI 72·6-94·9), the 2 year distant metastasis-free interval was 90·8% (82·2-99·5), the 2 year progression-free survival was 74·7% (61·8-87·6), and 2 year overall survival was 90·9% (82·3-99·4).\n\n\nCONCLUSIONS\nThe addition of bevacizumab to standard chemoradiation treatment for patients with nasopharyngeal carcinoma is feasible, and might delay the progression of subclinical distant disease.\n\n\nBACKGROUND\nNational Cancer Institute, USA.", "affiliations": "Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. [email protected]", "authors": "Lee|Nancy Y|NY|;Zhang|Qiang|Q|;Pfister|David G|DG|;Kim|John|J|;Garden|Adam S|AS|;Mechalakos|James|J|;Hu|Kenneth|K|;Le|Quynh T|QT|;Colevas|A Dimitrios|AD|;Glisson|Bonnie S|BS|;Chan|Anthony Tc|AT|;Ang|K Kian|KK|", "chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab", "country": "England", "delete": false, "doi": "10.1016/S1470-2045(11)70303-5", "fulltext": null, "fulltext_license": null, "issn_linking": "1470-2045", "issue": "13(2)", "journal": "The Lancet. Oncology", "keywords": null, "medline_ta": "Lancet Oncol", "mesh_terms": "D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D002277:Carcinoma; D059248:Chemoradiotherapy; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms; D009367:Neoplasm Staging", "nlm_unique_id": "100957246", "other_id": null, "pages": "172-80", "pmc": null, "pmid": "22178121", "pubdate": "2012-02", "publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural", "references": "20103659;15746043;12586799;10554016;15378492;16904519;9552031;10096545;19564532;15542811;17167137;15175435;10640954;15190138;15920746;15042677;12419787;20950416;12890841;7082756;20930754;17971582;10974445;20667969;15936155;18472356;20634482;10811107;15284255;12948418;19201650;10334236;11156384;20971520;16192584;19470921;16139912;11708497;10884741;19464823;12007936;16170180;17145528", "title": "Addition of bevacizumab to standard chemoradiation for locoregionally advanced nasopharyngeal carcinoma (RTOG 0615): a phase 2 multi-institutional trial.", "title_normalized": "addition of bevacizumab to standard chemoradiation for locoregionally advanced nasopharyngeal carcinoma rtog 0615 a phase 2 multi institutional trial" }

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{ "abstract": "To perform a meta-analysis of available cohort studies on the association between sertraline use by pregnant women in the first trimester and the findings of congenital anomalies in infants.\n\n\n\nA comprehensive search of articles published from the index date up to 31st December 2015 investigating the aforementioned associations was conducted on PubMed and Web of Science. Mesh headings used included the terms \"serotonin reuptake inhibitor,\" \"sertraline,\" \"congenital anomalies\" and \"obstetrical outcome.\"\n\n\n\nTwelve cohort studies that involved 6 468 241 pregnant women were identified. We summarized odds ratios (ORs) and 95% confidence intervals (CIs) of congenital anomalies using the random-effects model. Pregnant women who used sertraline in the first trimester had a statistically significant increased risk of infant cardiovascular-related malformations (OR = 1.36; 95% CI = 1.06-1.74; I2 = 64.4%; n = 12) as well as atrial and/or ventricular septal defects (OR = 1.36, 95% CI = 1.06-1.76; I2 = 62.2%; n = 8). Additionally, positive but nonsignificant associations between sertraline use and congenital anomalies of the nervous system (OR = 1.39; 95% CI = 0.83-2.32; I2 = 0%; n = 5), digestive system (OR = 1.23; 95% CI = 0.76-1.98; I2 = 0%; n = 5), eye, ear, face and neck (OR = 1.08; 95% CI = 0.33-3.55; I2 = 32.1%; n = 3), urogenital system (OR = 1.03; 95% CI = 0.73-1.46; I2 = 0%; n = 5), and musculoskeletal system (OR = 0.97; 95% CI = 0.69-1.36; I2 = 0%; n = 5) were observed.\n\n\n\nThis meta-analysis suggested that the use of sertraline use by pregnant women in the first trimester had an increased risk of cardiovascular-related malformations as well as atrial and/or ventricular septal defects in infants. Meanwhile, nonsignificant associations between sertraline use and other congenital anomalies were found. More cohort studies are warranted to provide detailed results of other congenital anomalies.", "affiliations": "Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.;Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China.;International Education College, China Medical University, Shenyang, China.;Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China.;Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.;Department of Cardiology, First Affiliated Hospital of Dalian Medical University, Dalian, China.;Department of Emergency, Shengjing Hospital of China Medical University, Shenyang, China.;Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.;Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China.;Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China.;Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China.;Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.", "authors": "Shen|Zi-Qi|ZQ|;Gao|Shan-Yan|SY|;Li|Shawn Xiang|SX|;Zhang|Tie-Ning|TN|;Liu|Cai-Xia|CX|;Lv|Hai-Chen|HC|;Zhang|Yuan|Y|;Gong|Ting-Ting|TT|;Xu|Xin|X|;Ji|Chao|C|;Wu|Qi-Jun|QJ|;Li|Da|D|", "chemical_list": "D017367:Serotonin Uptake Inhibitors; D020280:Sertraline", "country": "England", "delete": false, "doi": "10.1111/bcp.13161", "fulltext": null, "fulltext_license": null, "issn_linking": "0306-5251", "issue": "83(4)", "journal": "British journal of clinical pharmacology", "keywords": "antidepressive agents; cohort studies; congenital anomalies; meta-analysis; pregnancy; sertraline", "medline_ta": "Br J Clin Pharmacol", "mesh_terms": "D000014:Abnormalities, Drug-Induced; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007223:Infant; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D012306:Risk; D017367:Serotonin Uptake Inhibitors; D020280:Sertraline", "nlm_unique_id": "7503323", "other_id": null, "pages": "909-922", "pmc": null, "pmid": "27770542", "pubdate": "2017-04", "publication_types": "D016428:Journal Article; D017418:Meta-Analysis; D016454:Review; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't", "references": "25899043;22190957;14659992;26727146;20865100;24612301;10789670;17676579;17905176;25098615;3802833;10944220;26118971;26568366;12450956;25359305;25229932;16137987;18948314;19622511;10413337;17697910;26515595;8367830;25888213;23797870;17216624;25991012;7786990;21646927;22710132;14618156;20447455;22367660;26075658;25637841;19691085;26373341;27770542;26650439;16896784;23638179;17519397;9310563;26462150;23175139;23966430;23553059;21963886;21381184;26498356;23211939;22393202;26464438;18293409;21042552;17565615;26940835;12958120", "title": "Sertraline use in the first trimester and risk of congenital anomalies: a systemic review and meta-analysis of cohort studies.", "title_normalized": "sertraline use in the first trimester and risk of congenital anomalies a systemic review and meta analysis of cohort studies" }

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{ "abstract": "A 64-year-old asymptomatic man had an incidental finding of a giant left circumflex artery (LCX) aneurysm, with the distal LCX draining into a confluence receiving terminal portions of all coronary arteries and communicating with the left ventricle through a transmural fistulous tract. We believe that this is the first case reported with such a complex LCX abnormality. (Level of Difficulty: Beginner.).", "affiliations": "Division of Cardiology, John D. Dingell VA Medical Center, Detroit, Michigan.;Division of Cardiology, Department of Medicine, Wayne State University School of Medicine, Detroit, Michigan.;Henry Ford Health System, Detroit, Michigan.;Division of Cardiology, John D. Dingell VA Medical Center, Detroit, Michigan.;Division of Cardiology, John D. Dingell VA Medical Center, Detroit, Michigan.", "authors": "Touma|Rabih|R|;Palla|Mohan|M|;Alam|Khurshaid|K|;Mastromatteo|James F|JF|;Abidov|Aiden|A|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.jaccas.2020.04.059", "fulltext": "\n==== Front\nJACC Case Rep\nJACC Case Rep\nJACC Case Reports\n2666-0849\nElsevier\n\nS2666-0849(20)30632-X\n10.1016/j.jaccas.2020.04.059\nCase Report\nClinical Case\nGiant Calcified Left Circumflex Coronary Artery Aneurysm With Complex Coronary-to–Left Ventricular Communication\nTouma Rabih MD a\nPalla Mohan MD b\nAlam Khurshaid MD c\nMastromatteo James F. MD a\nAbidov Aiden MD, PhD [email protected]\nab∗\na Division of Cardiology, John D. Dingell VA Medical Center, Detroit, Michigan\nb Division of Cardiology, Department of Medicine, Wayne State University School of Medicine, Detroit, Michigan\nc Henry Ford Health System, Detroit, Michigan\n∗ Address for correspondence: Dr. Aiden Abidov, Division of Cardiology, John D. Dingell VA Medical Center, 4646 John R, Detroit, Michigan 48201. [email protected]\n22 7 2020\n9 2020\n22 7 2020\n2 11 18121817\n19 11 2019\n21 4 2020\n29 4 2020\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nA 64-year-old asymptomatic man had an incidental finding of a giant left circumflex artery (LCX) aneurysm, with the distal LCX draining into a confluence receiving terminal portions of all coronary arteries and communicating with the left ventricle through a transmural fistulous tract. We believe that this is the first case reported with such a complex LCX abnormality. (Level of Difficulty: Beginner.)\n\nGraphical abstract\n\nA 64-year-old asymptomatic man had an incidental finding of a giant left circumflex artery (LCX) aneurysm, with the distal LCX draining into a confluence…\n\nKey Words\n\ncoronary artery aneurysm\ncoronary fistula\nleft ventricular fistula\nAbbreviations and Acronyms\n\nCT, computed tomography\nCTA, computed tomography angiogram\nLCX, left circumflex artery\nLV, left ventricle\n==== Body\nHistory of Presentation\n\nA 64-year-old asymptomatic man underwent a computed tomography (CT) scan of the abdomen and pelvis for evaluation of hematuria. The scan revealed an incidental finding of left circumflex artery (LCX) aneurysm. His physical examination was unremarkable for any acute or chronic cardiovascular findings. Upon admission, his vital signs were as follows: blood pressure, 136/89 mm Hg; pulse, 74 beats/min and regular; respiratory rate, 18 breaths/min; temperature, 98.1°F; and pulse oximetry, 97% on room air.Learning Objectives\n\n• LCX aneurysm is an extremely rare clinical condition. Careful evaluation of the coronary anatomy is needed to identify any additional coronary anomalies in these patients. Our case represents a unique anatomy, with a giant LCX aneurysm and the distal LCX draining into a confluence receiving terminal portions of all coronary arteries and communicating with the LV through a transmural fistulous tract.\n\n• Complex coronary anomalies require in-depth evaluation, including multimodality imaging to assess the patients for presence of myocardial ischemia and significant left-to-right shunt. Cardiac CTA is a very helpful diagnostic tool in establishing definitive anatomy in these cases.\n\n• The treatment should be individualized on the basis of the patients’ symptoms, objective prediction of risk (presence of ischemia, progression of the lesion), and the presence of associated coronary and cardiac anomalies.\n\n• With a careful work-up and follow-up, this coronary anomaly may have a benign short-term clinical outcome.\n\nPast Medical History\n\nThe patient had history of well-controlled hypertension and no other modifiable or nonmodifiable risk factors or clinical markers of coronary artery disease.\n\nDifferential Diagnosis\n\nBecause of the incidental CT findings in this asymptomatic patient, the possibility of congenital versus acquired coronary aneurysm was raised. Given that the patient had not undergone any coronary interventions, the possibility of past iatrogenic causes or coronary manipulation was excluded.\n\nInvestigations\n\nSubsequent coronary CT angiography (CTA) showed a giant (3.7-cm), calcified proximal LCX aneurysm with a small thromboatheroma (Figure 1). An additional smaller, noncalcified distal LCX aneurysm was present. Furthermore, the distal LCX drained into a confluent structure receiving terminal portions of the remainder of the coronary arteries (Figures 2 and 3). This confluence communicated with the left ventricle (LV) through a moderate-caliber transmural fistulous tract (Figures 3 and 4). The left anterior descending artery was markedly enlarged and tortuous proximally, and it appeared to drain into the arterial confluence distally. The right coronary artery was dominant, with a normal caliber, and it terminated distally into the confluence. Increased trabeculation was present in the LV at the anterolateral segment. A transthoracic echocardiogram (Figure 5) showed normal left ventricular and right ventricular systolic function without any wall motion abnormalities or valvular heart disease. Cardiac magnetic resonance revealed normal resting myocardial perfusion, normal biventricular function, a normal pulmonary-to-systemic flow ratio, and no evidence of delayed gadolinium enhancement (Figures 6A and 6B). An exercise single-photon emission computed tomography myocardial perfusion imaging study demonstrated no inducible ischemia, with normal left ventricular ejection fraction. We could not identify any additional congenital abnormalities or signs of infection or vasculitis in the past medical history or during the index evaluation.Figure 1 3D VR CTA Image\n\nA 3-dimensional (3D) volume-rendered (VR) image of the lateral cardiac surface that shows a giant left circumflex (LCX) coronary artery aneurysm, left anterior descending artery (LAD), obtuse marginal branch, and part of the left ventricular (LV) transmural fistula. CTA = computed tomography angiography; LA = left atrium.\n\nFigure 2 3D VR and MPR CTA Images\n\nThese 3D VR images of the inferior and lateral cardiac surface show a giant LCX coronary artery aneurysm, an LV transmural fistula, and confluence receiving terminal portions of all the coronary arteries. Multiplanar reconstruction (MPR) images show a giant left circumflex coronary artery aneurysm and confluence receiving terminal portions of all the coronary arteries. RA = right atrium; RV = right ventricle; other abbreviations as in Figure 1.\n\nFigure 3 3D VR and MPR CTA Images\n\nThese 3D VR images of the apical and lateral cardiac surface show the LAD, LCX, LV transmural fistula, and confluence receiving terminal portions of all the coronary arteries. MPR images show an LV transmural fistula and confluence receiving terminal portions of all the coronary arteries. Abbreviations as in Figures 1 and 2.\n\nFigure 4 3D VR and MPR CTA Images\n\nThese 3D VR and MPR images show a giant LCX coronary artery aneurysm, an LV transmural fistula, and the LCX. Abbreviations as in Figure 1.\n\nFigure 5 Apical 4-Chamber Echocardiogram\n\nThis apical 4-chamber echocardiogram shows normal-size cardiac chambers, normal valves, and a calcified LCX aneurysm. Abbreviations as in Figures 1 and 2.\n\nFigure 6 CMR SSFP Images in Systole and Diastole\n\nImages obtained in (A) systole and (B) diastole demonstrate findings similar to those seen in the echocardiogram in Figure 5. A mild increase in the LCX aneurysm dimension in diastole is noted. CMR = cardiac magnetic resonance; SSFP = steady-state free precession; other abbreviations as in Figures 1, 2, and 5.\n\nManagement\n\nThe patient was managed conservatively using dual antiplatelet therapy (aspirin and clopidogrel) and a statin because coronary artery thrombosis and progressive stenosis within the aneurysm may cause myocardial ischemia, which increases the risk of myocardial infarction and sudden cardiac death in these patients. The patient took warfarin for a month, but it was stopped because of hematuria and hematospermia. He also underwent yearly coronary CTA for surveillance without significant change in the size of the aneurysm, and he has remained without cardiac complications to date for a total of 3 years. At present, nonradiation modalities such as cardiac magnetic resonance are not beneficial in this case because of the need in a 3-dimensional imaging modality with excellent all-axis spatial resolution (isometric voxels) for depiction of such a complex coronary anatomy.\n\nDiscussion\n\nThe incidence of coronary artery aneurysms is 0.02% to 0.04%, and these aneurysms are usually seen in the right coronary artery. To our knowledge, there has been no case reported of a patient with an LCX aneurysm communicating with a distal coronary arterial confluence, and this confluence further connected to the LV through a fistulous track. LCX aneurysms with fistulous communication have rarely been reported; among the reported aneurysms, most communicated with the coronary sinus (1). Only 1 case report described LCX aneurysm with a fistulous communication to the LV myocardium through several small vessels (2).\n\nCoronary artery aneurysms may represent a potentially life-threatening condition with important complications including thrombosis or rupture. Of note, our patient was asymptomatic. The available treatment options for coronary artery aneurysm with fistula are surgical or endovascular interventions (1). However, treatment depends on the complexity of the anomalous anatomy. Furthermore, the follow-up duration and treatment with surgical or endovascular interventions in asymptomatic patients are unknown. A systematic approach with possible multicenter registries, development of a specific diagnostic approach, and prognostic estimates in patients with this complex anatomy, requires further research.\n\nFollow-Up\n\nThe patient underwent yearly coronary CTA for surveillance without significant change in the size of the LCX aneurysm, and he has remained without cardiac complications to date for a total of 3 years.\n\nConclusions\n\nLCX aneurysm is an extremely rare clinical condition. Careful assessment of the coronary anatomy is needed to identify any additional coronary anomalies in these patients. Evaluation of such a unique anomaly as giant LCX aneurysm combined with distal LCX draining into a confluence receiving terminal portions of all coronary arteries and communicating with left ventricle through a transmural fistulous tract requires implementation of advanced 3-dimensional imaging methods.\n\nThe authors have reported that they have no relationships relevant to the contents of this paper to disclose.\n\nThe authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Case Reportsauthor instructions page.\n==== Refs\nReferences\n\n1 Gupta V. Truong Q.A. Okada D.R. Images in cardiovascular medicine. Giant left circumflex coronary artery aneurysm with arteriovenous fistula to the coronary sinus Circulation 118 2008 2304 2307 19029479\n2 Suh S.Y. Kim J.W. Yong H.S. Aneurysm of circumflex coronary artery caused by cardiac vein and fistulous connection to the left ventricle identified on MDCT Int J Cardiol 114 2007 e3 e4 16893576\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2666-0849", "issue": "2(11)", "journal": "JACC. Case reports", "keywords": "CT, computed tomography; CTA, computed tomography angiogram; LCX, left circumflex artery; LV, left ventricle; coronary artery aneurysm; coronary fistula; left ventricular fistula", "medline_ta": "JACC Case Rep", "mesh_terms": null, "nlm_unique_id": "101757292", "other_id": null, "pages": "1812-1817", "pmc": null, "pmid": "34317061", "pubdate": "2020-09", "publication_types": "D002363:Case Reports", "references": "16893576;19029479", "title": "Giant Calcified Left Circumflex Coronary Artery Aneurysm With Complex Coronary-to-Left Ventricular Communication.", "title_normalized": "giant calcified left circumflex coronary artery aneurysm with complex coronary to left ventricular communication" }

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{ "abstract": "To find a remedy for serpiginous choroiditis refractory to oral prednisone and chlorambucil treatment.\nEight eyes of four patients (all female) with advanced macular involvement secondary to serpiginous choroiditis were included in the study. The average age of the patients was 45.2 years. One eye of each patient was legally blind and the lesion was close to the fovea in the other eye. All four patients failed oral prednisone and chlorambucil therapy. However, case 1 responded to chlorambucil treatment after intravitreal dexamethasone implant implantation and discontinuation of oral prednisone. Case 2 responded to chlorambucil therapy when oral prednisone was stopped in combination with infliximab therapy. Due to long follow-up period of more than four years, these two cases are considered to be cured. Case 3 and case 4 were not able to achieve remission with chlorambucil and immunomodulatory therapy. They refused intravitreal steroid implant due to side effects profile.\nThe stability of WBC counts within toxic levels close to normal or lower limits of normal (3000-4500 cells/μl) during treatment with chlorambucil is an essential factor for the success of this therapy. A combination of dexamethasone intravitreal implant with chlorambucil therapy can be an effective and promising regimen in inducing and maintaining remission in refractory serpiginous choroiditis patients who fail a combination of systemic corticosteroid and chlorambucil therapy.", "affiliations": "Massachusetts Eye Research and Surgery Institution, Waltham, MA, United States.;Massachusetts Eye Research and Surgery Institution, Waltham, MA, United States.;Massachusetts Eye Research and Surgery Institution, Waltham, MA, United States.;Massachusetts Eye Research and Surgery Institution, Waltham, MA, United States.;Massachusetts Eye Research and Surgery Institution, Waltham, MA, United States.;Massachusetts Eye Research and Surgery Institution, Waltham, MA, United States.", "authors": "Maleki|Arash|A|;Maldonado Cerda|Anapatricia|A|;Garcia|Cristina M|CM|;Zein|Mike|M|;Manhapra|Ambika|A|;Foster|C Stephen|CS|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1016/j.ajoc.2021.101014", "fulltext": "\n==== Front\nAm J Ophthalmol Case Rep\nAm J Ophthalmol Case Rep\nAmerican Journal of Ophthalmology Case Reports\n2451-9936 Elsevier \n\nS2451-9936(21)00005-0\n10.1016/j.ajoc.2021.101014\n101014\nCase Report\nChlorambucil combination therapy in refractory serpiginous choroiditis: A cure?\nMaleki Arash ab Maldonado Cerda Anapatricia ab Garcia Cristina M. ab Zein Mike ab Manhapra Ambika ab Foster C. Stephen [email protected]∗ a Massachusetts Eye Research and Surgery Institution, Waltham, MA, United States\nb The Ocular Immunology and Uveitis Foundation, Waltham, MA, United States\nc Harvard Medical School, Department of Ophthalmology, Boston, MA, United States\n∗ Corresponding author. Massachusetts Eye Research and Surgery Institution, 1440 Main St. Ste. 201, Waltham, MA, USA. [email protected]\n30 1 2021 \n3 2021 \n30 1 2021 \n21 10101427 8 2020 7 12 2020 11 1 2021 © 2021 The Authors2021This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Purpose\nTo find a remedy for serpiginous choroiditis refractory to oral prednisone and chlorambucil treatment.\n\nObservations\nEight eyes of four patients (all female) with advanced macular involvement secondary to serpiginous choroiditis were included in the study. The average age of the patients was 45.2 years. One eye of each patient was legally blind and the lesion was close to the fovea in the other eye. All four patients failed oral prednisone and chlorambucil therapy. However, case 1 responded to chlorambucil treatment after intravitreal dexamethasone implant implantation and discontinuation of oral prednisone. Case 2 responded to chlorambucil therapy when oral prednisone was stopped in combination with infliximab therapy. Due to long follow-up period of more than four years, these two cases are considered to be cured. Case 3 and case 4 were not able to achieve remission with chlorambucil and immunomodulatory therapy. They refused intravitreal steroid implant due to side effects profile.\n\nConclusions and importance\nThe stability of WBC counts within toxic levels close to normal or lower limits of normal (3000–4500 cells/μl) during treatment with chlorambucil is an essential factor for the success of this therapy. A combination of dexamethasone intravitreal implant with chlorambucil therapy can be an effective and promising regimen in inducing and maintaining remission in refractory serpiginous choroiditis patients who fail a combination of systemic corticosteroid and chlorambucil therapy.\n\nHighlights\n• Serpiginous choroiditis may be recurrent or refractory to chlorambucil in conjunction with systemic corticosteroids.\n\n• The stability of WBC counts within lower limits of normal is an essential factor for the success of chlorambucil therapy.\n\n• This can be achieved with dexamethasone intravitreal implant or systemic immunomodulatory without systemic corticosteroid therapy.\n\n\n\nKeywords\nChlorambucilCyclophosphamideDexamethasone implantInfliximabSerpiginous choroiditis\n==== Body\n1 Introduction\nSerpiginous choroiditis (SC) is a rare, chronic, asymmetrically bilateral posterior uveitis with a recurrent course. The exact prevalence of SC is unknown; however, it is estimated between 1.6% and 5.3% of posterior uveitis cases in non-endemic areas for tuberculosis.1 Major features of SC include choriocapillaris occlusive vasculitis, secondary endothelial cell injury, and subsequent atrophy of the retinal pigment epithelium, outer retina, and choroid.2,3 Histopathology studies reveal lymphocytic infiltration in the choroid and, less commonly, around vessels.4 The peripapillary area is classically involved in SC and accounts for 80% of the cases.5 The prognosis of vision is poor when it involves the macula, especially in the macular variant of SC. Moreover, the macular variant has a higher risk of developing choroidal neovascularization in nearly half of the affected patients.6,7 Fluorescein angiography (FA), indocyanine green angiography (ICG), optical coherence tomography (OCT), fundus autofluorescence (FAF), and microperimetry are the ancillary diagnostic tools and tests which help in the diagnosis, follow-up, and monitoring for secondary complications.1\n\nHistorically, the administration of high doses of oral or intravenous steroids was considered as the standard of care for patients with SC.8 However, immunosuppressive agents such as azathioprine, cyclosporine, chlorambucil, and cyclophosphamide emerged as treatment options for steroid-free remission.4,9, 10, 11, 12 Of these, the alkylating agents cyclophosphamide and chlorambucil have been noted to have a high success rate in the treatment of SC.4,10,12 Chlorambucil, being a potent alkylating agent, can interfere with DNA replication and cell division.13 This medication can induce remission, maintain remission, and even cure this disease.12\n\nDespite successful treatment of SC with alkylating agents, in some patients the disease can recur frequently and progress to affect the central vision. This becomes more important in patients with poor vision in the other eye secondary to SC or advanced SC encroaching the fovea in the affected eye. In this case series, we decided to evaluate possible remedies for refractory and recurrent SC in patients who have been treated with chlorambucil and oral or intravenous corticosteroids.\n\n2 4 Cases\nCase 1. A sixty-year-old female was referred to us for the evaluation of macular SC OU. She had noticed blurry vision OS one month before her first visit with us. A geographic lesion with indistinct and irregular borders was observed in both eyes. The lesion was uni-centric OU, temporal to fovea OD and peripapillary with extension to fovea OS. FA and ICG showed the activity of the lesions in both eyes (Fig. 1A). Her best-corrected visual acuity (BCVA) was 20/20 OD and decreased OS to 20/100. Complete blood work-up for uveitis ruled out non-infectious and infectious posterior uveitis, including syphilis and tuberculosis. Based on these findings, she was diagnosed with autoimmune SC OU and was started on a combination of chlorambucil and daily oral prednisone. Chlorambucil was titrated based on her white blood cell (WBC) count. She had another flare-up while she was on 2 mg/day prednisone and had already stopped chlorambucil for three weeks due to WBC 3200 cells/μl. BCVA OS decreased to 20/125, and ICGA confirmed enlargement of the lesion. Chlorambucil was restarted to 2 mg every other day, and oral prednisone was increased to 5 mg/day. With this change in her regimen, the vision increased to the baseline before her last flare, to 20/40. Treatment with chlorambucil was stopped after one year. Her follow-up visit increased to every three months from monthly. Then, six months later, she was started on oral methotrexate 7.5 mg weekly by her rheumatologist because of her joint issues. She was followed every three months for seven months until she noticed a change in OS again. At that time, she was on oral methotrexate 15 mg weekly. BCVA OS decreased to 20/125, and ancillary tests showed activity at the border of the lesions on the foveal side (Fig. 1B). She received one dose of 1 g intravenous methylprednisolone, intravitreal injection of triamcinolone and bevacizumab, and was restarted on oral prednisone 80 mg/day. A week later, her methotrexate dose was boosted to methotrexate 25 mg weekly subcutaneous injections, and we tapered prednisone 10 mg weekly. In three months, oral prednisone was tapered and stopped. Three months later, her lesion became active and she developed choroidal neovascularization (CNV) for which she received a bevacizumab injection. She was restarted on chlorambucil and oral prednisone. The decision for local therapy with dexamethasone implant was made at this point, and she was put back on chlorambucil 2 mg every three days. She was on chlorambucil without oral prednisone, titrating the dose based on WBC for seventeen months, after which she was considered cured (Fig. 1C). In her last visit with us, her BCVA OD and OS were 20/20 and 20/50, respectively. The patient's average WBC count while on chlorambucil with prednisone, chlorambucil without prednisone, and chlorambucil after dexamethasone intravitreal implant were 5500 ± 2900, 4700 ± 1100 and 4100 ± 500 cells/μl, respectively. The total duration of treatment before dexamethasone intravitreal implant was 60 months and 17 months after dexamethasone intravitreal implant. The total length of follow-up is 132 months, and the total duration of remission off medication is 48 months (Table 1).Fig. 1 A patient with bilateral serpiginous choroidopathy. (A) Serpiginous lesions in both eyes, encroaching the fovea in right eye and with foveal involvement in left eye. Fluoresecein angiography shows activity in both eyes. (B) The middle row shows progression towards the fovea with leakage pointing toward the fovea in the right eye. (C) Shows the stability of fundus photos and fluorescein angiography in both eyes at one year after intravitreal dexamethasone implant and chlorambucil treatment.\n\nFig. 1Table 1 Demographics and clinical characteristics of patients with resistant serpiginous choroiditis.\n\nTable 1\tAge years\tSex\tLaterality\tBCVA first visit\tWBC (C + P) cells/μl\n(x 10c)\tWBC (C) cells/μl\n(x 10c)\tWBC (C + IMTor implan cells/μl (*10c)\tDuration of treatment before IMT\tDuration of treatment after IMT\tDuration of follow-up on chlorambucil\tDuration of follow-up off chlorambucil\tBCVA last visit\t\nPatient 1\t60\tF\tBilat\t20/20 20/100\t5.5 ± 2.9\t4.7 ± 1.1\t4.1 ± 0.5\t60a months\t17b months\t60 months\t83 months\t20/20 20/50\t\n OD\t\n OS\t\nPatient 2\t42\tF\tBilat\t1 mcf 20/20\t5.7 ± 2.2\tN/A\t3.8 ± 0.5\t40c months\t19d months\t49 months\t60 months\t1mcf\n20/15\t\n OD\t\n OS\t\nPatient 3\t32\tF\tBilat\tHM 20/20\t8.8 ± 3.4\tN/A\tN/A\t5 + 10 e months\tN/A\t5 months\tN/A\tHM 20/50\t\n OD\t\n OS\t\nPatient 4\t47\tF\tBilat\t20/30 1mcf\t6.2 ± 3.3\tN/A\tN/A\tN/A\tN/A\t12 months\tN/A\t20/50 1mcf\t\n OD\t\n OS\t\nBCVA:best corrected visual acuity; Bilat:bilateral; C:chlorambucil; CF:counting fingers; HM:hand motion; IMT:immunomodulatory therapy; P:prednisone; N/A:not applicable.\n\na Before intravitreal dexamethasone implant.\n\nb After intravitreal dexamethasone implant.\n\nc Before starting infliximab.\n\nd After starting infliximab.\n\ne 5 months chlorambucil and 10 months cyclophosphamide.\n\n\n\nCase 2. A 42-year-old female was referred to us with blurry vision and field distortion OD for ten years and OS for eight years. Her vision was counting fingers at 1 m OD and 20/20 OS. At the time of presentation, the patient had already received multiple intravitreal anti-VEGF (bevacizumab) and triamcinolone injections OD. The geographic lesions were peripapillary OU, with foveal involvement OD. Initial FA revealed chorioretinal scarring with window defects OU and leakage on borders OD (Fig. 2A). On ICG, the area of hypolucency OS extended further into the macula, which was not seen on FA (Fig. 2B). Complete blood work-up for uveitis ruled out non-infectious and infectious posterior uveitis, including syphilis and tuberculosis. Based on these findings, she was diagnosed with autoimmune SC OU and we recommended therapy with chlorambucil. She sought a second opinion elsewhere, where she was started on mycophenolate mofetil (MMF) 1 g daily with infliximab 300 mg IV every four weeks and oral prednisone 80 mg/day with taper. MMF and infliximab were eventually discontinued due to elevated LFTs. On follow up at our clinic eighteen months after the initial consult, chlorambucil was finally started with dose adjustment based on weekly monitoring of WBC count to reach the endpoint of WBC count 3000–4500 cells/μl. While on chlorambucil 20mg and prednisone 40mg daily, the patient became symptomatic OS with new changes and leakage on FA OS, prompting boosting of oral prednisone to 80 mg; she also received one ranibizumab injection OS locally. Six weeks after starting treatment with chlorambucil (20mg at this time) and oral prednisone 80 mg daily, WBC count dropped down to 4900 cells/μl, so we started tapering prednisone. Two months after initiation of chlorambucil therapy, chlorambucil was stopped while tapering prednisone at 30 mg/day with a WBC count of 3300 cells/μl. At this point, FA, FAF, and OCT showed stability and quiescence. On a subsequent visit with her local ophthalmologist, infliximab 600 mg infusions every four weeks was started for activity OS, and eventually increased to 900 mg every four weeks in combination with chlorambucil. WBC count increased to 7900 cells/μl while on prednisone 10 mg with taper, and chlorambucil was restarted at 4 mg daily, eventually going up to 6 mg daily (Fig. 2B). Chlorambucil dose adjustment with weekly WBC count was continued. Meanwhile, she received a bevacizumab injection with her local ophthalmologist due to central vision distortion OD. On her eight-month of treatment, WBC count dipped to 2000 cells/μl, and chlorambucil was stopped. After one week, with WBC count creeping back up to 4800 cells/μl, chlorambucil was restarted at 2 mg/day. Disease activity was then noted at ten months from treatment initiation with no interventions at that time. On follow up at our clinic fourteen months after starting chlorambucil, the activity noted at ten months prompted treatment extension, and the patient was educated on the risks vs. benefits of this decision. Chlorambucil treatment was continued for a total duration of twenty-one months. FA and OCT macula findings were stable and the patient was asymptomatic (Fig. 2C,D). Subsequent consults established disease stability with no new symptoms or activity. Infliximab was eventually tapered by 100 mg every four weeks. On her last consult at our clinic, she was on infliximab 100 mg infusions every four weeks with a final VA of 20/400 OD and 20/15 OS and stable findings on FA and macula OCT. Her average WBC count was 5700 ± 2200 cells/μl while on chlorambucil with prednisone, and 3800 ± 500 cells/μl when she was on chlorambucil after starting infliximab infusions without prednisone. The total duration of treatment before and after beginning infliximab infusions was 40 and 19 months, respectively. The total length of follow-up is 108 months. The total period of remission off chlorambucil is 60 months (Table 1).Fig. 2 (A) Fundus photo and fluorescein angiography of a patient with bilateral serpiginous choroiditis at the primary visit at our clinic. (B) The same patient during a recurrence in the left eye close to the fovea. (C,D) Stability of year after stopping chlorambucil while on infliximab tapering. (E) Macular optical coherence tomography at the first visit (left), during a recurrence (middle), and the last visit (right).\n\nFig. 2\n\nCase 3. A 32-year-old female presented with decreased vision, floaters, and photophobia OS. Vision OD was poor due to retinal detachment after a motor vehicle accident. Before presenting to her initial consultation at our clinic, complete blood work-up for uveitis had ruled out non-infectious and infectious posterior uveitis, including syphilis and tuberculosis and she had already been diagnosed with idiopathic SC. She had been on MMF 2 g daily, cyclosporin 25 mg and prednisone 30 mg daily for fourteen months. Her vision was hand-motion OD and 20/20 OS at presentation. A fundus examination revealed optic atrophy and a horizontal scar OD in addition to diffuse chorioretinal (CR) scarring in both eyes. Given the possibility of the activity of the lesion potentially affecting the fovea OS and her monocular status, chlorambucil and cyclophosphamide were discussed as treatment options.\n\nThe patient was started on chlorambucil 4 mg daily and continued on 25 mg of prednisone daily. A month later, her WBC count dropped from 14,800 to 12,100 cells/μl. However, she felt her vision had decreased once again after two weeks on chlorambucil. She was advised to increase chlorambucil to 6 mg/day from 4 mg/day, as well as increase prednisone to 40 mg daily. After one week at this dose, she reported stable vision OD. Chlorambucil dose adjustment with weekly WBC count and oral prednisone were continued until she reported stable vision and no other symptoms. At this time, she was advised to increase chlorambucil to 12 mg daily.\n\nApproximately four months after her initial visit, the patient presented to our clinic with worsening scotoma and floaters OS. At this point, she was on prednisone 5 mg daily and chlorambucil 10 mg daily. She had stopped chlorambucil for a week due to fever, and the WBC count was at 11,200 cells/μl. FA and ICG showed active choroidal inflammation at the lesion border, especially OS. Later on, she developed a diffuse, itchy rash, and because of this side effect, she was started on bi-weekly cyclophosphamide pulse therapy. She had five doses of cyclophosphamide pulse therapy, and her WBC count was between 4500 and 6300 cells/μl. However, a few days later, she complained of decreased vision OS with more central involvement. Her local ophthalmologist increased her prednisone to 60 mg, and she received her next cyclophosphamide infusion four days later with WBC count at 4000 cells/μl. Cyclophosphamide therapy was finally stopped due to persistent skin rash.\n\nIn the interim, she followed up with her local ophthalmologist while on oral prednisone with different doses based on disease activity. Her next visit with us was seven years later, and vision OS had deteriorated to 20/50. FA showed active inflammation OS in the form of enlarged CR lesions approaching the fovea with multifocal areas of leakage at the margins of the lesions (Fig. 3B). Up to that point, the patient had been off all immunomodulatory therapy (IMT) for seven years, yet only cyclophosphamide appeared to halt the progression of her disease. Monthly cyclophosphamide pulse therapy was resumed but was later stopped after eight months due to low WBC count. After this, she continued with oral prednisone 20 mg daily. At her last follow-up visit, chlorambucil was restarted due to the persistence of symptoms, worsening of vision OS, and the progression of lesion activity on imaging (Fig. 3C). Intravitreal steroid implants were also discussed. The patient was never able to taper off oral prednisone during treatment, and the average WBC count during her course of treatment was 8800 ± 3400 cells/μl. The total duration of treatment with chlorambucil was 5 months, cyclophosphamide was 10 months, and MMF plus cyclosporine was 14 months. The total duration of follow-up is 148 months. She has never been in remission for an extended period off medication (Table 1).Fig. 3 (A) Fundus photo of both eyes of a patient with bilateral serpiginous choroiditis. History of traumatic retinal detachment surgery with legal blindness in the right eye and active serpiginous choroiditis in the left eye. Fluorescein angiography shows an active lesion in the left eye. (B) Optical coherence tomography, fundus autofluorescence, and fluorescein angiography during a recurrence where the patient was started on cyclophosphamide pulse therapy. (C) Progression of the lesion in the left eye with an active lesion in fluorescein angiography at her last visit. Intravitreal dexamethasone and triamcinolone implants were discussed at this visit.\n\nFig. 3\n\nCase 4. A 47-year-old female was referred to our center with decreased vision OU for one month and had been started on prednisone 50 mg daily before her first visit with us. Her vision OD and OS were 20/30 and counting fingers at 1 m, respectively, at presentation. Dilated fundoscopy showed bilateral geographic lesions nasal to the fovea OD and involving the fovea OS (Fig. 4A). Complete blood work-up for uveitis ruled out non-infectious and infectious posterior uveitis, including syphilis and tuberculosis. Based on these findings, and she was diagnosed with autoimmune SC OU. Oral prednisone was increased to 60 mg daily, and due to significant vision loss OS, she was started on chlorambucil 6 mg daily. Chlorambucil treatment with WBC count monitoring and tapering of oral prednisone was continued for a year. Once the oral prednisone taper was completed, she continued with chlorambucil monotherapy for five more months, at which time she had achieved remission. After four months; however, she had a flare-up OD, which was first treated with 1 g IV methylprednisolone infusion and intravenous methotrexate 200 mg/day. Subsequently, she was continued on subcutaneous methotrexate 15 mg weekly along with folic acid 1 mg/day for two years. She developed another flare-up when tapering methotrexate; hence methotrexate dose was boosted, and a combination of chlorambucil and oral prednisone was restarted. The patient was on chlorambucil and oral prednisone for one year, with an average WBC count of 6200 ± 3300 cells/μl. The patient was then on chlorambucil alone for another two months. She had been flare-free for twenty months when she had another episode. This time she was treated with intravenous and subcutaneous methotrexate. She had another flare during tapering of methotrexate and she is currently on a combination of chlorambucil, prednisone, and subcutaneous methotrexate therapy. The total duration of follow-up has been 116 months. She has never been in remission for an extended period (Table 1).Fig. 4 A serpiginous choroiditis patient with multiple recurrences despite treatment with a combination of oral prednisone and chlorambucil therapy. (A) Color fundus photos and fluorescein angiography of both eyes at the first visit, which showed activity around the lesion in both eyes. (B) The second row shows the progression of lesions in both eyes during a recurrence on fundus photos and fundus autofluorescence. (C) Fundus autofluorescence and fluorescein angiography showed reactivation of the supratemporal area of the lesion in the right eye. (D) Optical coherence tomography shows the lesion, edema, and destruction of the supratemporal part of the lesion, compatible with fundus autofluorescence and fluorescein angiography. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)\n\nFig. 4\n\n3 Discussion\nThe pathogenesis of serpiginous choroiditis (SC) is unknown. The course of the disease is indolent and can be asymptomatic until it involves the macula and the central vision. Many patients can have old scars even at the first visit when they are diagnosed with SC.14 Laatikainen and Erkkila et al. reported that new lesions may appear at an interval of 3 months–4 years. They also demonstrated that active lesions resolve in a few weeks; however, signs of activity may last between 1 and 9 months.14 Central vision is involved in 20%–50% of cases, with the likelihood increasing with longer duration of follow-up and disease activity.8,14 Recurrences that affect the macula can cause severe visual loss of less than 20/200, which is typically irreversible and may induce CNV in the macula or around the optic disc.15\n\nThere are no controlled trials for the treatment of SC due to the rarity of the disease. Cytosine arabinoside, azathioprine, and oral prednisone were used with reported improved visual acuity in one month.16 Employment of a combination of cyclosporine and oral prednisone as a treatment of active SC had conflicting results. Hopper and Kaplan reported a triple-agent regimen of azathioprine, cyclosporine, and oral prednisone that resulted in rapid control of the active SC and vision recovery; however, disease recurrence was the study's main problem.9 Akpek et al. employed the same regimen in a more extended study and found that this regimen helped keep the inflammation quiet during treatment; however, it did not maintain remission off medication.17\n\nAlkylating agents can bind to DNA, interfere with DNA replication, and subsequently interfere with cell division. Cyclophosphamide is commonly used because of its predictable, dose-dependent, and reversible adverse effects on WBC count18; nonetheless, it can result in serious side effects, some of which are life-threatening. These side effects include reversible hematuria, hemorrhagic cystitis, reversible alopecia, sterility, bladder cancer, lymphoma, and leukemia. Chlorambucil is another alkylating agent primarily used for the treatment of several lymphoproliferative diseases. It is a stable derivative of the nitrogen mustard.19 Based on its ability to reduce circulating lymphocytes, chlorambucil is effective in the treatment of rheumatologic diseases, including juvenile rheumatoid arthritis, systemic lupus erythematosus, and nephrotic syndrome.20, 21, 22, 23 Given the availability of other conventional immunomodulatory agents and biologic response modifiers that yield better results with fewer unpredictable side effects, ophthalmologists are reluctant to use chlorambucil. Our knowledge about biologic response modifier agents is limited to a few case reports and some of our patients had already failed infliximab, mycophenolate mofetil, methotreaxte before their first presentation to us or during follow-up with us. Palmer et al. studied the side effects of chlorambucil and found that these side effects are related to the total dose and duration of treatment.24 However, Tessler et al. found chlorambucil to be a successful treatment for different types of uveitis with no severe complications during 12 years of follow-up. They also reported complete remission in all patients. Although chlorambucil dose in their study was administered regardless of body weight, it did not exceed 2.2 g per patient during the entire treatment.25 Based on these findings, recent studies still rely on alkylating agents including cyclophosphamide and chlorambucil for classical and macular SC.5,12,32\n\nIt may take more time for chlorambucil to show its therapeutic and toxic effects. Patients on this medication should be monitored with weekly blood counts, specifically WBC and platelet counts, since its side effects are not always dose-related.25 Chlorambucil is administered orally because it has excellent gastrointestinal absorption, and its superiority over cyclophosphamide is related to the absence of associated side effects such as hair loss, hemorrhagic cystitis, and bladder cancer.26\n\nThe recommendation for the daily and total dose of chlorambucil is equal to or less than 0.2 mg/kg and 2.2 g, respectively. These recommendations help avoid late complications such as lymphoma and leukemia.27 Various doses of chlorambucil have been employed in the past in the field of ophthalmology. The use of lower doses of chlorambucil over an extended period, such as more than one year, without provoking bone marrow toxicity is one approach.28, 29, 30, 31 However, it has been demonstrated that sustained remission of the disease is achievable when the WBC count remained depressed for at least six weeks. This finding suggests that effective treatment with chlorambucil requires the induction of a toxic hematologic response.25\n\nThe recent literature shows that alkylating agents are still the most potent and effective treatment in patients with SC.4,12,32 Venkatesh and colleagues showed that intravenous cyclophosphamide pulse therapy provided a rapid resolution of active lesions and helped maintain good functional visual acuity.4 However, they admitted that this treatment might not prevent recurrences in patients with SC.4 Venkatesh et al. also studied intravenous methylprednisolone and cyclophosphamide in macular SC; they, again demonstrated it could be effective in acute macular SC, yet admitted that this treatment had no effects on disease relapses in the long-term.32 Ebrahimiadib et al. retrospectively studied 17 patients on chlorambucil with dose escalation based on weekly WBC count, with the target of 3000–4500 white blood cells/μl. They concluded that chlorambucil was well tolerated by the patients and was effective in preventing recurrences.12 Although all these recent studies provided important facts regarding SC treatment, they did not discuss the next step for the patients who failed these treatments. In the current study, we decided to evaluate the possible causes of chlorambucil treatment failure in patients with resistant SC and to examine possible successful regimens in these patients. To the best of our knowledge, this study is the first one which evaluates the possible remedy for resistance to chlorambucil as one of the most commonly employed medications in SC patients.\n\nHistopathological studies in SC have demonstrated that lymphocytes infiltrate the choroid, and less commonly, vessels, leading to subsequent choriocapillaris occlusive vasculitis. This finding may indicate the important roles of lymphocytes in the pathogenesis of the disease.5 The histopathology in SC is very similar to birdshot chorioretinopathy.33,34 On the other hand, multiple studies have discussed the effects of long-term systemic corticosteroids on lymphocyte proliferation and T-cell population.35,36 Ferrari et al. reported increased lymphocytes, including increased absolute numbers of T cells, CD4+ and CD8+ cells, after four weeks of corticosteroid therapy in idiopathic thrombocytopenic purpura (ITP).35 Moreover, lymphocyte redistribution has been discussed in long-term steroid therapy.36 These changes associated with long-term corticosteroid use may interfere with the aim of chlorambucil treatment, since cells with higher proliferation rates are the target of this therapy. The negative effect of long-term systemic corticosteroids on birdshot chorioretinopathy has been studied in the past.37,38 Due to similarities between birdshot chorioretinopathy and SC in terms of histopathology, these facts can be applied to SC patients as well.\n\nThe target WBC count for chlorambucil therapy for SC is between 3000 and 4500 cells/μl. Chlorambucil dose adjustment is based on a weekly WBC count. In our experience, patients might be considered cured if there is no recurrence during the treatment period, which is around one year. Our observation in this case series showed that patients on high doses of systemic corticosteroids have unstable WBC count during chlorambucil therapy. Keeping this count in the satisfactory range for a reasonable period of at least six weeks can be challenging since it has been shown that induced toxic hematologic response is required for effective treatment with chlorambucil.25 The first two patients in this case series achieved durable remission and were likely cured after employing local corticosteroids or systemic immunomodulatory therapy, which allowed us to stop systemic corticosteroid use during chlorambucil therapy. However, the third and fourth patients are still experiencing recurrences since all systemic immunomodulatory therapies were unable to induce steroid-free remission. Local corticosteroid therapy was also recommended for both of the patients, but its potential side effects and the patients’ monocular statuses made this option unappealing.\n\nWe might be criticized for not employing local corticosteroid monotherapy without any systemic therapy. We believe that, although corticosteroids are the best option for controlling of acute ocular inflammation of any type, they are not potent enough to prime or re-program the immune system12 and not to respond to self-antigens as we expect with immunomodulatory therapy. This is similar to what occurs to pathologic cancer cells especially in blood cancers (lymphoma and leukemia) in patients who achieve remission with chemotherapy which is an advanced and more aggressive form of immunomodulatory therapy. Based on the above mentioned theory, corticosteroids as monotherapy cannot halt the inflammation thoroughly, so the ongoing inflammation can cause more cells destruction and epitopes exposures which might result in more resistant ocular inflammation which is believed to happen in patients with resistant autoimmune SC. we assume that the employment of systemic corticosteroid therapy, along with chlorambucil, is the main obstacle in achieving remission in patients with SC. This combination therapy is mostly seen in monocular patients or in vision-threatening SC where there is a lower threshold for aggressive systemic corticosteroid therapy in these patients.\n\nWe might also be criticized for using different therapies in one patient; however, we follow the strategy of “one change at a time” and this means that any time a conventional IMT is tried, we wait for three months with no changes to assess its effectiveness. For biologic response modifier agents, we wait for two months. This strategy makes interaction between medications unlikely. Moreover, since our mission is systemic steroid free remission, we only consider a medication to be effective if the inflammation stays in remission even after the effects of steroids are gone. Furthermore, none of these therapies induced long term remission in our patients.\n\nDexamethasone intravitreal implants have been employed in the treatment of active SC and serpiginous-like choroiditis.39,40 In these studies, the authors showed the success of this implant in controlling active SC. Based on these studies, dexamethasone can be an alternative to high dose oral or intravenous corticosteroid without systemic side effects including its effects on bone marrow, secondary lymphoid tissues, and peripheral blood regarding WBC counts, especially lymphocytes.\n\nOne common fact between all patients in this case series is the instability of WBC count during chlorambucil therapy plus systemic corticosteroids. This issue was addressed in one patient with dexamethasone intravitreal implant and in another patient with infliximab therapy. Both patients allowed us to taper and stop oral prednisone during chlorambucil therapy. The latter patient has been in remission for four years, which is the time frame during which one would expect a new lesion based on the Laatikainen and Erkkila et al. study.14 Despite this, this patient continues to take infliximab at a dose of 300 mg every four weeks since there is a fear of SC recurrence once infliximab therapy is terminated. However, this concept and hypothesis need further, more sophisticated examination.\n\nThis study had inherent limitations given its retrospective study design with a small sample size due to the rarity of cases of SC. It was even more challenging to find refractory cases with a reasonable follow-up period to expect a recurrence as all of these patients have at least 8 years of follow-up at our center without any serious side effects. Furthermore, all confounding factors cannot be controlled in a retrospective study. Regardless, we believe that confounding factors related to WBC might not interfere in this study since chlorambucil dose is adjusted based on WBC count and in clinical practice, changes in WBC count are typically more related to changes in corticosteroid dosage. Based on all these limitations, the results of this case series should be interpreted with caution and justifies the need for more potent studies.\n\n4 Conclusion\nThe stability of WBC counts within toxic levels close to normal or lower limits of normal (3000–4500 cells/μl) during treatment with chlorambucil is an essential factor for the success of this therapy. A combination of dexamethasone intravitreal implant with chlorambucil therapy can be an effective and promising regimen in inducing and maintaining remission in refractory SC patients who fail a combination of systemic corticosteroid and chlorambucil therapy as the first line therapy. However, this primitive hypothesis should be investigated with more potent studies and larger sample sizes.\n\nPatient consent\nConsent to publish the personal information and cases details was obtained from all the patients.\n\nFinancial supports\nNone.\n\nAll named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.\n\nDisclosures\nDr. C Stephen Foster declares the following: Consultancies with Aldeyra Therapeutics (Lexington, MA), Allakos (Redwood City, CA), Bausch & Lomb Surgical, Inc (Rancho Cucamonga, CA), Eyegate Pharma (Waltham, MA), Genentech (South San Francisco, CA), Novartis (Cambridge, MA), pSivida (Watertown, MA) Grants or grants pending with Aciont (Salt Lake City, UT), Alcon (Aliso Viejo, CA), Aldeyra Therapeutics (Lexington, MA), Bausch & Lomb (Rochester, NY), Clearside Biomedical (Alpharetta, GA), Dompé pharmaceutical (Milan, Italy), Eyegate Pharma (Waltham, MA), Mallinckrodt pharmaceuticals (Staines-upon-Thames, UK), Novartis Pharmaceuticals (Cambridge, MA), pSivida (Watertown, MA), Santen (Osaka, Japan). Payment for lectures including service on speaking bureaus: Alcon (Aliso Viejo, CA), Allergan (Dublin, Ireland), Mallinckrodt pharmaceuticals (Staines-upon-Thames, UK). Stock or Stock Options: Eyegate Pharma (Waltham, MA).\n\nThe other authors have nothing to declare.\n\nCompliance with ethics guidelines\nThis study was approved by the New England Institutional Review Board, which has issued a waiver of informed consent for the retrospective chart review analysis. This study was performed in accordance with the Helsinki Declaration of 1964, and its later amendments. All participants provided consent for publication if any identifying information is included in the manuscript.\n\nData availability\nThe data that support the findings of this study are available from the corresponding author, upon reasonable request.\n\nDeclaration of competing interest\nNo conflicting relationship exists for any author.\n==== Refs\nReferences\n1 Nazari H. Rao N.A. Serpiginous choroiditis and multifocal serpiginoid choroiditis Surv Ophthalmol 58 3 2013 203 232 23541041 \n2 Dutta Majumder P. Biswas J. Gupta A. Enigma of serpiginous choroiditis Indian J Ophthalmol 67 3 2019 Mar 325 333 30777946 \n3 Bouchenaki N. Cimino L. Auer C. Assessment and classification of choroidal vasculitis in posterior uveitis using indocyanine green angiography Klin Monbl Augenheilkd 219 4 2002 24399 \n4 Wu J.S. Lewis H. Fine S.L. Clinicopathologic findings in a patient with serpiginous choroiditis and treated choroidal neovascularization Retina 9 4 1989 292 301 2483464 \n5 Venkatesh P. Gogia V. Gupta S. Pulse cyclophosphamide therapy in the management of patients with macular serpiginous choroidopathy Indian J Ophthalmol 63 4 2015 318 322 26044470 \n6 Mansour A.M. Jampol L.M. Packo K.H. Hrisomalos N.F. Macular serpiginous choroiditis Retina 8 2 1988 125 131 2458620 \n7 Jampol L.M. Orth D. Daily M.J. Rabb M.F. Subretinal neovascularization with geographic (serpiginous) choroiditis Am J Ophthalmol 88 4 1979 683 689 92200 \n8 Weiss H. Annesley W.H. Jr. Shields J.A. The clinical course of serpiginous choroidopathy Am J Ophthalmol 87 1979 133 142 434065 \n9 Hooper P. Kaplan H. Triple agent immunosuppression in serpiginous choroiditis. Nussenblatt RB, discussion Ophthalmology 98 6 1991 944 951 1866149 \n10 Akpek E.K. Jabs D.A. Tessler H.H. Successful treatment of serpiginous choroiditis with alkylating agents Ophthalmology 109 8 2002 1506 1513 go 12153803 \n11 Sobacı G. Bayraktar Z. Bayer A. Interferon alpha-2A treatment for serpiginous choroiditis Ocul Immunol Inflamm 13 1 2005 59 66 15804771 \n12 Ebrahimiadib N. Modjtahedi B.S. Davoudi S. Foster C.S. Treatment of serpiginous choroiditis with chlorambucil: a report of 17 patients Ocul Immunol Inflamm 26 2 2018 228 238 27754769 \n13 Mangerich A. Debiak M. Birtel M. Sulfur and nitrogen mustards induce characteristic poly(ADP-ribosyl)ation responses in HaCaT keratinocytes with distinctive cellular consequences Toxicol Lett 244 2016 56 71 26383629 \n14 Laatikainen L. Erkkila L.H. A follow-up study on serpiginous choroiditis Acta Ophthalmol 59 1981 707 718 6171987 \n15 Bock C.J. Jampol L.M. Serpiginous choroiditis Jakobiec F.A. Albert D.M. Principles and Practice of Ophthalmology 1994 W.B. Saunders Philadelphia 517 523 chap. 35 \n16 Laatikainen L. Erkkila H. Serpiginous choroiditis Br J Ophthalmol 58 9 1974 777 783 4433491 \n17 Akpek E.K. Baltatzis S. Yang J. Foster C.S. Long-term immunosuppressive treatment of serpiginous choroiditis Ocul Immunol Inflamm 9 2001 153 167 11815884 \n18 Fauci A.S. Haynes B.F. Katz P. Wolff S.M. Wegener's granulomatosis: prospective clinical and therapeutic experience with 85 patients for 21 years Ann Intern Med 98 1983 76 85 6336643 \n19 Bianchi L. Hansel K. Pelliccia S. Systemic delayed hypersensitivity reaction to chlorambucil: a case report and literature review Contact Dermatitis 78 2 2018 171 173 29341183 \n20 Callis L. Nieto J. Vila A. Rende J. Chlorambucil treatment in minimal lesion nephrotic syndrome: a reappraisal of its gonadal toxicity J Pediatr 97 4 1980 653 656 7420231 \n21 Grupe W.E. Chlorambucil in steroid-dependent nephrotic syndrome J Pediatr 82 1973 598 606 4121460 \n22 Baluarte H.J. Hiner L. Gruskin A.B. Chlorambucil dosage in frequently relapsing nephrotic syndrome: a controlled clinical trial J Pediatr 92 1978 295 298 621612 \n23 Savolainen H.A. Chlorambucil in severe juvenile chronic arthritis: longterm follow-up with special reference to amyloidosis J Rheumatol 26 4 1999 898 903 10229413 \n24 Palmer R.G. Dore C.J. Denman A.M. Chlorambucil-induced chromosome damage to human lymphocytes is dose-dependent and cumulative Lancet 1 8371 1984 246 249 6142995 \n25 Tessler H.H. Jennings T. High-dose short-term chlorambucil for intractable sympathetic ophthalmia and Behcet's disease Br J Ophthalmol 74 6 1990 353 357 2378842 \n26 Goldstein D.A. Fontanilla F.A. Kaul S. Long-term follow-up of patients treated with short-term high-dose chlorambucil for sight-threatening ocular inflammation Ophthalmology 109 2 2002 Feb 370 377 11825825 \n27 Mudun B.A. Ergen A. Ipcioglu S.U. Short-term chlorambucil for refractory uveitis in Behcet's disease Ocul Immunol Inflamm 9 4 2001 219 229 11935432 \n28 Godfrey W.A. Epstein W.V. O'Connor G.R. The use of chlorambucil in intractable idiopathic uveitis Am J Ophthalmol 78 3 1974 415 428 4472398 \n29 Smulders F.M. Oosterhuis J.A. Treatment of Behcet's disease with chlorambucil Ophthalmologica 171 1975 347 352 1165913 \n30 Tricoulis D. Treatment of Behcet's disease with chlorambucil Br J Ophthalmol 60 1976 55 57 773421 \n31 Elliott J.H. Ballinger W.H. Behcet's syndrome: treatment with chlorambucil Trans Am Ophthalmol Soc 82 1984 264 281 6535326 \n32 Venkatesh P. Tayade A. Gogia V. Short-term intensive immunosuppression: a randomized, three-arm study of intravenous pulse methylprednisolone and cyclophosphamide in macular serpiginous choroiditis Ocul Immunol Inflamm 26 3 2018 469 476 27849419 \n33 Gaudio P.A. Kaye D.B. Crawford J.B. Histopathology of birdshot retinochoroidopathy Br J Ophthalmol 86 12 2002 1439 1441 12446382 \n34 Pulido J.S. Canal I. Salomao D. Histological findings of birdshot chorioretinopathy in an eye with ciliochoroidal melanoma Eye 26 6 2012 862 865 22402699 \n35 Ferrari A. Pasqualetti D. del Bianco P. Prednisolone versus deflazacort in the treatment of autoimmune thrombocy- topenia purpura: evaluation of clinical response and immunological modifications Haematologica 76 4 1991 342 345 1794742 \n36 Pountain G.D. Keogan M.T. Hazleman B.L. Brown D.L. Effects of single dose compared with three days' prednisolone treatment of healthy volunteers: contrasting effects on circulating lymphocyte subsets J Clin Pathol 46 12 1993 1089 1092 7904272 \n37 Minos E. Barry R.J. Southworth S. Birdshot chorioretinopathy: current knowledge and new concepts in pathophysiology, diagnosis, monitoring and treatment Orphanet J Rare Dis 11 1 2016 61 27175923 \n38 Silpa-Archa S. Maleki A. Roohipoor R. Analysis of three-dimensional choroidal volume with enhanced depth imaging findings in patients with birdshot retinochoroidopathy Retina 36 9 2016 1758 1766 26807626 \n39 Miserocchi E. Berchicci L. Iuliano L. Dexamethasone intravitreal implant in serpiginous choroiditis Br J Ophthalmol 101 3 2017 327 332 27256717 \n40 Fonollosa A. Valsero S. Artaraz J. Ruiz-Arruza I. Dexamethasone intravitreal implants in the management of tubercular multifocal serpiginoid choroiditis J Ophthalmic Inflamm Infect 6 1 2016 31 27576870\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2451-9936", "issue": "21()", "journal": "American journal of ophthalmology case reports", "keywords": "Chlorambucil; Cyclophosphamide; Dexamethasone implant; Infliximab; Serpiginous choroiditis", "medline_ta": "Am J Ophthalmol Case Rep", "mesh_terms": null, "nlm_unique_id": "101679941", "other_id": null, "pages": "101014", "pmc": null, "pmid": "33615036", "pubdate": "2021-03", "publication_types": "D002363:Case Reports", "references": "1866149;30777946;27849419;27175923;1165913;12153803;12022010;2458620;29341183;4472398;6336643;12446382;7904272;2378842;6171987;10229413;4121460;27256717;11825825;621612;26383629;26044470;6535326;2483464;6142995;434065;27576870;773421;11815884;23541041;11935432;26807626;15804771;27754769;1794742;4433491;92200;7420231;22402699", "title": "Chlorambucil combination therapy in refractory serpiginous choroiditis: A cure?", "title_normalized": "chlorambucil combination therapy in refractory serpiginous choroiditis a cure" }

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"reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Metamorphopsia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "White blood cell count decreased", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "FOSTER C. CHLORAMBUCIL COMBINATION THERAPY IN REFRACTORY SERPIGINOUS CHOROIDITIS: A CURE. AMERICAN JOURNAL OF OPHTHALMOLOGY CASE REPORTS. 2021 JAN 30?21:. DOI:10.1016/J.AJOC.2021.101014", "literaturereference_normalized": "chlorambucil combination therapy in refractory serpiginous choroiditis a cure", "qualification": "5", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210311", "receivedate": "20210311", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19000865, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210420" } ]

{ "abstract": "We herein report two cases of myelodysplastic syndrome with rheumatic manifestations. (Case 1) A 70-year-old man presented with fever, arthritis and bone pain and developed cranial nerve palsy caused by an epipharyngeal mass. Steroid therapy led to a prolonged remission of the febrile condition and mass lesion. (Case 2) An 82-year-old male was treated for intractable polyarthritis and fever with steroid therapy, and serious side effects resulted in lethal pneumonia. We herein describe the entire course of steroid therapy in these two cases. Various rheumatic manifestations in myelodyaplastic syndrome often require empirical steroid therapy. It was effective for the soft tissue mass in Case 1, in which indolent lymphoma could not be denied, and was only partially effective for Case 2 of the febrile and putatively benign conditions, suggesting heterogeneous nature of rheumatic complications in myelodysplastic syndrome.", "affiliations": "Division of Rheumatic Diseases, National Center for Global Health and Medicine , Tokyo , Japan.", "authors": "Inoue|Mariko|M|;Kano|Toshikazu|T|;Ozaki|Takashi|T|;Takahashi|Yuko|Y|;Yamashita|Hiroyuki|H|;Kaneko|Hiroshi|H|;Mimori|Akio|A|", "chemical_list": "D005938:Glucocorticoids; D013256:Steroids", "country": "England", "delete": false, "doi": "10.3109/14397595.2013.844300", "fulltext": null, "fulltext_license": null, "issn_linking": "1439-7595", "issue": "25(4)", "journal": "Modern rheumatology", "keywords": "Autoimmune manifestation; Glucocorticoid; Myelodysplastic syndrome", "medline_ta": "Mod Rheumatol", "mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D001168:Arthritis; D001172:Arthritis, Rheumatoid; D001706:Biopsy; D001842:Bone and Bones; D017809:Fatal Outcome; D005334:Fever; D005938:Glucocorticoids; D006801:Humans; D008297:Male; D009190:Myelodysplastic Syndromes; D010243:Paralysis; D010608:Pharyngeal Diseases; D049268:Positron-Emission Tomography; D013256:Steroids; D014057:Tomography, X-Ray Computed", "nlm_unique_id": "100959226", "other_id": null, "pages": "653-6", "pmc": null, "pmid": "24313918", "pubdate": "2015-07", "publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Rheumatic manifestations and an epipharyngeal mass accompanied by myelodysplastic syndrome.", "title_normalized": "rheumatic manifestations and an epipharyngeal mass accompanied by myelodysplastic syndrome" }

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RHEUMATIC MANIFESTATIONS AND AN EPIPHARYNGEAL MASS ACCOMPANIED BY MYELODYSPLASTIC SYNDROME. 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RHEUMATIC MANIFESTATIONS AND AN EPIPHARYNGEAL MASS ACCOMPANIED BY MYELODYSPLASTIC SYNDROME. 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null, "patientonsetage": "81", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pneumonia aspiration", "reactionmeddraversionpt": "19.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Pneumocystis jirovecii pneumonia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Systemic candida", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lung abscess", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201104" } }, "primarysource": { "literaturereference": "INOUE M, KANO T, OZAKI T, TAKAHASHI Y, YAMASHITA H, KANEKO H, ET AL. RHEUMATIC MANIFESTATIONS AND AN EPIPHARYNGEAL MASS ACCOMPANIED BY MYELODYSPLASTIC SYNDROME. MOD-RHEUMATOL 2015?25(4):653-656.", "literaturereference_normalized": "rheumatic manifestations and an epipharyngeal mass accompanied by myelodysplastic syndrome", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20160103", "receivedate": "20160103", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11884166, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160526" } ]

{ "abstract": "Outside of clinical trials, experience with daratumumab-based combination therapies (DCTs) using bortezomib (V)/lenalidomide (R)/pomalidomide (P), and dexamethasone (d) in relapsed/refractory multiple myeloma (RRMM) is limited. We reviewed the outcomes of 126 patients who received ≥ 1 cycle of any DCT. Median age at DCT initiation was 67 (range, 43-93) years. High-risk cytogenetics was present in 33% patients. Median number of prior therapies was 4 (range, 1-14) and time to first DCT from diagnosis was 4.3 years (range, 0.4-13.0). Seventeen (13%) patients were refractory to single agent daratumumab. Fifty-two (41%), 34 (27%), 23 (18%), and 17 (14%) received DPd, DRd, DVd and \"other\" DCTs, respectively. Overall response rate was 47%. Median follow-up was 5.5 months (95% CI, 4.2-6.1). Median progression-free survival (PFS) was 5.5 months (95% CI, 4.2-7.8). Median overall survival was not reached (NR) with any regimen. Median PFS (months) was worst for penta-refractory MM (n = 8) vs quadruple refractory MM (n = 18) and others (n = 100) (2.2 [95% CI, 1-2.4] vs 3.1 [95% CI, 2.1-NR] vs 5.9 [95% CI, 5.0-NR]; P < .001); those who were refractory to ≥1 agents used in the DCT vs others (4.9 [95% CI, 3.1-6.0] vs 8.2 [95% CI, 4.6-NR]; P = .02); and those who received >2 prior therapies vs others (5.0 months [95% CI, 3.7-5.9] vs NR [95% CI, NR-NR]; P = .002). Non-hematologic toxicities included infections (38%), fatigue (32%), and infusion reactions (18%). Grade 3 or higher hematological toxicities were seen in 41% of patients. DCTs are effective in RRMM. ORR and PFS in heavily pretreated patients are lower than those reported in clinical trials.", "affiliations": "Division of Hematology, Mayo Clinic, Rochester, Minnesota.;Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota.;Division of Hematology, Mayo Clinic, Rochester, Minnesota.;Division of Hematology, Mayo Clinic, Rochester, Minnesota.;Division of Hematology, Mayo Clinic, Rochester, Minnesota.;Division of Hematology, Mayo Clinic, Rochester, Minnesota.;Division of Hematology, Mayo Clinic, Rochester, Minnesota.;Division of Hematology, Mayo Clinic, Rochester, Minnesota.;Division of Hematology, Mayo Clinic, Rochester, Minnesota.;Division of Hematology, Mayo Clinic, Rochester, Minnesota.;Division of Hematology, Mayo Clinic, Rochester, Minnesota.;Division of Hematology, Mayo Clinic, Rochester, Minnesota.;Division of Hematology, Mayo Clinic, Rochester, Minnesota.;Division of Hematology, Mayo Clinic, Rochester, Minnesota.;Division of Hematology, Mayo Clinic, Rochester, Minnesota.;Division of Hematology, Mayo Clinic, Rochester, Minnesota.;Division of Hematology, Mayo Clinic, Rochester, Minnesota.;Division of Hematology, Mayo Clinic, Rochester, Minnesota.;Division of Hematology, Mayo Clinic, Rochester, Minnesota.;Division of Hematology, Mayo Clinic, Rochester, Minnesota.;Division of Hematology, Mayo Clinic, Rochester, Minnesota.;Division of Hematology, Mayo Clinic, Rochester, Minnesota.;Division of Hematology, Mayo Clinic, Rochester, Minnesota.", "authors": "Lakshman|Arjun|A|;Abeykoon|Jithma P|JP|http://orcid.org/0000-0003-3939-6252;Kumar|Shaji K|SK|;Rajkumar|S Vincent|SV|;Dingli|David|D|;Buadi|Francis K|FK|;Gonsalves|Wilson I|WI|http://orcid.org/0000-0001-6890-969X;Leung|Nelson|N|http://orcid.org/0000-0002-5651-1411;Dispenzieri|Angela|A|;Kourelis|Taxiarchis V|TV|;Go|Ronald S|RS|http://orcid.org/0000-0002-8284-3495;Lacy|Martha Q|MQ|;Hobbs|Miriam A|MA|;Lin|Yi|Y|;Warsame|Rahma|R|http://orcid.org/0000-0003-0240-0326;Lust|John|J|;Fonder|Amie L|AL|;Hwa|Yi L|YL|;Hayman|Suzanne R|SR|;Russell|Stephen J|SJ|;Kyle|Robert A|RA|;Gertz|Morie A|MA|;Kapoor|Prashant|P|", "chemical_list": "D000911:Antibodies, Monoclonal; D015415:Biomarkers; C556306:daratumumab", "country": "United States", "delete": false, "doi": "10.1002/ajh.24883", "fulltext": null, "fulltext_license": null, "issn_linking": "0361-8609", "issue": "92(11)", "journal": "American journal of hematology", "keywords": null, "medline_ta": "Am J Hematol", "mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal; D000971:Antineoplastic Combined Chemotherapy Protocols; D015415:Biomarkers; D002869:Chromosome Aberrations; D019008:Drug Resistance, Neoplasm; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D012008:Recurrence; D019233:Retreatment; D016019:Survival Analysis; D016896:Treatment Outcome", "nlm_unique_id": "7610369", "other_id": null, "pages": "1146-1155", "pmc": null, "pmid": "28799231", "pubdate": "2017-11", "publication_types": "D016428:Journal Article", "references": null, "title": "Efficacy of daratumumab-based therapies in patients with relapsed, refractory multiple myeloma treated outside of clinical trials.", "title_normalized": "efficacy of daratumumab based therapies in patients with relapsed refractory multiple myeloma treated outside of clinical trials" }

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"20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary oedema", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dyspnoea", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dehydration", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Infection", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Disease progression", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fatigue", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Infusion related reaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KAPOOR P, LAKSHMAN A, DINGLI D, ABEYKOON JP, KUMAR SK, RAJKUMAR SV, ET AL.. EFFICACY OF DARATUMUMAB-BASED THERAPIES IN PATIENTS WITH RELAPSED, REFRACTORY MULTIPLE MYELOMA TREATED OUTSIDE OF CLINICAL TRIALS.. AMERICAN JOURNAL OF HEMATOLOGY 2017. 2017;92(11):1146-1155", "literaturereference_normalized": "efficacy of daratumumab based therapies in patients with relapsed refractory multiple myeloma treated outside of clinical trials", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20171107", "receivedate": "20171107", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14165624, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180321" }, { "companynumb": "US-JNJFOC-20171104837", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": 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EFFICACY OF DARATUMUMAB-BASED THERAPIES IN PATIENTS WITH RELAPSED, REFRACTORY MULTIPLE MYELOMA TREATED OUTSIDE OF CLINICAL TRIALS. 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null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "16", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DARATUMUMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DARATUMUMAB" }, "drugadditional": "3", "drugadministrationroute": "041", "drugauthorizationnumb": "127058", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "16 MILLIGRAM/KILOGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "16", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DARATUMUMAB" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Infusion related reaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Constipation", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Renal impairment", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Muscle spasms", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Mood altered", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fatigue", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Plasma cell myeloma", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Transient ischaemic attack", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dyspnoea", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Infection", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hyperglycaemia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KAPOOR P. EFFICACY OF DARATUMUMAB-BASED THERAPIES IN PATIENTS WITH RELAPSED, REFRACTORY MULTIPLE MYELOMA TREATED OUTSIDE OF CLINICAL TRIALS. AMERICAN JOURNAL OF HEMATOLOGY.", "literaturereference_normalized": "efficacy of daratumumab based therapies in patients with relapsed refractory multiple myeloma treated outside of clinical trials", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170827", "receivedate": "20170827", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13908598, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" } ]

{ "abstract": "Hepatic glycogenosis (HG) has been reported after intravenous (IV) dextrose administration to treat insulin overdose. We describe a case of HG in a patient with type 1 diabetes mellitus (T1DM) due to insulin overdose treated with oral glucose administration.\nAn adolescent boy with T1DM on a basal bolus insulin regimen presented with abdominal discomfort, nausea, vomiting, and hypoglycemia of a few hours. His glucose was 71 mg/dL, aspartate transaminase (AST) 119 U/L, and alanine transaminase (ALT) 65 U/L. Hypoglycemia was treated with juice, and 12 hours later AST and ALT were 979 U/L and 700 U/L, respectively. Workup for infectious, autoimmune, metabolic, and toxic causes of hepatitis was negative. The transaminases improved by the next day and normalized within 3 weeks. Two weeks after discharge the patient returned with hypoglycemia, nausea, and right-sided abdominal pain of 13 hours. Hypoglycemia persisted despite multiple courses of glucose tablets and juice. Laboratory studies showed glucose of 58 mg/dL, AST of 776 U/L, ALT of 496 U/L, negative toxicology studies, and normal abdominal ultrasound. His serum insulin level was 249.7 mU/L and, C-peptide was less than 0.1 ng/mL, consistent with insulin overdose. He received IV fluids with dextrose, and insulin was held. Transaminases improved by the following day. Repeat serum insulin while on home regimen was normal.\nAlong with other diagnoses, HG should be considered in patients treated with insulin who present with hypoglycemia and acute hepatitis. HG can occur in cases of insulin overdose treated with repeated oral glucose administration.", "affiliations": "Division of Pediatric Endocrinology, Hasbro Children's Hospital, Providence, Rhode Island 02903, USA.;Division of Pediatric Endocrinology, Hasbro Children's Hospital, Providence, Rhode Island 02903, USA.;Division of Pediatric Endocrinology, Hasbro Children's Hospital, Providence, Rhode Island 02903, USA.", "authors": "Sasidharan Pillai|Sabitha|S|https://orcid.org/0000-0002-0391-3759;Quintos|Jose Bernardo|JB|https://orcid.org/0000-0003-1691-2293;Topor|Lisa Swartz|LS|https://orcid.org/0000-0002-1219-9921", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1210/jendso/bvab142", "fulltext": "\n==== Front\nJ Endocr Soc\nJ Endocr Soc\njes\nJournal of the Endocrine Society\n2472-1972\nOxford University Press US\n\n10.1210/jendso/bvab142\nbvab142\nCase Reports\nAcademicSubjects/MED00250\nAcute Hepatitis due to Hepatic Glycogenosis After Insulin Overdose and Oral Glucose Administration in an Adolescent\nhttps://orcid.org/0000-0002-0391-3759\nSasidharan Pillai Sabitha 12\nhttps://orcid.org/0000-0003-1691-2293\nQuintos Jose Bernardo 12\nhttps://orcid.org/0000-0002-1219-9921\nTopor Lisa Swartz [email protected]\n\n1 Division of Pediatric Endocrinology, Hasbro Children’s Hospital, Providence, Rhode Island 02903, USA\n2 Department of Pediatrics, The Warren Alpert Medical School of Brown University, Providence, Rhode Island 02903, USA\nCorrespondence: Lisa Swartz Topor, MD, MMSc, Department of Pediatrics, The Warren Alpert Medical School of Brown University, 593 Eddy St, Providence, RI 02903, USA. Email: [email protected].\n01 11 2021\n01 9 2021\n5 11 bvab14214 7 2021\n17 8 2021\n23 9 2021\n© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact [email protected]\n\nAbstract\n\nBackground\n\nHepatic glycogenosis (HG) has been reported after intravenous (IV) dextrose administration to treat insulin overdose. We describe a case of HG in a patient with type 1 diabetes mellitus (T1DM) due to insulin overdose treated with oral glucose administration.\n\nCase Presentation\n\nAn adolescent boy with T1DM on a basal bolus insulin regimen presented with abdominal discomfort, nausea, vomiting, and hypoglycemia of a few hours. His glucose was 71 mg/dL, aspartate transaminase (AST) 119 U/L, and alanine transaminase (ALT) 65 U/L. Hypoglycemia was treated with juice, and 12 hours later AST and ALT were 979 U/L and 700 U/L, respectively. Workup for infectious, autoimmune, metabolic, and toxic causes of hepatitis was negative. The transaminases improved by the next day and normalized within 3 weeks. Two weeks after discharge the patient returned with hypoglycemia, nausea, and right-sided abdominal pain of 13 hours. Hypoglycemia persisted despite multiple courses of glucose tablets and juice. Laboratory studies showed glucose of 58 mg/dL, AST of 776 U/L, ALT of 496 U/L, negative toxicology studies, and normal abdominal ultrasound. His serum insulin level was 249.7 mU/L and, C-peptide was less than 0.1 ng/mL, consistent with insulin overdose. He received IV fluids with dextrose, and insulin was held. Transaminases improved by the following day. Repeat serum insulin while on home regimen was normal.\n\nConclusion\n\nAlong with other diagnoses, HG should be considered in patients treated with insulin who present with hypoglycemia and acute hepatitis. HG can occur in cases of insulin overdose treated with repeated oral glucose administration.\n\nadolescent\ntype 1 diabetes mellitus\ninsulin overdose\nhepatic glycogenesis\n==== Body\npmcPierre Mauriac first described hepatic glycogenosis (HG) in 1930, a syndrome in children with poorly controlled type 1 diabetes mellitus (T1DM) characterized by glycogen accumulation in the liver causing hepatomegaly, growth failure, round facies, and delayed puberty [1, 2]. This constellation of symptoms is also referred to as Mauriac syndrome, liver glycogenosis, liver glycogen storage, diabetes mellitus-associated glycogen storage hepatomegaly, and glycogenic hepatopathy [3, 4].\n\nHG occurs when insulin levels are elevated in the presence of high levels of glucose and is typically seen in those with wide fluctuations in glucose and insulin levels. Hyperglycemia leads to increased glucose entry into the hepatocytes, and excess insulin promotes conversion of the glucose into glycogen. Liver injury is mediated by increased glucose uptake, glycogenesis, and inhibition of gluconeogenesis [4], and pathologic glycogen accumulation leads to elevated hepatic transaminases [5]. HG can also occur with isolated liver involvement, without the full phenotype of growth delay and hepatomegaly and has been reported in individuals across the lifespan [6]. Excess glycogenesis reverses rapidly once insulin and glucose levels are stabilized, and hepatic injury is reversible.\n\nMost cases of HG occur in individuals with T1DM, while a small percentage of cases occurs in those with type 2 diabetes mellitus. HG has also been reported in the setting of dumping syndrome following gastrostomy and in cases of hyperglycemia following high-dose glucocorticoid therapy [4, 5], as frequent hypoglycemia and its correction with glucose administration contributes to the pathogenesis.\n\nTransient hepatitis secondary to HG has been reported after intravenous (IV) dextrose administration to treat insulin overdose in adults. We describe an adolescent male with T1DM who developed 2 episodes of acute hepatitis due to HG following insulin overdoses and repeated oral glucose administration to treat hypoglycemia.\n\nCase Presentation\n\nA 16-year-old boy with T1DM for 7 years treated with a basal bolus insulin regimen presented in the evening to an emergency department (ED) of a tertiary care hospital with complaints of abdominal discomfort, nausea, nonbilious nonbloody vomiting, and hypoglycemia for the past 8 hours. Most recent glycated hemoglobin A1c was 9.5%. The abdominal symptoms started in the late afternoon the day of presentation. His blood sugar was in the 40-mg/dL range and was treated with oral glucose tablets. He described taking his usual insulin doses earlier in the day, and denied taking any other medications, substances, or excess insulin. His medications included glargine insulin each night, lispro insulin with meals, sertraline 100 mg daily, guanfacine 1 mg in the morning and 3 mg at night, and melatonin 3 mg nightly as needed. On examination, he was alert, afebrile, with stable vital signs and an exam notable for epigastric and right upper-quadrant tenderness. His initial laboratory workup showed elevated liver enzymes (Table 1) and hypoglycemia. Additional laboratory values including pH (7.36), blood gas, complete blood count with total white blood cell count 6100 cells/mm3, and basic metabolic profile, including bicarbonate 28 mEq/L, were normal. An extended respiratory viral panel and COVID-19 test were all negative. Testing for Epstein-Barr virus and enterovirus was also negative. Urinalysis was negative for ketones. Chest and abdominal plain films were unremarkable. The hypoglycemia was treated with juice, and he was admitted to the hospital for monitoring. He ate dinner and 2 snacks before bed. Overnight, he had 2 additional episodes of hypoglycemia and was treated with juice (total carbohydrate 60 g). The patient did not require IV dextrose to correct the hypoglycemia. Repeat laboratory values 12 hours after admission showed marked elevation in liver enzymes (see Table 1). Given concern for an undisclosed ingestion, infection, or other cause of hepatitis, additional laboratory studies were obtained (Table 2). An abdominal ultrasound showed normal liver size and texture, and Doppler ultrasound of the liver vasculature was also normal. He had normal thyroid function. Owing to the rapid rise in transaminase levels, the patient was treated empirically with a 21-hour NAC (N-acetylcysteine) protocol for presumed ingestion, as per the recommendation of the poison control team. Transaminases began to trend down by 25 hours after admission and normalized by 3 weeks (see Table 1).\n\nTable 1. Glucose and liver enzymes during the first presentation\n\nLaboratory test\tReference range\t0 h\t12 h\t25 h\t37 h\t53 h\tD 22\t\nGlucose, mg/dL\t67-99\t71\t219\t262\t287\t212\t89\t\nAST, U/L\t13-38\t119\t979\t377\t166\t78\t20\t\nALT, U/L\t8-36\t65\t700\t627\t475\t336\t28\t\nAbbreviations: ALT, alanine transaminase; AST, aspartate transaminase.\n\nTable 2. Laboratory evaluation for causes of abdominal pain and hepatitis\n\nVariable\tReference range\tResults\t\nCeliac panel: total IgA, mg/dL\t63-484\t102\t\n TTG IgA, units\t0-20\t4.2\t\nCortisol (7:45 am), μg/dL\t5.5-20\t15.8\t\nAlpha 1 antitrypsin phenotype\t–\tPI*M1N\t\nFerritin, ng/mL\t22-322\t20\t\nCeruloplasmin, mg/dL\t20-60\t34\t\nAcute hepatitis panel (hepatitis A antibody, IgM; hepatitis B core antibody, IgM; hepatitis B surface antigen; hepatitis C virus antibody)\t–\tNegative\t\nAutoimmune hepatitis panel: actin Ab IgG, anti-LKM Ab, anti- smooth muscle actin Ab, ANA\tNegative\tNegative\t\nToxicology (ethchlorvynol and phenothiazine, acetaminophen, salicylate, imipramine/desipramine, GC and MS)\tAcetaminophen: 11-20 mg/dL\nSalicylate: 15-30 mg/dL\tAcetaminophen < 10 μg/dL\nSalicylate: < 2.5 mg/dL\t\nUrine toxicology\t–\tNegative\t\nAbbreviations: Ab, antibody; ANA, antinuclear antibodies; GC, gas chromatography; Ig, immunoglobulin; LKM, liver kidney microsome; MS, mass spectrometry; TTG, tissue transglutaminase.\n\nThe patient was discharged home after a prolonged hospitalization that included a stay in a behavioral health unit because of concern of medication overdose, despite repeated denials. He did not have any hypoglycemia during the admission. Two weeks after his discharge home (30 days after the initial admission), the patient returned to the ED with complaints of nausea, vomiting, abdominal pain, and hypoglycemia. The patient was found to have hypoglycemia (40 mg/dL) the morning of admission, when his school nurse checked his blood sugar before breakfast. He did not receive prandial insulin with breakfast or lunch. He consumed more than 20 glucose tablets and servings of juice (4 ounces) to maintain blood glucose above 70 mg/dL. He developed nausea and right-sided abdominal pain of 8 out of 10 in intensity during the day, and symptoms worsened by late afternoon. He also had an episode of nonbilious, nonbloody emesis. He was brought to the ED about 13 hours after the detection of hypoglycemia. He did not have fever, sick contacts, or recent travel, and denied ingestion of any medications or substances. In the ED, examination was unremarkable except for right upper-quadrant abdominal tenderness. Laboratory evaluation showed elevated liver enzymes (Table 3) and hypoglycemia. He had a normal complete blood count with total white blood cell count 3800/mm3, normal basic metabolic profile (bicarbonate, 24 mEq/L), negative urine ketones, and negative COVID-19 testing. His insulin level was 250 mU/L with a C-peptide level of less than 0.1 ng/mL at the time of hypoglycemia, consistent with excess exogenous insulin (see Table 3). As his serum glucose levels improved, his IV fluids were weaned and then discontinued 22 hours after presentation. The abdominal pain and nausea subsided over 3 days. He resumed his home insulin regimen and did not have further hypoglycemia. Repeat serum insulin when he was receiving his home insulin regimen was 19.5 mU/L (see Table 3). His liver enzymes normalized within 2 months (see Table 3).\n\nTable 3. Glucose and liver enzymes during the second presentation\n\nLaboratory test\tReference range\t0 h\t5 h\t15 h\t26 h\tD 6\t2 mo\t\nGlucose, mg/dL\t67-99\t58\t42\t143\t259\t245\t356\t\nAST, U/L\t13-38\t776\t955\t441\t229\t40\t13\t\nALT, U/L\t8-36\t496\t747\t546\t444\t101\t12\t\nC peptide, ng/mL\t0.8-3.85\t\t< 0.10\t\t\t\t\t\nTotal serum insulin, mU/L\t3-25\t\t249.7\t\t\t19.5\t\t\nAbbreviations: ALT, alanine transaminase; AST, aspartate transaminase.\n\nWith improved supervision of insulin administration, the patient did not have further episodes of hypoglycemia episodes or elevated liver enzymes. He continued to deny insulin overdose.\n\nDiscussion\n\nWe describe HG that occurred after insulin overdose and solely oral glucose treatment of hypoglycemia, without classic features of Mauriac syndrome. Unlike previous case reports of HG in adults treated for insulin overdose with prolonged IV dextrose administration (Table 4), our patient developed HG following insulin overdose managed with repeated courses of oral glucose administration.\n\nTable 4. Case reports of hepatic glycogenosis following insulin overdose\n\nReference y\tDiabetes diagnosis\tAge, y; sex\tInsulin type and units\tPresenting symptoms\tTreatment before development of HG\tOnset of symptoms\t\n2001 [14]\tNondiabetic\t48, female\t1000 units of long-acting insulin along with benzodiazepines and ASA\tComa with severe hypoglycemia, requiring intubation for 3 d\tBoluses of 40% glucose, continuous infusion of 20% glucose (1200-1400 g daily × 3 d)\tOn d 3, nausea, RUQ abdominal pain, hepatomegaly with worsening of liver enzymes\t\n2012 [15]\tType 1\t26, male\t4800 units of glargine\tSevere hypoglycemia\tParenteral 20% glucose, 10% glucose, oral fruit concentrate\tOn d 3, nausea, right-sided abdominal pain and hepatomegaly, elevated liver enzymes, bilirubin elevation\t\n2006 [16]\tType 2\t41, male\t180 units of glargine\tLoss of consciousness\tParenteral glucose and hypercaloric feed\tDeranged hepatic function and hepatomegaly on d 3\t\n2020 [13]\tType 1\t25, male\t3600 units of insulin glargine and 2100 units of insulin lispro\tCold sweat, feeling groggy\tContinuous 17.5% glucose infusion. ~ 900 g of glucose/d × 4 d\tOn d 4 with general fatigue, persistent right hypochondral pain, abdominal discomfort, appetite loss, elevated liver enzymes\t\nOur patient\tType 1\t16, male\tUnknown\tSevere hypoglycemia, abdominal pain, nausea\tMultiple glucose tablets, juice\tAt admission, ~ 18 h after onset of hypoglycemia with pain abdomen, nausea, vomiting, elevated liver enzymes\t\nAbbreviations: ASA, acetylsalicylic acid; RUQ, right upper quadrant.\n\nDuring his second episode, our patient developed hypoglycemia during the school day and was treated repeatedly with glucose tablets and juice. HG may present with nausea, vomiting, abdominal pain, and hepatomegaly with elevated transaminases [5] due to increased glycogen synthesis and deposition in the setting of excess insulin and glucose levels. Increased serum glucose leads to increased glucose entry into the hepatocyte through insulin-independent facilitated diffusion via glucose transporter 2 (GLUT2). The excess insulin promotes conversion of this glucose into glycogen and inhibits glycogenolysis, leading to glycogen deposition. The rapid glycogen deposition causes elevation of liver enzymes, and the sudden increase in liver size with stretching of the liver capsule triggers the abdominal pain [7]. Though hepatomegaly is characteristic of HG in more than 90% of cases, it can occur without hepatomegaly [7-9]. Our patient did not have hepatomegaly on exam or by imaging.\n\nIt is essential to distinguish HG from nonalcoholic fatty liver disease (NAFLD). NAFLD is characterized by triglyceride deposition in hepatocytes due to factors other than alcohol intake and can also present with hepatomegaly and elevated transaminases. Obesity is a driving factor in NAFLD development, and it has been reported in children and adolescents with obesity [10]. NAFLD has also been described in children with T1DM [11]. NAFLD is associated with mild, persistent elevation of liver enzymes [6, 12] and can progress to fibrosis and cirrhosis, while the hepatomegaly and elevated liver enzymes of HG are transient and complete resolution occurs with improvement of glycemic control.\n\nDemonstration of glycogen deposition in hepatocytes by liver biopsy is the gold standard for the diagnosis of HG [6]. The characteristic histologic finding in HG is ballooned hepatocytes with intracytoplasmic glycogen deposition [13]. Other histological features include no or minimal fatty change, portal inflammation, nor necrosis or fibrosis with intact architect of the liver parenchyma [5, 7]. In contrast, liver biopsy in NAFLD typically shows macrovesicular steatosis and mild lobular and portal inflammation and fibrosis of varying degrees [7]. Ultrasound does not help in distinguishing HG from NAFLD as both conditions lead to increased echogenicity of the liver [13]. Computed tomography of the liver demonstrates high density in HG and low density in NAFLD. Magnetic resonance imaging (MRI) shows low density on T2-weighted images for HG. Gradient dual-echo MRI is more helpful in distinguishing between the glycogen and fat deposition by demonstrating low intensity in phase and high intensity out of phase with HG [13].\n\nWe identified 4 case reports in the literature that describe HG in adults following insulin overdose and subsequent IV dextrose administration to manage the profound and prolonged hypoglycemia (see Table 4) [13-16]. All of the cases describe administration of large doses of IV dextrose over multiple days. Three reports describe development of hepatomegaly and hepatitis the third day after insulin administration, and one case reported these symptoms on day 4. All patients had a dramatic recovery of liver enzymes after stabilization of glucose levels.\n\nIn contrast, during his initial presentation, our patient’s hypoglycemia was detected after the development of abdominal symptoms, and during the second admission, he presented with hepatitis the same day that he developed hypoglycemia, after treatment with multiple glucose tablets and juice. Our patient had poorly controlled T1DM, with chronic hyperglycemia and elevations in the glycated hemoglobin A1c over the past few years. One possible explanation for the onset of abdominal symptoms before the detection and treatment of hypoglycemia is that baseline hyperglycemia led to glucose influx into the liver cells via GLUT2 channels with trapping of glucose-6-phosphate in hepatocytes after phosphorylation by glucokinase. The addition of supraphysiological doses of insulin could have promoted glycogenesis from trapped glucose-6-phosphate, leading to HG [7]. Glucose administration to treat hypoglycemia would have further enhanced glycogenesis in the setting of high insulin, with worsening of abdominal symptoms.\n\nOur patient did not acknowledge excess insulin administration, though his markedly elevated plasma insulin and undetectable C-peptide at the time of hypoglycemia (see Table 1) and the return of plasma insulin to a normal level while receiving his typical doses suggested exogenous insulin administration. Infections, ingestions, and metabolic and autoimmune disease were ruled out with various laboratory studies (see Table 2). Two episodes with dramatic recovery of the liver enzymes with improved glycemic control and unremarkable liver ultrasound favors a diagnosis of HG, though he did not have a liver biopsy or MRI performed. Along with other diagnoses, HG should be considered in patients treated with insulin who present with hypoglycemia and acute hepatitis, as HG can develop after repeated administration of oral glucose for treatment of hypoglycemia.\n\nAcknowledgments\n\nFinancial Support: The authors received no financial support for the research, authorship, and/or publication of this article.\n\nAbbreviations\n\nALT alanine transaminase\n\nAST aspartate transaminase\n\nED emergency department\n\nGLUT2 glucose transporter 2\n\nHG hepatic glycogenosis\n\nIV intravenous\n\nMRI magnetic resonance imaging\n\nNAFLD nonalcoholic fatty liver disease\n\nT1DM type 1 diabetes mellitus\n\nAdditional Information\n\nDisclosures: The authors have nothing to disclose.\n\nData Availability\n\nData sharing is not applicable to this article because no data sets were generated or analyzed during the present study.\n==== Refs\nReferences\n\n1. MauriacP. Gros ventre, hepatomegalie, troubles de croissance chez les enfants diabetiques traites depuis plusiers annee par l’insuline. Gaz Hebd Med Bordeaux. 1930;26 :402-4102.\n2. KimMS, QuintosJB. Mauriac syndrome: growth failure and type 1 diabetes mellitus. Pediatr Endocrinol Rev. 2008;5 (Suppl 4 ):989-993.18806715\n3. AbaciA, BekemO, UnuvarT, et al. Hepatic glycogenosis: a rare cause of hepatomegaly in Type 1 diabetes mellitus. J Diabetes Complications. 2008;22 (5 ):325-328.18413182\n4. IkarashiY, KogisoT, HashimotoE, et al. Four cases of type 1 diabetes mellitus showing sharp serum transaminase increases and hepatomegaly due to glycogenic hepatopathy. Hepatol Res. 2017;47 (3 ):E201-E209.27027269\n5. GiordanoS, MartocchiaA, ToussanL, et al. Diagnosis of hepatic glycogenosis in poorly controlled type 1 diabetes mellitus. World J Diabetes. 2014;5 (6 ):882-888.25512791\n6. BuaJ, MarchettiF, FaleschiniE, VenturaA, BussaniR. Hepatic glycogenosis in an adolescent with diabetes. J Pediatr. 2010;157 (6 ):1042.20638077\n7. SherigarJM, CastroJ, YinYM, GussD, MohantySR. Glycogenic hepatopathy: a narrative review. World J Hepatol. 2018;10 (2 ):172-185.29527255\n8. ChatilaR, WestAB. Hepatomegaly and abnormal liver tests due to glycogenosis in adults with diabetes. Medicine (Baltimore). 1996;75 (6 ):327-333.8982149\n9. MukewarS, SharmaA, LackoreKA, et al. Clinical, biochemical, and histopathology features of patients with glycogenic hepatopathy. Clin Gastroenterol Hepatol. 2017;15 (6 ):927-933.28043933\n10. ScapaticciS, D’AdamoE, MohnA, ChiarelliF, GianniniC. Non-alcoholic fatty liver disease in obese youth with insulin resistance and type 2 diabetes. Front Endocrinol (Lausanne). 2021;12 :639548.33889132\n11. RegnellSE, LernmarkÅ. Hepatic steatosis in type 1 diabetes. Rev Diabet Stud. 2011;8 (4 ):454-467.22580727\n12. van den BrandM, ElvingLD, DrenthJP, van KriekenJH. Glycogenic hepatopathy: a rare cause of elevated serum transaminases in diabetes mellitus. Neth J Med. 2009;67 (11 ):394-396.20009116\n13. FujisakiN, KosakiY, NojimaT, et al. Glycogenic hepatopathy following attempted suicide by long-acting insulin overdose in patient with type 1 diabetes. J Am Coll Emerg Physicians Open. 2020;1 (5 ):1097-1100.33145563\n14. JollietP, LeverveX, PichardC. Acute hepatic steatosis complicating massive insulin overdose and excessive glucose administration. Intensive Care Med. 2001;27 (1 ):313-316.11280657\n15. WarrinerD, DebonoM, GandhiRA, ChongE, CreaghF. Acute hepatic injury following treatment of a long-acting insulin analogue overdose necessitating urgent insulin depot excision. Diabet Med. 2012;29 (2 ):232-235.21781150\n16. TsujimotoT, TakanoM, NishiofukuM, et al. Rapid onset of glycogen storage hepatomegaly in a type-2 diabetic patient after a massive dose of long-acting insulin and large doses of glucose. Intern Med. 2006;45 (7 ):469-473.16679704\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2472-1972", "issue": "5(11)", "journal": "Journal of the Endocrine Society", "keywords": "adolescent; hepatic glycogenesis; insulin overdose; type 1 diabetes mellitus", "medline_ta": "J Endocr Soc", "mesh_terms": null, "nlm_unique_id": "101697997", "other_id": null, "pages": "bvab142", "pmc": null, "pmid": "34568710", "pubdate": "2021-11-01", "publication_types": "D002363:Case Reports", "references": "22580727;25512791;28043933;20638077;18413182;18806715;27027269;21781150;16679704;8982149;20009116;29527255;11280657;33889132;33145563", "title": "Acute Hepatitis due to Hepatic Glycogenosis After Insulin Overdose and Oral Glucose Administration in an Adolescent.", "title_normalized": "acute hepatitis due to hepatic glycogenosis after insulin overdose and oral glucose administration in an adolescent" }

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"patientweight": null, "reaction": [ { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Glycogen storage disease type VIII", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypoglycaemia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hepatitis acute", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Sasidharan Pillai S, Quintos JB, Topor LS. Acute Hepatitis due to Hepatic Glycogenosis after Insulin Overdose and Oral Glucose Administration in an Adolescent. J-Endocr-Soc 2021;5(11):1-6.", "literaturereference_normalized": "acute hepatitis due to hepatic glycogenosis after insulin overdose and oral glucose administration in an adolescent", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220302", "receivedate": "20211112", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20062036, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220424" } ]

{ "abstract": "BACKGROUND\n5% minoxidil formulations twice daily are effective in treating vertex male androgenetic alopecia (AGA); however, efficacy and safety data in frontotemporal regions are lacking.\n\n\nOBJECTIVE\nTo assess the efficacy of 5% minoxidil topical foam (5% MTF) in the frontotemporal region of male AGA patients after 24 weeks of treatment compared to placebo treatment and to the vertex region.\n\n\nMETHODS\nSeventy males with moderate AGA applied 5% MTF or placebo foam (plaTF) twice daily for 24 weeks in frontotemporal and vertex regions. Target area non-vellus hair count (TAHC) was the primary end point.\n\n\nRESULTS\nFrontotemporal and vertex TAHC and target area cumulative non-vellus hair width (TAHW) showed similar responses to 5% MTF with significant increases up to week 16 compared to baseline (p < 0.001). After 24 weeks of treatment, frontotemporal TAHW increased significantly in the 5% MTF group compared to the plaTF group (p = 0.017), while TAHC showed a similar non-significant increase from baseline in both regions. At 24 weeks, 5% MTF users rated a significant improvement in scalp coverage for the frontotemporal (p = 0.016) and vertex areas (p = 0.027).\n\n\nCONCLUSIONS\n5% MTF twice a day promotes hair density and width in both frontotemporal and vertex regions in men with moderate stages of AGA. © 2015 S. Karger AG, Basel.", "affiliations": "Clinical Research Center for Hair and Skin Science, Department of Dermatology and Allergy, Charité-Universitätsmedizin Berlin, Berlin, Germany.", "authors": "Hillmann|Kathrin|K|;Garcia Bartels|Natalie|N|;Kottner|Jan|J|;Stroux|Andrea|A|;Canfield|Douglas|D|;Blume-Peytavi|Ulrike|U|", "chemical_list": "D014665:Vasodilator Agents; D008914:Minoxidil", "country": "Switzerland", "delete": false, "doi": "10.1159/000375320", "fulltext": null, "fulltext_license": null, "issn_linking": "1660-5527", "issue": "28(5)", "journal": "Skin pharmacology and physiology", "keywords": null, "medline_ta": "Skin Pharmacol Physiol", "mesh_terms": "D000279:Administration, Cutaneous; D000328:Adult; D000368:Aged; D000505:Alopecia; D004311:Double-Blind Method; D006197:Hair; D006801:Humans; D008297:Male; D008875:Middle Aged; D008914:Minoxidil; D013997:Time Factors; D016896:Treatment Outcome; D014665:Vasodilator Agents; D055815:Young Adult", "nlm_unique_id": "101188418", "other_id": null, "pages": "236-44", "pmc": null, "pmid": "25765348", "pubdate": "2015", "publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "A Single-Centre, Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Investigate the Efficacy and Safety of Minoxidil Topical Foam in Frontotemporal and Vertex Androgenetic Alopecia in Men.", "title_normalized": "a single centre randomized double blind placebo controlled clinical trial to investigate the efficacy and safety of minoxidil topical foam in frontotemporal and vertex androgenetic alopecia in men" }

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{ "abstract": "OBJECTIVE\nTo explore the safety and tolerability of atacicept in combination with rituximab in patients with active rheumatoid arthritis (RA) receiving rituximab re-treatment.\n\n\nMETHODS\nIn this randomized, double-blind, placebo-controlled pilot trial, 2 infusions (1,000 mg per infusion) of intravenous rituximab, given 2 weeks apart, were followed by once-weekly subcutaneous injections of 150 mg atacicept or placebo for 25 weeks. Primary end points were the nature, incidence, and severity of adverse events (AEs). Secondary end points were the effects on peripheral blood B cells, disease activity biomarkers, and American College of Rheumatology 20% (ACR20), 50% (ACR50), and 70% (ACR70) response rates.\n\n\nRESULTS\nEighteen patients were randomized to receive atacicept and 9 to receive placebo. AEs occurred in 17 atacicept-treated patients (94.4%) and in all 9 placebo-treated patients (100%). There were no infection-related serious adverse events. Hypersensitivity and injection site reactions were more common, and more patients withdrew due to AEs, in the atacicept group. Median reductions in Ig levels from baseline to week 32 were greater with atacicept (median change in IgG -31.2%, IgM -60.9%, and IgA -56.4%) than with placebo (median change in IgG -4.4%, IgM -15.9%, and IgA -8.2%). Peripheral B cell numbers remained low in all patients after rituximab-mediated B cell depletion, limiting comparison of time to recovery between treatment groups. There were no between-group differences in ACR20, ACR50, and ACR70 response rates.\n\n\nCONCLUSIONS\nIn this exploratory trial, atacicept in combination with rituximab showed no new safety issues. Peripheral B cell counts remained too low to determine whether atacicept delayed B cell re-expansion following rituximab-mediated depletion. Despite clear biologic effects, adding atacicept to rituximab in patients with active RA was not associated with clinical benefit.", "affiliations": "Karolinska Institute, Stockholm, Sweden.;EMD Serono, Inc., Rockland, Massachusetts.;EMD Serono, Inc., Rockland, Massachusetts.;Academic Medical Center and University of Amsterdam, Amsterdam, The Netherlands, University of Cambridge, Cambridge, UK, and GlaxoSmithKline, Stevenage, UK.", "authors": "van Vollenhoven|R F|RF|;Wax|S|S|;Li|Y|Y|;Tak|P P|PP|", "chemical_list": "D018501:Antirheumatic Agents; D011993:Recombinant Fusion Proteins; D000069283:Rituximab; C524618:TACI receptor-IgG Fc fragment fusion protein", "country": "United States", "delete": false, "doi": "10.1002/art.39262", "fulltext": "\n==== Front\nArthritis Rheumatol10.1002/(ISSN)2326-5205ARTArthritis & Rheumatology (Hoboken, N.j.)2326-51912326-5205John Wiley and Sons Inc. Hoboken 10.1002/art.39262ART39262Rheumatoid ArthritisRheumatoid ArthritisSafety and Efficacy of Atacicept in Combination With Rituximab for Reducing the Signs and Symptoms of Rheumatoid Arthritis: A Phase II, Randomized, Double‐Blind, Placebo‐Controlled Pilot Trial ATACICEPT IN RHEUMATOID ARTHRITISVAN VOLLENHOVEN ET ALvan Vollenhoven R. F. \n1\n\n†\nWax S. \n2\nLi Y. \n2\nTak P. P. \n3\n\n‡\n1 Karolinska InstituteStockholmSweden2 EMD Serono, Inc.RocklandMassachusetts3 Academic Medical Center and University of Amsterdam, Amsterdam, The Netherlands, University of Cambridge, Cambridge, UK, and GlaxoSmithKlineStevenageUKAddress correspondence to R. F. van Vollenhoven, MD, PhD, Unit for Clinical Therapy Research Inflammatory Diseases, Department of Medicine, Karolinska Institute, 171 76 Stockholm, Sweden. E‐mail: [email protected].† Dr. van Vollenhoven has received consulting fees from AbbVie, Biotest, Bristol‐Myers Squibb, Crescendo Bioscience, GlaxoSmithKline, Janssen, Lilly, Merck Serono, Pfizer, Roche, UCB, and Vertex (less than $10,000 each) and research grant support from AbbVie, Bristol‐Myers Squibb, GlaxoSmithKline, Pfizer, Roche, and UCB.\n\n‡ Dr. Tak has received consulting fees from Roche, Genentech, and Merck Serono (less than $10,000 each) and owns stock or stock options in GlaxoSmithKline.\n\n11 2015 28 10 2015 67 11 10.1002/art.v67.112828 2836 14 1 2015 23 6 2015 © 2015 The Authors. Arthritis & Rheumatology is published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Objective\nTo explore the safety and tolerability of atacicept in combination with rituximab in patients with active rheumatoid arthritis (RA) receiving rituximab re‐treatment.\n\nMethods\nIn this randomized, double‐blind, placebo‐controlled pilot trial, 2 infusions (1,000 mg per infusion) of intravenous rituximab, given 2 weeks apart, were followed by once‐weekly subcutaneous injections of 150 mg atacicept or placebo for 25 weeks. Primary end points were the nature, incidence, and severity of adverse events (AEs). Secondary end points were the effects on peripheral blood B cells, disease activity biomarkers, and American College of Rheumatology 20% (ACR20), 50% (ACR50), and 70% (ACR70) response rates.\n\nResults\nEighteen patients were randomized to receive atacicept and 9 to receive placebo. AEs occurred in 17 atacicept‐treated patients (94.4%) and in all 9 placebo‐treated patients (100%). There were no infection‐related serious adverse events. Hypersensitivity and injection site reactions were more common, and more patients withdrew due to AEs, in the atacicept group. Median reductions in Ig levels from baseline to week 32 were greater with atacicept (median change in IgG −31.2%, IgM −60.9%, and IgA −56.4%) than with placebo (median change in IgG −4.4%, IgM −15.9%, and IgA −8.2%). Peripheral B cell numbers remained low in all patients after rituximab‐mediated B cell depletion, limiting comparison of time to recovery between treatment groups. There were no between‐group differences in ACR20, ACR50, and ACR70 response rates.\n\nConclusion\nIn this exploratory trial, atacicept in combination with rituximab showed no new safety issues. Peripheral B cell counts remained too low to determine whether atacicept delayed B cell re‐expansion following rituximab‐mediated depletion. Despite clear biologic effects, adding atacicept to rituximab in patients with active RA was not associated with clinical benefit.\n\nMerck Serono S.A. (Geneva, Switzerland)Merck KGaA (Darmstadt, Germany) source-schema-version-number2.0component-idart39262cover-dateNovember 2015details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:4.9.4 mode:remove_FC converted:12.10.2016\nClinicalTrials.gov identifier: NCT00664521.\n==== Body\nUse of the B cell–depleting agent rituximab results in clinical improvements in disease activity in patients with rheumatoid arthritis (RA) 1, 2, 3, providing proof‐of‐concept for the importance of B cells in the pathogenesis of this chronic inflammatory autoimmune disorder 4. B cells act as antigen‐presenting cells, secrete proinflammatory cytokines, and produce autoantibodies in RA 4. In spite of the efficacy of rituximab in RA, not all patients respond 5, 6. Lack of response is associated with persistence of B‐lineage cells, in particular plasma cells, at the site of inflammation, the synovium 7.\n\nThe persistence of B‐lineage cells in the synovial tissue may be associated with increased levels of the B cell maturation/survival factors B lymphocyte stimulator (BLyS) and APRIL (a proliferation‐inducing ligand) 8, 9, 10. Importantly, serum BLyS levels rise sharply following B cell depletion by rituximab, returning to normal only after B cells recover to baseline levels 11. This supports the hypothesis that the beneficial effects of rituximab may be limited by the survival or re‐expansion of autoreactive B‐lineage cells supported by BLyS. It has previously been suggested that interfering with APRIL and BLyS may help to optimize the clinical response to rituximab treatment in RA 7. This could be achieved by treatment with atacicept, which is a soluble, fully human recombinant fusion protein that neutralizes the activity of BLyS and APRIL 12, 13.\n\nIn clinical trials featuring combinations of other biologic agents, an increased risk of infections has been observed 14, 15. The present study, the Atacicept for Reduction of Signs and Symptoms in Rheumatoid Arthritis Trial III (AUGUST III), was an exploratory study with the primary objective of assessing the safety and tolerability of atacicept in patients with active RA receiving rituximab re‐treatment. Secondary objectives focused on evaluating the effects of combination treatment with atacicept and rituximab on the proportions of peripheral B cell populations, levels of biomarkers reflecting disease activity and drug‐related mechanisms of action, and measures of efficacy.\n\nPATIENTS AND METHODS\nStudy design\nIn this multicenter, phase II, randomized, double‐blind, placebo‐controlled pilot trial (AUGUST III), we assessed the safety and tolerability of atacicept in combination with rituximab re‐treatment in patients with moderate or severe RA. The study comprised a 7‐week rituximab treatment period, a 25‐week atacicept/placebo treatment period, and a 32‐week posttreatment followup period. In the rituximab period, all patients received two 1000‐mg doses of rituximab by intravenous infusion, 2 weeks apart (weeks 1 and 3). At week 7 (after 28 days without treatment), patients were randomized 2:1 to receive subcutaneous atacicept at a dose of 150 mg or placebo, once weekly for 25 weeks. Randomization was stratified by rheumatoid factor (RF) status (positive or negative) and country, and an interactive voice response system was used to allocate treatment kit numbers.\n\nThis study was approved by the Institutional Review Boards and independent Ethics Committees at the participating institutions, and conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonisation guidelines, and any local requirements. All patients provided written informed consent.\n\nStudy population\nThe study population consisted of male and female patients ages ≥18 years who had been diagnosed as having RA according to the American College of Rheumatology (ACR) 1987 revised criteria 16, had a disease duration of ≥12 months, had previously responded to treatment with rituximab, and had residual disease activity. The patients were recruited from multiple European sites and were treated on an outpatient basis. Patients had to have a Disease Activity Score in 28 joints (DAS28) of >3.2 17, with a documented response to, and good tolerance of, previous rituximab treatment. They also were required to have significant residual disease (DAS28 >3.2) or clinical deterioration (an increase of ≥0.6 in the DAS28) after such treatment.\n\nPatients were not eligible for inclusion if they had an inflammatory joint disease other than RA, had displayed any contraindication to rituximab, had received disease‐modifying antirheumatic drug therapy for <3 months or changed their regimen within 28 days of study day 1, had received either methotrexate at a dosage of >25 mg/week, an anti–tumor necrosis factor agent (anakinra or tocilizumab) within 12 weeks of study day 1, or abatacept or another cell‐depleting therapy within 24 weeks of study day 1, or had received prednisone at a dosage of >10 mg/day or changed their steroid dosage within 28 days of day 1. One intraarticular steroid injection during each of the screening and treatment periods was permitted.\n\nStudy end points\nPrimary safety end points included the following: the nature, incidence, and severity of adverse events (AEs), particularly infection‐related AEs; the proportion of patients with an IgG level of <3 gm/liter; changes over time and abnormalities in vital signs and routine safety laboratory parameters; and changes over time in immunization status (titers of antibodies against tetanus toxoid, pneumococcus, and diphtheria toxin).\n\nSecondary end points included the following: changes over time in the proportion of peripheral B cell populations; changes over time in markers of disease activity, consisting of concentrations of C‐reactive protein (CRP), the erythrocyte sedimentation rate (ESR), and RF status, together with other ACR core set measures and the severity of morning stiffness, all comprising variables that enabled calculation of the ACR 20% [ACR20], ACR50, and ACR70 composite scores of improvement response [18]); and changes over time in the levels of IgG, IgM, and IgA. To preserve blinding, all joint evaluations were performed by independent efficacy assessors.\n\nStatistical analysis\nAs this was an exploratory pilot study, sample size was not based on formal calculations of statistical power. Data were summarized using descriptive statistics. The safety analysis was performed in the safety population, which included all patients who had received at least one dose of atacicept or placebo and for whom followup safety data were available. The intent‐to‐treat (ITT) population was identical to the safety population.\n\nRESULTS\nPatient characteristics\nThis study was conducted between March 25, 2008 and January 26, 2011. Twenty‐eight patients were enrolled and treated with rituximab. Of these patients, 27 were randomized to receive atacicept (n = 18) or placebo (n = 9) and were included in the safety and ITT analyses (Figure 1). Patient demographics and disposition were similar between the groups, except that there were more women in the atacicept group (Table 1).\n\nFigure 1 Disposition of the study patients treated with two 1,000‐mg infusions of rituximab given 2 weeks apart, followed by 150 mg atacicept or placebo given once weekly for 25 weeks. AE = adverse event; FU = followup; ITT = intent‐to‐treat.\n\nTable 1 Baseline demographic and clinical characteristics of the study patientsa\n\n\n\tRituximab then atacicept (n = 18)\tRituximab then placebo (n = 9)\tOverall (n = 27)\t\nAge, years\t57.0 ± 11.0\t57.7 ± 11.5\t57.2 ± 11.0\t\nFemale, no. (%)\t12 (66.7)\t8 (88.9)\t20 (74.1)\t\nWeight, kg\t76.5 ± 15.0\t74.9 ± 17.1\t76.0 ± 15.4\t\nDisease duration, years\t12.3 ± 5.6\t13.0 ± 5.8\t12.6 ± 5.5\t\nRF positive, no. (%)\t17 (94.4)\t8 (88.9)\t25 (92.6)\t\nOral corticosteroid use, no. (%)\t13 (72.2)\t6 (66.7)\t19 (70.4)\t\nMethotrexate use, no. (%)\t12 (66.7)\t7 (77.8)\t19 (70.4)\t\nCRP, mg/liter\t28.9 ± 35.2\t36.2 ± 36.8\t31.3 ± 35.2\t\nESR, mm/hour\t34.4 ± 22.8\t42.1 ± 23.1\t37.0 ± 22.8\t\nDAS28‐CRP\t5.5 ± 1.0\t5.8 ± 1.0\t5.6 ± 1.0\t\na Except where indicated otherwise, values are the mean ± SD. RF = rheumatoid factor; ESR = erythrocyte sedimentation rate; DAS28‐CRP = Disease Activity Score in 28 joints based on the C‐reactive protein (CRP) level.\n\nAmong the randomized patients, 4 (22.2%) in the atacicept group and 5 (55.6%) in the placebo group were re‐treated with rituximab during the posttreatment followup period, at the discretion of the treating physician. This imbalanced randomization posed a risk to the trial and to the identification of causality of AEs.\n\nPrimary end points\nSafety\nAtacicept/placebo treatment period\nThe majority of AEs were reported during the 25‐week atacicept/placebo treatment period, during which 295 AEs were reported by 26 (96.3%) of the 27 randomized patients (Table 2). The AEs were mostly mild or moderate in intensity and occurred with similar frequency across both treatment groups (17 patients [94.4%] in the atacicept group and 9 patients [100%] in the placebo group). Three patients experienced a total of 4 serious AEs (SAEs) during the atacicept/placebo treatment period: 2 in the placebo group (transient ischemic attack [TIA], ruptured cerebral aneurysm) and 1 in the atacicept group (drug hypersensitivity and TIA).\n\nTable 2 Incidence of SAEs and AEs during the 25‐week atacicept/placebo treatment period (safety population)a\n\n\nType of event, system\tRituximab then atacicept\tRituximab then placebo\tOverall\t\norgan class preferred term\tPatients\tEvents\tPatients\tEvents\tPatients\tEvents\t\nSAEs\t\t\t\t\t\t\t\nAll\t1/18 (5.6)\t2/2 (100.0)\t2/9 (22.2)\t2/2 (100.0)\t3/27 (11.1)\t4/4 (100.0)\t\nNervous system disorders Transient ischemic attack\t1/18 (5.6)\t1/2 (50.0)\t1/9 (11.1)\t1/2 (50.0)\t2/27 (7.4)\t2/4 (50.0)\t\nRuptured cerebral aneurysm\t\t\t1/9 (11.1)\t1/2 (50.0)\t1/27 (3.7)\t1/4 (25.0)\t\nImmune system disorders, drug hypersensitivity\t1/18 (5.6)\t1/2 (50.0)\t0\t0\t1/27 (3.7)\t1/4 (25.0)\t\nAEs\t\t\t\t\t\t\t\nAll\t17/18 (94.4)\t241/241 (100.0)\t9/9 (100.0)\t54/54 (100.0)\t26/27 (96.3)\t295/295 (100.0)\t\nGeneral disorders and administration site conditions\t13/18 (72.2)\t156/241 (64.7)\t4/9 (44.4)\t20/54 (37.0)\t17/27 (63.0)\t176/295 (59.7)\t\nInfections and infestations\t8/18 (44.4)\t11/241 (4.6)\t6/9 (66.7)\t10/54 (18.5)\t14/27 (51.9)\t21/295 (7.1)\t\nMusculoskeletal and connective tissue disorders\t6/18 (33.3)\t6/241 (2.5)\t5/9 (55.6)\t5/54 (9.3)\t11/27 (40.7)\t11/295 (3.7)\t\nSkin and subcutaneous tissue disorders\t8/18 (44.4)\t16/241 (6.6)\t2/9 (22.2)\t2/54 (3.7)\t10/27 (37.0)\t18/295 (6.1)\t\nGastrointestinal disorders\t5/18 (27.8)\t10/241 (4.1)\t3/9 (33.3)\t3/54 (5.6)\t8/27 (29.6)\t13/295 (4.4)\t\nNervous system disorders\t3/18 (16.7)\t8/241 (3.3)\t4/9 (44.4)\t8/54 (14.8)\t7/27 (25.9)\t16/295 (5.4)\t\nRespiratory, thoracic, and mediastinal disorders\t3/18 (16.7)\t22/241 (9.1)\t3/9 (33.3)\t3/54 (5.6)\t6/27 (22.2)\t25/295 (8.5)\t\nImmune system disorders\t4/18 (22.2)\t4/241 (1.7)\t0\t0\t4/27 (14.8)\t4/295 (1.4)\t\nEye disorders\t3/18 (16.7)\t3/241 (1.2)\t0\t0\t3/27 (11.1)\t3/295 (1.0)\t\nInjury, poisoning, and procedural complications\t2/18 (11.1)\t3/241 (1.2)\t0\t0\t2/27 (7.4)\t3/295 (1.0)\t\nVascular disorders\t1/18 (5.6)\t1/241 (0.4)\t1 (11.1)\t1 (1.9)\t2 (7.4)\t2/295 (0.7)\t\nCardiac disorders\t1/18 (5.6)\t1/241 (0.4)\t\t\t1 (3.7)\t1/295 (0.3)\t\nInvestigationsb\n\t0\t0\t1 (11.1)\t1 (1.9)\t1 (3.7)\t1/295 (0.3)\t\nReproductive system and breast disorders\t0\t0\t1 (11.1)\t1 (1.9)\t1 (3.7)\t1/295 (0.3)\t\na Serious adverse events (SAEs) and AEs were evaluated in the safety population (comprising patients who were randomized and received at least one study treatment dose and for whom safety data were available; n = 27). The atacicept period ranged from the date of the first atacicept/placebo dose to the date of the last atacicept/placebo dose plus 7 days. AEs were coded using MedDRA version 13.0. Values are the number/total number (percentage) of patients or events.\n\nb Defined as laboratory abnormalities.\n\nAEs leading to discontinuation were more frequent in the atacicept group than in the placebo group: 4 patients (22.2%) in the atacicept group (2 patients with a drug/type I hypersensitivity reaction, 1 patient with diarrhea and gastritis, and 1 patient with pruritus), and 1 patient (11.1%) in the placebo group (ruptured cerebral aneurysm).\n\nFewer infections occurred in the atacicept group (8 patients [44.4%] experienced 11 events) compared to the placebo group (6 patients [66.7%] experienced 10 events), and generally these represented commonly encountered infections: upper respiratory tract infection, influenza, nasopharyngitis, conjunctivitis, rhinitis, hordeolum, and urinary tract infection. There were no infection‐related SAEs during the treatment period.\n\nLocal injection‐site reactions were more frequent in atacicept‐treated patients (11 [61.1%]) than in placebo‐treated patients (2 [22.2%]). These reactions were consistent with those observed in previous studies of patients treated with atacicept 19 and comprised mild‐to‐moderate erythema, itching, and swelling.\n\nHypersensitivity reactions were more frequent in atacicept‐treated patients (9 [50.0%]) than in placebo‐treated patients (2 [22.2%]), and led to withdrawal in 2 atacicept‐treated patients. Six of the atacicept‐treated patients with hypersensitivity‐related events had skin and subcutaneous tissue disorders (including pruritus), 4 (22.2%) had immune system disorders (including drug hypersensitivity and type I hypersensitivity), and 2 (11.1%) had respiratory disorders (cough and dyspnea).\n\nFollowup period\nSix patients in the atacicept group experienced a total of 12 SAEs during the nontreatment followup period, distributed as follows: 1 patient with atrial fibrillation, 1 patient with cardiac arrest and ventricular fibrillation, 1 patient with pelvic fracture, joint capsule rupture, and arthropathy, 1 patient with visual impairment and muscular weakness, 1 patient with gastroenteritis, and 1 patient with demyelination, glioma, and nervous system disorder. This latter SAE occurred in a 30‐year‐old female patient who had no history of demyelinating disease. This patient experienced a suspected focal glioma or focal demyelination in the cerebellum, with symptoms beginning ∼3 months after atacicept treatment, which led to hospitalization. Magnetic resonance imaging (MRI) revealed a stable, nonprogressing lesion in the right cerebellum and medically significant multifocal changes of vascular origin in the white matter of both hemispheres. Symptoms did not progress over 6 months of followup. As of January 3, 2014, the investigator confirmed that this patient was still under his supervision, and no new neurologic signs and symptoms were present. The patient was doing well under a treatment regimen of biologic agents. With the exception of this patient, SAEs resolved in all other patients. No trends in the nature of the SAEs reported were observed in patients treated with atacicept.\n\nImmunologic status\nA reduction in IgG levels to <3 gm/liter was not observed in any patients, and there were no notable changes in clinical or laboratory parameters in any patients throughout the study treatment period. The median antibody titers at week 32 were reduced from baseline in the atacicept‐treated patients but not in the placebo‐treated patients, with median changes from baseline in the atacicept group versus the placebo group as follows: for anti–tetanus toxoid, −18.0% (interquartile range [IQR] −34.29, 0.00) versus 0.0% (IQR −7.67, 23.68); for anti–diphtheria toxin, −33.7% (IQR −50.00, 0.00) versus 8.4% (IQR 0.00, 0.00); and for antipneumococcus, −18.5% (IQR −35.18, 0.00) versus 0.0% (IQR 0.39, 33.93). These values returned to close to baseline levels by week 16 of the followup period. There were few shifts to below‐protective antibody titers, and there were no between‐group differences with respect to the frequency of shifts.\n\nSecondary end points\nFigure 2 shows the median percentage change in the levels of total, mature, and memory B cells over time. Following treatment with rituximab, the median levels of total, mature, and memory B cells were reduced to 0 (total B cells, median 0 [range 0–2.0 cells/mm3]; mature B cells, median 0 [range 0–0 cells/mm3]; and memory B cells, median 0 [range 0–1.0 cells/mm3]), and little recovery of B cells was observed in either treatment group. Mature B cell recovery at week 64 was <10% in the placebo group and ∼50% in the atacicept group. There were no notable differences in the proportions of T cells between treatment groups; median total T cell levels at week 32 in the atacicept and placebo treatment groups were 1,051/mm3 and 1,124/mm3, respectively, whereas the median levels of T helper cells were 769.5/mm3 and 744/mm3, respectively.\n\nFigure 2 Change in the levels of total, mature, and memory B cells over time in patients treated with two 1,000‐mg infusions of rituximab given 2 weeks apart, followed by 150 mg atacicept or placebo given once weekly for 25 weeks. Values are the percentage change from baseline, expressed as the median with interquartile range. The horizontal broken line indicates baseline.\n\nCombination treatment with atacicept was not associated with a greater decrease in the CRP level compared to re‐treatment with rituximab alone. Reductions from baseline in the median ESR were numerically greater with atacicept compared to placebo from week 12 onward, with the greatest difference observed at week 32 (see Supplementary Table 1, available on the Arthritis & Rheumatology web site at http://onlinelibrary.wiley.com/doi/10.1002/art.39262/abstract). The greatest reductions in the median levels of IgG‐RF, IgM‐RF and IgA‐RF were observed at week 32, and these reductions were all numerically greater with atacicept (see Supplementary Table 2, available on the Arthritis & Rheumatology web site at http://onlinelibrary.wiley.com/doi/10.1002/art.39262/abstract).\n\nTreatment with atacicept was associated with greater median reductions from baseline to week 32 in the levels of IgG, IgM, and IgA (median change from baseline −31.2% [IQR −49.6, −24.1], −60.9% [IQR −71.88, −54.43]), and −56.4% [IQR −66.84, −45.49], respectively) compared to placebo (median change from baseline −4.4% [IQR −10.17, −1.32], −15.9% [IQR −22.92, −7.82], and −8.2% [IQR −19.69, −2.02], respectively) (Figure 3). Median IgG and IgM levels were below the lower limits of normal in the atacicept group from week 20 to week 32. The median IgG levels recovered after cessation of treatment, to reach levels that were 10.9% lower than those at baseline by followup at week 64. However, the median IgM levels had not recovered in all patients by the end of the followup period.\n\nFigure 3 Change in levels of IgG, IgM, and IgA from baseline to week 32 in patients treated with two 1,000‐mg infusions of rituximab given 2 weeks apart, followed by 150 mg atacicept or placebo given once weekly for 25 weeks. In A, values are the levels of each immunoglobulin (in gm/liter) over time. The horizontal broken line indicates the lower limit of normal. In B, values are the percentage change from baseline. The horizontal broken line indicates baseline. All results are expressed as the median with interquartile range.\n\nClinical efficacy\nThere were no noteworthy between‐group differences in clinical response to treatment over time, as defined by the ACR20, ACR50, and ACR70 improvement response criteria based on the CRP level (Figure 4). The mean DAS28 (based on the CRP level or ESR) remained below the values observed at baseline from week 7 onward in both treatment groups (data not shown).\n\nFigure 4 Proportion of patients responding to combination treatment with atacicept versus those treated with placebo over time. Patients were treated with two 1,000‐mg infusions of rituximab given 2 weeks apart, followed by 150 mg atacicept or placebo given once weekly for 25 weeks. Responses were defined according to the American College of Rheumatology 20% improvement criteria (ACR20), the ACR50, and the ACR70 based on the C‐reative protein (CRP) level.\n\nDISCUSSION\nIn this phase II pilot study of atacicept in combination with rituximab re‐treatment in patients with moderate to severe RA, the safety profile of atacicept was consistent with previous experience, and no new safety trends were observed 15, 20. AEs were common (driven mainly by injection‐site reactions and infections), were mostly mild or moderate, and occurred with a similar frequency in both the active treatment and placebo groups.\n\nSAEs occurred in 8 patients during the study: 2 in the treatment period, 1 during the treatment and followup periods, and 5 during followup. The SAEs that occurred during followup were observed in patients who had received atacicept. There were, however, no notable trends in the types of SAEs that emerged, and all except one (focal demyelination/glioma) resolved. This patient developed a focal demyelination and demonstrated multifocal changes in the white matter on MRI, which did not progress over a 6‐month period, and symptoms did not progress over 4 years of followup.\n\nThe etiology of the white matter lesions identified by MRI in this patient is not clear, although the changes are consistent with a demyelinating process and ischemic changes. It should be noted that demyelination due to progressive multifocal leukoencephalopathy (PML) following rituximab treatment in RA patients, leading to estimates of increased risk in the order of 1 per 25,000 patients treated, has been reported in the literature 21. Rituximab‐induced depletion of B cells has been suggested to permit the reactivation of JC virus (JCV), which is responsible for PML 21. However, the JCV status of the patients in the present study was not investigated. In a clinical trial of patients with multiple sclerosis, atacicept treatment was associated with exacerbation of the disease. However, there have been no new diagnoses of demyelinating processes reported in any other atacicept clinical trial. It is not possible to tell from this small pilot study whether atacicept contributed to the demyelination event in this patient. The investigator, however, considered the focal demyelination, suspected focal glioma, and multifocal changes in the white matter to be either unrelated or unlikely to be related to the study medication. RA itself was reported as an alternative explanation for this SAE.\n\nInfection‐related AEs observed in this study were mostly infections that are commonly encountered, consistent with previous reports 15, 20. The infection rate was slightly higher than that previously reported to be associated with treatment with atacicept (44% in the present study versus 34–35% in prior studies [15,20]), but was still lower than that in patients treated with rituximab alone (66.7%). Rituximab re‐treatment has been associated with a reported rate of infection of 50–60% in clinical trials 22, 23. Thus, re‐treatment with rituximab may be contributing to the higher infection rate seen in patients also treated with atacicept. Importantly, no serious infections were reported among atacicept‐treated patients during the treatment period, despite the clear effect of atacicept on B cell levels established in other clinical trials of atacicept in RA patients; one event of severe gastroenteritis occurred 4 months after treatment in a patient who had recently visited Thailand.\n\nThe percentage of patients who withdrew due to AEs was twice as high with atacicept as with placebo. Injection‐site reactions with atacicept were more frequent than previously reported (72.2% in the present study versus 10–11% in prior studies [19,20]), and the incidence of hypersensitivity reactions was also higher in atacicept‐treated patients (50.0%) than in placebo‐treated patients (22.2%). The reasons for this remain unclear; the small sample size could have led to chance results, or rituximab could have increased hypersensitivity to atacicept.\n\nAs in other phase I and phase II trials 15, 20, atacicept was not associated with an increased rate of total infection, despite its Ig‐lowering effects. A small reduction in antibody titers was observed. The reduction in protective titers was, however, not greater than the reduction in total IgG levels. There was no apparent correlation between patients with infections and those with the lowest mean levels of each Ig subclass (data not shown).\n\nAtacicept demonstrated marked biologic activity, as indicated by the decreases in the ESR, B cell subset counts, and concentrations of Ig subclasses and RF in atacicept‐treated patients compared to placebo‐treated patients. The magnitude and pattern of the decrease in total Ig levels following treatment with rituximab and atacicept were similar to those observed in previous RA trials with atacicept alone 15, 20. Consistent with those earlier studies, atacicept‐associated reductions in the ESR were greater than the reductions in the CRP level, which may be attributed to the reduction in total Ig levels associated with atacicept 15, 20. As expected, B cell subsets in the peripheral blood were completely depleted by rituximab, but there was no indication that atacicept delayed the recovery of B cell populations. In some cases, particularly for mature B cells, recovery was quicker following atacicept treatment compared to placebo treatment. Interpretation of these data is, however, limited by a high degree of interindividual variability, the small study size, very low starting numbers of lymphocyte cell populations (typically <10 cells/mm3, with a resolution of 1 cell/mm3), and a between‐group difference in the proportion of patients who received rituximab re‐treatment during followup, which was numerically higher in the placebo group.\n\nThe mechanisms of action of rituximab and atacicept on B cell populations are understood to be complementary, suggesting a potential for additive or synergistic clinical benefit following their combination 7, 11, 12. However, no treatment benefit, as measured by the ACR response rates and DAS28, was observed following the addition of atacicept to rituximab re‐treatment in this study. Published phase II studies of atacicept in RA have previously demonstrated only modest clinical effects despite considerable biologic activity 15, 20. The reasons for this disparity remain unclear. BLyS and APRIL may regulate both B cell and T cell function, and could have both proinflammatory and antiinflammatory activities in RA 24. The possibility also exists that atacicept did not sufficiently block BLyS and APRIL locally in the synovium, leading to insufficient local reduction of B cells and plasma cells. In addition, it is possible that sequential therapy that starts with atacicept first, in order to mobilize memory B cells from niche compartments, followed by rituximab could have higher therapeutic benefit.\n\nIn this study, the rates of clinical response to rituximab were lower than those previously reported 1, 2. Patients in other studies had not been previously treated with rituximab at baseline, and thus may have had a larger response than those being re‐treated in the present study. Patients in this study may have experienced some residual therapeutic effect, meaning that re‐treatment with rituximab did not lower the CRP level as much as initial treatment.\n\nThe number of patients who were re‐treated with rituximab was lower in the atacicept group compared to the placebo group; thus, there is a possibility that atacicept treatment was associated with a more persistent response. Indeed, this was the original hypothesis that led to this trial. Unfortunately, no other measured outcome provides independent support for this hypothesis, and so it remains an intriguing possibility, at best. The study limitations included the small numbers of patients in each group, and the short duration of this pilot study.\n\nIn conclusion, this pilot study demonstrated that administering atacicept following rituximab re‐treatment presented no new safety concerns and was associated with an AE profile consistent with that reported previously for atacicept in phase II studies. Atacicept exerted clear biologic effects, but no additional clinical benefit was observed. Any evidence of an effect of atacicept on delayed B cell re‐expansion following rituximab‐mediated depletion could not be evaluated, since there was virtually no recovery of B cells in the placebo group during the followup period. These findings, therefore, do not suggest that the combination of atacicept and rituximab should be pursued as a therapeutic option for patients with RA.\n\nAUTHOR CONTRIBUTIONS\nAll authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. van Vollenhoven had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.\n\n\nStudy conception and design. van Vollenhoven, Wax, Li, Tak.\n\n\nAcquisition of data. van Vollenhoven, Wax, Li, Tak.\n\n\nAnalysis and interpretation of data. van Vollenhoven, Wax, Li, Tak.\n\nROLE OF THE STUDY SPONSOR\nMerck Serono was involved in the study design and in the collection, analysis, and interpretation of the data. Authors Wax and Li are employees of EMD Serono and were involved in writing the manuscript. All authors were jointed involved in the decision to submit the manuscript for publication. Publication of the article was not contingent upon approval by Merck Serono.\n\nADDITIONAL DISCLOSURES\nAuthor Tak is an employee of GlaxoSmithKline.\n\nSupporting information\n\nSupplementary Table 1. C‐reactive protein (CRP) levels and erythrocyte sedimentation rate (ESR) in patients treated with 1,000 mg rituximab followed by once‐weekly 150 mg atacicept or placebo\n\n\nSupplementary Table 2. Levels of Ig–rheumatoid factor in patients treated with 1,000 mg rituximab followed by once‐weekly 150 mg atacicept or placebo.\n\nClick here for additional data file.\n\n ACKNOWLEDGMENTS\nWe thank Marieke Herenius, MD and Danielle M. Gerlag, MD, PhD for including patients from the Academic Medical Center/University of Amsterdam. We also thank all patients and their families for their participation in the study. Editorial assistance and medical writing support were provided by Linda Edmondson, Paul FitzGerald, and Jose Heroys of Syntropy Medica Ltd. (Worthing, UK), which was supported by EMD Serono Inc. 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Rheumatology (Oxford) \n2010 ;49 :1683 –93 .\n20463186 \n23 \n\nEmery \nP \n, \n\nDeodhar \nA \n, \n\nRigby \nWF \n, \n\nIsaacs \nJD \n, \n\nCombe \nB \n, \n\nRacewicz \nAJ \n, et al. Efficacy and safety of different doses and retreatment of rituximab: a randomised, placebo‐controlled trial in patients who are biological naive with active rheumatoid arthritis and an inadequate response to methotrexate (Study Evaluating Rituximab's Efficacy in MTX iNadequate rEsponders (SERENE)) [published erratum appears in Ann Rheum Dis. 2011;70:1519] . Ann Rheum Dis \n2010 ;69 :1629 –35 .\n20488885 \n24 \n\nSeyler \nTM \n, \n\nPark \nYW \n, \n\nTakemura \nS \n, \n\nBram \nRJ \n, \n\nKurtin \nPJ \n, \n\nGoronzy \nJJ \n, et al. BLyS and APRIL in rheumatoid arthritis . J Clin Invest \n2005 ;115 :3083 –92 .\n16239971\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2326-5191", "issue": "67(11)", "journal": "Arthritis & rheumatology (Hoboken, N.J.)", "keywords": null, "medline_ta": "Arthritis Rheumatol", "mesh_terms": "D000368:Aged; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011993:Recombinant Fusion Proteins; D000069283:Rituximab; D016896:Treatment Outcome", "nlm_unique_id": "101623795", "other_id": null, "pages": "2828-36", "pmc": null, "pmid": "26137975", "pubdate": "2015-11", "publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't", "references": "21555606;16508933;17965121;18163485;7818570;22540992;16649186;18050206;16935912;20488885;18035324;21452294;16947627;20097226;16239971;20463186;3358796;7779114;12687540;20131284;21452293;11407690;11520463;22012969", "title": "Safety and efficacy of atacicept in combination with rituximab for reducing the signs and symptoms of rheumatoid arthritis: a phase II, randomized, double-blind, placebo-controlled pilot trial.", "title_normalized": "safety and efficacy of atacicept in combination with rituximab for reducing the signs and symptoms of rheumatoid arthritis a phase ii randomized double blind placebo controlled pilot trial" }

[ { "companynumb": "SE-ROCHE-1076577", "fulfillexpeditecriteria": "1", "occurcountry": "SE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ATACICEPT" }, "drugadditional": null, "drugadministrationroute": "058", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "FOR 25 WEEKS.", "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ATACICEPT" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "103705", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INFUSION", "drugdosagetext": "TWO DOSES AT WEEKS 1 AND 3", "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "2", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Ventricular fibrillation", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Visual impairment", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Transient ischaemic attack", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypersensitivity", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Joint capsule rupture", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Gastritis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Arthropathy", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Ruptured cerebral aneurysm", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Atrial fibrillation", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pelvic fracture", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Muscular weakness", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": ", WAX S, LI Y AND TAK P. SAFETY AND EFFICACY OF ATACICEPT IN COMBINATION WITH RITUXIMAB FOR REDUCING THE SIGNS AND SYMPTOMS OF RHEUMATOID ARTHRITIS: A PHASE II, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED PILOT TRIAL. ARTHRITIS + RHEUMATOLOGY (HOBOKEN, N.J.) 2015 NOV?67 (11):2828-2836.", "literaturereference_normalized": "safety and efficacy of atacicept in combination with rituximab for reducing the signs and symptoms of rheumatoid arthritis a phase ii randomized double blind placebo controlled pilot trial", "qualification": "1", "reportercountry": "SE" }, "primarysourcecountry": "SE", "receiptdate": "20151104", "receivedate": "20120622", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 8630319, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160305" } ]

{ "abstract": "Cervical spondylotic myelopathy is a disease of high variability and its progressive form leads to severe disability. This paper reports on a case of a 31-year-old woman with whiplash neck injury sustained at the age of 11, and subsequent neck pain and numbness of arms. Slow progression of symptoms led to tetraparesis, and C3C4 disc herniation along with cervical myelopathy were revealed at the age of 26. Previously, she started a treatment for hypothyroidism. She underwent anterior cervical discectomy and fusion. Two additional operative treatments were done during the next two years due to lack of clinical improvement. Because of chronic pain the number of medications and the number of symptoms have gradually increased. We emphasize the problem of long-term treatment for chronic non-malignant pain and therapeutic dilemma in situations of inadequate analgesia.", "affiliations": "Special Medical Rehabilitation Hospital, Varaždinske Toplice, Croatia. [email protected]", "authors": "Vrabec-Matković|Dragica|D|;Budisin|Vesna|V|;Pahić|Renato|R|", "chemical_list": null, "country": "Bosnia and Herzegovina", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1840-0132", "issue": "8(2)", "journal": "Medicinski glasnik : official publication of the Medical Association of Zenica-Doboj Canton, Bosnia and Herzegovina", "keywords": null, "medline_ta": "Med Glas (Zenica)", "mesh_terms": "D000328:Adult; D002574:Cervical Vertebrae; D059350:Chronic Pain; D005260:Female; D006801:Humans; D007405:Intervertebral Disc Displacement; D019547:Neck Pain; D059408:Pain Management; D010291:Paresis; D013118:Spinal Cord Diseases; D017211:Treatment Failure; D014911:Whiplash Injuries", "nlm_unique_id": "101250177", "other_id": null, "pages": "309-11", "pmc": null, "pmid": "21849962", "pubdate": "2011-08", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Failure in long-term treatment of chronic pain in cervical spondylotic myelopathy.", "title_normalized": "failure in long term treatment of chronic pain in cervical spondylotic myelopathy" }

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"drugtreatmentdurationunit": null, "medicinalproduct": "IBUPROFEN." } ], "patientagegroup": null, "patientonsetage": "31", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Depression", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Erythema", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Persistent depressive disorder", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Quadriparesis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Oedema", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Constipation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dizziness", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sedation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pruritus", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Disturbance in attention", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Loss of consciousness", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Feeling abnormal", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Musculoskeletal stiffness", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cognitive disorder", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Syncope", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Confusional state", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Asthenia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pain", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Conversion disorder", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Headache", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anxiety", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Schizophrenia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Euphoric mood", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fatigue", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sensory disturbance", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neurosis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diplopia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrointestinal motility disorder", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Psychomotor skills impaired", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VRABEC-MATKOVIC, DRAGICA? ET AL.. FAILURE IN LONG-TERM TREATMENT OF CHRONIC PAIN IN CERVICAL SPONDYLOTIC MYELOPATHY. MEDICINSKI GLASNIK. 2011?8 (2):309-311", "literaturereference_normalized": "failure in long term treatment of chronic pain in cervical spondylotic myelopathy", "qualification": "1", "reportercountry": "HR" }, "primarysourcecountry": "HR", "receiptdate": "20190214", "receivedate": "20190124", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15864416, "safetyreportversion": 5, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "HR-JNJFOC-20110904470", "fulfillexpeditecriteria": "1", "occurcountry": "HR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "SERTRALINE HYDROCHLORIDE" }, "drugadditional": "3", 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"BACLOFEN." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "FEXOFENADINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "180 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HEADACHE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "180", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FEXOFENADINE HYDROCHLORIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TRAMADOL" }, "drugadditional": "3", "drugadministrationroute": "065", 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"LEVOTHYROXINE SODIUM." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DIAZEPAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 UG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "200709", "drugstartdateformat": "610", "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIAZEPAM." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ESOMEPRAZOLE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2X20 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "ASTHENIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "201003", "drugstartdateformat": "610", "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESOMEPRAZOL /01479301/" } ], "patientagegroup": null, "patientonsetage": "31", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Euphoric mood", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fatigue", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Persistent depressive disorder", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Schizophrenia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Oedema", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Loss of consciousness", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Headache", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Musculoskeletal stiffness", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sedation", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Erythema", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neurosis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pain", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diplopia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Disturbance in attention", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Asthenia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pruritus", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cognitive disorder", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrointestinal motility disorder", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Confusional state", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Quadriparesis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sensory disturbance", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Feeling abnormal", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Psychomotor skills impaired", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Syncope", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dizziness", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anxiety", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Constipation", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Depression", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VRABEC-MATKOVIC D, BUDISIN V, PAHIC R.. FAILURE IN LONG-TERM TREATMENT OF CHRONIC PAIN IN CERVICAL SPONDYLOTIC MYELOPATHY. MED GLAS LJEK KOMORE ZENICKO-DOBOJ KANTONA. 2011?8(2):309-311", "literaturereference_normalized": "failure in long term treatment of chronic pain in cervical spondylotic myelopathy", "qualification": "3", "reportercountry": "HR" }, "primarysourcecountry": "HR", "receiptdate": "20191008", "receivedate": "20190125", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15867360, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "HR-PFIZER INC-2011204503", "fulfillexpeditecriteria": "1", "occurcountry": "HR", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "RANITIDINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "150 MG, 2X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": "200709", "drugstartdateformat": "610", "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RANITIDINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "200703", "drugstartdateformat": "610", "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBUPROFEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DIAZEPAM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "071583", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5MG 0,0,1", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "200709", "drugstartdateformat": "610", "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIAZEPAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ESOMEPRAZOLE MAGNESIUM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG, 2X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": "201003", "drugstartdateformat": "610", "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESOMEPRAZOLE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PIROXICAM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "200709", "drugstartdateformat": "610", "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PIROXICAM." }, { 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBAMAZEPINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "70 UG/72H", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "200904", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPRENORPHINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OXYCODONE" }, 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"drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "200805", "drugstartdateformat": "610", "drugstructuredosagenumb": "1.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALPRAZOLAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN\\TRAMADOL" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "PP", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201003", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAMADOL/ACETAMINOPHEN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEVOTHYROXINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "75 UG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201003", "drugstartdateformat": "610", "drugstructuredosagenumb": "75", "drugstructuredosageunit": "004", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOTHYROXINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BACLOFEN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, 3X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": "200709", "drugstartdateformat": "610", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BACLOFEN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEVOTHYROXINE" }, "drugadditional": null, "drugadministrationroute": null, 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"drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SERTRALINE HCL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN\\TRAMADOL" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3X2 (37.5/325MG)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "200709", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAMADOL/ACETAMINOPHEN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OXYCODONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, 3X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": "200904", "drugstartdateformat": "610", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXYCODONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYANOCOBALAMIN\\PYRIDOXINE HYDROCHLORIDE\\THIAMINE DISULFIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "2X1", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "200805", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NEUROBION FORTE" } ], "patientagegroup": null, "patientonsetage": "31", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Asthenia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pruritus", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fatigue", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Constipation", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rash", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sedation", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Confusional state", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dizziness", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Oedema", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ataxia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VRABEC?MATKOVIC, D.. FAILURE IN LONG?TERM TREATMENT OF CHRONIC PAIN IN CERVICAL SPONDYLOTIC MYELOPATHY. MEDICINSKI GLASNIK. 2011?8(2):309-311", "literaturereference_normalized": "failure in long term treatment of chronic pain in cervical spondylotic myelopathy", "qualification": "3", "reportercountry": "HR" }, "primarysourcecountry": "HR", "receiptdate": "20191017", "receivedate": "20190117", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15838291, "safetyreportversion": 6, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "HR-SANOFI-AVENTIS-2011SA056460", "fulfillexpeditecriteria": "1", "occurcountry": "HR", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "PIROXICAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG,UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "200709", "drugstartdateformat": "610", "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PIROXICAM." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "DIAZEPAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PAIN", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "200709", "drugstartdateformat": "610", "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIAZEPAM." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "LEVOTHYROXINE SODIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 UG,UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, 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"drugstartdateformat": "610", "drugstructuredosagenumb": "2", "drugstructuredosageunit": "032", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PARACETAMOL/TRAMADOL HYDROCHLORIDE" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "BACLOFEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25 MG, TID", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "8", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "200805", "drugstartdateformat": "610", "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, 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null, "drugstartdateformat": null, "drugstructuredosagenumb": "37.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAMADOL." } ], "patientagegroup": "5", "patientonsetage": "31", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Loss of consciousness", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrointestinal motility disorder", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Constipation", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neurosis", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Disturbance in attention", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Erythema", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Asthenia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rash", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sedation", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Conversion disorder", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pruritus", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Euphoric mood", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Quadriparesis", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Musculoskeletal stiffness", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Psychomotor skills impaired", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Oedema", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diplopia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Persistent depressive disorder", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Syncope", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Schizophrenia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Depression", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dizziness", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ataxia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sensory disturbance", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Feeling abnormal", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pain", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ill-defined disorder", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fatigue", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Headache", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Confusional state", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cognitive disorder", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anxiety", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VRABEC-MATKOVIC D, BUDISIN V, PAHIC R ET AL.. FAILURE IN LONG-TERM TREATMENT OF CHRONIC PAIN IN CERVICAL SPONDYLOTIC MYELOPATHY. MEDICINSKI GLASNIK. 2011?8 (2):309-311", "literaturereference_normalized": "failure in long term treatment of chronic pain in cervical spondylotic myelopathy", "qualification": "1", "reportercountry": "HR" }, "primarysourcecountry": "HR", "receiptdate": "20200520", "receivedate": "20110909", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 8128401, "safetyreportversion": 4, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200714" } ]

{ "abstract": "BACKGROUND\nThis registry evaluated the 24-month safety and efficacy of levodopa-carbidopa intestinal gel (LCIG) treatment in advanced Parkinson's disease (PD) patients under routine clinical care.\n\n\nMETHODS\nMotor fluctuations, dyskinesia, non-motor symptoms, quality of life, and safety were evaluated. Observations were fully prospective for treatment-naïve patients (60% of patients) and partially retrospective for patients with ≤12 months of pre-treatment with LCIG (40% of patients). Hours of \"On\" and \"Off\" time were assessed with a modified version of the Unified Parkinson's Disease Rating Scale part IV items 32 and 39.\n\n\nRESULTS\nOverall, 375 patients were enrolled by 75 movement disorder centers in 18 countries and 258 patients completed the registry. At 24 months LCIG treatment led to significant reductions from baseline in \"Off\" time (hours/day) (mean ± SD = -4.1 ± 3.5, P < 0.001), \"On\" time with dyskinesia (hours/day) (-1.1 ± 4.8, P = 0.006), Non-Motor Symptom Scale total (-16.7 ± 43.2, P < 0.001) and individual domains scores, and Parkinson's Disease Questionnaire-8 item total score (-7.1 ± 21.0, P < 0.001). Adverse events deemed to have a possible/probable causal relationship to treatment drug/device were reported in 194 (54%) patients; the most frequently reported were decreased weight (6.7%), device related infections (5.9%), device dislocations (4.8%), device issues (4.8%), and polyneuropathy (4.5%).\n\n\nCONCLUSIONS\nLCIG treatment led to sustained improvements in motor fluctuations, non-motor symptoms particularly sleep/fatigue, mood/cognition and gastrointestinal domains, as well as quality of life in advanced PD patients over 24 months. Safety events were consistent with the established safety profile of LCIG.", "affiliations": "Department of Neurosciences, University of Padua, Italy. Electronic address: [email protected].;Medical University of Innsbruck, Innsbruck, Austria. Electronic address: [email protected].;King's College and King's College Hospital, London, United Kingdom.;Department of Neurology, Center of Clinical Neurosciences, Charles University in Prague, General University Hospital in Prague, Prague, Czech Republic.;University Hospital Antwerp, Antwerp, Belgium; Michigan State University, Mercy Health Hauenstein Neurosciences, Grand Rapids, MI, USA.;University Medical Center Ljubljana, Ljubljana, Slovenia.;University of Medicine and Pharmacy Tirgu-Mures, Emergency Clinical County Hospital Mures, Tîrgu Mureş, Romania.;Clinical and Provincial Hospital of Barcelona, Barcelona, Spain.;Lindenbrunn Hospital, Coppenbrügge, Germany.;AbbVie Inc., North Chicago, IL, USA.;AbbVie Inc., North Chicago, IL, USA.;AbbVie Inc., North Chicago, IL, USA.;AbbVie Inc., North Chicago, IL, USA.;Lund University, Lund, Sweden.", "authors": "Antonini|Angelo|A|;Poewe|Werner|W|;Chaudhuri|K Ray|KR|;Jech|Robert|R|;Pickut|Barbara|B|;Pirtošek|Zvezdan|Z|;Szasz|Jozsef|J|;Valldeoriola|Francesc|F|;Winkler|Christian|C|;Bergmann|Lars|L|;Yegin|Ashley|A|;Onuk|Koray|K|;Barch|David|D|;Odin|Per|P|;|||", "chemical_list": "D000978:Antiparkinson Agents; D004338:Drug Combinations; D005782:Gels; C009265:carbidopa, levodopa drug combination; D007980:Levodopa; D002230:Carbidopa", "country": "England", "delete": false, "doi": "10.1016/j.parkreldis.2017.09.018", "fulltext": null, "fulltext_license": null, "issn_linking": "1353-8020", "issue": "45()", "journal": "Parkinsonism & related disorders", "keywords": "Levodopa-carbidopa intestinal gel; Motor symptoms; Non-motor symptoms; Parkinson's disease; Routine patient care", "medline_ta": "Parkinsonism Relat Disord", "mesh_terms": "D000368:Aged; D000978:Antiparkinson Agents; D002230:Carbidopa; D004338:Drug Combinations; D005260:Female; D005782:Gels; D006801:Humans; D007441:Intubation, Gastrointestinal; D007980:Levodopa; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease; D012042:Registries", "nlm_unique_id": "9513583", "other_id": null, "pages": "13-20", "pmc": null, "pmid": "29037498", "pubdate": "2017-12", "publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study", "references": null, "title": "Levodopa-carbidopa intestinal gel in advanced Parkinson's: Final results of the GLORIA registry.", "title_normalized": "levodopa carbidopa intestinal gel in advanced parkinson s final results of the gloria registry" }

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LEVODOPA-CARBIDOPA INTESTINAL GEL IN ADVANCED PARKINSON^S: FINAL RESULTS OF THE GLORIA REGISTRY. 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LEVODOPA-CARBIDOPA INTESTINAL GEL IN ADVANCED PARKINSON^S: FINAL RESULTS OF THE GLORIA REGISTRY. 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LEVODOPA-CARBIDOPA INTESTINAL GEL IN ADVANCED PARKINSON^S: FINAL RESULTS OF THE GLORIA REGISTRY. 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LEVODOPA-CARBIDOPA INTESTINAL GEL IN ADVANCED PARKINSON^S: FINAL RESULTS OF THE GLORIA REGISTRY. 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LEVODOPA-CARBIDOPA INTESTINAL GEL IN ADVANCED PARKINSON^S: FINAL RESULTS OF THE GLORIA REGISTRY. PARKINSON-RELAT-DIS. 2017?4513-20", "literaturereference_normalized": "levodopa carbidopa intestinal gel in advanced parkinson s final results of the gloria registry", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20180129", "receivedate": "20180129", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14453631, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" } ]

{ "abstract": "A 71-year-old woman on aspirin presented for a distal pancreatectomy, splenectomy, and partial colectomy with a T8/9 epidural catheter placed preoperatively in 3 attempts. Prophylactic 5000 units of subcutaneous heparin were given before the procedure. After catheter removal on postoperative day 2, the patient developed transient bilateral lower extremity paralysis, with near complete recovery within 30 minutes. An urgent MRI revealed a T4-T8 epidural hematoma prompting an emergent T3-T8 laminectomy. This case presentation highlights the need for heightened awareness regarding complications related to neuraxial analgesia in patients receiving unfractionated heparin for thromboembolism prophylaxis with concurrent aspirin use.", "affiliations": "From the Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts.", "authors": "VanderWielen|Beth|B|;Rubenstein|Lindsay|L|;Shnider|Marc|M|;Ku|Cindy|C|;Wakakuwa|Jason|J|", "chemical_list": "D000925:Anticoagulants; D005343:Fibrinolytic Agents; D010975:Platelet Aggregation Inhibitors", "country": "United States", "delete": false, "doi": "10.1213/XAA.0000000000000492", "fulltext": null, "fulltext_license": null, "issn_linking": "2325-7237", "issue": "8(11)", "journal": "A & A case reports", "keywords": null, "medline_ta": "A A Case Rep", "mesh_terms": "D000368:Aged; D000767:Anesthesia, Epidural; D000925:Anticoagulants; D002408:Catheters, Indwelling; D020878:Device Removal; D005260:Female; D005343:Fibrinolytic Agents; D046748:Hematoma, Epidural, Spinal; D006801:Humans; D007796:Laminectomy; D008279:Magnetic Resonance Imaging; D010243:Paralysis; D010975:Platelet Aggregation Inhibitors; D011237:Predictive Value of Tests; D012307:Risk Factors; D013904:Thoracic Vertebrae; D016896:Treatment Outcome", "nlm_unique_id": "101637720", "other_id": null, "pages": "294-296", "pmc": null, "pmid": "28079662", "pubdate": "2017-06-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Recognition of a Thoracic Epidural Hematoma in the Setting of Transient Paralysis: A Case Report.", "title_normalized": "recognition of a thoracic epidural hematoma in the setting of transient paralysis a case report" }

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"Diplegia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "VANDERWIELEN B,RUBENSTEIN L,SHNIDER M,KU C,WAKAKUWA J. RECOGNITION OF A THORACIC EPIDURAL HEMATOMA IN THE SETTING OF TRANSIENT PARALYSIS: A CASE REPORT. A+A CASE REPORTS 2017 JUN 01;8(11):294-6.", "literaturereference_normalized": "recognition of a thoracic epidural hematoma in the setting of transient paralysis a case report", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170629", "receivedate": "20170629", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13700551, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170830" }, { "companynumb": "US-SHENZHEN TECHDOW PHARMACEUTICAL CO. LTD-US-2017TEC0000055", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "HEPARIN SODIUM" }, "drugadditional": null, "drugadministrationroute": "058", "drugauthorizationnumb": "202732", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5000 IU, SINGLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "THROMBOSIS PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5000", "drugstructuredosageunit": "025", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HEPARIN SODIUM INJECTION USP, PRESERVATIVE FREE" }, { "actiondrug": "6", 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"drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "81 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "81", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN /00002701/" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "HEPARIN SODIUM" }, "drugadditional": null, "drugadministrationroute": "058", "drugauthorizationnumb": "202732", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5000 IU, BID", "drugenddate": null, 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null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "325", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN /00002701/" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "HYDROMORPHONE" }, "drugadditional": null, "drugadministrationroute": "008", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MCG/ML", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROMORPHONE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "HYDROMORPHONE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROMORPHONE" } ], "patientagegroup": null, "patientonsetage": "71", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Diplegia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Extradural haematoma", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "VANDERWIELEN B, RUBENSTEIN L, SHNIDER M, KU C, WAKAKUWA J. RECOGNITION OF A THORACIC EPIDURAL HEMATOMA IN THE SETTING OF TRANSIENT PARALYSIS: A CASE REPORT. A-A-CASE-REP. 2017;8(11):294-296", "literaturereference_normalized": "recognition of a thoracic epidural hematoma in the setting of transient paralysis a case report", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170926", "receivedate": "20170926", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14013011, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20171128" } ]

{ "abstract": "An 82-year-old bedridden man with sequelae from a cerebral infarction was admitted to a welfare institution for the elderly. He developed a high fever and hematuria and was prescribed levofloxacin for the treatment of a suspected urinary tract infection. Although his condition improved, the symptoms subsequently recurred; therefore, levofloxacin was again administered. He remained febrile and was admitted to a hospital due to recalcitrant urinary tract infection. Immediately after admission, he developed ischuria and pyuria. Urine and blood cultures at admission indicated the presence of levofloxacin-resistant Oligella urethralis (O. urethralis). He recovered with ceftriaxone medication. To our knowledge, this is the first report of bacteremia associated with a urinary tract infection caused by O. urethralis in Japan.", "affiliations": null, "authors": "Murase|Kyoko|K|;Noda|Kazushige|K|;Otaki|Yoshihiro|Y|;Yasuda|Jun-ichi|J|;Oda|Toshimi|T|;Yokozawa|Takayuki|T|;Kikuchi|Ken|K|", "chemical_list": null, "country": "Japan", "delete": false, "doi": "10.11150/kansenshogakuzasshi.89.274", "fulltext": null, "fulltext_license": null, "issn_linking": "0387-5911", "issue": "89(2)", "journal": "Kansenshogaku zasshi. The Journal of the Japanese Association for Infectious Diseases", "keywords": null, "medline_ta": "Kansenshogaku Zasshi", "mesh_terms": "D000369:Aged, 80 and over; D016470:Bacteremia; D016946:Gram-Negative Aerobic Rods and Cocci; D016905:Gram-Negative Bacterial Infections; D006801:Humans; D008297:Male; D014552:Urinary Tract Infections", "nlm_unique_id": "0236671", "other_id": null, "pages": "274-8", "pmc": null, "pmid": "26552126", "pubdate": "2015-03", "publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article", "references": null, "title": "A Case of Bacteremia Which Followed a Urinary Tract Infection by Oligella urethralis.", "title_normalized": "a case of bacteremia which followed a urinary tract infection by oligella urethralis" }

[ { "companynumb": "JP-LUPIN PHARMACEUTICALS INC.-2015-04401", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "LEVOFLOXACIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "078424", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOFLOXACIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEVOFLOXACIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "078424", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "URINARY TRACT INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOFLOXACIN." } ], "patientagegroup": null, "patientonsetage": "82", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug resistance", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MURASE K, NODA K, OTAKI Y, YASUDA J, ODA T, YOKOZAWA T, KIKUCHI K. A CASE OF BACTEREMIA WHICH FOLLOWED A URINARY TRACT INFECTION BY OLIGELLA URETHRALIS. KANSENSHOGAKU ZASSHI. 2015 MAR?89(2):274-278.", "literaturereference_normalized": "a case of bacteremia which followed a urinary tract infection by oligella urethralis", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20151230", "receivedate": "20151230", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 11878009, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160305" } ]

{ "abstract": "We present a case of a 30-year-old woman who suffered a central retinal artery occlusion while taking tranexamic acid. She had no vascular risk factors and was placed on the drug for treatment of menorrhagia. After 1 month of taking the drug, she suffered a central retinal artery occlusion in her left eye. Tranexamic acid was discontinued to prevent vision loss in the following eye. She remains with no perception of light vision in the affected eye.", "affiliations": "Cardiff Eye Unit, Cardiff and Vale University Health Board, Cardiff, UK.;Cardiff Eye Unit, Cardiff and Vale University Health Board, Cardiff, UK.;Ophthalmology Department, Singleton Hospital, Swansea, UK.", "authors": "Wijetilleka|Sidath|S|;Yeo|Damien Chia Ming|DCM|;Sharma|Bhavana|B|", "chemical_list": "D000933:Antifibrinolytic Agents; D014148:Tranexamic Acid", "country": "England", "delete": false, "doi": "10.1136/bcr-2016-218246", "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "2017()", "journal": "BMJ case reports", "keywords": "Retina; Unwanted Effects / Adverse Reactions", "medline_ta": "BMJ Case Rep", "mesh_terms": "D000328:Adult; D000933:Antifibrinolytic Agents; D005260:Female; D005451:Fluorescein Angiography; D006801:Humans; D008595:Menorrhagia; D015356:Retinal Artery Occlusion; D014148:Tranexamic Acid", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "28705840", "pubdate": "2017-07-13", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "3163896;9033905", "title": "Central retinal artery occlusion in a 30-year-old woman taking tranexamic acid.", "title_normalized": "central retinal artery occlusion in a 30 year old woman taking tranexamic acid" }

[ { "companynumb": "GB-MYLANLABS-2017M1052484", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TRANEXAMIC ACID" }, "drugadditional": "2", "drugadministrationroute": "065", "drugauthorizationnumb": "091657", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MENORRHAGIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRANEXAMIC ACID." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Blindness", "reactionmeddraversionpt": "20.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Retinal artery occlusion", "reactionmeddraversionpt": "20.1", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "WIJETILLEKA S, YEO DCM, SHARMA B. CENTRAL RETINAL ARTERY OCCLUSION IN A 30-YEAR-OLD WOMAN TAKING TRANEXAMIC ACID. BMJ-CASE-REP 2017;2017:218246.", "literaturereference_normalized": "central retinal artery occlusion in a 30 year old woman taking tranexamic acid", "qualification": "1", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20170824", "receivedate": "20170824", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13903984, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" } ]

{ "abstract": "Adefovir dipivoxil (ADV) was an important cause of adult-onset hypophosphatemic osteomalacia. However, its clinical characteristics and mechanisms have not been well defined.\n\n\n\nThe objective of the study was to summarize the clinical characteristics of ADV-induced osteomalacia and to explore the association between ADV-associated tubulopathy and polymorphisms in genes encoding drug transporters.\n\n\n\nSeventy-six affected patients were clinically studied. The SLC22A6 and ABCC2 genes were screened and compared with healthy people from the HapMap.\n\n\n\nHypophosphatemia, high serum alkaline phosphatase (ALP) levels, hypouricemia, nondiabetic glycosuria, proteinuria, metabolic acidosis and high bone turnover markers were the main metabolic characteristics. Fractures and pseudofractures occurred in 39 patients. Stopping ADV administration, supplementing calcitriol and calcium was effective during the follow-up period. Single SNP analysis revealed a higher percentage of the G/A genotype at c.2934 in exon 22 of the ABCC2 gene (rs3740070) in patients than in healthy people (12% [7 of 58 patients] vs. 0% [0 of 45 patients]; P=0.017), while there was no subject with homozygosity for the A allele at c.2934.\n\n\n\nADV can be nephrotoxic at a conventional dosage. The G/A genotype at c.2934 of the ABCC2 gene may be a predictor of patients at greater risk for developing ADV-associated tubulopathy. Larger case-control studies are needed to further verify this finding.", "affiliations": "Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.;Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.;Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.;Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China. Electronic address: [email protected].", "authors": "Wei|Zhe|Z|;He|Jin-Wei|JW|;Fu|Wen-Zhen|WZ|;Zhang|Zhen-Lin|ZL|", "chemical_list": "C000715087:ABCC2 protein, human; D000089762:Multidrug Resistance-Associated Protein 2; D027425:Multidrug Resistance-Associated Proteins; D027362:Organic Anion Transport Protein 1; D063065:Organophosphonates; D000225:Adenine; C106812:adefovir dipivoxil", "country": "United States", "delete": false, "doi": "10.1016/j.bone.2016.09.017", "fulltext": null, "fulltext_license": null, "issn_linking": "1873-2763", "issue": "93()", "journal": "Bone", "keywords": "ABCC2; Adefovir dipivoxil; Clinical characteristic; Hypophosphatemic osteomalacia; Risk genotype; SLC22A6", "medline_ta": "Bone", "mesh_terms": "D000225:Adenine; D000595:Amino Acid Sequence; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:Multidrug Resistance-Associated Proteins; D027362:Organic Anion Transport Protein 1; D063065:Organophosphonates; D010018:Osteomalacia; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D017386:Sequence Homology, Amino Acid", "nlm_unique_id": "8504048", "other_id": null, "pages": "97-103", "pmc": null, "pmid": "27664568", "pubdate": "2016-12", "publication_types": "D016428:Journal Article", "references": null, "title": "Osteomalacia induced by long-term low-dose adefovir dipivoxil: Clinical characteristics and genetic predictors.", "title_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors" }

[ { "companynumb": "CN-GILEAD-2016-0247457", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "0 MG, QD", "drugenddate": "201206", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2007", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK UNKNOWN, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "60", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010944, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247455", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "201102", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2007", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK UNKNOWN, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "43", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201008" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161207", "receivedate": "20161207", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13007554, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247610", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "6", "patientonsetage": "76", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201310" } }, "primarysource": { "literaturereference": "WEI Z, HE J-W, FU W-Z, Z Z-L. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010834, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247589", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20121203", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2005", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": "20121203", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2005", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "50", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201202" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13009974, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247582", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": "20140324", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2009", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20140324", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2009", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "51", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201303" } }, "primarysource": { "literaturereference": "WEI, Z. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13011094, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247585", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20130508", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2000", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": "20130508", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2000", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "6", "patientonsetage": "71", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13009874, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247616", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20160628", "drugenddateformat": "102", "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2001", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "48", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201506" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161209", "receivedate": "20161209", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13013797, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247415", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20150205", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2009", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "57", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201402" } }, "primarysource": { "literaturereference": "WEI Z.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010567, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247604", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20151026", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2007", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK UNKNOWN, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "36", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201310" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161209", "receivedate": "20161209", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13013747, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247460", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "201203", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2003", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": "201203", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2003", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201111" } }, "primarysource": { "literaturereference": "WEI Z, ET AL. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010917, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247583", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20130722", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2005", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": "20130722", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2005", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "50", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201107" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13009828, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247299", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20130301", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2006", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "46", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201104" } }, "primarysource": { "literaturereference": "WEI, Z.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161209", "receivedate": "20161209", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13013748, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247459", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "201203", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2007", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": "201203", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2007", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "46", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WEI Z. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010948, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247606", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20150624", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2007", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": "20150624", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2007", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "6", "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201206" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161209", "receivedate": "20161209", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13014528, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247289", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "200806", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2003", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 200706" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010188, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247613", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20140514", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2009", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": "20140514", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2009", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "25", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201205" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010458, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247303", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "201103", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2007", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "47", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 200912" } }, "primarysource": { "literaturereference": "ZHE WEI. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161209", "receivedate": "20161209", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13013628, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247304", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "200910", "drugenddateformat": "610", "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2003", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "58", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 200810" } }, "primarysource": { "literaturereference": "WEI Z, HE J-W, FU W-Z, ZHANG Z-L. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161207", "receivedate": "20161207", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13005966, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247458", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "201209", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2009", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": "201209", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2009", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR /01480802/" } ], "patientagegroup": "5", "patientonsetage": "47", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201109" } }, "primarysource": { "literaturereference": "WEI Z, HE J-W, FU W-Z, ZHANG Z-L. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010946, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0239203", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161207", "receivedate": "20161020", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 12867616, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247300", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "201203", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2007", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "6", "patientonsetage": "65", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201109" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161209", "receivedate": "20161209", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13013696, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247615", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20160718", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2009", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": "20160718", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2009", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "6", "patientonsetage": "68", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201407" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161209", "receivedate": "20161209", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13013786, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247419", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20140708", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2008", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "45", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201304" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010549, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247414", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20150902", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2000", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "58", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201405" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010659, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247297", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20140217", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2010", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "49", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201307" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010279, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247306", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "200809", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2004", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "57", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 200709" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010259, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247301", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "201106", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2006", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "46", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201105" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161209", "receivedate": "20161209", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13013699, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247298", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20130701", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2005", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "61", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201107" } }, "primarysource": { "literaturereference": "WEI., Z.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010339, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247462", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, UNK", "drugenddate": "201111", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2006", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, UNK", "drugenddate": "201111", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2006", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR" } ], "patientagegroup": "5", "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201011" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010929, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247416", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, UNK", "drugenddate": "20150202", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2009", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "53", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201402" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010672, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247456", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": "201211", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2010", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "201211", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2010", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201205" } }, "primarysource": { "literaturereference": "ZHE WEI. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "1", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13011082, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247417", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20141110", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2005", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "58", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201402" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010472, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247302", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "201103", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2005", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "46", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 200803" } }, "primarysource": { "literaturereference": "ZHE WEI. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161209", "receivedate": "20161209", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13013662, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247587", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK UNK, QD", "drugenddate": "201212", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2005", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK UNK, QD", "drugenddate": "201212", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2005", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "28", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201112" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13009952, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247618", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "201512", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2012", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, UNK", "drugenddate": "201512", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2012", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "54", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201404" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "1", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010832, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247617", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20160510", "drugenddateformat": "102", "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2006", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": "20160510", "drugenddateformat": "102", "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2006", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "56", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201305" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161209", "receivedate": "20161209", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13013802, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247586", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": "201304", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2008", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "201304", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2008", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WEI, Z. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13009892, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247464", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "201104", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2004", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": "201104", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2004", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "49", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 200804" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010932, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247411", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20160201", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2007", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "53", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201402" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13011052, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247413", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20141207", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2007", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201412" } }, "primarysource": { "literaturereference": "WEI Z.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010662, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247580", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK UNK, QD", "drugenddate": "20140514", "drugenddateformat": "102", "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2006", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK UNK, QD", "drugenddate": "20140514", "drugenddateformat": "102", "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2006", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "54", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201205" } }, "primarysource": { "literaturereference": "WEI Z. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161209", "receivedate": "20161209", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13013720, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247611", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK", "drugenddate": "20140825", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2009", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "52", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201208" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161209", "receivedate": "20161209", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13013770, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247608", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "6", "patientonsetage": "70", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201401" } }, "primarysource": { "literaturereference": "WEI Z, HE J-W, FU W-Z, Z Z-L. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010830, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247581", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20140512", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201205" } }, "primarysource": { "literaturereference": "WEI Z, HE J-W, FU W-Z, ZHANG Z-L. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13009820, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247461", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "201202", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2009", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": "201202", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2009", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "6", "patientonsetage": "74", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201008" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010925, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247305", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "200812", "drugenddateformat": "610", "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2004", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "34", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 200612" } }, "primarysource": { "literaturereference": "WEI Z, HE J-W, FU W-Z, ZHANG Z-L. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13009875, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247588", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20121224", "drugenddateformat": "102", "drugindication": "CHRONIC HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2008", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": "20121224", "drugenddateformat": "102", "drugindication": "CHRONIC HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2008", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "44", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201203" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13009965, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247418", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, UNK", "drugenddate": "20140928", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2009", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "51", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201309" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010465, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247619", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20160223", "drugenddateformat": "102", "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2008", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": "20160223", "drugenddateformat": "102", "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2008", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "46", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201308" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "1", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161209", "receivedate": "20161209", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13013825, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247612", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK", "drugenddate": "20140714", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2009", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "52", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201401" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161209", "receivedate": "20161209", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13013795, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247609", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201210" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010835, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247584", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": "20130713", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2009", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20130713", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2009", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "40", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201304" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ AND ZHANG ZL. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103.", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13009851, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247607", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": "20150318", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2007", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20150318", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2007", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "49", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201203" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161209", "receivedate": "20161209", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13013751, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247412", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK", "drugenddate": "20151230", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2006", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "6", "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201412" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-1036", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010671, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247403", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20140603", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2006", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "61", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201404" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010661, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247410", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20160827", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2010", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": "20160827", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2010", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "5", "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201308" } }, "primarysource": { "literaturereference": "WEI Z, ET AL. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010663, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247605", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": "20150810", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2011", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20150810", "drugenddateformat": "102", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2011", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "6", "patientonsetage": "75", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201308" } }, "primarysource": { "literaturereference": "WEI Z, HE JW, FU WZ, ZHANG ZL.. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS.. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161209", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13009993, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "CN-GILEAD-2016-0247463", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "201105", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2005", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADEFOVIR DIPIVOXIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": "201105", "drugenddateformat": "610", "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2005", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADEFOVIR DIPIVOXIL." } ], "patientagegroup": "6", "patientonsetage": "66", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201011" } }, "primarysource": { "literaturereference": "WEI Z. OSTEOMALACIA INDUCED BY LONG-TERM LOW-DOSE ADEFOVIR DIPIVOXIL: CLINICAL CHARACTERISTICS AND GENETIC PREDICTORS. BONE. 2016;93:97-103", "literaturereference_normalized": "osteomalacia induced by long term low dose adefovir dipivoxil clinical characteristics and genetic predictors", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20161208", "receivedate": "20161208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13010943, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" } ]

{ "abstract": "A 64-year-old woman with refractory cellulitis in the lower legs was referred for inadequate glycaemic control. Physical examination revealed cushingoid features including central obesity. CT of the abdomen revealed a right adrenal mass that was positive on 131I-adosterol imaging. Findings on endocrine evaluation confirmed a diagnosis of Cushing's syndrome, which was cured with a right adrenalectomy. Two months after surgery, the patient complained of pain and marked swelling of the hands during hydrocortisone replacement therapy (20 mg per day) given for postoperative adrenal insufficiency. Laboratory examination was unremarkable. However, contrast-enhanced T2-weighted MRI of the hands revealed enhanced signals surrounding the flexor tendons, leading to a diagnosis of remitting seronegative symmetrical synovitis with pitting oedema. Prednisolone (15 mg per day) was then initiated, and the symptoms disappeared within a few days. This case illustrates the possibility that successful treatment of Cushing's syndrome may trigger emergence of a glucocorticoid-responsive disease.", "affiliations": "Department of Internal Medicine, Toshiba Rinkan Hospital, Sagamihara, Kanagawa, Japan [email protected].;Department of Urology, Toshiba Rinkan Hospital, Sagamihara, Kanagawa, Japan.;Department of Pathology, Toshiba Rinkan Hospital, Sagamihara, Kanagawa, Japan.", "authors": "Iwasaki|Hiroaki|H|;Kanno|Hitomi|H|;Jiang|Shi-Xu|SX|", "chemical_list": "D006854:Hydrocortisone", "country": "England", "delete": false, "doi": "10.1136/bcr-2019-232959", "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "13(3)", "journal": "BMJ case reports", "keywords": "adrenal disorders; rheumatoid arthritis", "medline_ta": "BMJ Case Rep", "mesh_terms": "D000306:Adrenal Cortex Neoplasms; D018246:Adrenocortical Adenoma; D003480:Cushing Syndrome; D004487:Edema; D005260:Female; D020249:Hormone Replacement Therapy; D006801:Humans; D006854:Hydrocortisone; D008875:Middle Aged; D013585:Synovitis", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "32234852", "pubdate": "2020-03-31", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Remitting seronegative symmetrical synovitis with pitting oedema after surgical remission of Cushing's syndrome.", "title_normalized": "remitting seronegative symmetrical synovitis with pitting oedema after surgical remission of cushing s syndrome" }

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"drugdosagetext": "200 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ARTHROPATHY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CELECOXIB." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "HYDROCORTISONE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "008697", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "150 MG PER DAY TAPERED TO 75 MG PER DAY WITHIN 3 DAYS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ADRENAL INSUFFICIENCY", 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"drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SITAGLIPTIN" } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Seronegative arthritis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "IWASAKI, H.. REMITTING SERONEGATIVE SYMMETRICAL SYNOVITIS WITH PITTING OEDEMA AFTER SURGICAL REMISSION OF CUSHING^S SYNDROME. BMJ CASE REPORTS. 2020?13(3):10.1136/BCR?2019?232959", "literaturereference_normalized": "remitting seronegative symmetrical synovitis with pitting oedema after surgical remission of cushing s syndrome", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20210113", "receivedate": "20210113", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18735156, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210419" } ]

{ "abstract": "There are no standardized treatments for giant cell tumors of the bone (GCTB) in rare locations such as the spine and pelvis or for those that are inoperable and recurrent, let alone for multicentric GCTB. This study reports a novel case of multicentric GCTB treated with a promising antiangiogenic drug, apatinib, a small-molecule tyrosine kinase inhibitor. The efficacy of apatinib in the treatment of GCTB has not been reported previously.\nA 27-year-old female presented with two giant cell tumors of the spine and sacrum-ilium diagnosed on December 15, 2016. Surgery and selective arterial embolization (SAE) were not reasonable options for this patient, and denosumab was unavailable; therefore, the antiangiogenic drug apatinib and the osteoclast inhibitor zoledronic acid were administered. Apatinib was initially administered at a dose of 850 mg daily, which was decreased to 425 mg daily after 7 months, and then increased again to 635 mg after 11 months. The patient was prescribed a maintenance dose of 500 mg daily after 16 months. The patient reported side effects of Grades I-III nausea, vomiting, and Grades II-III hand-foot syndrome. The patient underwent SAE at 26 months, and at that time, she was switched to denosumab instead of zoledronic acid.\nThe patient showed noticeable symptomatic improvement and visibly reduced tumor size after the first month of treatment. Computed tomography in the 4th month identified a partial response based on the RECIST criteria. The patient has achieved an objective reduction in tumor size at 32 months.\nComprehensive treatment including apatinib represents a potential new treatment strategy for inoperable GCTB, with tolerable side effects. However, further clinical trials are now necessary to confirm an effective dose and determine the efficacy and safety of apatinib in the treatment of GCTB.", "affiliations": "Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University; Li Chengli Innovation Studio, Jinan, China.;Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.;Department of Chemistry and Biochemistry, University of California, Santa Barbara, California, USA.;Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.;Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.", "authors": "Li|Jun|J|;Zhou|Jun|J|;Liu|Yuntong|Y|;Sun|Xiaogang|X|;Song|Wei|W|", "chemical_list": "D011725:Pyridines; C553458:apatinib; D000077211:Zoledronic Acid", "country": "India", "delete": false, "doi": "10.4103/jcrt.JCRT_892_19", "fulltext": null, "fulltext_license": null, "issn_linking": "1998-4138", "issue": "16(5)", "journal": "Journal of cancer research and therapeutics", "keywords": "Apatinib; denosumab; multicentric giant cell tumor of the bone; selective arterial embolization; zoledronic acid", "medline_ta": "J Cancer Res Ther", "mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001859:Bone Neoplasms; D005260:Female; D018212:Giant Cell Tumor of Bone; D006801:Humans; D010386:Pelvic Neoplasms; D011725:Pyridines; D013125:Spinal Neoplasms; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D000077211:Zoledronic Acid", "nlm_unique_id": "101249598", "other_id": null, "pages": "1020-1026", "pmc": null, "pmid": "33004743", "pubdate": "2020-09", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Comprehensive treatment for multicentric giant cell tumors of the pelvis and spine using apatinib: A case report and literature review.", "title_normalized": "comprehensive treatment for multicentric giant cell tumors of the pelvis and spine using apatinib a case report and literature review" }

[ { "companynumb": "CN-AMGEN-CHNSP2020162991", "fulfillexpeditecriteria": "2", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DENOSUMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "125320", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN FORMULATION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE GIANT CELL TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "XGEVA" } ], "patientagegroup": "5", "patientonsetage": "25", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Bone giant cell tumour", "reactionmeddraversionpt": "23.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Therapy non-responder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "L JUN.? ZHOU J.? L YUNTONG. ET. AL.. COMPREHENSIVE TREATMENT FOR MULTICENTRIC GIANT CELL TUMORS OF THE PELVIS AND SPINE USING APATINIB: A CASE REPORT AND LITERATURE REVIEW. JOURNAL OF CANCER RESEARCH AND THERAPEUTICS. 2020?16 (5):1020-1026", "literaturereference_normalized": "comprehensive treatment for multicentric giant cell tumors of the pelvis and spine using apatinib a case report and literature review", "qualification": "1", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20201014", "receivedate": "20201014", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18380928, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210114" } ]

{ "abstract": "BACKGROUND\nOptimal anti-epileptic drug (AED) treatment maximises therapeutic response and minimises adverse effects (AEs). Key to therapeutic AED treatment is adherence. Non-adherence is often related to severity of AEs. Frequently, patients do not spontaneously report, and clinicians do not specifically query, critical AEs that lead to non-adherence, including sexual dysfunction. Sexual dysfunction prevalence in patients with epilepsy ranges from 40 to 70%, often related to AEDs, epilepsy or mood states. This case reports lamotrigine-induced sexual dysfunction leading to periodic non-adherence.\n\n\nOBJECTIVE\nTo report lamotrigine-induced sexual dysfunction leading to periodic lamotrigine non-adherence in the context of multiple comorbidities and concurrent antidepressant and antihypertensive pharmacotherapy.\n\n\nMETHODS\nCase analysis with PubMed literature review.\n\n\nRESULTS\nA 56-year-old male patient with major depression, panic disorder without agoraphobia and post-traumatic stress disorder was well-controlled with escitalopram 20 mg bid, mirtazapine 22.5 mg qhs and alprazolam 1 mg tid prn. Comorbid conditions included complex partial seizures, psychogenic non-epileptic seizures (PNES), hypertension, gastroesophageal reflux disease and hydrocephalus with patent ventriculoperitoneal shunt that were effectively treated with lamotrigine 100 mg tid, enalapril 20 mg qam and lansoprazole 30 mg qam. He acknowledged non-adherence with lamotrigine secondary to sexual dysfunction. With lamotrigine 300 mg total daily dose, he described no libido with impotence/anejaculation/anorgasmia. When off lamotrigine for 48 h, he described becoming libidinous with decreased erectile dysfunction but persistent anejaculation/anorgasmia. When off lamotrigine for 72 h to maximise sexual functioning, he developed auras. Family confirmed patient's consistent monthly non-adherence for 2-3 days during the past year.\n\n\nCONCLUSIONS\nSexual dysfunction is a key AE leading to AED non-adherence. This case describes dose-dependent lamotrigine-induced sexual dysfunction with episodic non-adherence for 12 months. Patient/clinician education regarding AED-induced sexual dysfunction is warranted as are routine sexual histories to ensure adherence.\n\n\nBACKGROUND\nNo financial interests. K.R.K. is Editor of BJPsych Open; he took no part in the peer-review of this work.\n© The Royal College of Psychiatrists 2017. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) license.", "affiliations": ", MD, FRCPsych, DLFAPA, FAES, Departments of Psychiatry, Neurology and Anesthesiology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.;, BS, Department of Psychiatry, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.;, MD, Department of Neurology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.;, BA, Department of Psychiatry, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.", "authors": "Kaufman|Kenneth R|KR|;Coluccio|Melissa|M|;Sivaraaman|Kartik|K|;Campeas|Miriam|M|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1192/bjpo.bp.117.005538", "fulltext": "\n==== Front\nBJPsych OpenBJPsych OpenbjporcpsychbjporcpsychBJPsych Open2056-4724The Royal College of Psychiatrists bjporcpsych00553810.1192/bjpo.bp.117.005538Short ReportLamotrigine-induced sexual dysfunction and non-adherence: case analysis with literature review† Sex, lamotrigine, non-adherenceKaufman et alKaufman Kenneth R. Coluccio Melissa Sivaraaman Kartik Campeas Miriam Kenneth R. Kaufman, MD, FRCPsych, DLFAPA, FAES, Departments of Psychiatry, Neurology and Anesthesiology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USAMelissa Coluccio, BS, Department of Psychiatry, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USAKartik Sivaraaman, MD, Department of Neurology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USAMiriam Campeas, BA, Department of Psychiatry, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USACorrespondence: Kenneth R. Kaufman, Departments of Psychiatry, Neurology and Anesthesiology, Rutgers Robert Wood Johnson Medical School, 125 Paterson Street, Suite #2200, New Brunswick, NJ 08901, USA. E-mail:[email protected]† Presented in part at the 19th Annual Conference of the International Society of Bipolar Disorders, Washington DC, 4–7 May 2017.\n\n4 10 2017 9 2017 3 5 249 253 7 7 2017 7 8 2017 23 8 2017 © 2017 The Royal College of Psychiatrists2017The Royal College of PsychiatristsThis is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Background\nOptimal anti-epileptic drug (AED) treatment maximises therapeutic response and minimises adverse effects (AEs). Key to therapeutic AED treatment is adherence. Non-adherence is often related to severity of AEs. Frequently, patients do not spontaneously report, and clinicians do not specifically query, critical AEs that lead to non-adherence, including sexual dysfunction. Sexual dysfunction prevalence in patients with epilepsy ranges from 40 to 70%, often related to AEDs, epilepsy or mood states. This case reports lamotrigine-induced sexual dysfunction leading to periodic non-adherence.\n\nAims\nTo report lamotrigine-induced sexual dysfunction leading to periodic lamotrigine non-adherence in the context of multiple comorbidities and concurrent antidepressant and antihypertensive pharmacotherapy.\n\nMethod\nCase analysis with PubMed literature review.\n\nResults\nA 56-year-old male patient with major depression, panic disorder without agoraphobia and post-traumatic stress disorder was well-controlled with escitalopram 20 mg bid, mirtazapine 22.5 mg qhs and alprazolam 1 mg tid prn. Comorbid conditions included complex partial seizures, psychogenic non-epileptic seizures (PNES), hypertension, gastroesophageal reflux disease and hydrocephalus with patent ventriculoperitoneal shunt that were effectively treated with lamotrigine 100 mg tid, enalapril 20 mg qam and lansoprazole 30 mg qam. He acknowledged non-adherence with lamotrigine secondary to sexual dysfunction. With lamotrigine 300 mg total daily dose, he described no libido with impotence/anejaculation/anorgasmia. When off lamotrigine for 48 h, he described becoming libidinous with decreased erectile dysfunction but persistent anejaculation/anorgasmia. When off lamotrigine for 72 h to maximise sexual functioning, he developed auras. Family confirmed patient’s consistent monthly non-adherence for 2–3 days during the past year.\n\nConclusions\nSexual dysfunction is a key AE leading to AED non-adherence. This case describes dose-dependent lamotrigine-induced sexual dysfunction with episodic non-adherence for 12 months. Patient/clinician education regarding AED-induced sexual dysfunction is warranted as are routine sexual histories to ensure adherence.\n\nDeclaration of interest\nNo financial interests. K.R.K. is Editor of BJPsych Open; he took no part in the peer-review of this work.\n\nCopyright and usage\n© The Royal College of Psychiatrists 2017. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) license.\n==== Body\nOptimal anti-epileptic drug (AED) treatments for persons with epilepsy (PWE) and psychotropic treatments for persons with mood disorders maximise therapeutic response and minimise adverse effects (AEs).1,2 The key to successful pharmacotherapies, whether AEDs or psychotropics, remains medicine adherence. The degree of non-adherence is often underappreciated both by patients and clinicians.3,4 One review of treatment adherence in bipolar patients extracted from a VA database (N=44,637) noted that only 54.1% of all patients were fully adherent.5 A recent UK primary care study of PWE (n=398) found that 36.7% had low adherence,4 which is consistent with a US study addressing elderly PWE with data extracted from the Integrated Health Care Information Services Managed Care Benchmark Database (N=1278) that reported a 40.7% non-adherence rate.6\n\nIn light of the degree of non-adherence and the associated negative effect on acute and long-term treatment outcomes for PWE and persons with mood disorders, especially when considering the direct and indirect costs of these illnesses to society,6–9 research has focused on potential predictive and risk factors. Specific significant predictive and risk factor associations for medication adherence and non-adherence have been reported with, but not limited to, ethnicity, socioeconomics, education, culture, stigma, age, illness status/duration, comorbid substance use disorders, understanding illness process, perceptions related to medication and AEs.4,5,10–13\n\nAE severity is a critical determinant of non-adherence that can be readily addressed during meaningful clinical interactions wherein dosing, alternative pharmacotherapy or even treatment for a specific AE can be considered. Frequently, PWE and persons with mood disorders do not spontaneously report and clinicians do not specifically query critical AEs that lead to non-adherence, including sexual dysfunction.14–17 Sexual functioning is an important marker of quality of life. Sexual dysfunction prevalence in PWE ranges from 40 to 70%, often related to the AEDs, epilepsy, hormonal status or mood states.18,19 Similarly, sexual dysfunction prevalence in patients with mood disorders ranges from 25 to 80% with attribution to psychotropics, mood state and hormonal status.16,20–22\n\nThis case reports lamotrigine-induced sexual dysfunction leading to periodic lamotrigine non-adherence in the context of multiple comorbidities and concurrent antidepressant and antihypertensive pharmacotherapy.\n\nMethod\nCase analysis with PubMed literature review was employed. Search terms utilised in the PubMed literature review included but were not limited to: (1) sexual dysfunction (expanded to all forms of sexual dysfunction – decreased libido, lack of libido, erectile dysfunction, impotence, ejaculatory inhibition, anejaculation, delayed orgasm, anorgasmia, priapism, premature ejaculation, retrograde ejaculation and hypersexuality); (2) general aetiologies (from general reviews this was expanded to reviews addressing neurologic disorders, hypertension, cardiovascular disease, hormonal disorders, psychiatric and substance use disorders, medication and psychotropics); (3) specific aetiologies by patient’s psychiatric diagnoses (mood disorders, anxiety disorders, major depression, panic disorder and post-traumatic stress disorder (PTSD)); (4) specific aetiologies by the patient’s medical diagnoses (epilepsy, complex partial seizures, psychogenic non-epileptic seizures (PNES), hypertension, gastroesophageal reflux disease (GERD) and hydrocephalus); (5) specific aetiologies by the patient’s psychotropics (antidepressants, selective serotonin reuptake inhibitors (SSRIs), escitalopram, mirtazapine, anxiolytics, benzodiazepines and alprazolam); (6) specific aetiologies by the patient’s pharmacotherapy utilised for medical conditions (anticonvulsants, AEDs, lamotrigine, antihypertensive agents, angiotensin converting enzyme (ACE) inhibitors, enalapril, proton pump inhibitors (PPIs) and lansoprazole); (7) lamotrigine and drug interactions; (8) adherence (therapeutic drug monitoring (TDM), discontinuation syndrome and reporting of AEs) and (9) probability rating scale.\n\nResults\nA 56-year-old male patient with major depression, panic disorder without agoraphobia, and PTSD was well-controlled with escitalopram 20 mg bid, mirtazapine 22.5 mg qhs and alprazolam 1 mg tid prn. Comorbid medical conditions included complex partial seizures, PNES, hypertension, GERD and hydrocephalus with patent ventriculoperitoneal shunt that were effectively treated with lamotrigine 100 mg tid, enalapril 20 mg qam and lansoprazole 30 mg qam.\n\nThe patient did not spontaneously report sexual dysfunction; however, he acknowledged such on direct questioning. He desired to maintain his current rational polypharmacy as opposed to potential alternative psychotropics or dose reductions as he focused on his stable psychiatric status. Further, he emphasised adherence to his entire medication regimen, which had remained unchanged over an extended time period.\n\nWhen an issue arose regarding an inappropriately delayed lamotrigine script refill, the patient was confronted with apparent lamotrigine non-adherence and the potential need to reinitiate lamotrigine titration to avoid Stevens–Johnson syndrome. Only then did he acknowledge non-adherence with lamotrigine secondary to sexual dysfunction. Specifically, with lamotrigine 300 mg total daily dose, he described total sexual dysfunction with lack of libido, impotence, anejaculation and anorgasmia.\n\nWhen off lamotrigine for 48 h, he described becoming libidinous with difficult intercourse secondary to erectile dysfunction and persistent anejaculation/anorgasmia. When off lamotrigine for 72 h to maximise sexual functioning (decreased erectile dysfunction but persistent anejaculation/anorgasmia), he developed auras without sexual content. His family confirmed the patient’s consistent monthly non-adherence for 2–3 days during the past year. Though the treating psychiatrist warned the patient that this non-adherence posed the risk of further seizures and even depressive decompensation, he admitted continuing this periodic non-adherence until instructed to cease by his wife.\n\nDiscussion\nMale sexual dysfunction has multiple presentations (decreased libido, lack of libido, erectile dysfunction, impotence, ejaculatory inhibition, anejaculation, delayed orgasm, anorgasmia, priapism, premature ejaculation and retrograde ejaculation)23,24 with multiple reported aetiologies (medical conditions including, but not limited to, neurologic disorders, hypertension, cardiovascular disease and hormonal disorders; psychiatric disorders including, but not limited to mood, anxiety, trauma-related and substance use disorders; and pharmacotherapies).16,18–30 This unique case permits discussion of these issues in the context of the patient’s comorbid conditions and pharmacotherapies from which a determination of probable aetiology for this patient’s lack of libido can be ascertained.31\n\nFirst, the patient had three psychiatric diagnoses: major depression, panic disorder and PTSD. Depression is clearly associated with sexual dysfunction, and decreased libido is a cardinal symptom during a major depressive episode (MDE).20 Erectile dysfunction is associated with both untreated non-MDE depression32 and untreated MDE depression.33 Further, ejaculatory delay has been reported in untreated MDE depression.33 Though there is literature supporting the interrelationship between anxiety and sexual dysfunction,24,34 there is limited research addressing panic disorder in men with associated sexual dysfunction with findings suggesting that panic disorder has a small effect after controlling for comorbid conditions and pharmacotherapies.35 Male military veterans with PTSD have a marked increased prevalence of sexual dysfunctions (including decreased libido, erectile dysfunction and orgasmic difficulties) with recent research addressing the joint neuroendocrine underpinnings of sexual dysfunctions and PTSD.29,36\n\nSecond, the patient had five comorbid medical diagnoses: complex partial seizures, PNES, hypertension, GERD and hydrocephalus. Significant literature, including animal and pre/post-epilepsy neurosurgery studies, supports increased prevalence of multiple sexual dysfunctions (especially decreased libido, as well as erectile dysfunction and orgasm disturbances) in PWE ranging from 40 to 70% with an emphasis on limbic discharges (complex partial seizures), hormonal status and seizure frequency though these factors are confounded by AED treatment and comorbid mood disorders.18,19,37,38 In addition to decreased sexual functioning in PWE, sexual auras and ictal hypersexuality have been reported.39,40 Though prevalence rates for physical and sexual abuse associated with PNES is well-researched,41,42 there are no prevalence rates reported for sexual dysfunction in patients with PNES. Hypertension has negative effects on vascular function and structure resulting in significant sexual dysfunction (erectile dysfunction and impotence in men) with: (1) approximately two-fold increased prevalence when comparing hypertensive patients with normotensive individuals26,43 and (2) large epidemiologic studies revealing increased relative risk range for developing erectile dysfunction in hypertension of 1.3–6.9.43 Sexual dysfunction has been reported with GERD; specifically, untreated patients with GERD have an increased difficulty in obtaining orgasm when compared with healthy individuals.44 Chronic hydrocephalus may be associated with sexual dysfunction (decreased libido, erectile dysfunction and decreased ejaculation), which in one study markedly improved following shunt placement.45\n\nThird, the patient was treated with three psychotropics (escitalopram, mirtazapine and alprazolam), which all have reported treatment-emergent sexual dysfunction. SSRIs, including escitalopram, negatively impact all spheres of sexual functioning in men (libido, erection, ejaculation and orgasm); SSRIs as a class of antidepressants have a significantly increased prevalence of total sexual dysfunction ranging from 25 to 80% of treated patients (escitalopram 37%).16,46 In a prospective study comparing sexual dysfunction among 10 antidepressants, mirtazapine had a prevalence rate of 24.5% involving all spheres; however, the prevalence rate and severity of symptoms were less when compared to SSRIs.47 Though there are limited studies addressing benzodiazepines and alprazolam in particular, one retrospective audit of male veteran PTSD patients treated with benzodiazepines noted significant sexual dysfunction (erectile dysfunction) only with clonazepam, whereas one report of two patients receiving alprazolam in a double-blind protocol noted dose-dependent decreased libido, erectile dysfunction, anejaculation and anorgasmia.48,49\n\nFourth, the patient was also treated with three additional medical condition pharmacotherapies (lamotrigine, enalapril and lansoprazole) which all may be associated with changes in sexual functioning. Lamotrigine, a sodium channel inhibitor with antiglutamatergic properties, is an AED with FDA approval for monotherapy treatment of partial seizures and is used to treat multiple psychiatric disorders including mood disorders.50 Hepatic cytochrome P450 enzyme inducing AEDs, and even some non-enzyme inducing AEDs, have well-reported multiple sexual dysfunction presentations (decreased libido, erectile dysfunction, impotence, delayed ejaculation, anejaculation and anorgasmia).19,22,23,51 Lamotrigine does not have enzyme inducing properties and monotherapy lamotrigine treatment was noted to have minimal sexual effects in men but improvement in all spheres in women.52,53 This finding was supported by a further study comparing Arizona Sexual Experience Scale (ASEX) scores among different AEDs and healthy controls noting improvement in ASEX scores in women but not men treated with lamotrigine.54 Further, one report of three male patients with epilepsy on AEDs with sexual dysfunction noted improvement in sexual functioning with the addition of lamotrigine;55 however all three case were confounded by the discontinuation of gabapentin which has been reported to cause total loss of libido, impotence, anorgasmia and anejaculation at 300 mg total daily dose.23 Patients receiving antihypertensive agents have an increased prevalence of sexual dysfunction compared with untreated patients with hypertension;43 however, this depends both on the class of antihypertensive agent utilised and the generation within that class.56–58 Enalapril is an ACE inhibitor antihypertensive agent; ACE inhibitors are noted to have minimally negative or neutral effect on sexual functioning.56,57,59 Lansoprazole is a PPI without published reports of sexual dysfunction; however, its potential for causing sexual dysfunction must be considered for it induces testosterone metabolism60 and omeprazole, another PPI, is associated with decreased libido, erectile dysfunction and impotence.61,62\n\nFifth, key to determining the aetiology of an AE is a time-line incorporating all diagnostic conditions and pharmacotherapies. In this case, all medical and psychiatric conditions had prolonged stability suggesting that these were not immediate factors in the patient’s decreased libido. With regard to pharmacotherapies, only lamotrigine was changed with an on/off/on/off protocol determined by the patient’s monthly non-adherence. When off lamotrigine for 48 h, he went from no libido to being libidinous. The degree to which the patient’s being off lamotrigine for an additional day improved his erectile dysfunction, he describes improved though still difficult sexual performance (decreased erectile dysfunction but persistent anejaculation/anorgasmia), is unclear. Since multiple medical conditions and pharmacotherapies could cause erectile dysfunction, anejaculation and anorgasmia individually or in combination as described above, the determination of probability by the Naranjo Scale will be limited to lamotrigine and lack of libido. By the Naranjo Scale (a 10-item weighted adverse drug effect scale which is used to determine the probability of such AE being definite, probable, possible or doubtful),31 the decreased libido adverse drug effect is scored as probable.\n\nThis report presents lamotrigine-induced decreased libido as a probable treatment-emergent adverse drug effect. The mechanism for such is unknown. Potentially, there may exist pharmacokinetic or pharmacodynamic interactions;63 however, such interactions impacting sexual functioning and lamotrigine have not been reported. Nonetheless, to better address potential mechanisms, time-sensitive TDM of all pharmacotherapies with sexual hormones would be of benefit.\n\nThis case has multiple limitations. (1) As a case report (N=1), the findings cannot be generalised. (2) No sexual psychometric scale was used to judge degree of sexual dysfunction on lamotrigine and during the periods of lamotrigine non-adherence. (3) No hormone levels were obtained to verify whether concomitant monthly hormonal variations occurred with lamotrigine non-adherence and increased libido. (4) No electroencephalograms (EEGs) were performed during the periods of lamotrigine non-adherence though the patient denied any sexual content to his auras. (5) Lamotrigine concentration-dependent decreased libido could not be determined in the absence of routine lamotrigine TDM. The patient acknowledged that he was non-adherent with ordered lamotrigine TDM, to a large extent because the insurance mandated laboratory was inconvenient. (6) TDM monitoring and daily pill counts were not obtained to ensure that the patient was adherent with all other medications negatively impacting sexual functioning as such additional non-adherence would have confounded the purported impact of lamotrigine non-adherence. Though possible, this was unlikely for 48–72 h psychotropic non-adherence (escitalopram and/or mirtazapine) would have resulted in discontinuation syndrome symptoms (rebound depression, anxiety, confusion, etc.), which the patient denied. This patient had been advised regarding the significance of non-adherence – for his AED, potential recurrent seizures; and for his psychotropics, potential discontinuation syndrome requiring psychiatric hospitalisation. When queried regarding this point, the patient emphasised his desire to avoid any psychiatric decompensation, but did acknowledge his willingness to even develop auras with lamotrigine non-adherence to permit increased sexual functioning. (7) Though an on/off/on/off case design based on patient’s recurrent non-adherence, for ethical reasons the patient could not be requested to redo such non-adherence with additional testing.\n\nSexual dysfunction is a key AE leading to AED non-adherence which is often not volunteered by the patient. This case describes dose-dependent lamotrigine-induced sexual dysfunction with episodic non-adherence for 12 months. Patient/clinician education regarding AED-induced sexual dysfunction is warranted, as are routine sexual histories to ensure adherence, and optimal treatment.\n==== Refs\nReferences\n1 Boon \nP , Engelborghs \nS , Hauman \nH , Jansen \nA , Lagae \nL , Legros \nB , et al\nRecommendations for the treatment of epilepsy in adult patients in general practice in Belgium: an update . Acta Neurol Belg \n2012 ; 112 : 119 –31 .22544726 \n2 Ketter \nTA , Miller \nS , Dell’Osso \nB , Calabrese \nJR , Frye \nMA , Citrome \nL . Balancing benefits and harms of treatments for acute bipolar depression . J Affect Disord \n2014 ; 169 (suppl 1 ): S24 –33 .25533911 \n3 Buelow \nJM , Smith \nMC . Medication management by the person with epilepsy: perception versus reality . Epilepsy Behav \n2004 ; 5 : 401 –6 .15145311 \n4 Chapman \nSC , Horne \nR , Chater \nA , Hukins \nD , Smithson \nWH . 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Dtsch Arztebl Int \n2012 ; 109 : 546 –56 .23152742\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2056-4724", "issue": "3(5)", "journal": "BJPsych open", "keywords": null, "medline_ta": "BJPsych Open", "mesh_terms": null, "nlm_unique_id": "101667931", "other_id": null, "pages": "249-253", "pmc": null, "pmid": "29034101", "pubdate": "2017-09", "publication_types": "D016428:Journal Article", "references": "21478749;16434217;3348461;15145311;14550749;11229449;24781439;24222012;17353980;15184917;18162417;21471773;28053370;16596030;21178782;15582828;23152742;10728528;27371882;26469800;15324820;11399748;19716343;17324145;23489403;25658103;17535948;19823916;1392958;12404311;9160580;26940022;12003702;17962080;17570434;16953246;22544726;16946181;9039073;26953830;21482195;21498130;26529050;12764707;25596624;25818906;1447396;27989023;19440080;19028602;18058849;21612983;24290250;25405774;16217052;22560189;23737245;25533911;22175760;20089460;21907627", "title": "Lamotrigine-induced sexual dysfunction and non-adherence: case analysis with literature review.", "title_normalized": "lamotrigine induced sexual dysfunction and non adherence case analysis with literature review" }

[ { "companynumb": "US-CIPLA LTD.-2017US11044", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LAMOTRIGINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "077783", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": "300", "drugcumulativedosageunit": "003", "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PSYCHOGENIC SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMOTRIGINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ENALAPRIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG, QAM (EVERY MORNING)", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ENALAPRIL" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LAMOTRIGINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "077783", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": "300", "drugcumulativedosageunit": "003", "drugdosageform": null, "drugdosagetext": "100 MG, TID", "drugenddate": null, "drugenddateformat": null, "drugindication": "FOCAL DYSCOGNITIVE SEIZURES", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMOTRIGINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LANSOPRAZOLE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MG, QAM (EVERY MORNING)", "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROOESOPHAGEAL REFLUX DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LANSOPRAZOLE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Aura", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Treatment noncompliance", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sexual dysfunction", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KAUFMAN KR, COLUCCIO M, SIVARAAMAN K, CAMPEAS M. LAMOTRIGINE-INDUCED SEXUAL DYSFUNCTION AND NON-ADHERENCE: CASE ANALYSIS WITH LITERATURE REVIEW. 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LAMOTRIGINE-INDUCED SEXUAL DYSFUNCTION AND NON-ADHERENCE: CASE ANALYSIS WITH LITERATURE REVIEW. DOI: 10.1192/BJPO.BP.117.005538. BJPSYCH OPEN. 2017?3:249-253", "literaturereference_normalized": "lamotrigine induced sexual dysfunction and non adherence case analysis with literature review", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190306", "receivedate": "20190306", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16038965, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190418" }, { "companynumb": "US-009507513-1810USA011791", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "MIRTAZAPINE" }, "drugadditional": null, 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"reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anorgasmia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Erectile dysfunction", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Loss of libido", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ejaculation failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KAUFMAN KR, COLUCCIO M, SIVARAAMAN K, CAMPEAS M. LAMOTRIGINE-INDUCED SEXUAL DYSFUNCTION AND NON-ADHERENCE: CASE ANALYSIS WITH LITERATURE REVIEW. 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"drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "22.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MIRTAZAPINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LAMOTRIGINE" }, "drugadditional": "2", "drugadministrationroute": "065", "drugauthorizationnumb": "76420", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "TID", "drugenddate": null, "drugenddateformat": null, "drugindication": "FOCAL DYSCOGNITIVE SEIZURES", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "1", "drugrecurrence": [ { "drugrecuraction": "Loss of libido" } ], "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMOTRIGINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ESCITALOPRAM OXALATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "076765", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PANIC DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESCITALOPRAM" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALPRAZOLAM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "074342", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "TID WHEN NECESSARY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALPRAZOLAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALPRAZOLAM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "074342", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PANIC DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALPRAZOLAM." } ], "patientagegroup": null, "patientonsetage": "6", "patientonsetageunit": "800", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Anorgasmia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Loss of libido", "reactionmeddraversionpt": "21.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Ejaculation failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Erectile dysfunction", "reactionmeddraversionpt": "21.1", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "KAUFMAN KR, COLUCCIO M, SIVARAAMAN K, CAMPEAS M. LAMOTRIGINE-INDUCED SEXUAL DYSFUNCTION AND NON-ADHERENCE: CASE ANALYSIS WITH LITERATURE REVIEW. BJPSYCH-OPEN 2017?3(5):249-253.", "literaturereference_normalized": "lamotrigine induced sexual dysfunction and non adherence case analysis with literature review", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20181108", "receivedate": "20181108", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15597623, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" } ]

{ "abstract": "This case report describes an intentional intoxication with 18 g of hydroxychloroquine (HCQ) presenting with unconsciousness, ventricular dysrhythmias, cardiogenic shock and pulmonary oedema. Initial treatment consisted of sodium bicarbonate, lipid emulsion, diazepam and norepinephrine. Because of persistent cardiogenic shock veno-arterial extracorporeal membrane oxygenation (V-A ECMO) was successfully used as a bridge to recovery. This case underscores the possible side effects of HCQ and the importance of considering ECMO in cardiogenic shock caused by HCQ intoxication which may occur also in patients with coronavirus disease 2019 (COVID-19) based on the currently frequent use of such a compound.", "affiliations": "Department of Cardiology, Ziekenhuis Oost-Limburg, Genk, Belgium.;Department of Clinical Pharmacy, Maastricht University Medical Center, Maastricht, The Netherlands.;Department of Clinical Pharmacy, Maastricht University Medical Center, Maastricht, The Netherlands.;Department of Cardio-thoracic Surgery, Maastricht University Medical Center, Maastricht, The Netherlands.;Department of Intensive Care, Maastricht University Medical Center, Maastricht, The Netherlands.;Department of Intensive Care and Cardiology, Maastricht University Medical Center, Maastricht, The Netherlands.", "authors": "Holvoet|Wouter|W|https://orcid.org/0000-0002-7951-5239;van Soest|Kaja|K|;Havenith|Thomas|T|;Lorusso|Roberto|R|;van Mook|Walther N K A|WNKA|;Delnoij|Thijs|T|", "chemical_list": "D018501:Antirheumatic Agents; D006886:Hydroxychloroquine", "country": "England", "delete": false, "doi": "10.1080/00015385.2020.1802903", "fulltext": null, "fulltext_license": null, "issn_linking": "0001-5385", "issue": "76(2)", "journal": "Acta cardiologica", "keywords": "COVID-19; Hydroxychloroquine; cardiogenic shock; extracorporeal membrane oxygenation; intoxication", "medline_ta": "Acta Cardiol", "mesh_terms": "D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D000086382:COVID-19; D017028:Caregivers; D015897:Comorbidity; D015199:Extracorporeal Membrane Oxygenation; D005260:Female; D006801:Humans; D006886:Hydroxychloroquine; D008875:Middle Aged", "nlm_unique_id": "0370570", "other_id": null, "pages": "200-203", "pmc": null, "pmid": "33308005", "pubdate": "2021-04", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Bail-out extracorporeal membrane oxygenation for hydroxychloroquine intoxication: a warning for COVID-19 health-care givers.", "title_normalized": "bail out extracorporeal membrane oxygenation for hydroxychloroquine intoxication a warning for covid 19 health care givers" }

[ { "companynumb": "BE-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-304624", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "201691", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "18 GRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "18", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROXYCHLOROQUINE" } ], "patientagegroup": null, "patientonsetage": "54", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Coma scale abnormal", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Electrocardiogram ST segment depression", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Atrial fibrillation", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Suicide attempt", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Coma", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Electrocardiogram QT prolonged", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "HOLVOET W, VAN SOEST K, HAVENITH T, LORUSSO R, VAN MOOK WNKA DELNOIJ T.. BAIL?OUT EXTRACORPOREAL MEMBRANE OXYGENATION FOR HYDROXYCHLOROQUINE INTOXICATION: A WARNING FOR COVID?19 HEALTH?CARE GIVERS. ACTA CARDIOL. 2021?76(2):200?03", "literaturereference_normalized": "bail out extracorporeal membrane oxygenation for hydroxychloroquine intoxication a warning for covid 19 health care givers", "qualification": "3", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20210720", "receivedate": "20210720", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19582148, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20211014" } ]

{ "abstract": "Pneumonia caused by methicillin-resistant Staphylococcus aureus (MRSA) is associated with poor clinical outcomes. We surveyed clinical outcomes of MRSA pneumonia in daily practice to identify risk factors for the clinical failure and mortality in patients with MRSA pneumonia. This multicenter prospective observational study was performed across 48 Japanese medical institutions. Adult patients with culture-positive MRSA pneumonia were recruited and treated with anti-MRSA antibiotics. The relationships between clinical and microbiological characteristics and clinical outcomes at test of cure (TOC) or 30-day all-cause mortality were analyzed. In total, 199 eligible patients, including nursing and healthcare-associated pneumonia (n = 95), hospital-acquired pneumonia (n = 76), and community-acquired pneumonia (n = 25), received initial treatment with anti-MRSA agents such as vancomycin (n = 135), linezolid (n = 36), or teicoplanin (n = 22). Overall clinical failure rate at TOC and the 30-day mortality rate were 51.1% (48/94 patients) and 33.7% (66/196 patients), respectively. Multivariable logistic regression analyses for vancomycin-treated populations revealed that abnormal white blood cell count (odds ratio [OR] 4.34, 95% confidence interval [CI] 1.31-14.39) was a risk factor for clinical failure and that no therapeutic drug monitoring (OR 3.10, 95% CI 1.35-7.12) and abnormally high C-reactive protein level (OR 3.54, 95% CI 1.26-9.92) were risk factors for mortality. In conclusion, this study provides evidence that majority of MRSA pneumonia patients are initially treated with vancomycin in Japan, and the absence of therapeutic drug monitoring for vancomycin is significantly associated with the mortality in patients with MRSA pneumonia.", "affiliations": "Department of Respiratory Medicine, Nagasaki University Hospital, Nagasaki, Japan; Department of Infectious Diseases, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. Electronic address: [email protected].;Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.;Department of Infection Control Science, Graduate School of Medicine, Osaka City University, Osaka, Japan.;Department of Infectious Diseases, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.;Department of Respiratory Medicine, Nagasaki University Hospital, Nagasaki, Japan.;Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Aichi, Japan.;Department of Clinical Infectious Diseases, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Toyama, Japan.;Department of Microbiology and Infectious Diseases, Toho University School of Medicine, Tokyo, Japan.;Division of Infection Control and Prevention, Osaka University Hospital, Osaka, Japan.;Department of Respiratory Medicine, Kurashiki Central Hospital, Okayama, Japan.;Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Aichi, Japan.;Division of Clinical Infectious Diseases, Department of Medicine, School of Medicine, Showa University, Tokyo, Japan.;Research Division for Development of Anti-Infective Agents, Institute of Development, Aging and Cancer, Tohoku University, Miyagi, Japan.;Emergency Medical Center, Kitasato University Hospital, Kanagawa, Japan.;Department of Respiratory Medicine, Nagasaki University Hospital, Nagasaki, Japan.", "authors": "Miyazaki|Taiga|T|;Yanagihara|Katsunori|K|;Kakeya|Hiroshi|H|;Izumikawa|Koichi|K|;Mukae|Hiroshi|H|;Shindo|Yuichiro|Y|;Yamamoto|Yoshihiro|Y|;Tateda|Kazuhiro|K|;Tomono|Kazunori|K|;Ishida|Tadashi|T|;Hasegawa|Yoshinori|Y|;Niki|Yoshihito|Y|;Watanabe|Akira|A|;Soma|Kazui|K|;Kohno|Shigeru|S|", "chemical_list": "D000900:Anti-Bacterial Agents; D017334:Teicoplanin; D014640:Vancomycin; D000069349:Linezolid", "country": "Netherlands", "delete": false, "doi": "10.1016/j.jiac.2019.08.018", "fulltext": null, "fulltext_license": null, "issn_linking": "1341-321X", "issue": "26(2)", "journal": "Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy", "keywords": "Linezolid; MRSA; Prospective study; Therapeutic drug monitoring; Vancomycin", "medline_ta": "J Infect Chemother", "mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D015331:Cohort Studies; D003428:Cross Infection; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D007564:Japan; D000069349:Linezolid; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus; D008875:Middle Aged; D011023:Pneumonia, Staphylococcal; D011379:Prognosis; D011446:Prospective Studies; D012307:Risk Factors; D017334:Teicoplanin; D016896:Treatment Outcome; D014640:Vancomycin", "nlm_unique_id": "9608375", "other_id": null, "pages": "242-251", "pmc": null, "pmid": "31575499", "pubdate": "2020-02", "publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study", "references": null, "title": "Daily practice and prognostic factors for pneumonia caused by methicillin-resistant Staphylococcus aureus in Japan: A multicenter prospective observational cohort study.", "title_normalized": "daily practice and prognostic factors for pneumonia caused by methicillin resistant staphylococcus aureus in japan a multicenter prospective observational cohort study" }

[ { "companynumb": "JP-TEVA-2020-JP-1203640", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "PIPERACILLIN SODIUM\\TAZOBACTAM SODIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMONIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PIPERACILLIN/TAZOBACTAM" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VANCOMYCIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "065510", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMONIA STAPHYLOCOCCAL", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VANCOMYCIN" } ], "patientagegroup": "6", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "MIYAZAKI T, YANAGIHARA K, KAKEYA H, IZUMIKAWA K, MUKAE H, SHINDO Y, ET AL. DAILY PRACTICE AND PROGNOSTIC FACTORS FOR PNEUMONIA CAUSED BY METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS IN JAPAN: A MULTICENTER PROSPECTIVE OBSERVATIONAL COHORT STUDY. J-INFECT-CHEMOTHER 2020?26(2):242-251.", "literaturereference_normalized": "daily practice and prognostic factors for pneumonia caused by methicillin resistant staphylococcus aureus in japan a multicenter prospective observational cohort study", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20200317", "receivedate": "20200317", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17548714, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200409" }, { "companynumb": "JP-TEVA-2020-JP-1203635", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CLARITHROMYCIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "065145", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMONIA PSEUDOMONAL", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLARITHROMYCIN." } ], "patientagegroup": "6", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "MIYAZAKI T, YANAGIHARA K, KAKEYA H, IZUMIKAWA K, MUKAE H, SHINDO Y, ET AL. DAILY PRACTICE AND PROGNOSTIC FACTORS FOR PNEUMONIA CAUSED BY METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS IN JAPAN: A MULTICENTER PROSPECTIVE OBSERVATIONAL COHORT STUDY. J-INFECT-CHEMOTHER 2020?26(2):242-251.", "literaturereference_normalized": "daily practice and prognostic factors for pneumonia caused by methicillin resistant staphylococcus aureus in japan a multicenter prospective observational cohort study", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20200317", "receivedate": "20200317", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17551394, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200409" }, { "companynumb": "JP-MYLANLABS-2020M1026835", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "VANCOMYCIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "065397", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMONIA STAPHYLOCOCCAL", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VANCOMYCIN" } ], "patientagegroup": "6", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MIYAZAKI T, YANAGIHARA K, KAKEYA H, IZUMIKAWA K, MUKAE H, SHINDO Y, ET AL. DAILY PRACTICE AND PROGNOSTIC FACTORS FOR PNEUMONIA CAUSED BY METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS IN JAPAN: A MULTICENTER PROSPECTIVE OBSERVATIONAL COHORT STUDY. J-INFECT-CHEMOTHER 2020?26(2):242-251.. 2020?26(2):242-251", "literaturereference_normalized": "daily practice and prognostic factors for pneumonia caused by methicillin resistant staphylococcus aureus in japan a multicenter prospective observational cohort study", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20200312", "receivedate": "20200312", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17532964, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200409" }, { "companynumb": "JP-MYLANLABS-2020M1026830", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "VANCOMYCIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "065397", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMONIA STAPHYLOCOCCAL", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VANCOMYCIN" } ], "patientagegroup": "6", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pulmonary haemorrhage", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MIYAZAKI T, YANAGIHARA K, KAKEYA H, IZUMIKAWA K, MUKAE H, SHINDO Y, ET AL. DAILY PRACTICE AND PROGNOSTIC FACTORS FOR PNEUMONIA CAUSED BY METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS IN JAPAN: A MULTICENTER PROSPECTIVE OBSERVATIONAL COHORT STUDY. 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DAILY PRACTICE AND PROGNOSTIC FACTORS FOR PNEUMONIA CAUSED BY METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS IN JAPAN: A MULTICENTER PROSPECTIVE OBSERVATIONAL COHORT STUDY. 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DAILY PRACTICE AND PROGNOSTIC FACTORS FOR PNEUMONIA CAUSED BY METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS IN JAPAN: A MULTICENTER PROSPECTIVE OBSERVATIONAL COHORT STUDY. 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DAILY PRACTICE AND PROGNOSTIC FACTORS FOR PNEUMONIA CAUSED BY METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS IN JAPAN: A MULTICENTER PROSPECTIVE OBSERVATIONAL COHORT STUDY. 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DAILY PRACTICE AND PROGNOSTIC FACTORS FOR PNEUMONIA CAUSED BY METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS IN JAPAN: A MULTICENTER PROSPECTIVE OBSERVATIONAL COHORT STUDY. 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DAILY PRACTICE AND PROGNOSTIC FACTORS FOR PNEUMONIA CAUSED BY METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS IN JAPAN: A MULTICENTER PROSPECTIVE OBSERVATIONAL COHORT STUDY.. 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DAILY PRACTICE AND PROGNOSTIC FACTORS FOR PNEUMONIA CAUSED BY METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS IN JAPAN: A MULTICENTER PROSPECTIVE OBSERVATIONAL COHORT STUDY. 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DAILY PRACTICE AND PROGNOSTIC FACTORS FOR PNEUMONIA CAUSED BY METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS IN JAPAN: A MULTICENTER PROSPECTIVE OBSERVATIONAL COHORT STUDY. 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{ "abstract": "The increasing incidence of diffuse large B-cell lymphoma (DLBCL) in ageing populations places a significant burden on healthcare systems. Co-morbidity, frailty, and reduced organ and physiological reserve contribute to treatment-related complications. The optimal dose intensity of R-CHOP to optimize outcome across different ages with variable frailty and comorbidity burden is unclear.\n\n\n\nWe examined the influence of intended (IDI) and relative (RDI) dose intensity of the combination of cyclophosphamide and doxorubicin, age and comorbidity on outcomes for DLBCL patients ≥70 years in a representative, consecutive cohort across eight UK centres (2009-2018). We determined predictors of survival using multivariable Cox regression, and predictors of recurrence before death using competing risks regression.\n\n\n\nPorgression-free survival (PFS) and overall survival (OS) were significantly inferior in patients ≥80 vs. 70-79 years (P < 0.001). In contrast, 2-year cumulative relapse incidence, when accounting for non-relapse mortality as a competing risk, was no different between 70-79 vs. ≥80 years (P = 0.27) or comorbidity status (CIRS-G: 0-6 vs. >6) (P = 0.27). In 70-79 years, patients with an IDI ≥80% had a significantly improved PFS and OS (P < 0.001) compared to IDI < 80%. Conversely, in patients ≥80 years, there was no difference in PFS (P = 0.88) or OS (P = 0.75) according to IDI <80% vs. ≥80%. On multivariable analysis, when comparing by age, there was a significantly higher cumulative relapse rate for patients aged 70-79 years with an IDI <80% (vs. >80%) (P = 0.04) but not for patients ≥80 years comparing IDI (P = 0.32).\n\n\n\n'R-mini-CHOP' provides adequate lymphoma-specific disease control and represents a reasonable treatment option in elderly patients ≥80 years aiming for cure.", "affiliations": "Department of Haematology, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.;Department of Clinical Haematology, Nottingham University Hospitals NHS Trust, Nottingham, UK.;Department of Haematology, Milton Keynes Hospital, Milton Keynes, UK.;Nuffield Department of Medicine, University of Oxford, Oxford, UK.;Oxford University Medical School, Oxford, UK.;Department of Haematology, Great Western Hospital, Swindon, UK.;Department of Haematology, Great Western Hospital, Swindon, UK.;Department of Haematology, Guys and St Thomas' Hospitals NHS Foundation Trust, London, UK.;Department of Haematology, Guys and St Thomas' Hospitals NHS Foundation Trust, London, UK.;Department of Haematology, University Hospitals Bristol NHS Foundation Trust, Bristol, UK.;Department of Cancer Pharmacy, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.;Department of Haematology, Royal Berkshire Hospital NHS Foundation Trust, Reading, UK.;Department of Clinical Haematology, Nottingham University Hospitals NHS Trust, Nottingham, UK.;Department of Clinical Haematology, Nottingham University Hospitals NHS Trust, Nottingham, UK.;Department of Clinical Haematology, Nottingham University Hospitals NHS Trust, Nottingham, UK.;Department of Haematology, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.;Department of Haematology, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.", "authors": "Eyre|T A|TA|0000-0002-6631-9749;Martinez-Calle|N|N|;Hildyard|C|C|;Eyre|D W|DW|;Plaschkes|H|H|;Griffith|J|J|;Wolf|J|J|;Fields|P|P|;Gunawan|A|A|;Oliver|R|R|;Djebbari|F|F|0000-0001-9578-7632;Booth|S|S|;McMillan|A|A|;Fox|C P|CP|;Bishton|M J|MJ|;Collins|G P|GP|;Hatton|C S R|CSR|", "chemical_list": "C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone", "country": "England", "delete": false, "doi": "10.1111/joim.12889", "fulltext": null, "fulltext_license": null, "issn_linking": "0954-6820", "issue": "285(6)", "journal": "Journal of internal medicine", "keywords": "R-CHOP; diffuse large B-cell lymphoma; dose intensity; elderly", "medline_ta": "J Intern Med", "mesh_terms": "D017677:Age Distribution; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D015331:Cohort Studies; D015897:Comorbidity; D003520:Cyclophosphamide; D004317:Doxorubicin; D005260:Female; D006801:Humans; D015994:Incidence; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D011241:Prednisone; D012008:Recurrence; D012189:Retrospective Studies; D000069283:Rituximab; D016896:Treatment Outcome; D014750:Vincristine", "nlm_unique_id": "8904841", "other_id": null, "pages": "681-692", "pmc": null, "pmid": "30811713", "pubdate": "2019-06", "publication_types": "D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Impact of intended and relative dose intensity of R-CHOP in a large, consecutive cohort of elderly diffuse large B-cell lymphoma patients treated with curative intent: no difference in cumulative incidence of relapse comparing patients by age.", "title_normalized": "impact of intended and relative dose intensity of r chop in a large consecutive cohort of elderly diffuse large b cell lymphoma patients treated with curative intent no difference in cumulative incidence of relapse comparing patients by age" }

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IMPACT OF INTENDED AND RELATIVE DOSE INTENSITY OF R-CHOP IN A LARGE, CONSECUTIVE COHORT OF ELDERLY DIFFUSE LARGE B-CELL LYMPHOMA PATIENTS TREATED WITH CURATIVE INTENT: NO DIFFERENCE IN CUMULATIVE INCIDENCE OF RELAPSE COMPARING PATIENTS BY AGE. 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IMPACT OF INTENDED AND RELATIVE DOSE INTENSITY OF R-CHOP IN A LARGE, CONSECUTIVE COHORT OF ELDERLY DIFFUSE LARGE B-CELL LYMPHOMA PATIENTS TREATED WITH CURATIVE INTENT: NO DIFFERENCE IN CUMULATIVE INCIDENCE OF RELAPSE COMPARING PATIENTS BY AGE. 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IMPACT OF INTENDED AND RELATIVE DOSE INTENSITY OF R-CHOP IN A LARGE, CONSECUTIVE COHORT OF ELDERLY DIFFUSE LARGE B-CELL LYMPHOMA PATIENTS TREATED WITH CURATIVE INTENT: NO DIFFERENCE IN CUMULATIVE INCIDENCE OF RELAPSE COMPARING PATIENTS BY AGE. 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"drugindication": "DIFFUSE LARGE B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "375", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "017469", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MG/M2, UNK (DAY 1-5)", "drugenddate": null, "drugenddateformat": null, "drugindication": "DIFFUSE LARGE B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOXORUBICIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG/M2, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "DIFFUSE LARGE B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Second primary malignancy", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Prostate cancer", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "EYRE TA, MARTINEZ-CALLE N, HILDYARD C, EYRE DW, PLASCHKES H, GRIFFITH J ET AL. IMPACT OF INTENDED AND RELATIVE DOSE INTENSITY OF R-CHOP IN A LARGE, CONSECUTIVE COHORT OF ELDERLY DIFFUSE LARGE B-CELL LYMPHOMA PATIENTS TREATED WITH CURATIVE INTENT: NO DIFFERENCE IN CUMULATIVE INCIDENCE OF RELAPSE COMPARING PATIENTS BY AGE. JOURNAL OF INTERNAL MEDICINE. 2019?1-12", "literaturereference_normalized": "impact of intended and relative dose intensity of r chop in a large consecutive cohort of elderly diffuse large b cell lymphoma patients treated with curative intent no difference in cumulative incidence of relapse comparing patients by age", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20190413", "receivedate": "20190413", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16193971, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190711" }, { "companynumb": "PHHY2019GB085440", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOXORUBICIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG/M2, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "DIFFUSE LARGE B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MG, UNK (TYPICALLY ON DAY1)", "drugenddate": null, "drugenddateformat": null, "drugindication": "DIFFUSE LARGE B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "375 MG/M2, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "DIFFUSE LARGE B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "375", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "017469", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MG/M2, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "DIFFUSE LARGE B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "GRANULOCYTE COLONY-STIMULATING FACTOR NOS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "G-CSF" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "750 MG/M2, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "DIFFUSE LARGE B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "750", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." } ], "patientagegroup": "6", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Second primary malignancy", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neuroendocrine tumour", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "EYRE TA, MARTINEZ-CALLE N, HILDYARD C, EYRE DW, PLASCHKES H, GRIFFITH J ET AL. IMPACT OF INTENDED AND RELATIVE DOSE INTENSITY OF R-CHOP IN A LARGE, CONSECUTIVE COHORT OF ELDERLY DIFFUSE LARGE B-CELL LYMPHOMA PATIENTS TREATED WITH CURATIVE INTENT: NO DIFFERENCE IN CUMULATIVE INCIDENCE OF RELAPSE COMPARING PATIENTS BY AGE. JOURNAL OF INTERNAL MEDICINE. 2019?1-12", "literaturereference_normalized": "impact of intended and relative dose intensity of r chop in a large consecutive cohort of elderly diffuse large b cell lymphoma patients treated with curative intent no difference in cumulative incidence of relapse comparing patients by age", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20190413", "receivedate": "20190413", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16193973, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190711" } ]

{ "abstract": "Five patients developed symmetrical paraparesis due to a combination of: compartment syndrome, rhabdomyolysis, renal failure, and demyelinative sensory-motor polyneuropathy, after prolonged sleep in a sitting position. The long deep sleep was induced by consumption of alcohol or drugs. Long-term follow-up showed that these patients remained paraparetic. No damage to the autonomic nervous system was found. Although some suspected that these patients developed \"intensive care neuropathy\", we suggest that this syndrome is different, and should be regarded as a \"new syndrome\".", "affiliations": "Department of Rehabilitation Medicine, Reuth Medical Center, Tel Aviv.;Department of Rehabilitation Medicine, Reuth Medical Center, Tel Aviv.;Department of Rehabilitation Medicine, Reuth Medical Center, Tel Aviv.;Department of Rehabilitation Medicine, Reuth Medical Center, Tel Aviv.;Department of Rehabilitation Medicine, Reuth Medical Center, Tel Aviv.", "authors": "Ohry|Avi|A|;Shemesh|Frida|F|;Haddad|Najib|N|;Lifshitz|Anatoly|A|;Goldin|Diana|D|", "chemical_list": null, "country": "Israel", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0017-7768", "issue": "157(9)", "journal": "Harefuah", "keywords": null, "medline_ta": "Harefuah", "mesh_terms": "D003161:Compartment Syndromes; D006801:Humans; D020335:Paraparesis; D012206:Rhabdomyolysis; D000077708:Sitting Position", "nlm_unique_id": "0034351", "other_id": null, "pages": "582-584", "pmc": null, "pmid": "30221858", "pubdate": "2018-09", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "PARAPARESIS DUE TO RHABDOMYOLYSIS AND A COMPARTMENT SYNDROME IN FIVE PATIENTS WHO HAD BEEN IN A PROLONGED SLEEP IN A SITTING POSITION.", "title_normalized": "paraparesis due to rhabdomyolysis and a compartment syndrome in five patients who had been in a prolonged sleep in a sitting position" }

[ { "companynumb": "IL-TEVA-2019-IL-1070642", "fulfillexpeditecriteria": "1", "occurcountry": "IL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "74569", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "TOOK TWO TABLETS", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "032", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." } ], "patientagegroup": null, "patientonsetage": "22", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Compartment syndrome", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Confusional state", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Paraparesis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Demyelinating polyneuropathy", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Anuria", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Blood lactate dehydrogenase increased", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Depression", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Rhabdomyolysis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Aspartate aminotransferase increased", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Platelet count increased", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hypersomnia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "OHRY A, SHEMESH F, HADDAD N, LIFSHITZ A, GOLDIN D. PARAPARESIS DUE TO RHABDOMYOLYSIS AND A COMPARTMENT SYNDROME IN FIVE PATIENTS WHO HAD BEEN IN A PROLONGED SLEEP IN A SITTING POSITION. HAREFUAH 2018?157(9):582-584.", "literaturereference_normalized": "paraparesis due to rhabdomyolysis and a compartment syndrome in five patients who had been in a prolonged sleep in a sitting position", "qualification": "3", "reportercountry": "IL" }, "primarysourcecountry": "IL", "receiptdate": "20190704", "receivedate": "20190704", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16530046, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": 1, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20191004" } ]

{ "abstract": "BACKGROUND\nPsoriasis is an emerging paradoxical side effect in patients with inflammatory bowel disease (IBD) when treated with anti-TNF alpha. Patients with severe skin lesions unresponsive to topical therapy need to withdraw from treatment.\n\n\nOBJECTIVE\nTo estimate the incidence of paradoxical psoriasis in a large cohort of IBD patients treated with anti-TNF alpha and to analyse its clinical correlates.\n\n\nMETHODS\nA retrospective cohort study on all IBD patients who started anti-TNF alpha at our IBD Centre from January 2008 to December 2013 was performed. Proportional hazards regression models were used to estimate the association between each predictor and time to the development of psoriasis. Time-dependent predictors were updated at each available time point.\n\n\nRESULTS\nFour hundred and two patients were included. Participants contributed a total of 839 person-years of follow-up, during which 42 incident cases of psoriasis were recorded, with an incidence rate of five per 100 person-years. Cox-regression survival analysis revealed smoking as independent predictor of psoriasis (HR: 2.37, 95% CI: 1.36-4.48; P = 0.008). Conversely, concomitant immunosuppressive therapy was inversely related to psoriasis (HR: 0.33, 95% CI: 0.12-0.92; P = 0.03).\n\n\nCONCLUSIONS\nParadoxical psoriasis is a relevant side effect of anti-TNF alpha therapy, with an incidence rate of five per 100 person-years. Smoking is confirmed as the main risk factor for developing lesions. The combination therapy with anti-TNF alpha plus immunosuppressants is associated with a reduced risk of paradoxical psoriasis.", "affiliations": "IBD Unit, Internal Medicine and Gastroenterology, Complesso Integrato Columbus, Catholic University, Rome, Italy.;IBD Unit, Internal Medicine and Gastroenterology, Complesso Integrato Columbus, Catholic University, Rome, Italy.;Nephrology, Complesso Integrato Columbus, Catholic University, Rome, Italy.;IBD Unit, Internal Medicine and Gastroenterology, Complesso Integrato Columbus, Catholic University, Rome, Italy.;IBD Unit, Internal Medicine and Gastroenterology, Complesso Integrato Columbus, Catholic University, Rome, Italy.;Dermatology, Complesso Integrato Columbus, Catholic University, Rome, Italy.;IBD Unit, Internal Medicine and Gastroenterology, Complesso Integrato Columbus, Catholic University, Rome, Italy.;IBD Unit, Internal Medicine and Gastroenterology, Complesso Integrato Columbus, Catholic University, Rome, Italy.;IBD Unit, Internal Medicine and Gastroenterology, Complesso Integrato Columbus, Catholic University, Rome, Italy.;IBD Unit, Internal Medicine and Gastroenterology, Complesso Integrato Columbus, Catholic University, Rome, Italy.;IBD Unit, Internal Medicine and Gastroenterology, Complesso Integrato Columbus, Catholic University, Rome, Italy.;IBD Unit, Internal Medicine and Gastroenterology, Complesso Integrato Columbus, Catholic University, Rome, Italy.;IBD Unit, Internal Medicine and Gastroenterology, Complesso Integrato Columbus, Catholic University, Rome, Italy.", "authors": "Pugliese|D|D|;Guidi|L|L|;Ferraro|P M|PM|;Marzo|M|M|;Felice|C|C|;Celleno|L|L|;Landi|R|R|;Andrisani|G|G|;Pizzolante|F|F|;De Vitis|I|I|;Papa|A|A|;Rapaccini|G L|GL|;Armuzzi|A|A|", "chemical_list": "D007166:Immunosuppressive Agents; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000068879:Adalimumab", "country": "England", "delete": false, "doi": "10.1111/apt.13352", "fulltext": null, "fulltext_license": null, "issn_linking": "0269-2813", "issue": "42(7)", "journal": "Alimentary pharmacology & therapeutics", "keywords": null, "medline_ta": "Aliment Pharmacol Ther", "mesh_terms": "D000068879:Adalimumab; D000328:Adult; D000368:Aged; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007166:Immunosuppressive Agents; D015994:Incidence; D015212:Inflammatory Bowel Diseases; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D011565:Psoriasis; D012189:Retrospective Studies; D012307:Risk Factors; D014409:Tumor Necrosis Factor-alpha", "nlm_unique_id": "8707234", "other_id": null, "pages": "880-8", "pmc": null, "pmid": "26235565", "pubdate": "2015-10", "publication_types": "D016428:Journal Article", "references": null, "title": "Paradoxical psoriasis in a large cohort of patients with inflammatory bowel disease receiving treatment with anti-TNF alpha: 5-year follow-up study.", "title_normalized": "paradoxical psoriasis in a large cohort of patients with inflammatory bowel disease receiving treatment with anti tnf alpha 5 year follow up study" }

[ { "companynumb": "IT-JNJFOC-20150912554", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "INFLIXIMAB" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "103772", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "LYOPHILIZED POWDER", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "INFLAMMATORY BOWEL DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INFLIXIMAB, RECOMBINANT" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Alopecia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Psoriasis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Eczema", "reactionmeddraversionpt": "18.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "ARMUZZI A, GUIDI L, FERRARO PM, MARZO M, FELICE C, CELLENO L, ET AL. PARADOXICAL PSORIASIS IN A LARGE COHORT OF PATIENTS WITH INFLAMMATORY BOWEL DISEASE RECEIVING TREATMENT WITH ANTI-TNF ALPHA: 5-YEAR FOLLOW-UP STUDY. ALIMENTARY PHARMACOLOGY AND THERAPEUTICS 01-OCT-2015;42(7):880-888.", "literaturereference_normalized": "paradoxical psoriasis in a large cohort of patients with inflammatory bowel disease receiving treatment with anti tnf alpha 5 year follow up study", "qualification": "1", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20150924", "receivedate": "20150924", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11546126, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20151125" } ]

{ "abstract": "Multiple myeloma (MM) is characterized by the neoplastic proliferation of monoclonal plasma cells in the bone marrow and results in complications. In Taiwan, melphalan and several novel agents are used to treat myeloma patients who are not candidate for hematopoietic stem cell transplant (HSCT). This retrospective study aimed to evaluate the characteristics, treatment outcome, and prognostic factors of MM patients who were ineligible for HSCT at our institution from October 2000 until November 2012. A total of 101 MM patients were reviewed. The median age was 71.0 years, and median overall survival (OS) was 22.0 months. Most of patients were diagnosed as IgG-type myeloma (55.4 %). The initial presentations included anemia (89.1 %), skeletal events (49.5 %), severe renal insufficiency (30.7 %), and hypercalcemia (28.7 %). With regard to the frontline therapy, thalidomide/steroid was the most common. Infection was the leading cause of death and adverse effects. Treatment with bortezomib, almost in the second- or third-line setting, was associated with longer median OS (35.5 months) and the median time to progression (TTP) (6.0 months). Bortezomib treatment, chemotherapy, International Staging System (ISS) stage I, and better performance status significantly correlated with survival benefit. In the bortezomib-treated subgroup, better treatment response caused excellent median OS (67.7 months) and also significantly delayed TTP. Therefore, this current analysis concluded a median OS of 22 months in myeloma patients ineligible for HSCT at our institution during the past 10 years. The use of bortezomib with better treatment response also achieved significantly better median OS and TTP.", "affiliations": "Division of Hematology/Oncology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, No. 325, Cheng-Kung Road, Sec. 2, Neihu 114, Taipei, Taiwan.", "authors": "Huang|Tzu-Chuan|TC|;Chen|Jia-Hong|JH|;Wu|Yi-Ying|YY|;Chang|Ping-Ying|PY|;Dai|Ming-Shen|MS|;Chao|Tsu-Yi|TY|;Kao|Woei-Yau|WY|;Chen|Yeu-Chin|YC|;Ho|Ching-Liang|CL|", "chemical_list": "D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib", "country": "Germany", "delete": false, "doi": "10.1007/s00277-014-2165-2", "fulltext": null, "fulltext_license": null, "issn_linking": "0939-5555", "issue": "94(1)", "journal": "Annals of hematology", "keywords": null, "medline_ta": "Ann Hematol", "mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D001897:Boronic Acids; D000069286:Bortezomib; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D011719:Pyrazines; D012189:Retrospective Studies; D013624:Taiwan; D016896:Treatment Outcome", "nlm_unique_id": "9107334", "other_id": null, "pages": "107-15", "pmc": null, "pmid": "25047657", "pubdate": "2015-01", "publication_types": "D016428:Journal Article", "references": null, "title": "The treatment outcome of multiple myeloma patients ineligible for hematopoietic transplantation--a single institutional experience in Taiwan.", "title_normalized": "the treatment outcome of multiple myeloma patients ineligible for hematopoietic transplantation a single institutional experience in taiwan" }

[ { "companynumb": "TW-CELGENEUS-153-20785-14080020", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DOXORUBICIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "THALIDOMIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "020785", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Capsules", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "THALIDOMIDE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BORTEZOMIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BORTEZOMIB" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LENALIDOMIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "021880", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Capsules", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "REVLIMID" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cytomegalovirus infection", "reactionmeddraversionpt": "17.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Sedation", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Somnolence", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urinary tract infection", "reactionmeddraversionpt": "17.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Osteonecrosis of jaw", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrointestinal disorder", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venous thrombosis", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pancytopenia", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Plasma cell myeloma", "reactionmeddraversionpt": "17.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Tuberculosis", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Renal failure acute", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumocystis jirovecii infection", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neuropathy peripheral", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bacteraemia", "reactionmeddraversionpt": "17.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Pneumonia bacterial", "reactionmeddraversionpt": "17.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Candida infection", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fatigue", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rash", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HO C,HUANG T,CHEN J,WU Y,CHANG P,DAI M. THE TREATMENT OUTCOME OF MULTIPLE MYELOMA PATIENTS INELIGIBLE FOR HEMATOPOIETIC TRANSPLANTATION-A SINGLE INSTITUTIONAL EXPERIENCE IN TAIWAN.. ANN HEMATOL 2014;.", "literaturereference_normalized": "the treatment outcome of multiple myeloma patients ineligible for hematopoietic transplantation a single institutional experience in taiwan", "qualification": "1", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20140813", "receivedate": "20140806", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10364681, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150326" } ]

{ "abstract": "Lung cancer is diagnosed at a late stage although we have novel diagnostic tools. The association of smoking and other environmental factors are well known. However; there are cases where a malignancy is associated with previous radiation treatment. There is an association between radiotherapy treatment and cancer incidence. We present a case where lung cancer and laryngeal cancer was induced 20 years after radiation therapy of a hogkin lymphoma.", "affiliations": "3rd Department of Surgery, \"AHEPA\" University Hospital, Aristotle University of Thessaloniki, Medical School, Thessaloniki, Greece.;3rd Department of Surgery, \"AHEPA\" University Hospital, Aristotle University of Thessaloniki, Medical School, Thessaloniki, Greece.;Anesthesiology Department, \"AHEPA\" University General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.;3rd Department of Surgery, \"AHEPA\" University Hospital, Aristotle University of Thessaloniki, Medical School, Thessaloniki, Greece.;3rd Department of Surgery, \"AHEPA\" University Hospital, Aristotle University of Thessaloniki, Medical School, Thessaloniki, Greece.;3rd Department of Surgery, \"AHEPA\" University Hospital, Aristotle University of Thessaloniki, Medical School, Thessaloniki, Greece.;Ear, Nose and Throat Department, \"Saint Luke\" Private Hospital, Thessaloniki, Panorama, Greece.;Ear, Nose and Throat Department, \"Saint Luke\" Private Hospital, Thessaloniki, Panorama, Greece.;Radiotherapy Department-Oncology Unit, \"Theageneio\" Cancer Hospital, Thessaloniki, Greece.;Pulmonary Department-Oncology Unit, \"Theageneio\" Cancer Hospital, Thessaloniki, Greece.;Thoracic Surgery Department, University General Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece.;Surgery Department (NHS), University General Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece.;Surgery Department (NHS), University General Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece.;Department of Pharmacology & Clinical Pharmacology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece.;Thoracic Surgery Department (NHS), \"Theageneio\" Cancer Hospital, Thessaloniki, Greece.;Thoracic Surgery Department (NHS), \"Theageneio\" Cancer Hospital, Thessaloniki, Greece.;Hellenic Open University, Cyprus.;Pulmonary Department-Oncology Unit, \"Theageneio\" Cancer Hospital, Thessaloniki, Greece.;3rd Department of Surgery, \"AHEPA\" University Hospital, Aristotle University of Thessaloniki, Medical School, Thessaloniki, Greece.", "authors": "Sapalidis|Konstantinos|K|;Laskou|Stella|S|;Amaniti|Aikaterini|A|;Mantalovas|Stylianos|S|;Giannakidis|Dimitris|D|;Koulouris|Charilaos|C|;Karapantzos|Ilias|I|;Karapantzou|Chrysa|C|;Mponiou|Konstantina|K|;Tsiouda|Theodora|T|;Konstantinou|Fotis|F|;Kougioumtzi|Ioanna|I|;Katsikogiannis|Nikos|N|;Sardeli|Chrysa|C|;Gogakos|Apostolos|A|;Schizas|Nikos|N|;Domeyer|Philip|P|;Zarogoulidis|Paul|P|;Kesisoglou|Isaak|I|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1016/j.rmcr.2018.03.013", "fulltext": "\n==== Front\nRespir Med Case RepRespir Med Case RepRespiratory Medicine Case Reports2213-0071Elsevier S2213-0071(18)30073-X10.1016/j.rmcr.2018.03.013Case ReportLung cancer induced from chemotherapy a 20 years old case Sapalidis Konstantinos aLaskou Stella aAmaniti Aikaterini bMantalovas Stylianos aGiannakidis Dimitris aKoulouris Charilaos aKarapantzos Ilias cKarapantzou Chrysa cMponiou Konstantina dTsiouda Theodora eKonstantinou Fotis fKougioumtzi Ioanna gKatsikogiannis Nikos gSardeli Chrysa hGogakos Apostolos iSchizas Nikos iDomeyer Philip jZarogoulidis Paul [email protected]∗Kesisoglou Isaak aa 3rd Department of Surgery, “AHEPA” University Hospital, Aristotle University of Thessaloniki, Medical School, Thessaloniki, Greeceb Anesthesiology Department, “AHEPA” University General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greecec Ear, Nose and Throat Department, “Saint Luke” Private Hospital, Thessaloniki, Panorama, Greeced Radiotherapy Department-Oncology Unit, “Theageneio” Cancer Hospital, Thessaloniki, Greecee Pulmonary Department-Oncology Unit, “Theageneio” Cancer Hospital, Thessaloniki, Greecef Thoracic Surgery Department, University General Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greeceg Surgery Department (NHS), University General Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greeceh Department of Pharmacology & Clinical Pharmacology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greecei Thoracic Surgery Department (NHS), “Theageneio” Cancer Hospital, Thessaloniki, Greecej Hellenic Open University, Cyprus∗ Corresponding author. [email protected] 3 2018 2018 27 3 2018 24 32 34 19 3 2018 21 3 2018 25 3 2018 © 2018 The Authors2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Lung cancer is diagnosed at a late stage although we have novel diagnostic tools. The association of smoking and other environmental factors are well known. However; there are cases where a malignancy is associated with previous radiation treatment. There is an association between radiotherapy treatment and cancer incidence. We present a case where lung cancer and laryngeal cancer was induced 20 years after radiation therapy of a hogkin lymphoma.\n\nKeywords\nHodgkin lymphomaLaryngeal cancerLung cancerRadiationEBUS\n==== Body\n1 Introduction\nWe have recent advances in the diagnosis and treatment of lung cancer with novel instruments and therapies. The convex-probe endobronchial ultrasound and the radial endobronchial ultrasound (EBUS) brought a revolution to the diagnosis of lung cancer, however; they are not tools that can be used in every pulmonary department [[1], [2], [3]]. On the other hand we have novel therapies for non-small cell lung cancer (NSCLC) such as; immunotherapy (nivolumab and pembrolizumab) and targeted therapies with tyrosine kinase inhibitors (TKIs) for epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), murine sarcoma viral oncogene homolog B (BRAF) and proto-oncogene tyrosine-protein kinase (ROS-1) [4]. Radiotherapy can be used either as a primary therapy for NSCLC or palliative care [5]. In any case the medical history of the patient might reveal co-occurrence of multiple primary cancers. There is also the case where radiotherapy or chemotherapy pretreatment induced another type of cancer [6]. In the current case we will present a patient diagnosed with Hodgkin lymphoma in 1997 and presented in situ laryngeal cancer after 15 years and lung cancer after 20 years. Occurrence of a cancer after radiotherapy treatment has been previously reported and the association of radiotherapy treatment and cancer has been established [7].\n\n2 Case presentation\nA 57 year old patient (age today) was diagnosed with Hodgkin lymphoma in 1997 from a tracheal lymph-node. Smoking history when diagnosed with Hodgkin lymphoma with 15 p/y. He received in total 3000 rad of radiotherapy as primary therapy. The disease was stable until 2010 were the patient presented in the outpatient cabinet with enlarged lymph-nodes in the whole body. Again a biopsy from a tracheal lymph node revealed Hodgkin disease relapse. He received 6 cycles of Andriamycin 45mg Bleomycin 670mg Viblastine 10mg Detisene 680mg for 6 months. A positron emission tomography 3 months after the last chemotherapy was negative for active disease. The patient remained under observation as an outpatient for 4 years without disease relapse. However; early in 2016 he presented in the outpatient cabinet with hemoptysis and a in situ laryngeal cancer was diagnosed (Fig. 1). He received 6000 rad as radiotherapy treatment and platinum analog for six cycles carboplatin AUC 600mg. The patient remained under observation. In 2017 a CT thorax revealed a mass in the right lower lobe and enlarged mesothorax lymph-nodes positive with PET-CT (Fig. 2). Biopsy of the lymph-nodes with a convex probe endobronchial ultrasound revealed adenocarcinoma with EGFR and ALK negative expression(Fig. 3). He received 6 cycles of carboplatin AUC 600 and pemetrexed 1000mg. He was disease free for 4 months until a new staging with PET-CT revealed disease relapse and 4 cycles of carboplatin AUC 600 and taxane 370 derivative was administered. A further investigation in the first biopsy for BRAF, ROS-1 and PD-L1 expression revealed negative expression.Fig. 1 Figure from microlaryngoscopy.\n\nFig. 1Fig. 2 CT of the thorax.\n\nFig. 2Fig. 3 Endoscopy with convex probe endobronchial ultrasound (EBUS) blue arrow indicating the block of lymph-nodes.\n\nFig. 3\n\n3 Discussion\nIt is known from the epidemiological study of survivors of atomic bomb irradiation [8,9] and it has been suggested and observed in clinical practice that irradiation of surrounding tissues can cause second cancers [10,11]. The benefits of radiotherapy outweigh the risks of developing subsequent cancers, therefore methods of minimizing the radiation dose delivered to surrounding tissues or the volume should be further investigated. However; there also other factors contributing to carcinogenesis like; environmental exposure to carcinogens, genetic predisposition, misdiagnosis of metastases as primary cancers, reproductive factors. Therefore increased medical surveillance should follow the first cancer for treatment-related effects. It has been observed that genetic and environmental predisposition may increase the incidence of a second cancer, while treatment related tumors are expected to develop some time after an iatrogenic effect. Previous clinical observations indicate that second cancers after an exposure to radiation would develop within a time window of 5 years for leukemia and 10 years for solid tumors [[12], [13], [14], [15], [16], [17]]. Previously it has been suggested that a certain latency period passes before a new tumor appears. There is a clear association between latency time and cancer type. Moreover; chemotherapy can induce second cancer development [18]. An excess incidence of acute myeloid leukemia and myelodysplastic syndrome has been associated with therapy in those patients who received doxorubicin when compared with those who received doxorubicin combined with cyclophosphamide therapy [16]. The incidence was higher in those patients that received intensified cyclophosphamide doses (requiring granulocyte colony-stimulating factor support). An excess incidence of lung cancer has been observed at 10 years or more after radiotherapy, in several studies [17,19]. In our case we have an association of radiotherapy, chemotherapy and secondary factors which we believe were smoking history and genetic predisposition. The patient is under close follow-up to date.\n\nDisclosure\nThe authors declare no conflict of interest.\n==== Refs\nReferences\n1 Zarogoulidis P. Huang H. Bai C. Kosmidis C. Trakada G. Veletza L. Tsiouda T. Barbetakis N. Paliouras D. Athanasiou E. Hatzibougias D. Kallianos A. Panagiotopoulos N. Papaemmanouil L. Hohenforst-Schmidt W. Endobronchial ultrasound convex probe for lymphoma, sarcoidosis, lung cancer and other thoracic entities. A case series Res. Med. Case Rep. 22 2017 187 196 \n2 Haidong H. Yunye N. Wei Z. Zarogoulidis P. Hohenforst-Schmidt W. Man Y.G. Yuguang Y. Yuchao D. Chong B. Multiple guided technologies based on radial probe endobronchial ultrasound for the diagnosis of solitary peripheral pulmonary lesions: a single-center study J. Cancer 8 17 2017 3514 3521 29151936 \n3 Hohenforst-Schmidt W. Zarogoulidis P. Pitsiou G. Linsmeier B. Tsavlis D. Kioumis I. Papadaki E. Freitag L. Tsiouda T. Turner J.F. Browning R. Simoff M. Sachpekidis N. Tsakiridis K. Zaric B. Yarmus L. Baka S. Stratakos G. Rittger H. Drug eluting stents for malignant airway obstruction: a critical review of the literature J. Cancer 7 4 2016 377 390 26918052 \n4 Moya-Horno I. Viteri S. Karachaliou N. Rosell R. Combination of immunotherapy with targeted therapies in advanced non-small cell lung cancer (NSCLC) Ther. Adv Med. Oncol. 10 2018 1758834017745012 \n5 Christodoulou M. Bayman N. McCloskey P. Rowbottom C. Faivre-Finn C. New radiotherapy approaches in locally advanced non-small cell lung cancer Eur. J. Cancer 50 3 2014 525 534 24333095 \n6 Roychoudhuri R. Evans H. Robinson D. Moller H. Radiation-induced malignancies following radiotherapy for breast cancer Br J. Cancer 91 5 2004 868 872 15292931 \n7 Weber D.C. Johanson S. Peguret N. Cozzi L. Olsen D.R. Predicted risk of radiation-induced cancers after involved field and involved node radiotherapy with or without intensity modulation for early-stage hodgkin lymphoma in female patients Int. J. Radiat. Oncol. Biol. Phys. 81 2 2011 490 497 20800383 \n8 Land C.E. Tokunaga M. Koyama K. Soda M. Preston D.L. Nishimori I. Tokuoka S. Incidence of female breast cancer among atomic bomb survivors, Hiroshima and Nagasaki, 1950-1990 Radiat. Res. 160 6 2003 707 717 14640793 \n9 Preston D.L. Shimizu Y. Pierce D.A. Suyama A. Mabuchi K. Studies of mortality of atomic bomb survivors Report 13: Solid cancer and noncancer disease mortality: 1950-1997 Radiat. Res. 160 4 2003 381 407 12968934 \n10 Neugut A.I. Weinberg M.D. Ahsan H. Rescigno J. Carcinogenic effects of radiotherapy for breast cancer Oncology 13 9 1999 1245 1256 discussion 1257, 1261-5 10509322 \n11 Harvey E.B. Brinton L.A. Second cancer following cancer of the breast in Connecticut, 1935-82 Natl. Canc. Inst. Monogr. 68 1985 99 112 \n12 Boice J.D. Jr. Day N.E. Andersen A. Brinton L.A. Brown R. Choi N.W. Clarke E.A. Coleman M.P. Curtis R.E. Flannery J.T. Second cancers following radiation treatment for cervical cancer. An international collaboration among cancer registries J Nat. Cancer Ins. 74 5 1985 955 975 \n13 Land C.E. Boice J.D. Jr. Shore R.E. Norman J.E. Tokunaga M. Breast cancer risk from low-dose exposures to ionizing radiation: results of parallel analysis of three exposed populations of women J Nat. Cancer Ins. 65 2 1980 353 376 \n14 Neugut A.I. Robinson E. Lee W.C. Murray T. Karwoski K. Kutcher G.J. Lung cancer after radiation therapy for breast cancer Cancer 71 10 1993 3054 3057 8490833 \n15 Rubino C. de Vathaire F. Shamsaldin A. Labbe M. Le M.G. Radiation dose, chemotherapy, hormonal treatment and risk of second cancer after breast cancer treatment Br. J. Cancer 89 5 2003 840 846 12942115 \n16 Smith R.E. Bryant J. DeCillis A. Anderson S. National Surgical Adjuvant B. Bowel Project E. Acute myeloid leukemia and myelodysplastic syndrome after doxorubicin-cyclophosphamide adjuvant therapy for operable breast cancer: the National Surgical Adjuvant Breast and Bowel Project Experience J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 21 7 2003 1195 1204 \n17 Zablotska L.B. Neugut A.I. Lung carcinoma after radiation therapy in women treated with lumpectomy or mastectomy for primary breast carcinoma Cancer 97 6 2003 1404 1411 12627503 \n18 Vega-Stromberg T. Chemotherapy-induced secondary malignancies J. Infus. Nurs. Off. Pub Infus. Nurses Soc. 26 6 2003 353 361 \n19 Deutsch M. Land S.R. Begovic M. Wieand H.S. Wolmark N. Fisher B. The incidence of lung carcinoma after surgery for breast carcinoma with and without postoperative radiotherapy. Results of National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trials B-04 and B-06 Cancer 98 7 2003 1362 1368 14508821\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2213-0071", "issue": "24()", "journal": "Respiratory medicine case reports", "keywords": "EBUS; Hodgkin lymphoma; Laryngeal cancer; Lung cancer; Radiation", "medline_ta": "Respir Med Case Rep", "mesh_terms": null, "nlm_unique_id": "101604463", "other_id": null, "pages": "32-34", "pmc": null, "pmid": "29977753", "pubdate": "2018", "publication_types": "D002363:Case Reports", "references": "20800383;8490833;15292931;12942115;14640793;26918052;14508821;12968934;10509322;24333095;12627503;29151936;6931253;3858584;12663705;4088315;29383034;14624175;28879075", "title": "Lung cancer induced from chemotherapy a 20 years old case.", "title_normalized": "lung cancer induced from chemotherapy a 20 years old case" }

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"drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "670 MG, 6 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "HODGKIN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "670", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BLEOMYCIN" } ], "patientagegroup": null, "patientonsetage": "57", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Second primary malignancy", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lung adenocarcinoma", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2017" } }, "primarysource": { "literaturereference": "SAPALIDIS, K.. LUNG CANCER INDUCED FROM CHEMOTHERAPY A 20 YEARS OLD CASE. RESPIRATORY MEDICINE CASE REPORTS. 2018?24:32?34", "literaturereference_normalized": "lung cancer induced from chemotherapy a 20 years old case", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20180706", "receivedate": "20180606", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14979521, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" }, { "companynumb": "GR-MYLANLABS-2018M1027806", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VINBLASTINE" }, "drugadditional": null, "drugadministrationroute": "065", 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADRIAMYCIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DACARBAZINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HODGKIN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "680", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DETICENE" } ], "patientagegroup": null, "patientonsetage": "57", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Laryngeal cancer", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lung adenocarcinoma", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2016" } }, "primarysource": { "literaturereference": "SAPALIDIS K, LASKOU S, AMANITI A, MANTALOVAS S, GIANNAKIDIS D, KOULOURIS C, ET AL. LUNG CANCER INDUCED FROM CHEMOTHERAPY A 20 YEARS OLD CASE. RESPIRAT-MED-CASE-REPORT 2018?24:32-34.", "literaturereference_normalized": "lung cancer induced from chemotherapy a 20 years old case", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20180503", "receivedate": "20180503", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14843371, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180711" } ]

{ "abstract": "Malignant hyperthermia (MH), an inherited myopathia varying in severity and course, is induced by halogenated anesthetic agents and depolarizing muscle relaxants. First recognized as a distinct disease entity in 1960, MH is defined as an anesthesia-related disease due to the agents by which it is triggered. Given the wide use of these preparations in prehospital emergency medicine and intensive care treatment, physicians in other disciplines may also encounter MH.", "affiliations": "Klinik für Anästhesie, operative Intensivmedizin und Schmerztherapie, Helios St. Johannes Klinik Duisburg, An der Abtei 7-11, 47166, Duisburg, Deutschland.", "authors": "Wendlandt|B|B|;Turinsky|S|S|;Schmitz|M|M|", "chemical_list": "D007530:Isoflurane", "country": "Germany", "delete": false, "doi": "10.1007/s00063-014-0450-4", "fulltext": null, "fulltext_license": null, "issn_linking": "2193-6218", "issue": "110(2)", "journal": "Medizinische Klinik, Intensivmedizin und Notfallmedizin", "keywords": null, "medline_ta": "Med Klin Intensivmed Notfmed", "mesh_terms": "D000280:Administration, Inhalation; D016887:Cardiopulmonary Resuscitation; D003131:Combined Modality Therapy; D016292:Conscious Sedation; D004554:Electric Countershock; D006336:Heart Massage; D006801:Humans; D007036:Hypothermia, Induced; D007362:Intensive Care Units; D007530:Isoflurane; D008297:Male; D008305:Malignant Hyperthermia; D008875:Middle Aged; D009203:Myocardial Infarction; D015912:Thrombolytic Therapy", "nlm_unique_id": "101575086", "other_id": null, "pages": "155-8", "pmc": null, "pmid": "25585653", "pubdate": "2015-04", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "1536407;20081135;20837722;8383206", "title": "Isoflurane-induced malignant hyperthermia during intensive-care treatment.", "title_normalized": "isoflurane induced malignant hyperthermia during intensive care treatment" }

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null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SUFENTANIL" } ], "patientagegroup": null, "patientonsetage": "53", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hyperthermia malignant", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "WENDLANDT B, TURINSKY S, SCHMITZ M. ISOFLURANE-INDUCED MALIGNANT HYPERTHERMIA DURING INTENSIVE-CARE TREATMENT. MEDIZINISCHE KLINIK - INTENSIVMEDIZIN UND NOTFALLMEDIZIN. 2015 APR?110(2):155-158.", "literaturereference_normalized": "isoflurane induced malignant hyperthermia during intensive care treatment", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20190322", "receivedate": "20190322", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16108308, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190418" } ]

{ "abstract": "The possible onset of cardiotoxic manifestations during chemotherapy with 5-fluorouracil (5-FU) was evaluated in 1083 patients treated with the drug for various kinds of neoplasm. We recognized 17 cases of 5-FU cardiopathy (usually anginous crises but also myocardial infarction). The comprehensive incidence was 1.6%, with a significantly greater risk (4.5% vs 1.1%) for patients with a positive anamnesis of previous cardiopathy. On the contrary, age and combination with other antiblastic drugs had no affect on the appearance of cardiopathy. We conclude that 5-FU cardiopathy, although rare, has to be taken into account in oncologic practice, chiefly in those patients already affected with cardiac diseases.", "affiliations": null, "authors": "Labianca|R|R|;Beretta|G|G|;Clerici|M|M|;Fraschini|P|P|;Luporini|G|G|", "chemical_list": "D005472:Fluorouracil", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0300-8916", "issue": "68(6)", "journal": "Tumori", "keywords": null, "medline_ta": "Tumori", "mesh_terms": "D000368:Aged; D000787:Angina Pectoris; D004359:Drug Therapy, Combination; D005260:Female; D005472:Fluorouracil; D006321:Heart; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction; D009369:Neoplasms; D012306:Risk", "nlm_unique_id": "0111356", "other_id": null, "pages": "505-10", "pmc": null, "pmid": "7168016", "pubdate": "1982-12-31", "publication_types": "D016428:Journal Article", "references": null, "title": "Cardiac toxicity of 5-fluorouracil: a study on 1083 patients.", "title_normalized": "cardiac toxicity of 5 fluorouracil a study on 1083 patients" }

[ { "companynumb": "IT-PFIZER INC-2013297329", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "202668", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK (7 DAYS AFTER THE 3RD DOSE OF 5?FU IN THE 3RD CYCLE PREVIOUSLY: REPEATED ANGINOUS CRISES IN CONC", "drugenddate": null, "drugenddateformat": null, "drugindication": "NEOPLASM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUOROURACIL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK UNK, CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "NEOPLASM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "202668", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUOROURACIL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTOXAN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK UNK, CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "NEOPLASM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTOXAN" } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Angina pectoris", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Myocardial infarction", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LABIANCA, R.. CARDIAC TOXICITY OF 5?FLUOROURACIL: A STUDY ON 1083 PATIENTS. TUMORI. 1982?68 (6):505?510", "literaturereference_normalized": "cardiac toxicity of 5 fluorouracil a study on 1083 patients", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20210125", "receivedate": "20131018", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 9632122, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210420" } ]

{ "abstract": "Gene transfer targeting hematopoietic stem cells (HSC) in children has shown sustained therapeutic benefit in the treatment of genetic diseases affecting the immune system, most notably in severe combined immunodeficiencies affecting T-cell function. The HSC compartment has also been successfully targeted using gene transfer in children with genetic diseases affecting the central nervous system, such as metachromatic leukodystrophy and adrenoleukodystrophy. HSCs are also a target for genetic modification in strategies aiming to confer drug resistance to chemotherapy agents so as to reduce off-target toxicity, and to allow for chemotherapy dose escalation with the possibility of enhanced therapeutic benefit. In a trial of this strategy in adult glioma patients, significant engraftment of gene-modified HSCs expressing a mutant of the DNA repair protein O6-methyl-guanine-methyl-transferase (MGMT(P140K)) showed potential in conferring drug resistance against the combined effect of O6-benzylguanine (O6BG)/temozolomide (TMZ) chemotherapy. The aim was to test the safety and feasibility of this approach in children with poor prognosis brain tumors. In this Phase I trial, seven patients received gene-modified HSC following myelo-suppressive conditioning, but with only transient low-level engraftment of MGMT(P140K) gene-modified cells detectable in four patients. All patients received O6BG/TMZ chemotherapy following infusion of gene-modified cells, with five patients eligible for chemotherapy dose escalation, though in the absence of demonstrable transgene-mediated chemoprotection. Since all gene-modified cell products met the criteria for release and assays for engraftment potential met expected outcome measures, inadequate cell dose, conditioning chemotherapy, and/or underlying bone-marrow function may have contributed to the lack of sustained engraftment of gene-modified cells. We were able to demonstrate safe conduct of a technically complex Phase I study encompassing manufacture of the gene therapy vector, genetically modified cells, and a drug product specifically for the trial in compliance with both local and national regulatory requirements.", "affiliations": "1 Children's Cancer Research Unit, The Children's Hospital at Westmead, Westmead, Australia.;1 Children's Cancer Research Unit, The Children's Hospital at Westmead, Westmead, Australia.;1 Children's Cancer Research Unit, The Children's Hospital at Westmead, Westmead, Australia.;1 Children's Cancer Research Unit, The Children's Hospital at Westmead, Westmead, Australia.;1 Children's Cancer Research Unit, The Children's Hospital at Westmead, Westmead, Australia.;1 Children's Cancer Research Unit, The Children's Hospital at Westmead, Westmead, Australia.;1 Children's Cancer Research Unit, The Children's Hospital at Westmead, Westmead, Australia.;2 Gene Therapy Research Unit, Children's Medical Research Institute, Westmead, Australia and the Children's Hospital at Westmead, Westmead, Australia.;4 Children's Cancer Centre, The Children's Hospital at Westmead, Westmead, Australia.", "authors": "Kramer|Belinda|B|;Singh|Radhika|R|;Wischusen|Jessica|J|;Dent|Rebecca|R|;Rush|Amanda|A|;Middlemiss|Shiloh|S|;Ching|Yu Wooi|YW|;Alexander|Ian E|IE|;McCowage|Geoffrey|G|", "chemical_list": "D025521:Tumor Suppressor Proteins; C064976:O(6)-benzylguanine; D006147:Guanine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide", "country": "United States", "delete": false, "doi": "10.1089/hum.2017.235", "fulltext": null, "fulltext_license": null, "issn_linking": "1043-0342", "issue": "29(8)", "journal": "Human gene therapy", "keywords": "cancer; clinical trial; gene therapy; pediatric brain tumors", "medline_ta": "Hum Gene Ther", "mesh_terms": "D001932:Brain Neoplasms; D002648:Child; D015254:DNA Modification Methylases; D045643:DNA Repair Enzymes; D019008:Drug Resistance, Neoplasm; D005260:Female; D015316:Genetic Therapy; D006147:Guanine; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells; D006801:Humans; D008297:Male; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins", "nlm_unique_id": "9008950", "other_id": null, "pages": "874-885", "pmc": null, "pmid": "29385852", "pubdate": "2018-08", "publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Clinical Trial of MGMT(P140K) Gene Therapy in the Treatment of Pediatric Patients with Brain Tumors.", "title_normalized": "clinical trial of mgmt p140k gene therapy in the treatment of pediatric patients with brain tumors" }

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CYCLE 5 AND 6", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "133", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TEMOZOLOMIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TEMOZOLOMIDE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "205227", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AT THE CONCLUSION OF THE 1 H INFUSION OF BENZYLGUANINE (CONDITIONING)", "drugenddate": null, "drugenddateformat": null, "drugindication": "BRAIN STEM GLIOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "472", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TEMOZOLOMIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PEGFILGRASTIM" }, "drugadditional": null, "drugadministrationroute": "058", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AT THE END OF EACH 5?DAY CYCLE OF CHEMOTHERAPY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "008", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PEGFILGRASTIM" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TEMOZOLOMIDE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "205227", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "ADMINISTERED 30MIN AFTER BENZYLGUANINE (POST?INFUSION); LEVEL 0 (CYCLE 1 AND 2)", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TEMOZOLOMIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TEMOZOLOMIDE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "205227", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "LEVEL 3; CYCLE 7 AND 8", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "175", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TEMOZOLOMIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "6-O-BENZYLGUANINE" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "120 MG/M2 INFUSION OVER ONE HOUR ON DAY ?3", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "O6?BENZYLGUANINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "6-O-BENZYLGUANINE" }, "drugadditional": null, "drugadministrationroute": "041", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "OVER 60 MIN", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "120", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "O6?BENZYLGUANINE" } ], "patientagegroup": null, "patientonsetage": "12", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Blood lactic acid increased", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Bone marrow failure", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Alanine aminotransferase increased", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Blood disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KRAMER B, SINGH R, WISCHUSEN J, DENT R, RUSH A, MIDDLEMISS S, ET AL. CLINICAL TRIAL OF MGMT(P140K) GENE THERAPY IN THE TREATMENT OF PEDIATRIC PATIENTS WITH BRAIN TUMORS. HUM?GENE?THER 2018?29(8):874?885.", "literaturereference_normalized": "clinical trial of mgmt p140k gene therapy in the treatment of pediatric patients with brain tumors", "qualification": "1", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20180924", "receivedate": "20180924", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15419742, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" }, { "companynumb": "AU-MYLANLABS-2018M1068027", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TEMOZOLOMIDE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "205227", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "LEVEL 1 (CYCLE 3 AND 4)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TEMOZOLOMIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TEMOZOLOMIDE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "205227", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "LEVEL 2; 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LEVEL 0 (CYCLE 1 AND 2)", "drugenddate": null, "drugenddateformat": null, "drugindication": "BRAIN STEM GLIOMA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TEMOZOLOMIDE." } ], "patientagegroup": null, "patientonsetage": "5", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Bone marrow failure", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Tachypnoea", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blood disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KRAMER B, SINGH R, WISCHUSEN J, DENT R, RUSH A, MIDDLEMISS S, ET AL. CLINICAL TRIAL OF MGMT(P140K) GENE THERAPY IN THE TREATMENT OF PEDIATRIC PATIENTS WITH BRAIN TUMORS. HUM?GENE?THER 2018?29(8):874?885.", "literaturereference_normalized": "clinical trial of mgmt p140k gene therapy in the treatment of pediatric patients with brain tumors", "qualification": "1", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20180925", "receivedate": "20180925", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15423833, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" }, { "companynumb": "AU-MYLANLABS-2018M1068002", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "6-O-BENZYLGUANINE" }, "drugadditional": null, "drugadministrationroute": "041", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "OVER 60 MIN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BRAIN STEM GLIOMA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "120", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "O6?BENZYLGUANINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TEMOZOLOMIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "205227", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "ADMINISTERED 30MIN AFTER BENZYLGUANINE (POST?INFUSION); 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CLINICAL TRIAL OF MGMT(P140K) GENE THERAPY IN THE TREATMENT OF PEDIATRIC PATIENTS WITH BRAIN TUMORS. HUM?GENE?THER 2018?29(8):874?885.", "literaturereference_normalized": "clinical trial of mgmt p140k gene therapy in the treatment of pediatric patients with brain tumors", "qualification": "1", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20180919", "receivedate": "20180919", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15403823, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" } ]

{ "abstract": "Objective To illustrate an unusual case of Listeria cerebral abscess. Material and methods A 32-year-old pregnant woman with thrombotic antiphospholipid syndrome (APS) received corticotherapy for two weeks due to hemolysis, elevated liver enzymes, low platelet (HELLP) syndrome. After delivery she presented with neurological symptoms and fever. Results The MRI scan confirmed the presence of a brain abscess, and Listeria monocytogenes was isolated in blood cultures. After eight weeks of antibiotic treatment, the patient presented no sequelae. Conclusion L. monocytogenes should be included in the differential diagnosis of patients with fever and neurological dysfunction, especially in those with a recent history of corticotherapy.", "affiliations": "1 Maternal Fetal Medicine Department, Hospital Clinic, Barcelona, Catalonia, Spain.;2 Infectious Diseases Department, Hospital Clinic, Barcelona, Catalonia, Spain.;3 Medical Intensive Care Unit, Hospital Clinic, Barcelona, Catalonia, Spain.;1 Maternal Fetal Medicine Department, Hospital Clinic, Barcelona, Catalonia, Spain.;1 Maternal Fetal Medicine Department, Hospital Clinic, Barcelona, Catalonia, Spain.;4 Autoimmune Diseases Department, Hospital Clinic, Barcelona, Catalonia, Spain.;4 Autoimmune Diseases Department, Hospital Clinic, Barcelona, Catalonia, Spain.", "authors": "Fervienza|A|A|;Bodro|M|M|;Castro|P|P|;Hernández|S|S|;Teixidó|I|I|;Espinosa|G|G|;Cervera|R|R|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1177/0961203316682856", "fulltext": null, "fulltext_license": null, "issn_linking": "0961-2033", "issue": "26(9)", "journal": "Lupus", "keywords": "Antiphospholipid syndrome; Listeria monocytogenes; pregnancy", "medline_ta": "Lupus", "mesh_terms": "D000328:Adult; D016736:Antiphospholipid Syndrome; D001922:Brain Abscess; D003937:Diagnosis, Differential; D005260:Female; D005334:Fever; D017359:HELLP Syndrome; D006801:Humans; D008089:Listeria monocytogenes; D008088:Listeriosis; D008279:Magnetic Resonance Imaging; D009422:Nervous System Diseases; D011247:Pregnancy; D011248:Pregnancy Complications; D016896:Treatment Outcome", "nlm_unique_id": "9204265", "other_id": null, "pages": "1002-1004", "pmc": null, "pmid": "27927881", "pubdate": "2017-08", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Brain abscess due to Listeria monocytogenes after HELLP syndrome in a patient with antiphospholipid syndrome.", "title_normalized": "brain abscess due to listeria monocytogenes after hellp syndrome in a patient with antiphospholipid syndrome" }

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"activesubstancename": "HEPARIN SODIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HEPARIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HEPARIN SODIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HEPARIN" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "084916", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HELLP SYNDROME", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "8", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE INJECTION (MANUFACTURER UNKNOWN)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HEPARIN SODIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HEPARIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MAGNESIUM SULFATE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HELLP SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MAGNESIUM SULPHATE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": null, "patientonsetage": "32", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Brain abscess", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Listeriosis", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Maternal exposure during pregnancy", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "FERVIENZA A,BODRO M,CASTRO P,HERNANDEZ S,TEIXIDO I,ET AL.. BRAIN ABSCESS DUE TO LISTERIA MONOCYTOGENES AFTER HELLP SYNDROME IN A PATIENT WITH ANTIPHOSPHOLIPID SYNDROME. LUPUS 2017;NO. 9:1002-1004.", "literaturereference_normalized": "brain abscess due to listeria monocytogenes after hellp syndrome in a patient with antiphospholipid syndrome", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20170918", "receivedate": "20170918", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13982984, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20171128" }, { "companynumb": "ES-FRESENIUS KABI-FK201707750", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "HEPARIN SODIUM" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "017029", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HEPARIN (MANUFACTURER UNKNOWN)" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "084916", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HELLP SYNDROME", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "8", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE INJECTION (MANUFACTURER UNKNOWN)" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MAGNESIUM SULFATE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "019316", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HELLP SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MAGNESIUM SULFATE (MANUFACTURER UNKNOWN)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": null, "patientonsetage": "3", "patientonsetageunit": "804", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Pulmonary haemorrhage", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "FERVIENZA A,BODRO M,CASTRO P,HERNANDEZ S,TEIXIDO I,ET AL.. BRAIN ABSCESS DUE TO LISTERIA MONOCYTOGENES AFTER HELLP SYNDROME IN A PATIENT WITH ANTIPHOSPHOLIPID SYNDROME. LUPUS 2017;NO. 9:1002-1004.", "literaturereference_normalized": "brain abscess due to listeria monocytogenes after hellp syndrome in a patient with antiphospholipid syndrome", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20170914", "receivedate": "20170914", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13970397, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20171128" }, { "companynumb": "ES-BAYER-2017-146346", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021317", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "GASTRO-RESISTANT COATED TABLET", "drugdosagetext": "100 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "4 MG/24HR (2MG/12H), UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "OPTIC NERVE INJURY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HEPARIN SODIUM" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HEPARIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HEPARIN SODIUM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DECREASED TO A PROPHYLACTIC DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HEPARIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HEPARIN SODIUM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "ANTICOAGULATION DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HEPARIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "4 MG, TID", "drugenddate": null, "drugenddateformat": null, "drugindication": "HELLP SYNDROME", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LINEZOLID" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1200 MG/24HR (600 MG/12 H), UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BRAIN ABSCESS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LINEZOLID." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LINEZOLID" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "LISTERIOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LINEZOLID." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HEPARIN SODIUM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "ANTICOAGULATION DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HEPARIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG/24HR ((10MG/12HR)), UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HELLP SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": "5", "patientonsetage": "32", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug administration error", "reactionmeddraversionpt": "20.1", "reactionoutcome": null }, { "reactionmeddrapt": "Cerebral haemorrhage", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "HELLP syndrome", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Premature delivery", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Listeriosis", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "20.1", "reactionoutcome": null }, { "reactionmeddrapt": "Brain abscess", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Maternal exposure during pregnancy", "reactionmeddraversionpt": "20.1", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "FERVIENZA A; BODRO M; CASTRO P; HERNANDEZ S; TEIXIDO I; ESPINOSA G; CERVERA R. BRAIN ABSCESS DUE TO LISTERIA MONOCYTOGENES AFTER HELLP SYNDROME IN A PATIENT WITH ANTIPHOSPHOLIPID SYNDROME. LUPUS. 2017;26:9:1002-1004", "literaturereference_normalized": "brain abscess due to listeria monocytogenes after hellp syndrome in a patient with antiphospholipid syndrome", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20170807", "receivedate": "20170807", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13841316, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" }, { "companynumb": "PHHY2017ES131434", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "FOETAL EXPOSURE DURING PREGNANCY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "HEPARIN SODIUM" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "FOETAL EXPOSURE DURING PREGNANCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HEPARIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "FOETAL EXPOSURE DURING PREGNANCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MAGNESIUM SULFATE" }, "drugadditional": "3", "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "FOETAL EXPOSURE DURING PREGNANCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MAGNESIUM SULPHATE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Premature baby", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary haemorrhage", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "FERVIENZA A, BODRO M, CASTRO P, HERNANDEZ S, TEIXIDO I, ESPINOSA G, ET AL.. BRAIN ABSCESS DUE TO LISTERIA MONOCYTOGENES AFTER HELLP SYNDROME IN A PATIENT WITH ANTIPHOSPHOLIPID SYNDROME. LUPUS. 2017;26(9):1002-4", "literaturereference_normalized": "brain abscess due to listeria monocytogenes after hellp syndrome in a patient with antiphospholipid syndrome", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20170908", "receivedate": "20170908", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13948956, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171128" }, { "companynumb": "ES-SUN PHARMACEUTICAL INDUSTRIES LTD-2017R1-154990", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "UNSPECIFIED INGREDIENT" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOW MOLECULAR WEIGHT HEPARIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "084764", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "4 MG, TID", "drugenddate": null, "drugenddateformat": null, "drugindication": "HELLP SYNDROME", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "8", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MAGNESIUM SULFATE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HELLP SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MAGNESIUM SULPHATE" } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pulmonary haemorrhage", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Premature baby", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "FERVIENZA A, BODRO M, CASTRO P, HERNANDEZ S, TEIXIDO I, ESPINOSA G ET AL. BRAIN ABSCESS DUE TO LISTERIA MONOCYTOGENES AFTER HELLP SYNDROME IN A PATIENT WITH ANTIPHOSPHOLIPID SYNDROME. LUPUS. 2017;26(9):1002-4", "literaturereference_normalized": "brain abscess due to listeria monocytogenes after hellp syndrome in a patient with antiphospholipid syndrome", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20171124", "receivedate": "20171124", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14222019, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180321" }, { "companynumb": "ES-SUN PHARMACEUTICAL INDUSTRIES LTD-2017R1-149987", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MAGNESIUM SULFATE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HELLP SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MAGNESIUM SULPHATE" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "UNSPECIFIED INGREDIENT" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOW MOLECULAR WEIGHT HEPARIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "084764", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "4 MG, TID", "drugenddate": null, "drugenddateformat": null, "drugindication": "HELLP SYNDROME", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "8", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": null, "patientonsetage": "32", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Brain abscess", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Premature delivery", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Listeriosis", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Nervous system disorder", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Foetal growth restriction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Infarction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Platelet count decreased", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "FERVIENZA A, BODRO M, CASTRO P, HERNANDEZ S, TEIXIDO I, ESPINOSA G ET AL. BRAIN ABSCESS DUE TO LISTERIA MONOCYTOGENES AFTER HELLP SYNDROME IN A PATIENT WITH ANTIPHOSPHOLIPID SYNDROME. LUPUS. 2017;26(9):1002-4", "literaturereference_normalized": "brain abscess due to listeria monocytogenes after hellp syndrome in a patient with antiphospholipid syndrome", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20171124", "receivedate": "20170918", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13981210, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180321" }, { "companynumb": "PHHY2017ES132029", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MAGNESIUM SULFATE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HELLP SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MAGNESIUM SULFATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPHOSPHOLIPID SYNDROME", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETYLSALICYLIC ACID" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "HEPARIN SODIUM" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "91659", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPHOSPHOLIPID SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HEPARIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "4 MG, Q8H", "drugenddate": null, "drugenddateformat": null, "drugindication": "HELLP SYNDROME", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "8", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, Q12H", "drugenddate": null, "drugenddateformat": null, "drugindication": "PLATELET COUNT DECREASED", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "12", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "32", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Abdominal pain upper", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "HELLP syndrome", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Premature delivery", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Maternal exposure during pregnancy", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "FERVIENZA A, BODRO M, CASTRO P, HERNANDEZ S, TEIXIDO I, ESPINOSA G, ET AL.. BRAIN ABSCESS DUE TO LISTERIA MONOCYTOGENES AFTER HELLP SYNDROME IN A PATIENT WITH ANTIPHOSPHOLIPID SYNDROME. LUPUS. 2017;26(9):1002-4", "literaturereference_normalized": "brain abscess due to listeria monocytogenes after hellp syndrome in a patient with antiphospholipid syndrome", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20170927", "receivedate": "20170913", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13966135, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171128" }, { "companynumb": "ES-BAYER-2017-146351", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "021317", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETYLSALICYLIC ACID({=100 MG)" } ], "patientagegroup": "1", "patientonsetage": "3", "patientonsetageunit": "804", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "20.1", "reactionoutcome": null }, { "reactionmeddrapt": "Premature baby", "reactionmeddraversionpt": "20.1", "reactionoutcome": null }, { "reactionmeddrapt": "Pulmonary haemorrhage", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Foetal growth restriction", "reactionmeddraversionpt": "20.1", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "FERVIENZA A; BODRO M; CASTRO P; HERNANDEZ S; TEIXIDO I; ESPINOSA G; CERVERA R. BRAIN ABSCESS DUE TO LISTERIA MONOCYTOGENES AFTER HELLP SYNDROME IN A PATIENT WITH ANTIPHOSPHOLIPID SYNDROME. LUPUS. 2017;26:9:1002-1004", "literaturereference_normalized": "brain abscess due to listeria monocytogenes after hellp syndrome in a patient with antiphospholipid syndrome", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20170807", "receivedate": "20170807", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13840325, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" }, { "companynumb": "ES-MYLANLABS-2017M1057440", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "MAGNESIUM SULFATE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HELLP SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MAGNESIUM SULFATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "080292", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HELLP SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN /00002701/" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "LATER DOSE WAS REDUCED TO 2 MG/12 HOURS", "drugenddate": null, "drugenddateformat": null, "drugindication": "HELLP SYNDROME", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "8", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." } ], "patientagegroup": null, "patientonsetage": "32", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Brain abscess", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cerebral haemorrhage", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cerebral infarction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Maternal exposure during pregnancy", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Listeriosis", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "FERVIENZA A, BODRO M, CASTRO P, HERNANDEZ S, TEIXIDO I, ESPINOSA G, ET AL. BRAIN ABSCESS DUE TO LISTERIA MONOCYTOGENES AFTER HELLP SYNDROME IN A PATIENT WITH ANTIPHOSPHOLIPID SYNDROME. LUPUS 2017;26(9):1002-1004.", "literaturereference_normalized": "brain abscess due to listeria monocytogenes after hellp syndrome in a patient with antiphospholipid syndrome", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20170918", "receivedate": "20170918", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13984213, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20171128" } ]

{ "abstract": "This study assessed trends in transesophageal echocardiography (TEE) use, rate of left atrial appendage (LAA) thrombus detection, and incidence of periprocedural cerebrovascular accident (CVA) since transitioning to a strategy of uninterrupted warfarin or briefly interrupted novel oral anticoagulant therapy in 2010.\n\n\n\nTEE is routinely performed before ablation for atrial fibrillation (AF) to ensure absence of LAA thrombus.\n\n\n\nPatients with AF ablation presenting between January 2010 and September 2015 at Johns Hopkins Hospital were enrolled in an AF ablation registry; TEE and ablation outcomes were retrospectively analyzed. Presence of LAA thrombus, dense spontaneous echo contrast (SEC), or patent foramen ovale (PFO) were recorded. CVA incidence from procedure onset to 30 days post-procedure was evaluated using electronic medical record review.\n\n\n\nPre-procedure TEE was performed in 646 of 1,224 AF ablation cases (52.8%). There was a decline in pre-procedure TEE use from 86% in 2010 to 42% in 2015 (p < 0.001). CVA incidence was 4/1,224 (0.33%) cases, and did not change during the study period. TEE findings included LAA thrombus (n = 6; 0.93%), PFO (n = 23; 3.6%), and dense spontaneous echo contrast (n = 99; 15.3%). Both SEC and LAA thrombus were associated with persistent AF, higher CHA2DS2VASC score, increased LA size, reduced LAA flow velocity, and decreased left ventricular ejection fraction. PFO was not associated with prior AF ablation, and SEC was not associated with increased CVA incidence.\n\n\n\nCVA is a rare complication of AF ablation in patients with minimally interrupted anticoagulation. Pre-ablation TEE may be reasonably avoided in patients without high-risk features.", "affiliations": "Johns Hopkins Hospital Heart and Vascular Institute, Baltimore, Maryland.;Johns Hopkins Hospital Heart and Vascular Institute, Baltimore, Maryland.;Johns Hopkins Hospital Heart and Vascular Institute, Baltimore, Maryland.;Johns Hopkins Hospital Heart and Vascular Institute, Baltimore, Maryland.;Johns Hopkins Hospital Heart and Vascular Institute, Baltimore, Maryland.;Johns Hopkins Hospital Heart and Vascular Institute, Baltimore, Maryland.;Johns Hopkins Hospital Heart and Vascular Institute, Baltimore, Maryland.;Johns Hopkins Hospital Heart and Vascular Institute, Baltimore, Maryland.;Johns Hopkins Hospital Heart and Vascular Institute, Baltimore, Maryland.;Johns Hopkins Hospital Heart and Vascular Institute, Baltimore, Maryland.;Johns Hopkins Hospital Heart and Vascular Institute, Baltimore, Maryland. Electronic address: [email protected].", "authors": "Balouch|Muhammad|M|;Gucuk Ipek|Esra|E|;Chrispin|Jonathan|J|;Bajwa|Rizma J|RJ|;Zghaib|Tarek|T|;Berger|Ronald D|RD|;Ashikaga|Hiroshi|H|;Calkins|Hugh|H|;Nazarian|Saman|S|;Marine|Joseph E|JE|;Spragg|David D|DD|", "chemical_list": "D000925:Anticoagulants", "country": "United States", "delete": false, "doi": "10.1016/j.jacep.2016.09.011", "fulltext": null, "fulltext_license": null, "issn_linking": "2405-500X", "issue": "3(4)", "journal": "JACC. Clinical electrophysiology", "keywords": "ablation; atrial fibrillation; transesophageal echocardiography", "medline_ta": "JACC Clin Electrophysiol", "mesh_terms": "D000368:Aged; D000925:Anticoagulants; D001281:Atrial Fibrillation; D017115:Catheter Ablation; D017548:Echocardiography, Transesophageal; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012042:Registries; D012189:Retrospective Studies; D020521:Stroke; D013927:Thrombosis; D016896:Treatment Outcome", "nlm_unique_id": "101656995", "other_id": null, "pages": "329-336", "pmc": null, "pmid": "29759444", "pubdate": "2017-04", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Trends in Transesophageal Echocardiography Use, Findings, and Clinical Outcomes in the Era of Minimally Interrupted Anticoagulation for Atrial Fibrillation Ablation.", "title_normalized": "trends in transesophageal echocardiography use findings and clinical outcomes in the era of minimally interrupted anticoagulation for atrial fibrillation ablation" }

[ { "companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2017-BI-029724", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DABIGATRAN ETEXILATE MESYLATE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "022512", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ATRIAL FIBRILLATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PRADAXA" } ], "patientagegroup": null, "patientonsetage": "47", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Transient ischaemic attack", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SPRAGG D, BALOUCH M, IPEK E, CHRISPIN J, CHRISPIN J, BAJWA R, ET AL. TRENDS IN TRANSESOPHAGEAL ECHOCARDIOGRAPHY USE, FINDINGS, AND CLINICAL OUTCOMES IN THE ERA OF MINIMALLY INTERRUPTED ANTICOAGULATION FOR ATRIAL FIBRILLATION ABLATION. JACC. CLINICAL ELECTROPHYSIOLOGY. 2017;3:4:329-336.", "literaturereference_normalized": "trends in transesophageal echocardiography use findings and clinical outcomes in the era of minimally interrupted anticoagulation for atrial fibrillation ablation", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170529", "receivedate": "20170529", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13590959, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" } ]

{ "abstract": "Progressive multifocal leukoencephalopathy (PML) is a severe opportunistic infection of the central nervous system. A 52-year-old man with HIV infection, recently started on antiretroviral therapy, presented with symptoms of mental cloudiness, blurry vision and ataxia. MRI of the brain showed nodular perivascular space enhancement with surrounding vasogenic oedema and midline shift. A lumbar puncture revealed non-inflammatory cerebrospinal fluid and was positive for JC virus. As the patient developed worsening symptoms in the setting of initiation of antiretroviral therapy with immune recovery, a diagnosis of JC virus-associated immune reconstitution inflammatory syndrome (IRIS) was made. With recent literature on the use of CCR5 antagonist maraviroc in PML, our patient was started on maraviroc and noted to have improvement in PML IRIS. This is the first case of an HIV-positive patient successfully treated for PML IRIS with maraviroc, as verified by our literature review; also, our case has clinical implications in improving outcome in PML IRIS.", "affiliations": "Department of Internal Medicine, Baylor College of Medicine, Houston, Texas, USA.;Department of Internal Medicine, Baylor College of Medicine, Houston, Texas, USA.;Department of Internal Medicine, Baylor College of Medicine, Houston, Texas, USA Department of Medicine, Michael E DeBakey Veterans Affairs Medical Center, Houston, Texas, USA.", "authors": "Shahani|Lokesh|L|;Shah|Minal|M|;Tavakoli-Tabasi|Shahriar|S|", "chemical_list": "D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes; D014230:Triazoles; D000077592:Maraviroc", "country": "England", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "2015()", "journal": "BMJ case reports", "keywords": null, "medline_ta": "BMJ Case Rep", "mesh_terms": "D065100:CCR5 Receptor Antagonists; D018414:CD8-Positive T-Lymphocytes; D003510:Cyclohexanes; D018450:Disease Progression; D015658:HIV Infections; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome; D007577:JC Virus; D007968:Leukoencephalopathy, Progressive Multifocal; D008297:Male; D000077592:Maraviroc; D008875:Middle Aged; D016896:Treatment Outcome; D014230:Triazoles", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "26063110", "pubdate": "2015-06-10", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": "11517410;12086750;20298966;12218391;8451420;15750393;24476450;22687798;19901246;19129505;23733308;21908480;9571254;10194089;18753934;22382480;21840066", "title": "Immune reconstitution inflammatory syndrome in a patient with progressive multifocal leukoencephalopathy.", "title_normalized": "immune reconstitution inflammatory syndrome in a patient with progressive multifocal leukoencephalopathy" }

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IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME IN A PATIENT WITH PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY. BMJ CASE REPORTS. 2015;ARTICLE NO A904:1-3", "literaturereference_normalized": "immune reconstitution inflammatory syndrome in a patient with progressive multifocal leukoencephalopathy", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150803", "receivedate": "20150803", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11334257, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20151125" }, { "companynumb": "US-JNJFOC-20150721565", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DARUNAVIR" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "021976", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLETS", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HIV INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DARUNAVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TENOFOVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HIV INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TENOFOVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITONAVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HIV INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITONAVIR." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "EMTRICITABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HIV INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EMTRICITABINE" } ], "patientagegroup": "5", "patientonsetage": "52", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Immune reconstitution inflammatory syndrome", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Progressive multifocal leukoencephalopathy", "reactionmeddraversionpt": "18.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SHAHANI L, SHAH M, TAVAKOLI-TABASI S. 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{ "abstract": "We report the case of a 40-year-old patient followed for post-traumatic stress disorder. A re-evaluation of its pharmacological treatment with the introduction of mirtazapine (30 mg/day) was associated with a rhabdomyolysis (CK> 20,000 IU/L at day 3). The diagnosis of mirtazapine induced rhabdomyolysis was made. After withdrawal of this drug combined with a symptomatic treatment (hydratation), the patient recovered well and was discharged without any nephrological sequelae. This article is intended to underline the diagnostic approach to elevated CK activity and the potential role of the \"medical biologist\" as a consultant for the relevant use of biological examinations. A physiopathological mechanism of this rhabdomyolysis is also proposed.", "affiliations": "Département des laboratoires, Hôpital d'instruction des armées Bégin, Saint Mandé, France.;Service de psychiatrie, Hôpital d'instruction des armées Bégin, Saint Mandé, France.;Service de psychiatrie, Hôpital d'instruction des armées Bégin, Saint Mandé, France.;Département des laboratoires, Hôpital d'instruction des armées Bégin, Saint Mandé, France.;Service de psychiatrie, Hôpital d'instruction des armées Bégin, Saint Mandé, France.;Service de psychiatrie, Hôpital d'instruction des armées Bégin, Saint Mandé, France, Ecole du Val-de-Grâce, Paris, France.;Département des laboratoires, Hôpital d'instruction des armées Bégin, Saint Mandé, France, Ecole du Val-de-Grâce, Paris, France.", "authors": "Ratnam|Caroline|C|;Saguin|Emeric|E|;Keou|Symphonie|S|;Plantamura|Julie|J|;Mennessier|Coralie|C|;Lahutte|Bertrand|B|;Delacour|Hervé|H|", "chemical_list": "D014150:Antipsychotic Agents; D008803:Mianserin; D000078785:Mirtazapine", "country": "France", "delete": false, "doi": "10.1684/abc.2018.1351", "fulltext": null, "fulltext_license": null, "issn_linking": "0003-3898", "issue": "76(3)", "journal": "Annales de biologie clinique", "keywords": "advisory service; antipsychotic agents; creatine kinase; interpretative comments; mirtazapine; rhabdomyolysis", "medline_ta": "Ann Biol Clin (Paris)", "mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D006801:Humans; D008297:Male; D008803:Mianserin; D000078785:Mirtazapine; D012206:Rhabdomyolysis; D013313:Stress Disorders, Post-Traumatic", "nlm_unique_id": "2984690R", "other_id": null, "pages": "329-335", "pmc": null, "pmid": "29862972", "pubdate": "2018-06-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Antipsychotic induced rhabdomyolysis.", "title_normalized": "antipsychotic induced rhabdomyolysis" }

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{ "abstract": "OBJECTIVE\nWe present a case report of a patient who developed an epidural hematoma following an interlaminar epidural steroid injection with no risk factors aside from old age and aspirin use for secondary prevention.\n\n\nMETHODS\nA 79-year-old man developed an epidural hematoma requiring surgical treatment following an uncomplicated interlaminar epidural steroid injection performed for neurogenic claudication. In the periprocedural period, he continued aspirin for secondary prophylaxis following a myocardial infarction.\n\n\nCONCLUSIONS\nFor patients taking aspirin for primary or secondary prophylaxis, the American Society of Regional Anesthesia and Pain Medicine antiplatelet and anticoagulation guidelines for spine and pain procedures recommend a shared assessment and risk stratification when deciding to hold the medication for intermediate-risk neuraxial procedures. Cases such as this serve to highlight the importance of giving careful consideration to medical optimization of a patient even when a low- or intermediate-risk procedure is planned.", "affiliations": "From the Pain Division, Mayo Clinic Department of Anesthesiology and Perioperative Medicine, Rochester, MN.", "authors": "Sanders|Rebecca A|RA|;Bendel|Markus A|MA|;Moeschler|Susan M|SM|;Mauck|William D|WD|", "chemical_list": "D010975:Platelet Aggregation Inhibitors; D013256:Steroids; D001241:Aspirin", "country": "England", "delete": false, "doi": "10.1097/AAP.0000000000000730", "fulltext": null, "fulltext_license": null, "issn_linking": "1098-7339", "issue": "43(3)", "journal": "Regional anesthesia and pain medicine", "keywords": null, "medline_ta": "Reg Anesth Pain Med", "mesh_terms": "D000368:Aged; D001241:Aspirin; D046748:Hematoma, Epidural, Spinal; D006801:Humans; D007268:Injections, Epidural; D017116:Low Back Pain; D008279:Magnetic Resonance Imaging; D008297:Male; D010975:Platelet Aggregation Inhibitors; D012307:Risk Factors; D055502:Secondary Prevention; D013256:Steroids; D016896:Treatment Outcome", "nlm_unique_id": "9804508", "other_id": null, "pages": "310-312", "pmc": null, "pmid": "29319605", "pubdate": "2018-04", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Epidural Hematoma Following Interlaminar Epidural Injection in Patient Taking Aspirin.", "title_normalized": "epidural hematoma following interlaminar epidural injection in patient taking aspirin" }

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"6", "activesubstance": { "activesubstancename": "NIFEDIPINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NIFEDIPINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ROSUVASTATIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ROSUVASTATIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ZINC" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ZINC." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ATENOLOL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ATENOLOL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "NITROGLYCERIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NITROGLYCERIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "TAMSULOSIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TAMSULOSIN" } ], "patientagegroup": null, "patientonsetage": "79", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Extradural haematoma", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SANDERS RA, BENDEL MA, MOESCHLER SM, MAUCK WD. EPIDURAL HEMATOMA FOLLOWING INTERLAMINAR EPIDURAL INJECTION IN PATIENT TAKING ASPIRIN. REGION-ANESTH-PAIN-MED. 2018?43(3):310-312", "literaturereference_normalized": "epidural hematoma following interlaminar epidural injection in patient taking aspirin", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180625", "receivedate": "20180625", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15059095, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180711" } ]

{ "abstract": "The objective of this study was to compare short-term outcomes of neonatal opioid withdrawal syndrome (NOWS) treatment in infants exposed in-utero to opioids and selective serotonin reuptake inhibitors (SSRIs) or opioids alone.\n\n\n\nThis was a retrospective cohort study of mother-infant dyads, 34 weeks or greater gestation, receiving opioids and/or SSRIs during pregnancy. Intravenous or oral methadone was administered according to a pre-existing protocol for NOWS treatment guided by withdrawal scores. Primary outcome was length of treatment (LOT). Secondary outcomes included length of stay (LOS), total methadone exposure, time to symptom control, need for a second agent, and NOWS medications at discharge.\n\n\n\nFifty-five mother-infant dyads were included in the study. LOT was longer in the infants in the SSRI plus opioid group but not significantly different [24 ± 23 days (SSRI plus opioid) vs 20 ± 14 days (opioid alone); P = 0.78]. There was a trend towards shorter LOS (30 ± 22 day vs 27 ± 15 days; P = 0.86), lower total methadone exposure (3.2 ± 4.3 mg/kg vs 2.7 ± 5.1 mg/kg; P = 0.66), less time to control symptoms (1 ± 1.7 days vs 0.5 ± 0.36 days; P = 0.31) and less need for a second agent (OR 2.65, 95% CI 0.69-10.5) in the opioid only group, although these observations also did not reach statistical significance.\n\n\n\nThis study could not demonstrate a statistically significant difference in short-term NOWS outcome of LOT between the 2 groups. However, there was a trend towards longer LOT and LOS in the SSRI plus opioid group which could be clinically significant. A larger cohort may detect a true significant difference in these short-term outcomes.", "affiliations": "Department of Clinical Pharmacy, College of Pharmacy (VB-M); Department of Pediatrics, Michigan Medicine, University of Michigan (VB-M, JS, RES); Department of Pharmacy, Ascension St. John Hospital, Ann Arbor, MI (JR).", "authors": "Bhatt-Mehta|Varsha|V|;Richards|Jessika|J|;Sturza|Julie|J|;Schumacher|Robert E|RE|", "chemical_list": "D000701:Analgesics, Opioid; D017367:Serotonin Uptake Inhibitors", "country": "United States", "delete": false, "doi": "10.1097/ADM.0000000000000484", "fulltext": null, "fulltext_license": null, "issn_linking": "1932-0620", "issue": "13(3)", "journal": "Journal of addiction medicine", "keywords": null, "medline_ta": "J Addict Med", "mesh_terms": "D000328:Adult; D000701:Analgesics, Opioid; D003863:Depression; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007902:Length of Stay; D008297:Male; D008824:Michigan; D009357:Neonatal Abstinence Syndrome; D009293:Opioid-Related Disorders; D011247:Pregnancy; D011248:Pregnancy Complications; D011297:Prenatal Exposure Delayed Effects; D012189:Retrospective Studies; D017367:Serotonin Uptake Inhibitors; D062606:Tertiary Care Centers; D055815:Young Adult", "nlm_unique_id": "101306759", "other_id": null, "pages": "227-234", "pmc": null, "pmid": "30489344", "pubdate": "2019", "publication_types": "D016428:Journal Article", "references": null, "title": "Impact of In-utero Exposure to Selective Serotonin Reuptake Inhibitors and Opioids on Neonatal Opioid Withdrawal Syndrome.", "title_normalized": "impact of in utero exposure to selective serotonin reuptake inhibitors and opioids on neonatal opioid withdrawal syndrome" }

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IMPACT OF IN-UTERO EXPOSURE TO SELECTIVE SEROTONIN REUPTAKE INHIBITORS AND OPIOIDS ON NEONATAL OPIOID WITHDRAWAL SYNDROME. JOURNAL OF ADDICTION MEDICINE. 2019?13(3):227-234", "literaturereference_normalized": "impact of in utero exposure to selective serotonin reuptake inhibitors and opioids on neonatal opioid withdrawal syndrome", "qualification": "2", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190924", "receivedate": "20190924", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16847224, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20191005" }, { "companynumb": "US-ALLERGAN-1938627US", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "UNSPECIFIED INGREDIENT" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "EXPOSURE DURING PREGNANCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OPIOIDS" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "FLUOXETINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "021860", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "EXPOSURE DURING PREGNANCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUOXETINE HCL UNK" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug withdrawal syndrome neonatal", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Pregnancy", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BHATT-MEHTA V, RICHARDS J, STURZA J, SCHUMACHER RE. IMPACT OF IN-UTERO EXPOSURE TO SELECTIVE SEROTONIN REUPTAKE INHIBITORS AND OPIOIDS ON NEONATAL OPIOID WITHDRAWAL SYNDROME. 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IMPACT OF IN-UTERO EXPOSURE TO SELECTIVE SEROTONIN REUPTAKE INHIBITORS AND OPIOIDS ON NEONATAL OPIOID WITHDRAWAL SYNDROME. JOURNAL OF ADDICTION MEDICINE. 2019?13(3):227-234", "literaturereference_normalized": "impact of in utero exposure to selective serotonin reuptake inhibitors and opioids on neonatal opioid withdrawal syndrome", "qualification": "2", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190924", "receivedate": "20190924", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16847225, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20191005" }, { "companynumb": "US-ALLERGAN-1938629US", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "UNSPECIFIED INGREDIENT" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "EXPOSURE DURING PREGNANCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OPIOIDS" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "FLUOXETINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "021860", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "EXPOSURE DURING PREGNANCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUOXETINE HCL UNK" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug withdrawal syndrome neonatal", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Pregnancy", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BHATT-MEHTA V, RICHARDS J, STURZA J, SCHUMACHER RE. IMPACT OF IN-UTERO EXPOSURE TO SELECTIVE SEROTONIN REUPTAKE INHIBITORS AND OPIOIDS ON NEONATAL OPIOID WITHDRAWAL SYNDROME. JOURNAL OF ADDICTION MEDICINE. 2019?13(3):227-234", "literaturereference_normalized": "impact of in utero exposure to selective serotonin reuptake inhibitors and opioids on neonatal opioid withdrawal syndrome", "qualification": "2", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190924", "receivedate": "20190924", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16847223, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20191005" } ]

{ "abstract": "This paper reports the first case of a patient with hepatocellular carcinoma with lymph node metastasis treated by sorafenib combined with gemcitabine plus oxaliplatin, with a partial response and normalization of α fetoprotein, which allowed curative surgery. The potential synergy between these three drugs needs to be confirmed, and is currently being investigated in a randomized phase II trial.", "affiliations": "Department of Gastroenterology, Europeen Georges Pompidou Hospital, Medical University, 75908 Paris, France. [email protected]", "authors": "Williet|Nicolas|N|;Dubreuil|Olivier|O|;Boussaha|Tarek|T|;Trouilloud|Isabelle|I|;Landi|Bruno|B|;Housset|Martin|M|;Botti|Muriel|M|;Rougier|Philippe|P|;Belghiti|Jacques|J|;Taieb|Julien|J|", "chemical_list": "D001557:Benzenesulfonates; D009944:Organoplatinum Compounds; D010671:Phenylurea Compounds; D011725:Pyridines; D000077150:Oxaliplatin; D003841:Deoxycytidine; D009536:Niacinamide; D000077157:Sorafenib; C056507:gemcitabine", "country": "United States", "delete": false, "doi": "10.3748/wjg.v17.i17.2255", "fulltext": null, "fulltext_license": null, "issn_linking": "1007-9327", "issue": "17(17)", "journal": "World journal of gastroenterology", "keywords": "Gemcitabine; Hepatocellular carcinoma; Neoadjuvant therapy; Oxaliplatin; Sorafenib", "medline_ta": "World J Gastroenterol", "mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001557:Benzenesulfonates; D006528:Carcinoma, Hepatocellular; D003841:Deoxycytidine; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009536:Niacinamide; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D010671:Phenylurea Compounds; D011725:Pyridines; D000077157:Sorafenib", "nlm_unique_id": "100883448", "other_id": null, "pages": "2255-8", "pmc": null, "pmid": "21633538", "pubdate": "2011-05-07", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "19106535;15231247;10412945;17376045;16622265;10951336;15913915;15864213;16728631;18172362;20075738;16798837;14669287;17160521;18650514;15637262;18412149;21351269;19160192;12181257;20207091;19581537;17330837", "title": "Neoadjuvant sorafenib combined with gemcitabine plus oxaliplatin in advanced hepatocellular carcinoma.", "title_normalized": "neoadjuvant sorafenib combined with gemcitabine plus oxaliplatin in advanced hepatocellular carcinoma" }

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METER, ADMINISTERED ON DAY 1 OF THE CYCLE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2010", "drugstartdateformat": "602", "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": "205529", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "ADMINISTERED ON DAY 2; CYCLICAL THERAPY (GEMOX REGIMEN)", "drugenddate": "2010", "drugenddateformat": "602", "drugindication": "Hepatocellular carcinoma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2010", "drugstartdateformat": "602", "drugstructuredosagenumb": "100", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "SORAFENIB" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "800 MILLIGRAM, ONCE A DAY (ADMINISTERED ALONGSIDE THE GEMOX REGIMEN)", "drugenddate": "2010", "drugenddateformat": "602", "drugindication": "Hepatocellular carcinoma", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2010", "drugstartdateformat": "602", "drugstructuredosagenumb": "800", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SORAFENIB" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "SORAFENIB" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MILLIGRAM, ONCE A DAY", "drugenddate": "2010", "drugenddateformat": "602", "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2010", "drugstartdateformat": "602", "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SORAFENIB" } ], "patientagegroup": null, "patientonsetage": "61", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "94", "reaction": [ { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "24.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Asthenia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20100101" } }, "primarysource": { "literaturereference": "Williet N.Dubreuil O, Boussaha T, Trouilloud I, Landi B, Housset M.. Neoadjuvant sorafenib combined with gemcitabine plus oxaliplatin in advanced hepatocellular carcinoma.. World Journal of Gastroenterology. 2011;17(17):2255-2258", "literaturereference_normalized": "neoadjuvant sorafenib combined with gemcitabine plus oxaliplatin in advanced hepatocellular carcinoma", "qualification": "1", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20220201", "receivedate": "20200306", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17507556, "safetyreportversion": 8, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "FR-PFIZER INC-2020068217", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "SORAFENIB" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG, 2X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATOCELLULAR CARCINOMA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SORAFENIB" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "078813", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG/M2, CYCLIC, (FOUR CYCLES,ON DAY 2, REPEATED EVERY 2 WK )", "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATOCELLULAR CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "GEMCITABINE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "200795", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "UNK, CYCLIC (1 G/M2 ON DAY 1, FOUR CYCLES, REPEATED EVERY 2 WK)", "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATOCELLULAR CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": "61", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "94", "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Asthenia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILLIET, N.. NEOADJUVANT SORAFENIB COMBINED WITH GEMCITABINE PLUS OXALIPLATIN IN ADVANCED HEPATOCELLULAR CARCINOMA. WORLD JOURNAL OF GASTROENTEROLOGY. 2011?17 (17):10.3748/WJG.V17.I17.2255", "literaturereference_normalized": "neoadjuvant sorafenib combined with gemcitabine plus oxaliplatin in advanced hepatocellular carcinoma", "qualification": "1", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20210407", "receivedate": "20200221", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17445749, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210716" }, { "companynumb": "FR-BAYER-2011-048711", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "SORAFENIB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021923", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Film-coated tablet", "drugdosagetext": "400 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Hepatocellular carcinoma", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NEXAVAR" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SORAFENIB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021923", "drugbatchnumb": null, "drugcharacterization": "1", 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"drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2010", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE HYDROCHLORIDE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG/M2, ON DAY 2 EVERY 2 WK", "drugenddate": "2010", "drugenddateformat": "602", "drugindication": "Hepatocellular carcinoma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2010", "drugstartdateformat": "602", "drugstructuredosagenumb": "100", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN" } ], "patientagegroup": "5", "patientonsetage": "61", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "94", "reaction": [ { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "24.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Asthenia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20100101" } }, "primarysource": { "literaturereference": "Williet N, Dubreuil O, Boussaha T, Trouilloud I, Landi B, Rougier P, Taieb J, Housset M, Botti M, Belghiti J. Neoadjuvant sorafenib combined with gemcitabine plus oxaliplatin in advanced hepatocellular carcinoma. 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"drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "800", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SORAFENIB" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "SORAFENIB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2010", "drugstartdateformat": "602", "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SORAFENIB" } ], "patientagegroup": null, "patientonsetage": "61", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "94", "reaction": [ { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "24.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Asthenia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20100101" } }, "primarysource": { "literaturereference": "Williet N, Dubreuil O, Boussaha T, Trouilloud I, Landi B, Housset M, et al.. Neoadjuvant sorafenib combined with gemcitabine plus oxaliplatin in advanced hepatocellular carcinoma.. World Journal of Gastroenterology.. 2011;17 (17):2255-2258", "literaturereference_normalized": "neoadjuvant sorafenib combined with gemcitabine plus oxaliplatin in advanced hepatocellular carcinoma", "qualification": "1", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20220303", "receivedate": "20200319", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17562655, "safetyreportversion": 8, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220424" }, { "companynumb": "FR-FRESENIUS KABI-FK202104321", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "GEMCITABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090242", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "1 G/M2, EVERY 2 WK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATOCELLULAR CARCINOMA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "2", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "078811", "drugbatchnumb": "UNKNOWN,UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "DOSE:100 MG/M2, EVERY 2 WK?FOUR CYCLES OF THE GEMOX REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATOCELLULAR CARCINOMA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "2", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN (MANUFACTURER UNKNOWN)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SORAFENIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "400 MG, TWICE, EVERY DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATOCELLULAR CARCINOMA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SORAFENIB" } ], "patientagegroup": null, "patientonsetage": "61", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "94", "reaction": [ { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Asthenia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILLIET N, DUBREUIL O, BOUSSAHA T, TROUILLOUD I, LANDI B, HOUSSET M. NEOADJUVANT SORAFENIB COMBINED WITH GEMCITABINE PLUS OXALIPLATIN IN ADVANCED HEPATOCELLULAR CARCINOMA.. WORLD JOURNAL OF GASTROENTEROLOGY. 2011 MAY 07?17(17):2255?2258.", "literaturereference_normalized": "neoadjuvant sorafenib combined with gemcitabine plus oxaliplatin in advanced hepatocellular carcinoma", "qualification": "1", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20210429", "receivedate": "20210429", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19195483, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" } ]

{ "abstract": "OBJECTIVE\nDiffuse high-grade gliomas are known to develop in children after cranial irradiation for other malignancies. Here, clinicopathological characteristics are outlined.\n\n\nMETHODS\nNine children received cranial irradiation and chemotherapy for medulloblastoma (n=2) or acute lymphoblastic leukemia (n=7). They developed a high-grade glioma 7-14 years thereafter. Clinical charts, radiologic findings, and pathologic specimens were reviewed. Archival material was stained immunohistochemically.\n\n\nCONCLUSIONS\nGliomas evolving as second malignant neoplasms show peculiarities and differ in some aspects from their \"spontaneous\" counterparts. Most are supratentorial, contrast-enhancing, space-occupying lesions. They are composed mainly of small undifferentiated cells, which are mainly negative for glial fibrillary acidic protein and positive for microtubule associated proteins 2 (MAP2). Epidermal growth factor receptor labeling could not be detected in any of them. Ki67-labeling was usually high, whereas p53- and h-ras p21-staining was variable. The median survival was only 12 months despite intensive treatment.", "affiliations": "Institut für Neuropathologie, Universitätsklinikum des Saarlandes, 66421, Homburg/Saar, Germany. [email protected]", "authors": "Romeike|Bernd F M|BF|;Kim|Yoo-Jin|YJ|;Steudel|Wolf-Ingo|WI|;Graf|Norbert|N|", "chemical_list": "D005904:Glial Fibrillary Acidic Protein; D019394:Ki-67 Antigen; C489788:MAP2 protein, human; D008869:Microtubule-Associated Proteins", "country": "Germany", "delete": false, "doi": "10.1007/s00381-006-0199-z", "fulltext": null, "fulltext_license": null, "issn_linking": "0256-7040", "issue": "23(2)", "journal": "Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery", "keywords": null, "medline_ta": "Childs Nerv Syst", "mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001932:Brain Neoplasms; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005904:Glial Fibrillary Acidic Protein; D005910:Glioma; D006801:Humans; D019394:Ki-67 Antigen; D008279:Magnetic Resonance Imaging; D008297:Male; D008869:Microtubule-Associated Proteins; D016609:Neoplasms, Second Primary; D010372:Pediatrics; D012189:Retrospective Studies", "nlm_unique_id": "8503227", "other_id": null, "pages": "185-93", "pmc": null, "pmid": "17021727", "pubdate": "2007-02", "publication_types": "D016430:Clinical Trial; D016428:Journal Article", "references": "14714135;176331;2536806;10406363;10329596;8468607;14704813;8374881;15146346;1845944;12865017;12651207;1905840;9228960;6326557;3072075;9007876;3173432;16550739;9810442;10779419;6251397;12917300;11058888;15926395;1922234;11878577", "title": "Diffuse high-grade gliomas as second malignant neoplasms after radio-chemotherapy for pediatric malignancies.", "title_normalized": "diffuse high grade gliomas as second malignant neoplasms after radio chemotherapy for pediatric malignancies" }

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LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" } ], "patientagegroup": "3", "patientonsetage": "12", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Glioblastoma multiforme", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intracranial pressure increased", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neurological examination abnormal", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Glioma", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ROMEIKE B, KIM YJ, STEUDEL WI, GRAF N. DIFFUSE HIGH-GRADE GLIOMAS AS SECOND MALIGNANT NEOPLASMS AFTER RADIO-CHEMOTHERAPY FOR PEDIATRIC MALIGNANCIES. CHILDS NERV SYST 2007?23:185-93.", "literaturereference_normalized": "diffuse high grade gliomas as second malignant neoplasms after radio chemotherapy for pediatric malignancies", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20190417", "receivedate": "20190410", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16180274, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "DE-JNJFOC-20190415624", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "THIOGUANINE ANHYDROUS" }, "drugadditional": null, 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"medicinalproduct": "CYTARABINE." } ], "patientagegroup": "3", "patientonsetage": "11", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Glioblastoma multiforme", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Nervous system disorder", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Intracranial pressure increased", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Glioma", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ROMEIKE BF, KIM YJ, STEUDEL WI, GRAF N. DIFFUSE HIGH-GRADE GLIOMAS AS SECOND MALIGNANT NEOPLASMS AFTER RADIO-CHEMOTHERAPY FOR PEDIATRIC MALIGNANCIES. CHILD^S NERVOUS SYSTEM 2007?23 (2):185-93.", "literaturereference_normalized": "diffuse high grade gliomas as second malignant neoplasms after radio chemotherapy for pediatric malignancies", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20190419", "receivedate": "20190412", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16189364, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "DE-SA-200712043GDDC", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", 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"medicinalproduct": "CYCLOPHOSPHAMIDE" } ], "patientagegroup": null, "patientonsetage": "11", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Glioblastoma multiforme", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "Romeike BFM, Kim Y-J, Steudel W-I, Graf N... Diffuse high-grade gliomas as second malignant neoplasms after radio-chemotherapy for pediatric malignancies. Childs Nerv Syst.. 2007;23:185-93", "literaturereference_normalized": "diffuse high grade gliomas as second malignant neoplasms after radio chemotherapy for pediatric malignancies", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20211022", "receivedate": "20190829", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16756567, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 1, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220303" }, { "companynumb": "DE-PFIZER INC-2007024611", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VINCRISTINE SULFATE" }, "drugadditional": null, 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"drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CORTISONE" } ], "patientagegroup": null, "patientonsetage": "13", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Glioma", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Second primary malignancy", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ROMEIKE, B.. DIFFUSE HIGH-GRADE GLIOMAS AS SECOND MALIGNANT NEOPLASMS AFTER RADIO-CHEMOTHERAPY FOR PEDIATRIC MALIGNANCIES. CHILDS NERV SYST. 2007?23/2:185 - 193", "literaturereference_normalized": "diffuse high grade gliomas as second malignant neoplasms after radio chemotherapy for pediatric malignancies", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20190423", "receivedate": "20070331", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 6276657, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190711" }, { "companynumb": "DE-JNJFOC-20190409361", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CORTISONE\\HYDROCORTISONE" }, 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null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": "START PERIOD 10 YEARS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MERCAPTOPURINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, 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"drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE SULFATE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOXORUBICIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "050718", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "LIPOSOME INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ASPARAGINASE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" } ], "patientagegroup": "4", "patientonsetage": "15", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Nervous system disorder", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Intracranial pressure increased", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Glioma", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Astrocytoma", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Glioblastoma multiforme", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ROMEIKE B, KIM YJ, STEUDEL WI, GRAF N. DIFFUSE HIGH GRADE GLIOMAS AS SECOND MALIGNANT NEOPLASMS AFTER RADIO-CHEMOTHERAPY FOR PEDIATRIC MALIGNANCIES. CHILDS NERVOUS SYSTEM 2007?23 (2):185-193.", "literaturereference_normalized": "diffuse high grade gliomas as second malignant neoplasms after radio chemotherapy for pediatric malignancies", "qualification": "5", "reportercountry": "FR" }, "primarysourcecountry": "DE", "receiptdate": "20190430", "receivedate": "20190416", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16202958, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "DE-SA-200712047GDDC", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "4", 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Diffuse high-grade gliomas as second malignant neoplasms after radio-chemotherapy for pediatric malignancies.. Childs Nerv Syst.. 2007;23:185-93", "literaturereference_normalized": "diffuse high grade gliomas as second malignant neoplasms after radio chemotherapy for pediatric malignancies", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20211018", "receivedate": "20190829", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16756558, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 1, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220304" }, { "companynumb": "DE-SA-200712041GDDC", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "4", "drugadministrationroute": 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"patientweight": null, "reaction": [ { "reactionmeddrapt": "Glioblastoma multiforme", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Nervous system disorder", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Intracranial pressure increased", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Glioma", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ROMEIKE BFM, KIM YJ, STEUDEL WI, GRAF N. DIFFUSE HIGH GRADE GLIOMAS AS SECOND MALIGNANT NEOPLASMS AFTER RADIO-CHEMOTHERAPY FOR PEDIATRIC MALIGNANCIES. Childs Nerv Syst. 2007;23 (02):185-93", "literaturereference_normalized": "diffuse high grade gliomas as second malignant neoplasms after radio chemotherapy for pediatric malignancies", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20211022", "receivedate": "20190830", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16760476, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 1, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220303" }, { "companynumb": "DE-SA-200712053GDDC", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "4", 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"summary": null }, "primarysource": { "literaturereference": "Romeike BFM, Kim Y-J, Steudel W-I, Graf N.. Diffuse high grade gliomas as second malignant neoplasms after radio-chemotherapy for pediatric malignancies.. 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DIFFUSE HIGH-GRADE GLIOMAS AS SECOND MALIGNANT NEOPLASMS AFTER RADIO-CHEMOTHERAPY FOR PEDIATRIC MALIGNANCIES. 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use in unapproved indication", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Glioblastoma multiforme", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ROMEIKE B, KIM YJ, STEUDEL WI, GRAF N. DIFFUSE HIGH GRADE GLIOMAS AS SECOND MALIGNANT NEOPLASMS AFTER RADIO-CHEMOTHERAPY FOR PEDIATRIC MALIGNANCIES. . 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null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." } ], "patientagegroup": null, "patientonsetage": "12", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Intracranial pressure increased", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Glioblastoma multiforme", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Glioma", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Neurological examination abnormal", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ROMEIKE BFM, KIM Y-J, STEUDEL W-I, GRAF N... DIFFUSE HIGH-GRADE GLIOMAS AS SECOND MALIGNANT NEOPLASMS AFTER RADIO-CHEMOTHERAPY FOR PEDIATRIC MALIGNANCIES.. CHILDS NERV SYST... 2007?23(2):185-93", "literaturereference_normalized": "diffuse high grade gliomas as second malignant neoplasms after radio chemotherapy for pediatric malignancies", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20190417", "receivedate": "20190410", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 16178850, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "DE-PFIZER INC-2007024620", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "POWDER FOR SOLUTION FOR INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "071484", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MERCAPTOPURINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MERCAPTOPURINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, 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"drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DAUNORUBICIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DAUNORUBICIN HYDROCHLORIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOXORUBICIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "050467", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN" } ], "patientagegroup": null, "patientonsetage": "19", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Glioma", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Second primary malignancy", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ROMEIKE, B.. DIFFUSE HIGH-GRADE GLIOMAS AS SECOND MALIGNANT NEOPLASMS AFTER RADIO-CHEMOTHERAPY FOR PEDIATRIC MALIGNANCIES. 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{ "abstract": "Cytomegalovirus encephalitis is a rare but life-threatening infection in non-AIDS patients. To our knowledge, no case that followed conventional treatment for Hodgkin's lymphoma has been reported. We present a patient with Hodgkin's disease in complete remission after combined modality treatment who was succesfully treated with a combination of ganciclovir and foscarnet.", "affiliations": "Antwerp University Hospital, Division of Hematology, Edegem, Belgium. [email protected]", "authors": "Van Droogenbroeck|J|J|;De Ceuninck|M|M|;Snoeck|H W|HW|;Schroyens|W|W|;Berneman|Z|Z|", "chemical_list": "D000998:Antiviral Agents; D017245:Foscarnet; D015774:Ganciclovir", "country": "Germany", "delete": false, "doi": "10.1007/s002770050384", "fulltext": null, "fulltext_license": null, "issn_linking": "0939-5555", "issue": "76(3-4)", "journal": "Annals of hematology", "keywords": null, "medline_ta": "Ann Hematol", "mesh_terms": "D000998:Antiviral Agents; D003131:Combined Modality Therapy; D003586:Cytomegalovirus Infections; D018792:Encephalitis, Viral; D005260:Female; D017245:Foscarnet; D015774:Ganciclovir; D006689:Hodgkin Disease; D006801:Humans; D008875:Middle Aged; D012074:Remission Induction", "nlm_unique_id": "9107334", "other_id": null, "pages": "179-81", "pmc": null, "pmid": "9619737", "pubdate": "1998", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Successful treatment of cytomegalovirus encephalitis in a patient with Hodgkin's disease in remission.", "title_normalized": "successful treatment of cytomegalovirus encephalitis in a patient with hodgkin s disease in remission" }

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"801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Encephalitis cytomegalovirus", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Retinitis viral", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VAN, D.. SUCCESSFUL TREATMENT OF CYTOMEGALOVIRUS ENCEPHALITIS IN A PATIENT WITH HODGKIN^S DISEASE IN REMISSION. ANN HEMATOL. 1998?76:179-181", "literaturereference_normalized": "successful treatment of cytomegalovirus encephalitis in a patient with hodgkin s disease in remission", "qualification": "3", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20181015", "receivedate": "20181015", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15500468, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "BE-BAUSCH-BL-2018-028978", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FOSCARNET" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ENCEPHALITIS CYTOMEGALOVIRUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FOSCARNET" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "GANCICLOVIR" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "022211", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RETINITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GANCICLOVIR." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FOSCARNET" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RETINITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FOSCARNET" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "GANCICLOVIR" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "022211", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ENCEPHALITIS CYTOMEGALOVIRUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GANCICLOVIR." } ], "patientagegroup": null, "patientonsetage": "50", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "VAN D, DE CEUNINCK M, SNOECK H, SCHROYENS W, BERNEMAN Z. SUCCESSFUL TREATMENT OF CYTOMEGALOVIRUS ENCEPHALITIS IN A PATIENT WITH HODGKIN^S DISEASE IN REMISSION. ANNALS OF HEMATOLOGY. 1998?76:179-181.", "literaturereference_normalized": "successful treatment of cytomegalovirus encephalitis in a patient with hodgkin s disease in remission", "qualification": "3", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20181231", "receivedate": "20181024", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15545702, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" } ]

{ "abstract": "Cutaneous eruptions and hypersensitivity represent frequently reported side effects of anti-seizure medications. However, these side-effects have rarely been previously reported for lacosamide, a newer-generation anti-seizure medication with a novel mechanism of action. Here, we report a case of diffuse skin eruption in a patient with history of epilepsy soon after initiation of lacosamide. The rash resolved after discontinuation of lacosamide and use of antihistamines and steroids. We also review the information on drug hypersensitivity syndrome.", "affiliations": "Department of Neurology.;Department of Neurology.;Department of Dermatology, George Washington University, Washington DC, USA.", "authors": "Koubeissi|Mohamad Z|MZ|;Vismer|Marta|M|;Ehrlich|Alison|A|", "chemical_list": "D000081:Acetamides; D000927:Anticonvulsants; D000078334:Lacosamide", "country": "France", "delete": false, "doi": "10.1684/epd.2014.0667", "fulltext": null, "fulltext_license": null, "issn_linking": "1294-9361", "issue": "16(3)", "journal": "Epileptic disorders : international epilepsy journal with videotape", "keywords": "allergic; lacosamide; rash", "medline_ta": "Epileptic Disord", "mesh_terms": "D000081:Acetamides; D000328:Adult; D000927:Anticonvulsants; D004827:Epilepsy; D005076:Exanthema; D005260:Female; D006801:Humans; D000078334:Lacosamide", "nlm_unique_id": "100891853", "other_id": null, "pages": "380-3", "pmc": null, "pmid": "25035958", "pubdate": "2014-09", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Lacosamide-induced rash.", "title_normalized": "lacosamide induced rash" }

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"ZONISAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "EPILEPSY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ZONISAMIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEVETIRACETAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "500 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVEPSY" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEVETIRACETAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "FOR THREE YEARS", "drugenddate": null, "drugenddateformat": null, "drugindication": "EPILEPSY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVEPSY" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ZONISAMIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ZONISAMIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ZONISAMIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ZONISAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TOPIRAMATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "EPILEPSY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOPIRAMATE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Rash", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rash papular", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Migraine", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Depression", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Aggression", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Erythema", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pruritus", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KOUBEISSI MZ, VISMER M., EHRLICH A. LACOSAMIDE-INDUCED RASH. EPILEPTIC DISORDERS. 2014?16 (3):380-383", "literaturereference_normalized": "lacosamide induced rash", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20151016", "receivedate": "20151016", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11636584, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" }, { "companynumb": "US-JNJFOC-20141017547", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "LEVETIRACETAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVETIRACETAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DIPHENHYDRAMINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RASH PAPULAR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIPHENHYDRAMINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LACOSAMIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LACOSAMIDE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LACOSAMIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LACOSAMIDE" } ], "patientagegroup": "5", "patientonsetage": "36", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rash", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective for unapproved indication", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Therapeutic response unexpected", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KOUBEISSI MZ, VISMER M, EHRLICH A. LACOSAMIDE-INDUCED RASH. EPILEPTIC DISORDERS 2014;16 (3):380-3.", "literaturereference_normalized": "lacosamide induced rash", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20141103", "receivedate": "20141103", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10559034, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150529" }, { "companynumb": "US-JNJFOC-20141014596", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TOPIRAMATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "020505", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "EPILEPSY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOPIRAMATE." } ], "patientagegroup": "5", "patientonsetage": "36", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Migraine", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KOUBEISSI MZ, VISMER M, EHRLICH A. LACOSAMIDE-INDUCED RASH. EPILEPTIC DISORDERS 2014;16(3):380-3.", "literaturereference_normalized": "lacosamide induced rash", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150525", "receivedate": "20150321", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10938959, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150821" } ]

{ "abstract": "We report a 61-year-old man with intracranial multiple myeloma (MM) presenting as a posttransplant lymphoproliferative disorder (PTLD) following a kidney transplant. Two months after his transplant, the man developed acute rejection with Epstein-Barr virus (EBV) viremia, requiring aggressive immunosuppression. Twenty months following transplantation, the patient presented with multiple neurologic deficits. Imaging revealed numerous lytic lesions in the skull, most conspicuously a 4.1cm right frontal skull mass with prominent intracranial extension. Histologic sections of the frontal bone lesion showed sheets of atypical plasma cells that were positive for CD138 and kappa immunoglobulin light chains. Chromogenic in situ hybridization for EBV-encoded small RNA was also positive. Plasma cell neoplasms, either as MM or a plasmacytoma, are one of the least common forms of PTLD, and their rarity limits the possibility of major studies to detail their behavior. Most often seen after renal transplantation, the majority are EBV-driven, similarly to other PTLD. While studies have demonstrated several risk factors, behavior and optimal management of PTLD plasma cell neoplasms are unknown. Plasma cell neoplasms affect the nervous system in a variety of ways but rarely via intracranial disease. MM usually presents initially with several classic signs and symptoms, but our patient's presentation was typical of a localized brain tumor with generalized and focal gross neurologic defects.", "affiliations": "Department of Pathology, Cleveland Clinic, Level 25, 9500 Euclid Avenue, Cleveland, OH 44195, USA; Department of Pathology, University of Colorado School of Medicine, Aurora, CO, USA.;Department of Pathology, Cleveland Clinic, Level 25, 9500 Euclid Avenue, Cleveland, OH 44195, USA. Electronic address: [email protected].", "authors": "Wilberger|Adam C|AC|;Prayson|Richard A|RA|", "chemical_list": null, "country": "Scotland", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0967-5868", "issue": "22(11)", "journal": "Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia", "keywords": "Brain; Epstein–Barr virus; Multiple myeloma; Posttransplant lymphoproliferative disorder", "medline_ta": "J Clin Neurosci", "mesh_terms": "D001932:Brain Neoplasms; D020031:Epstein-Barr Virus Infections; D004854:Herpesvirus 4, Human; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D012307:Risk Factors", "nlm_unique_id": "9433352", "other_id": null, "pages": "1850-1", "pmc": null, "pmid": "26375326", "pubdate": "2015-11", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Intracranial involvement of posttransplant lymphoproliferative disorder multiple myeloma.", "title_normalized": "intracranial involvement of posttransplant lymphoproliferative disorder multiple myeloma" }

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INTRACRANIAL INVOLVEMENT OF POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDER MULTIPLE MYELOMA. 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INTRACRANIAL INVOLVEMENT OF POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDER MULTIPLE MYELOMA. 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INTRACRANIAL INVOLVEMENT OF POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDER MULTIPLE MYELOMA. J CLIN NEUROSCI. 2015;22(11):1850-1", "literaturereference_normalized": "intracranial involvement of posttransplant lymphoproliferative disorder multiple myeloma", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170719", "receivedate": "20170719", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13767449, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" }, { "companynumb": "US-TEVA-678747USA", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "KIDNEY TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "4 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "KIDNEY TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "65457", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "KIDNEY TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." } ], "patientagegroup": null, "patientonsetage": "61", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Post transplant lymphoproliferative disorder", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Plasma cell myeloma", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILBERGER AC, PRAYSON RA. INTRACRANIAL INVOLVEMENT OF POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDER MULTIPLE MYELOMA. J-CLIN-NEUROSCI 2015;22(11):1850-1.", "literaturereference_normalized": "intracranial involvement of posttransplant lymphoproliferative disorder multiple myeloma", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160722", "receivedate": "20160722", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12582505, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" } ]

{ "abstract": "OBJECTIVE\nThe pathogenesis, viral localization and histopathological features of Middle East respiratory syndrome - coronavirus (MERS-CoV) in humans are not described sufficiently. The aims of this study were to explore and define the spectrum of histological and ultrastructural pathological changes affecting various organs in a patient with MERS-CoV infection and represent a base of MERS-CoV histopathology.\n\n\nRESULTS\nWe analysed the post-mortem histopathological findings and investigated localisation of viral particles in the pulmonary and extrapulmonary tissue by transmission electron microscopic examination in a 33-year-old male patient of T cell lymphoma, who acquired MERS-CoV infection. Tissue needle biopsies were obtained from brain, heart, lung, liver, kidney and skeletal muscle. All samples were collected within 45 min from death to reduce tissue decomposition and artefact. Histopathological examination showed necrotising pneumonia, pulmonary diffuse alveolar damage, acute kidney injury, portal and lobular hepatitis and myositis with muscle atrophic changes. The brain and heart were histologically unremarkable. Ultrastructurally, viral particles were localised in the pneumocytes, pulmonary macrophages, renal proximal tubular epithelial cells and macrophages infiltrating the skeletal muscles.\n\n\nCONCLUSIONS\nThe results highlight the pulmonary and extrapulmonary pathological changes of MERS-CoV infection and provide the first evidence of the viral presence in human renal tissue, which suggests tissue trophism for MERS-CoV in kidney.", "affiliations": "Division of Anatomical Pathology, Department of Pathology and Laboratory Medicine, King Abdulaziz Medical City, Riyadh, Saudi Arabia.;King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.;King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.;King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.;Division of Anatomical Pathology, Department of Pathology and Laboratory Medicine, King Abdulaziz Medical City, Riyadh, Saudi Arabia.;Division of Anatomical Pathology, Department of Pathology and Laboratory Medicine, King Abdulaziz Medical City, Riyadh, Saudi Arabia.;King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.;King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.;King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.;King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.;King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.;King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.;King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.", "authors": "Alsaad|Khaled O|KO|http://orcid.org/0000-0003-3389-9035;Hajeer|Ali H|AH|;Al Balwi|Mohammed|M|;Al Moaiqel|Mohammed|M|;Al Oudah|Nourah|N|;Al Ajlan|Abdulaziz|A|;AlJohani|Sameera|S|;Alsolamy|Sami|S|;Gmati|Giamal E|GE|;Balkhy|Hanan|H|;Al-Jahdali|Hamdan H|HH|;Baharoon|Salim A|SA|;Arabi|Yaseen M|YM|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1111/his.13379", "fulltext": null, "fulltext_license": null, "issn_linking": "0309-0167", "issue": "72(3)", "journal": "Histopathology", "keywords": "MERS-CoV; Middle East respiratory syndrome coronavirus; electron microscopy; extra pulmonary; histopathology; pulmonary; renal", "medline_ta": "Histopathology", "mesh_terms": "D000328:Adult; D018352:Coronavirus Infections; D006801:Humans; D008297:Male; D046529:Microscopy, Electron, Transmission; D065207:Middle East Respiratory Syndrome Coronavirus", "nlm_unique_id": "7704136", "other_id": null, "pages": "516-524", "pmc": null, "pmid": "28858401", "pubdate": "2018-02", "publication_types": "D002363:Case Reports", "references": "27426423;23075143;26486634;23486063;16009768;27572168;24474051;24364985;27051251;15609228;24062443;26857507;23727167;28858401;14767982;26713056;17392154", "title": "Histopathology of Middle East respiratory syndrome coronovirus (MERS-CoV) infection - clinicopathological and ultrastructural study.", "title_normalized": "histopathology of middle east respiratory syndrome coronovirus mers cov infection clinicopathological and ultrastructural study" }

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HISTOPATHOLOGY OF MIDDLE EAST RESPIRATORY SYNDROME CORONOVIRUS (MERS-COV) INFECTION - CLINICOPATHOLOGICAL AND ULTRASTRUCTURAL STUDY.. 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null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "CYCLICAL", "drugenddate": "2015", "drugenddateformat": "602", "drugindication": "MYCOSIS FUNGOIDES", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201507", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "CYCLICAL", "drugenddate": "2015", "drugenddateformat": "602", "drugindication": "MYCOSIS 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{ "abstract": "Kidney transplantation is the treatment of choice in pediatric patients with end-stage renal disease. This population presents technical challenges particularly in those less than 20 kg due to anomalous anatomy, vascular access issues prior to transplantation, and a generally small size for age. Standard allograft outflow is usually achieved utilizing the iliac veins or IVC. When use of the iliocaval system is not feasible, alternative anastomosis must be considered. Herein, we report a case of a pediatric kidney transplantation where successful allograft outflow was achieved using the SMV when he was found to have an atretic IVC intraoperatively. In this setting, use of the portal system was required to achieve adequate allograft outflow. We created a donor iliac graft for added length to anastomose the renal vein with the SMV. In the setting of IVC occlusion with poor drainage, we utilized a patent vessel with larger caliber for outflow to reduce the risk of high venous pressures, allograft failure, venous rotation, and thrombosis. We conclude that the SMV may serve as an alternative outflow tract in the small pediatric patient and provides the vessel caliber needed to reduce the risks of complications.", "affiliations": "Division of Abdominal Transplantation, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas.;Division of Abdominal Transplantation, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas.;Division of Abdominal Transplantation, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas.;Division of Abdominal Transplantation, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas.;Division of Abdominal Transplantation, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas.;Division of Abdominal Transplantation, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas.;Division of Abdominal Transplantation, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas.;Division of Abdominal Transplantation, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas.;Renal Section, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.;Division of Abdominal Transplantation, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas.;Renal Section, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.;Division of Abdominal Transplantation, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas.", "authors": "Geha|John A|JA|0000-0003-0916-3589;Geha|Joseph D|JD|;Goss|Matthew|M|;Kueht|Michael L|ML|;Cotton|Ronald T|RT|;Rana|Abbas|A|0000-0003-2979-0598;Goss|John A|JA|;Bhakta|Kirti|K|;Swartz|Sarah J|SJ|;O'Mahony|Christine A|CA|;Brewer|Eileen D|ED|;Galvan|Nhu T N|NTN|0000-0002-1289-4692", "chemical_list": "D057911:Angiotensin Receptor Antagonists; D007093:Imidazoles; D013777:Tetrazoles; C437965:olmesartan", "country": "Denmark", "delete": false, "doi": "10.1111/petr.13497", "fulltext": null, "fulltext_license": null, "issn_linking": "1397-3142", "issue": "23(6)", "journal": "Pediatric transplantation", "keywords": "inferior vena cava; kidney transplantation; pediatric; superior mesenteric vein; surgical technique; thrombosis", "medline_ta": "Pediatr Transplant", "mesh_terms": "D064591:Allografts; D000714:Anastomosis, Surgical; D057911:Angiotensin Receptor Antagonists; D001011:Aorta; D002675:Child, Preschool; D006801:Humans; D007084:Iliac Vein; D007093:Imidazoles; D007668:Kidney; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008297:Male; D010372:Pediatrics; D011184:Postoperative Period; D012082:Renal Veins; D013777:Tetrazoles; D013927:Thrombosis; D058017:Vascular Grafting; D014682:Vena Cava, Inferior; D020246:Venous Thrombosis", "nlm_unique_id": "9802574", "other_id": null, "pages": "e13497", "pmc": null, "pmid": "31210008", "pubdate": "2019-09", "publication_types": "D002363:Case Reports", "references": null, "title": "Successful kidney transplantation in a small child with end-stage renal disease due to angiotensin receptor blocker fetopathy and atretic inferior vena cava.", "title_normalized": "successful kidney transplantation in a small child with end stage renal disease due to angiotensin receptor blocker fetopathy and atretic inferior vena cava" }

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SUCCESSFUL KIDNEY TRANSPLANTATION IN A SMALL CHILD WITH END?STAGE RENAL DISEASE DUE TO ANGIOTENSIN RECEPTOR BLOCKER FETOPATHY AND ATRETIC INFERIOR VENA CAVA. PEDIATR?TRANSPLANT 2019?23(6):E13497.", "literaturereference_normalized": "successful kidney transplantation in a small child with end stage renal disease due to angiotensin receptor blocker fetopathy and atretic inferior vena cava", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200827", "receivedate": "20200813", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18146618, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 1, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "US-DSJP-DSU-2020-122874", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "OLMESARTAN MEDOXOMIL" }, "drugadditional": "3", "drugadministrationroute": "064", "drugauthorizationnumb": "021286", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLMESARTAN AG" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chronic kidney disease", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hepatoblastoma", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "End stage renal disease", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "JOHN A.GEHA ELT. SUCCESSFUL KIDNEY TRANSPLANTATION IN A SMALL CHILD WITH END?STAGE RENAL DISEASE DUE TO ANGIOTENSIN RECEPTOR BLOCKER FETOPATHY AND ATRETIC INFERIOR VENA CAVA. PEDIATRIC TRANSPLANTATION. 2019?1?4", "literaturereference_normalized": "successful kidney transplantation in a small child with end stage renal disease due to angiotensin receptor blocker fetopathy and atretic inferior vena cava", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200811", "receivedate": "20200811", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18136203, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" } ]

{ "abstract": "Differentiation and fate of virus-specific CD8+ T cells after cessation of chronic antigen stimulation is unclear. Here we show that a TCF1+CD127+PD1+ hepatitis C virus (HCV)-specific CD8+ T-cell subset exists in chronically infected patients with phenotypic features of T-cell exhaustion and memory, both before and after treatment with direct acting antiviral (DAA) agents. This subset is maintained during, and for a long duration after, HCV elimination. After antigen re-challenge the less differentiated TCF1+CD127+PD1+ population expands, which is accompanied by emergence of terminally exhausted TCF1-CD127-PD1hi HCV-specific CD8+ T cells. These results suggest the TCF1+CD127+PD1+ HCV-specific CD8+ T-cell subset has memory-like characteristics, including antigen-independent survival and recall proliferation. We thus provide evidence for the establishment of memory-like virus-specific CD8+ T cells in a clinically relevant setting of chronic viral infection and we uncover their fate after cessation of chronic antigen stimulation, implicating a potential strategy for antiviral immunotherapy.", "affiliations": "Department of Medicine II, University Hospital Freiburg - Faculty of Medicine, University of Freiburg, Hugstetter Straße 55, Freiburg 79106, Germany.;Department of Medicine II, University Hospital Freiburg - Faculty of Medicine, University of Freiburg, Hugstetter Straße 55, Freiburg 79106, Germany.;Department of Medicine II, University Hospital Freiburg - Faculty of Medicine, University of Freiburg, Hugstetter Straße 55, Freiburg 79106, Germany.;Institute for Cell and Gene Therapy, University Hospital Freiburg, Hugstetter Straße 55, 79106 Freiburg, Germany.;Institute of Molecular Immunology and Experimental Oncology, Technische Universität München, Klinikum rechts der Isar, Ismaningerstr. 22, München 81675, Germany.;Department of Medicine II, University Hospital Freiburg - Faculty of Medicine, University of Freiburg, Hugstetter Straße 55, Freiburg 79106, Germany.;Ludwig Center for Cancer Research, Department of Fundamental Oncology, University of Lausanne, 155, Ch. Des Boveresses, Epalinges 1066, Switzerland.;Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University Munich, Freising, Weihenstephaner Berg 3, Freising 85354, Germany.;Department of Medicine II, University Hospital Freiburg - Faculty of Medicine, University of Freiburg, Hugstetter Straße 55, Freiburg 79106, Germany.;Department of Medicine II, University Hospital Freiburg - Faculty of Medicine, University of Freiburg, Hugstetter Straße 55, Freiburg 79106, Germany.", "authors": "Wieland|Dominik|D|;Kemming|Janine|J|;Schuch|Anita|A|;Emmerich|Florian|F|;Knolle|Percy|P|;Neumann-Haefelin|Christoph|C|;Held|Werner|W|0000-0003-3292-1536;Zehn|Dietmar|D|;Hofmann|Maike|M|;Thimme|Robert|R|", "chemical_list": "D000998:Antiviral Agents; C496487:HNF1A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha", "country": "England", "delete": false, "doi": "10.1038/ncomms15050", "fulltext": "\n==== Front\nNat CommunNat CommunNature Communications2041-1723Nature Publishing Group ncomms1505010.1038/ncomms1505028466857ArticleTCF1+ hepatitis C virus-specific CD8+ T cells are maintained after cessation of chronic antigen stimulation Wieland Dominik 123Kemming Janine 13Schuch Anita 13Emmerich Florian 4Knolle Percy 5Neumann-Haefelin Christoph 1Held Werner 6http://orcid.org/0000-0003-3292-1536Zehn Dietmar 7Hofmann Maike 1*Thimme Robert a1*1 Department of Medicine II, University Hospital Freiburg — Faculty of Medicine, University of Freiburg, Hugstetter Straße 55, Freiburg 79106, Germany2 Spemann Graduate School of Biology and Medicine, University of Freiburg, Freiburg 79104, Germany3 Faculty of Biology, University of Freiburg, Freiburg 79104, Germany4 Institute for Cell and Gene Therapy, University Hospital Freiburg, Hugstetter Straße 55, 79106 Freiburg, Germany5 Institute of Molecular Immunology and Experimental Oncology, Technische Universität München, Klinikum rechts der Isar, Ismaningerstr. 22, München 81675, Germany6 Ludwig Center for Cancer Research, Department of Fundamental Oncology, University of Lausanne, 155, Ch. Des Boveresses, Epalinges 1066, Switzerland7 Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University Munich, Freising, Weihenstephaner Berg 3, Freising 85354, Germanya [email protected]* These authors jointly supervised this work.\n\n03 05 2017 2017 8 1505003 09 2016 23 02 2017 Copyright © 2017, The Author(s)2017The Author(s)This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/Differentiation and fate of virus-specific CD8+ T cells after cessation of chronic antigen stimulation is unclear. Here we show that a TCF1+CD127+PD1+ hepatitis C virus (HCV)-specific CD8+ T-cell subset exists in chronically infected patients with phenotypic features of T-cell exhaustion and memory, both before and after treatment with direct acting antiviral (DAA) agents. This subset is maintained during, and for a long duration after, HCV elimination. After antigen re-challenge the less differentiated TCF1+CD127+PD1+ population expands, which is accompanied by emergence of terminally exhausted TCF1-CD127-PD1hi HCV-specific CD8+ T cells. These results suggest the TCF1+CD127+PD1+ HCV-specific CD8+ T-cell subset has memory-like characteristics, including antigen-independent survival and recall proliferation. We thus provide evidence for the establishment of memory-like virus-specific CD8+ T cells in a clinically relevant setting of chronic viral infection and we uncover their fate after cessation of chronic antigen stimulation, implicating a potential strategy for antiviral immunotherapy.\n\nVirus-specific CD8+ T cells lose effector function over the course of chronic infection, a process called ‘exhaustion', but the fate of these cells after treatment-induced antigen elimination is unknown. Here the authors show that exhausted cells persist in patients even after direct-acting antiviral therapy removes antigen exposure, and that these cells are responsive on re-exposure to antigen.\n==== Body\nHuman chronic viral infections with hepatitis C virus (HCV), hepatitis B virus (HBV) and human immunodeficiency virus (HIV) are a major global health problem. A rheostat that determines control versus active persistence of these viral infections is the virus-specific CD8+ T-cell response12. Virus-specific CD8+ T cells are polyfunctional in controlled infection, whereas virus-specific CD8+ T-cell function is compromised in actively persisting infection. One important mechanism underlying impaired virus-specific CD8+ T-cell responses in human chronic viral infection is the progressive loss of effector functions, a phenomenon called T-cell exhaustion345. Thus, immunotherapeutic strategies that interfere with virus-specific CD8+ T-cell exhaustion and consequently boost polyfunctional CD8+ T-cell responses are considered to be promising approaches to combat or prevent chronic viral infections in humans.\n\nMajor advances in the understanding of CD8+ T-cell exhaustion during chronic viral infection in general have been made using the lymphocytic choriomeningitis virus (LCMV) mouse model. In particular, exhausted CD8+ T cells can be defined by a reduced cytokine production, an impaired proliferative capacity, the expression of multiple co-inhibitory molecules, the up-regulation of ectonucleotidase CD39 and an altered global transcriptional program and epigenetic profile6789. Several of these characteristics have also been reported for exhausted virus-specific CD8+ T cells in human chronic infections including functional impairment, co-expression of inhibitory receptors and the increased expression of CD39 and the transcription factor Eomes1011121314. Importantly, in chronic LCMV infection, exhausted virus epitope-specific CD8+ T-cell populations are not homogeneous. Two subsets of exhausted LCMV epitope-specific CD8+ T cells are defined by differential levels of the inhibitory receptor PD1 and the two transcription factors Tbet and Eomes15. TbethiEomesdimPD1int LCMV-specific CD8+ T cells are progenitor cells that can give rise to terminally exhausted TbetdimEomeshiPD1hi cells. Both progenitor and terminal subsets of exhausted LCMV epitope-specific CD8+ T cells are required to sustain viral control during viral persistence15. With respect to chronic infections in humans, however, our knowledge about subsets, differentiation and maintenance of virus-specific CD8+ T cells is limited and efficient immunotherapeutic approaches are required.\n\nAlthough, the mechanisms responsible for CD8+ T-cell exhaustion are not completely understood, an important feature seems to be prolonged and continuous exposure to antigen and, consequently, progressive terminal differentiation161718. Additional factors, including lack of CD4+ T-cell help, immunosuppressive cytokines and instructive signals directly from inhibitory receptors also contribute to T-cell exhaustion61920. Remarkably, blockade of the PD1/PDL1 inhibitory pathway leads to functional restoration of exhausted virus-specific CD8+ T cells212223. Therefore, despite ongoing antigen recognition and consequently progressive terminal differentiation, functional T-cell exhaustion, in principle, is reversible. Importantly, only a distinct sub-population of less differentiated PD1+ virus-specific CD8+ T cells is rescued by blockade of the PD1/PDL1 pathway in chronic LCMV infection, whereas terminally exhausted subsets do not respond well24. PD1+ LCMV-specific CD8+ T cells that provide the proliferative burst after PD1/PDL1 pathway blockade are characterized by CXCR5 and TCF1 expression and by a unique gene signature25262728. Interestingly, this LCMV-specific CD8+ T-cell population possesses self-renewal capacity, gives rise to terminally exhausted effector subsets and therefore sustains the virus-specific CD8+ T-cell pool during antigen persistence. Furthermore, the LCMV-specific TCF1+CD8+ T-cell subset readily expands after transfer into naive mice and upon re-challenge with LCMV, suggesting memory-like characteristics27.\n\nThe fate of exhausted virus-specific CD8+ T cells after cessation of chronic antigen stimulation in a previously persistently infected organism has not been defined - neither in mice nor in humans. In the LCMV mouse model, drugs that efficiently eliminate the virus are not available. The same holds true for human persistent infections with the exception of IFNα-based therapies for chronic viral hepatitis. IFNα has a known immunomodulatory effect during therapy, rendering studies of immune function difficult to interpret2930. The fate of exhausted virus-specific CD8+ T cells after removal of persistent antigen, however, is of central clinical relevance since it has implications for protection from re-infection after antigen elimination. By approval of direct acting antiviral (DAA) agents for HCV therapy that are highly efficient at viral elimination this important question can now be addressed for the first time. Here we take advantage of a well-defined cohort of chronically HCV-infected patients who have been treated successfully with DAAs. We comprehensively study virus-specific CD8+ T-cell responses during and after chronic antigen exposure at a single-cell level. Importantly, we identify a CD127+PD1+ population of exhausted HCV epitope-specific CD8+ T cells during antigen persistence that is maintained long-term after cessation of chronic antigen stimulation. This CD127+PD1+ subset is further characterized by the expression of TCF1 and BCL2 and thus shows phenotypic features of both T-cell memory and exhaustion. When re-stimulated in vitro the TCF1+CD127+PD1+ subset contains the proliferative capacity of the HCV-specific CD8+ T-cell population both during and after antigen persistence. Moreover, this subset expands in response to viral relapse in vivo. In sum, TCF1 defines a CD127+PD1+ subset of HCV-specific CD8+ T cells that exhibits memory-like characteristics and therefore appear to be a promising target to boost HCV-specific CD8+ T cell responses for immunotherapeutic interventions and protection from re-infection.\n\nResults\nT-cell heterogeneity during persistent antigen recognition\nIn chronic HCV infection, the expression levels of the inhibitory receptor PD1 and the IL7R α-chain, CD127, have been proposed to discriminate between virus-specific CD8+ T cells that are exhausted due to persistent recognition of autologous viral epitopes and virus-specific CD8+ T cells that do not recognize autologous viral epitopes due to the emergence of viral escape mutations1031. Indeed, HCV-specific CD8+ T-cell populations that predominantly express CD127 indicate the presence of viral sequence variations in the corresponding viral epitope. In contrast, in the absence of viral sequence variations and thus ongoing antigen triggering, HCV-specific CD8+ T cells exhibit high expression of PD1, co-expression of additional inhibitory receptors and low proliferative capacity, suggesting exhaustion of this T-cell population. However, whether an exhausted HCV-specific CD8+ T-cell population targeting a single epitope is a homogeneous population has not been analysed previously. To address this question we performed co-expression analyses of PD1 and CD127 on single HCV epitope-specific CD8+ T cells and applied the peptide/MHCI tetramer-associated magnetic bead enrichment technique to allow high sensitivity HCV epitope-specific CD8+ T-cell characterization (Supplementary Fig. 1). Peptide/MHCI tetramers specific for three well-described HLA-A*02-restricted epitopes (NS31073; NS31406; NS52594) were utilized and naive HCV epitope-specific CD8+ T cells were excluded from the analyses (Supplementary Fig. 2). CD127/PD1 co-expression of 24 HCV epitope-specific CD8+ T-cell populations derived from 19 chronically HCV-infected patients that target autologous viral epitopes (Table 1) is depicted in Fig. 1a with a representative dot plot shown on the left. Interestingly, most HCV epitope-specific CD8+ T-cell populations did not display a homogenous but rather a heterogeneous phenotype that included CD127+PD1+ (Mdn: 45.7%; IQR: 22.0-65.7%), CD127-PD1lo (Mdn: 17.7; IQR: 6.6-25.7%) and CD127-PD1hi (Mdn: 17.1; IQR: 11.0-51.1%) subsets, rendering a subset of the HCV epitope-specific CD8+ T cells responsive to the T-cell maintenance factor IL-7.\n\nTo determine whether this heterogeneous phenotype of HCV epitope-specific CD8+ T cells is linked to persistent antigen recognition, we next analysed CD127 and PD1 co-expression on 5 HCV epitope-specific CD8+ T-cell populations derived from 5 chronically HCV-infected patients that did not recognize the autologous viral epitope due to the presence of viral escape mutations (Table 1). As shown in Fig. 1b, HCV epitope-specific CD8+ T cells that target variant epitopes and are thus not triggered by ongoing antigen recognition do not show strong heterogeneity but rather consist of a predominantly CD127+PD1+ population (Mdn: 82.7%; IQR: 73.8-93.1%). These results clearly demonstrate that persistent antigen recognition induces heterogeneity of a single HCV epitope-specific CD8+ T-cell population and more specifically the occurrence of a CD127-PD1hi HCV epitope-specific CD8+ T-cell subset.\n\nTCF1 defines a memory-like HCV-specific CD8+ T-cell subset\nNext we set out to define the molecular signatures of the different CD127/PD1 subsets of HCV epitope-specific CD8+ T cells. CD127-PD1hi HCV epitope-specific CD8+ T cells exhibited increased levels of the inhibitory receptors 2B4 and TIGIT (Fig. 2a), expressed the ectonucleotidase CD39 (Fig. 2b) and displayed high levels of the transcription factor Eomes (Fig. 2c). Thus, this subset displayed typical features of terminal T-cell exhaustion. In contrast, CD127+PD1+ HCV epitope-specific CD8+ T cells expressed low levels of inhibitory receptors, CD39 and Eomes (Fig. 2a–c). Of note, all HCV-specific CD8+ T cells are T-betdim (Supplementary Fig. 3). To further address the differentiation stage of the particular CD127/PD1 subsets, we stained for the effector cell molecule perforin and the transcription factor TCF1 that is required for the differentiation and persistence of memory CD8+ T cells323334. While 14.9% (IQR: 5.6–47.4%) of CD127-PD1hi HCV epitope-specific CD8+ T cells expressed perforin, CD127+PD1+ subsets almost completely lacked perforin expression (Fig. 2d). On the other hand, CD127+PD1+ HCV epitope-specific CD8+ T cells harboured the highest proportion of TCF1 expressing cells (Mdn: 80.0%; IQR: 66.5–91.0%) compared to CD127-PD1lo (Mdn: 38.3%; IQR: 19.7–60.8%) and CD127-PD1hi (Mdn: 26.2%; IQR: 16.3–33.7%) subsets (Fig. 2e). Of note, we did not observe expression of CXCR5 on TCF1+ HCV epitope-specific CD8+ T cells (Supplementary Fig. 4). Altogether, these data suggest that CD127+PD1+ HCV epitope-specific CD8+ T cells represent less differentiated memory-like cells while CD127-PD1hi cells define terminally exhausted effector subsets of HCV epitope-specific CD8+ T cells. As shown in Fig. 2f, this hypothesis was further supported by the finding, that similar to memory CD8+ T cells CD127+PD1+ HCV epitope-specific CD8+ T cells expressed the anti-apoptotic molecule BCL2 to a great extent (Mdn: 78.8%; IQR: 60.7–91.1%) whereas CD127-PD1hi subsets showed minor expression of BCL2 (Mdn: 20.2%; IQR: 6.8-33.2%). The low expression of BCL2 in this terminal differentiated sub-population was accompanied by high caspase-8 activity (Fig. 2g) suggesting depletion of the CD127-PD1hi sub-population by apoptosis. Interestingly, CD127-PD1hi HCV epitope-specific CD8+ T cells are positive for CD122 (Mdn: 84.6%; IQR: 69.1-90.3%; Supplementary Fig. 5) rendering these cells susceptible for IL-15-mediated bystander proliferation as has been reported for effector and effector-memory CD8+ T cells.\n\nMemory-like T cells are maintained antigen-independently\nAntigen-independent survival is a hallmark of memory CD8+ T cells in resolved infections. In the LCMV mouse model of chronic infection, antigen-independent maintenance and consequently memory potential of exhausted virus-specific CD8+ T cells has also been demonstrated after transfer in naive mice1835. However, in humans, very little is known about memory potential including survival characteristics of exhausted virus-specific CD8+ T-cell subsets. To assess whether CD127/PD1 subsets reveal differences in survival depending on the presence of antigen we longitudinally analysed HCV epitope-specific CD8+ T cells of 22 chronically HCV-infected patients after initiation of DAA therapy (Table 1 and Supplementary Fig. 6). As shown in Fig. 3a and Table 1, DAA therapy led to a rapid decline of viremia early after therapy initiation and to a sustained virological response (SVR), defined as undetectable HCV RNA 12 weeks post treatment in all but one treated patients. The single patient with viral relapse was excluded from the SVR cohort (n=21) and analysed separately. Inhibition of viral replication and most likely removal of viral antigen led to significant dynamic changes in the CD127/PD1 subset distribution within single HCV epitope-specific CD8+ T-cell populations (Fig. 3b). As shown in Fig. 3c–e and Supplementary Fig. 7b, we found a dramatic decrease in the frequency of CD127-PD1hi HCV epitope-specific CD8+ T cells (Fig. 3c) with a concomitant increase in the frequency of the CD127+PD1+ subset (Fig. 3d and Supplementary Fig. 8) while the CD127-PD1lo T-cell population remained rather unchanged (Fig. 3e). Of note, we did not observe changes in the overall frequency of HCV epitope-specific CD8+ T cells (Supplementary Fig. 7a). In agreement with our finding that the CD127-PD1hi subset represents terminally exhausted T cells, we also observed a significant decrease in the frequencies of HCV epitope-specific CD8+ T cells that highly express CD39 (Fig. 3f) and Eomes (Fig. 3g) after initiation of DAA therapy and consequent cessation of chronic antigen stimulation. In addition, initiation of DAA therapy led to a significant relative increase of TCF1+ HCV epitope-specific CD8+ T cells (Fig. 3h,i) that can be ascribed to the increased frequency of CD127+PD1+ HCV epitope-specific CD8+ T cells since TCF1 expression remained stable within the CD127+PD1+ subset (Fig. 3h,j and Supplementary Fig. 9). To confirm that the dynamic changes of HCV epitope-specific CD8+ T cells induced by DAA therapy are indeed due to the cessation of chronic antigen stimulation we additionally analysed HLA-A*0201-restricted Flu M158 - and CMV pp65495-specific CD8+ T cells derived from DAA-treated HCV-infected patients (Supplementary Table 1). Importantly, these virus-specific CD8+ T cells remained phenotypically stable (Supplementary Fig. 10a–e) clearly indicating that the observed changes in HCV epitope-specific CD8+ T cells are linked to cessation of chronic antigen stimulation rather than abrogation of the inflammatory milieu. To further confirm antigen-dependency and to exclude DAA-specific effects, we analysed HCV epitope-specific CD8+ T-cell responses of patients successfully treated with IFNα-based therapy. Due to the immunomodulatory effects of IFNα-based therapy, we comapred patient samples acquired before therapy and at a late time point following IFNα administration. The observed changes in CD127/PD1, CD39, Eomes and TCF1 expression of HCV epitope-specific CD8+ T cells based on IFNα therapy (Supplementary Table 2 and Supplementary Fig. 10f–k) were similar to the ones observed with IFNα-free DAA therapy. These results confirm the impact of persistent antigen on virus-specific CD8+ T cells and the presence of memory-like HCV epitope-specific CD8+ T cells that are maintained after antigen elimination.\n\nMemory-like and conventional memory T cells differ\nNext, we asked whether the HCV epitope-specific CD8+ T-cell populations that are maintained after spontaneous or DAA-mediated viral clearance show a similar phenotype (Table 1). As shown in Fig. 4a-d, the CD127/PD1 subset distribution of HCV epitope-specific CD8+ T cells differed between the two cohorts. Specifically, HCV epitope-specific CD8+ T cells derived from donors with spontaneous HCV elimination contained a CD127+PD1- subset (Mdn: 33.1%; IQR: 19.8-43.9%) that was almost completely absent in HCV epitope-specific CD8+ T cells from DAA-treated donors (Fig. 4c). This difference in CD127/PD1 subset distribution was accompanied on a transcriptional level by a lower expression of Eomes (Fig. 4e) and a higher expression of TCF1 (Fig. 4f). Taken together, these results clearly show phenotypical differences between memory-like HCV epitope-specific CD8+ T cells that are maintained after DAA-mediated viral clearance and conventional memory HCV epitope-specific CD8+ T cells that persist after spontaneous viral clearance. Hence, HCV-specific CD8+ T-cell differentiation varies in chronic and acute resolved infection, although persisting memory and short-lived effector subsets are established in both differentiation programs.\n\nImpaired T-cell effector function after antigen elimination\nIn chronic infection, HCV-specific CD8+ T cells display impaired cytokine secretion and consequently diminished antiviral efficacy due to their functional exhaustion13637. This is in contrast to memory HCV-specific CD8+ T cells after spontaneous virus elimination that exhibit potent antiviral efficacy136. To assess the capability of memory-like HCV epitope-specific CD8+ T cells that are maintained after DAA-mediated HCV elimination to produce cytokines, we performed a combined peptide/MHCI tetramer and intracellular cytokine-staining assay. As shown in Fig. 5a,b, peptide stimulation did not induce ex vivo production of IFNγ or TNF by HCV epitope-specific CD8+ T cells that persisted following DAA therapy.\n\nIn contrast, FLU epitope-specific CD8+ T cells were able to produce IFNγ and TNF after FLU M158 peptide stimulation (Fig. 5b and Supplementary Fig. 11). Of note, we also could not detect ex vivo cytokine production after peptide stimulation of HCV epitope-specific CD8+ T cells derived from donors that spontaneously eliminated HCV possibly reflecting reduced assay sensitivity due to the combination of peptide/MHCI tetramer staining and peptide stimulation (Fig. 5b and Supplementary Fig. 12).\n\nNext, we determined the capability of HCV epitope-specific CD8+ T cells to produce cytokines after HCV peptide-specific expansion of CD8+ T cells. Importantly, we could detect cytokine production by HCV epitope-specific CD8+ T cells after a 14-day expansion (Fig. 5c,d). Interestingly, peptide-expanded HCV-specific CD8+ T cells derived from donors at the end of DAA therapy exhibited increased IFNγ production (Mdn: 1.13%; IQR: 0.23–1.86%) compared to therapy baseline (Mdn: 0.14%; IQR: 0–0.53%) (Fig. 5d). To dissect cytokine production from proliferation, we analysed TNF production by IFNγ+ expanded HCV epitope-specific CD8+ T cells (Fig. 5e). Strikingly, TNF production was elevated among IFNγ+ HCV epitope-specific CD8+ T cells after DAA therapy (Baseline: Mdn: 2.88%; IQR: 0.39–8.52%; end of therapy (EOT): Mdn: 6.39%; IQR: 4.05–23.22%). However, TNF production was still decreased compared to IFNγ+ HCV epitope-specific CD8+ T cells present after spontaneous viral elimination (Mdn: 32.10%; IQR: 16.15–54.32%) suggesting reduced poly-functionality of HCV epitope-specific CD8+ T cells present after DAA-mediated viral elimination as compared to spontaneous HCV resolution.\n\nTCF1 expression correlates with proliferative capacity\nA further aspect of T-cell functionality is the proliferative capacity upon antigen encounter. Therefore, we tested HCV epitope-specific CD8+ T-cell proliferation before and after DAA-mediated HCV elimination. For this, we determined the fold expansion of HCV epitope-specific CD8+ T cells after 14-day HCV peptide-specific expansion assays. As previously shown38, the majority of analysed patients showed a significant increase in the expansion of HCV epitope-specific CD8+ T cells after antigen removal (Fig. 6a). However, the proliferative capacity of HCV epitope-specific CD8+ T cells obtained at the end of DAA treatment (expansion factor: Mdn: 0.63; IQR: 0.13–1.16) was reduced compared to HCV epitope-specific CD8+ T cells obtained from patients with spontaneous viral clearance (expansion factor: Mdn: 2.32; IQR: 1.63–2.87). We next addressed the question whether the abundance of CD127+PD1+ HCV epitope-specific CD8+ T cells accounts for the proliferative potential of the HCV epitope-specific CD8+ T-cell population. Indeed, the proliferative capacity of HCV epitope-specific CD8+ T-cell populations correlated with the abundance of CD127+PD1+ and particularly with that of TCF1+ HCV epitope-specific CD8+ T cells (Fig. 6b,c). These results suggest that TCF1 defines the proliferative capacity of CD127+PD1+ virus-specific CD8+ T cells during and after chronic antigen stimulation.\n\nMemory-like T cells provide recall response\nWe had the single opportunity to analyse the re-expansion capacity of memory-like TCF1+CD127+PD1+ HCV epitope-specific CD8+ T cells in vivo, since one DAA-treated patient presented with viral relapse at the 12-week follow-up (FU12) visit (Table 1 and Fig. 7a). Importantly, as shown in Fig. 7b, viral relapse and thus antigen re-exposure led to a vigorous expansion of HCV NS31073-specific CD8+ T cells that was accompanied with CD127/PD1 subset re-distribution (Fig. 7c and Supplementary Fig. 13) and concomitant phenotypic changes (Fig. 7d–f). More specifically, viral relapse led to a 2.9-fold increase of CD127-PD1hi HCV NS31073-specific T cells that were roughly maintained at a 1-year follow-up visit (2.4-fold increase relative to EOT). In concert with this, expression of CD39 and Eomes increased (Fig. 7d,e) while expression of TCF1 decreased (Fig. 7f) indicative of the re-generation of terminally exhausted effector subsets. These results, therefore, clearly suggest that memory-like TCF1+CD127+PD1+ HCV epitope-specific CD8+ T cells are able to re-expand efficiently in response to antigen re-exposure and can give rise to terminally exhausted effector subsets characterized by TCF1-CD127-PD1hi expression in the context of viral relapse.\n\nDiscussion\nIn this study, we analysed circulating HCV epitope-specific CD8+ T cells in a clinically relevant model. We could define key characteristics of distinct heterogeneous HCV epitope-specific CD8+ T-cell subsets during antigen persistence and elimination in the peripheral blood. Based on CD127/PD1 co-expression analyses, we found that CD127+PD1+, CD127-PD1lo and CD127-PD1hi subsets contribute to the HCV epitope-specific CD8+ T-cell pool during antigen persistence. Intriguingly, however, only the CD127+PD1+ HCV epitope-specific CD8+ T-cell subset is maintained after DAA-mediated HCV clearance indicating memory-like survival characteristics. The CD127+PD1+ HCV-specific CD8+ T-cell subset is characterized by a high expression of the transcription factor TCF1 that has been shown to be essential for the establishment and persistence of CD8+ T-cell responses2527323339. More specifically, it has been reported that TCF1 defines the proliferative capacity of virus-specific CD8+ T cells in the LCMV mouse model of acute and chronic infection252740. In line with this, we could correlate the in vitro proliferative capacity of HCV epitope-specific CD8+ T cells with TCF1 expression clearly suggesting that the TCF1 expressing subset contains the proliferative capacity within the HCV epitope-specific CD8+ T-cell pool. This was further supported by two in vivo observations. First, an increased proliferative capacity of HCV epitope-specific CD8+ T cells after cessation of chronic antigen stimulation occurred in parallel with the increase of the TCF1+CD127+PD1+ HCV epitope-specific T-cell subset. Second, TCF1+CD127+PD1+ HCV epitope-specific CD8+ T cells robustly expanded in a patient with viral relapse. This capacity of robust secondary expansion represents a hallmark of CD8+ T-cell memory clearly supporting the memory-like character of this HCV-specific CD8+ T-cell subset. Consistently, a recent study in the mouse model of chronic LCMV infection has shown that TCF1+ virus-specific CD8+ T cells contain recall proliferative capacity after transfer in acutely infected mice27. Hence, in humans and mice, antigen persistence does not completely abrogate memory potential regarding survival and proliferation characteristics of virus-specific CD8+ T-cell pools. Of note, in human HCV infection, this holds true after years of persistent antigen exposure at least in the peripheral blood broadening the prospects for therapeutic interventions.\n\nRemarkably, memory-like TCF1+CD127+PD1+ HCV epitope-specific CD8+ T cells present after DAA-mediated HCV elimination do not fully resemble memory CD8+ T cells present after spontaneous viral clearance. Although they share phenotypic and molecular memory properties, like CD127, BCL2 and TCF1 expression, memory-like HCV-specific CD8+ T cells display a higher expression of PD1 and Eomes indicative of T-cell exhaustion. This fits to the unique transcriptome of TCF1+ LCMV-specific CD8+ T cells in chronically infected mice that includes key factors of both signatures, T-cell memory and exhaustion2527. Furthermore, TCF1+ virus-specific CD8+ T cells from chronic LCMV infection also maintained an exhausted cytokine profile after re-expansion in vivo27. Similarly, memory-like HCV-specific CD8+ T cells also revealed impaired cytokine production after DAA-mediated compared to spontaneous antigen elimination. These cells therefore exhibit phenotypic and functional characteristics of T-cell memory and exhaustion. Hence, memory-like HCV-specific CD8+ T cells and TCF1+ LCMV-specific CD8+ T cells, both induced during chronic infections, are clearly distinct from memory CD8+ T cells generated in self-limiting infections suggesting a divergent T-cell differentiation program. While conventional memory T cells are equipped with extensive polyfunctionality to rapidly clear re-infection, memory-like T cells established during chronic infection might acquire a differentiation program that is adjusted to the setting of persistent antigen allowing pathogen control without immunopathology. This might have important implications for vaccination strategies aiming to boost virus-specific CD8+ T-cell responses during and after chronic antigen stimulation.\n\nNoteworthy, memory-like TCF1+ LCMV-specific CD8+ T cells from chronically infected mice were able to control LCMV infection after transfer in acutely infected mice27. In humans, however, it is unclear whether memory-like TCF1+CD127+PD1+ HCV-specific CD8+ T cells that persist after DAA-mediated HCV clearance will be able to provide protection against re-infection. In the chimpanzee model of chronic HCV infection, a recent study has suggested that exhausted HCV-specific CD8+ T-cell populations do not functionally recover after DAA-mediated cure and are unable to prevent virus persistence after re-infection4142. In line with this, multiple re-infections of DAA-treated patients have been reported also questioning the presence of protective immune memory after DAA clearance although the role of genotypes and viral escape has not been addressed. Clearly, additional studies are needed to address the protective potential of memory-like HCV-specific CD8+ T cells. Our finding, however, of a significant re-expansion of this HCV-specific CD8+ T-cell subset combined with a decent production of cytokines indicates that protective immunity may be possible at least in a subset of subjects.\n\nImportantly, recall expansion of memory-like TCF1+CD127+PD1+ HCV-specific CD8+ T cells was accompanied by re-occurrence of the TCF1-CD127-PD1hi subset after re-exposure to persisting antigen suggesting a progenitor-progeny relationship of these two subsets during chronic antigen recognition. The CD127-PD1hi subset of HCV epitope-specific CD8+ T cells highly expressed inhibitory receptors and CD39 and exhibited the transcriptional TbetdimEomeshi signature that is characteristic for terminal exhaustion61215. Of note, it has previously been shown that intrahepatic HCV-specific CD8+ T cells obtained from chronically HCV-infected patients exclusively displayed a TbetdimEomeshigh profile15 raising the question of the CD127/PD1 subset distribution at the site of HCV persistence. Furthermore, CD127-PD1hi HCV epitope-specific CD8+ T cells also expressed perforin, at least to some extent, and increased levels of CD122 indicative of effector cell differentiation34434445. Thus, the TCF1-CD127-PD1hi subset of HCV-specific CD8+ T cells contains terminally exhausted effector cells. Importantly, this terminally exhausted TCF1-CD127-PD1hi effector subset was absent or disappeared from the HCV epitope-specific CD8+ T-cell population when the corresponding viral epitope was removed either naturally in the context of viral escape mutations or therapeutically by DAA therapy. In sum, these results clearly indicate that terminal exhaustion of HCV epitope-specific CD8+ T cells is linked to ongoing antigen recognition and support previous findings from the LCMV model showing antigen dependence of terminal exhausted virus-specific CD8+ T cells464748. The mechanism responsible for the disappearance of the TCF1-CD127-PD1hi HCV epitope-specific CD8+ T cells after antigen elimination is not entirely clear but may be linked to a reduced lifespan of these cells due to terminal differentiation. In agreement with this hypothesis, we found low expression of the pro-survival molecule BCL-2 that has been associated with a higher apoptosis rate of virus-specific CD8+ T cells49. Furthermore, the lack of CD127 expression on the TCF1-CD127-PD1hi subset of HCV epitope-specific CD8+ T cells abrogates sensing of IL-7 that is required for antigen-independent survival of CD8+ T cells50. Persisting antigen is therefore required to drive the generation of terminal exhausted HCV-specific CD8+ T cells possibly arising from less differentiated memory-like subsets similar to progenitor and terminal subsets of virus-specific CD8+ T cells found in the mouse model of chronic LCMV infection15252627. Since both subsets are required to sustain the virus-specific CD8+ T-cell response during antigen persistence in mice it is tempting to speculate that a similar mechanism also exists in chronic human infection.\n\nIn conclusion, we demonstrate for the first time the emergence of a less differentiated circulating memory-like subset of virus-specific CD8+ T cells during antigen persistence in a relevant chronic human infection that is maintained after cessation of chronic antigen stimulation. Thus, our results give clinical significant insights into virus-specific CD8+ T-cell immunity after elimination of chronic viral infection and have implications for re-infection and therapeutic vaccination. In particular, memory-like HCV epitope-specific CD8+ T cells contain the proliferative potential and provide recall responses including re-expansion of HCV epitope-specific CD8+ T cells and re-occurrence of terminally exhausted subsets. Thus, this memory-like subset appears to be central to maintain virus-specific CD8+ T-cell responses during chronic infection and after consequent DAA-mediated viral clearance rendering this subset of virus-specific CD8+ T cells a promising target to boost CD8+ T-cell responses in immune therapeutic interventions.\n\nMethods\nStudy cohort\nPatients were recruited at the Department of Medicine II of the University Hospital Freiburg, Germany. 35 HLA-A*02 positive patients with chronic HCV infection were included in this study. Twenty nine of these patients could be followed through IFNα-free DAA therapy and five patients were treated with IFNα-based regiments. All patients included in the study were infected with HCV genotype 1a or 1b. Viral loads were determined as part of the clinical diagnostics at the University Hospital Freiburg. In addition, 15 HLA-A*02 positive patients who spontaneously resolved HCV infection (anti-HCV positive, HCV-RNA negative) were included. Confirmation of HLA-A*02 was performed by antibody staining and four-digit HLA-typing by next generation sequencing. Characteristics of the patient cohort can be found in Table 1.\n\nWritten informed consent was obtained in all cases and the study was conducted according to federal guidelines, local ethics committee regulations (Albert-Ludwigs-Universität, Freiburg, Germany) and the Declaration of Helsinki (1975).\n\nPBMC isolation\nPBMCs were isolated from EDTA anticoagulated blood patient samples through Pancoll (Pan-Biotech) density gradient centrfugation. For best data comparability, all PBMC samples from one patient during therapy were frozen and thawed simultaneously at the day of experiment. PBMCs were thawed in complete medium (RPMI 1640 with 10% fetal bovine serum, 1% penicillin-streptomycin and 1.5% 1 M HEPES (all Thermo Fisher, Germany)) and incubated for 15–30 min at 37 °C in complete medium containing 50 U ml−1 benzonase (Sigma, Germany) before processing.\n\nPeptides and tetramers\nPeptides of HLA-A*02-restricted HCV-derived epitopes ((I) genotype 1a: NS31073, CINGVCWTV; NS31406, KLVALGINAV; NS52594, ALYDVVTKL; (II) genotype 1b: NS31073, CVNGVCWTV; NS31406, KLSGLGLNAV; NS52594, ALYDVVSTL), variant epitopes matching patient viral sequences (Table 1), cytomegalovirus (CMV)-derived epitope pp65495, NLVPMVATV, influenza virus (FLU)-derived epitope M158, GILGFVFTL, and Epstein—Barr Virus (EBV)-derived epitope BMFL1280, GLCTLVAML, were obtained from Genaxxon, Germany. Peptides were dissolved in dimethyl sulfoxide (Sigma, Germany) at 20 mg ml−1 and diluted in complete medium to 1 mg ml−1 before usage. Major histocompatibility complex (MHC) class I epitope-specific tetramers were generated by conjugation of biotinylated peptide-MHC class I monomers (kind gift from David Price, Cardiff University) with PE- or APC-conjugated streptavidin at a MHCI:Strepatividin molar ratio of 5:1.\n\nTetramer enrichment\nTetramer enrichment was performed as previously described51. Briefly, PBMCs were labelled with peptide/HLA-A*02 tetramers coupled to either phycoerythrin (PE) or allophycocyanin (APC). Subsequent enrichment was performed with anti-PE/APC beads applying MACS technology (Miltenyi Biotec, Germany) according to the manufacturer's protocol. Enriched virus-specific CD8+ T cells were used for flow cytometry or ex vivo stimulation assays. To restrict analysis only to those cells that actually encountered antigen before, CD45RA+CCR7+ or CD45RA+CD27+ naive virus-specific CD8+ T cells were excluded (Supplementary Fig. 2). Samples were excluded when <5 cells could be detected after peptide/HLA-A*02 tetramer-based enrichment. Frequencies of virus-specific CD8+ T cells were calculated as described by Alanio et al.51.\n\nMultiparametric flow cytometry\nThe following reagents were used for multi-parametric flow cytometry: anti-HLA-A*02 (BB7.2, 1:100), anti-HLA-B*27 (FD705-9E1E10, 1:100), anti-CD8 (SK1, 1:50), anti-Eomes (WD1928, 1:30), anti-T-bet (4B10, 1:30), anti-CD14 (61D3, 1:100), anti-CD19 (HIB19, 1:100), anti-TIGIT (MBSA43, 1:30) (eBioscience, Germany). Anti-CCR7 (G043H7, 1:30), anti-CCR7 (G043H7, 1:30), anti-CD127 (A019D5, 1:30), anti-CD45RA (HI100, 1:200), anti-PD1 (EH12.2H7, 1:30), anti-TCF1 (C63D9, 1:30), anti-CD8 (HIT8a, 1:50), anti-2B4 (C1.7, 1:100), anti-CCR7 (150503, 1:30), anti-Rabbit IgG (Poly4064, 1:200), anti-CD45RA (HI100, 1:200), anti-Perforin (dG9, 1:50), anti-CD122 (TU27, 1:30), anti-IFN-γ (4S.B3, 1:50) (BioLegend, UK). Anti-IFN-γ (25723.11, 1:30), anti-Bcl-2 (Bcl-2/100, 1:100), anti-TNF (MAb11, 1:50), anti-CD39 (TU66, 1:30), anti-CD8 (RPA-T8, 1:100), anti-CD14 (MϕP9, 1:100), anti-CD19 (SJ25C1, 1:100) (BD Biosciences, Germany). Anti-TCF1 (C63D9, 1:100) (Cell signaling, Germany). Fixable Viability Dyes (eFluor506 (1:100) or eFluor780 (1:5000), eBioscience, Germany) and 7-AAD (1:30) (BD Biosciences, Germany) were used for live/dead discrimination. FoxP3/Transcription Factor Staining Buffer Set (eBioscience, Germany) was applied according to the manufacturer's instructions to stain for cytoplasmic and nuclear molecules. Cells were fixed with paraformaldehyde (2% PFA) before sample acquisition on a FACSCanto II or an LSRFortessa (BD Biosciences, Germany).\n\nT-cell expansion and calculation of expansion factor\nAround 1–2 × 106 PBMCs were stimulated with epitope-specific peptides (10 μg ml−1) and anti-CD28 (clone CD28.2, 0.5 μg ml−1, BD Biosciences, Germany) in 1 ml complete medium and incubated at 37 °C for 14 days. At day 3, 7 and 10, culture was supplemented with 0.5 ml of fresh medium including 20 IU ml−1 rIL-2 (Miltenyi Biotec, Germany). Tetramer and intracellular cytokine staining were performed at day 14. The expansion index was calculated as follows: [A] The absolute number of virus-specific CD8+ T cells added at day 0 of in vitro expansion was calculated based on peptide/MHCI tetramer enrichments (see above). [B] At day 14 of in vitro expansion, the absolute number of expanded virus-specific CD8+ T cells was determined based on direct FACS analyses. The expansion index was then calculated as (([B]/[A])+1), allowing subsequent logarithmic calculation despite zero values, resulting in the expansion factor=log(expansion index).\n\nCytokine production\nCytokine production of virus-specific CD8+ T cells after 14 days of in vitro expansion or directly ex vivo after peptide/MHCI tetramer enrichment of virus-specific CD8+ T cells was induced by re-stimulating cells with epitope-specific peptides (10 μg ml−1) in the presence of brefeldin A (GolgiPlug; 0.5 μl ml−1) and monensin (GolgiStop; 0.325 μl ml−1) (BD Biosciences, Germany) for 5 h at 37 °C. Stimulation with phorbol 12-myristate 13-acetate (PMA; 50 ng ml−1, Sigma, Germany) and Ionomycin (1 μg ml−1, Sigma, Germany) was performed as positive control. Subsequently, cells were stained as described above.\n\nViral sequencing\nRNA was extracted from sera using the QIAmp viral RNA minikit (Qiagen, Germany) followed by reverse transcription (RT; SuperScript III First-Strand Kit, Invitrogen, Germany) and DNA amplification by nested PCR (both PCRs via GoTaq G2 Flexi DNA Polymerase Kit, Promega, Germany) according to manufacturers' protocols. Specific primers for HCV genotype 1a and 1b can be found in Supplementary Table 3.\n\nT-cell cross-reactivity with viral sequence variations\nEpitope-specific T-cell lines were generated from PBMCs by stimulation with viral peptides (wildtype sequences) and expansion for 14 days as described above. On day 14, T-cell lines were tested for IFNγ production upon peptide-specific stimulation as described above. For stimulation, HLA-A*02:01 positive EBV-transformed B-LCLs were loaded with peptides ((a) wildtype peptide; (b) viral sequence variation peptide; (10 μg ml−1)) overnight, then washed extensively and finally co-cultured with T-cell lines at an E:T ratio of 1:1. For production of EBV-transformed B-LCLs from HLA-A*02 positive subjects, supernatant from the EBV-producing B95-8 marmoset lymphoblastoid cell line was incubated with donor PBMCs of patients with known HLA-A*02 genotype followed by cyclosporine treatment52.\n\nCross-recognition definitions were based on Cox et al.53. Briefly, loss of recognition was defined as at least 20-fold reduction in IFNγ production upon variant peptide stimulation compared to wildtype peptide stimulation; 2-fold and less reduction in IFNγ production was defined as cross-recognition.\n\nStatistics\nFlow cytometry data were analysed using FlowJo software version 9 and 10 (Treestar, USA). During data analysis by FlowJo, no further sub-gate analysis was performed when <5 cells were detected. Statistical analysis was performed with GraphPad 6 software (GraphPad Prism Software Inc., USA). Bar charts show median values with interquartile range. Two-tailed tests were applied to a significance level of 95%. Statistical tests used are indicated in the figure legends. When patients did not appear to one single study time point for unknown reasons, missing at random (MAR) was assumed for statistical analysis. Paired analysis of these data sets was then performed by applying the lastly collected value to the missing time point. (*P<0.05; **P<0.01; ***P<0.001; ****P<0.0001.)\n\nData availability\nThe data that support the findings of this study are available from the corresponding author on request.\n\nAdditional information\nHow to cite this article: Wieland, D. et al. TCF1+ hepatitis C virus-specific CD8+ T cells are maintained after cessation of chronic antigen stimulation. Nat. Commun.\n8, 15050 doi: 10.1038/ncomms15050 (2017).\n\nPublisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nSupplementary Material\nSupplementary Information\nSupplementary Figures and Supplementary Tables\n\n Peer Review File\n First, we thank all patients for participating in the current study. We also thank Marie Follow and the Core Facility of the University Medical Center Freiburg for expert advice in design of flow cytometry experiments, and David Price, Cardiff University, for peptide/MHCI momomer supply. Work presented was supported by the SFB/TRR 179 (Project 01) of the German Research Foundation (DFG).\n\nThe authors declare no competing financial interests.\n\nAuthor contributions D.W. designed, performed and analysed experiments, interpreted data and wrote the manuscript. J.K. performed viral sequencing. A.S. participated in developing experimental procedures. F.E. performed four-digit HLA-typing by next generation sequencing. P.K., C.N.-H., W.H. and D.Z. contributed to data interpretation. M.H. and R.T. designed the study, contributed to experimental design and planning, interpreted data and wrote the manuscript.\n\nFigure 1 Persistent antigen recognition drives heterogeneity of HCV-specific CD8+ T cells.\n(a) CD127/PD1 co-expression analysis of 24 HCV epitope-specific CD8+ T-cell populations derived from 19 chronically HCV-infected patients targeting autologous viral epitopes. Subset definition, specifically CD127+PD1+, CD127-PD1lo and CD127-PD1hi cells, is depicted in the representative flow cytometry dot plot on the left (red: HCV epitope-specific CD8+ T cells; grey: corresponding bulk CD8+ T cells of the appropriate patient). (b) Analysis of CD127/PD1 co-expression of five HCV epitope-specific CD8+ T-cell populations from five chronically HCV-infected patients that do not recognize viral antigen due to viral escape mutations. Representative dot plot on the left shows HCV epitope-specific (red) and bulk (grey) CD8+ T cells. Bar charts show the median value with interquartile range. Friedman and Dunn's multiple comparison tests were applied for paired statistical analyses. (*P<0.05)\n\nFigure 2 TCF1 defines CD127+PD1+ HCV-specific CD8+ T cells that are less differentiated.\nHCV epitope-specific CD8+ T cells were analysed for expression levels (MFI=median fluorescence intensity) of the inhibitory receptors PD1, 2B4, TIGIT (a) and the relative expression of CD39 (b), Eomes (c), Perforin (d), TCF1 (e), BCL2 (f) and active caspase-8 (g) with respect to the CD127/PD1 subsets (n=7–19). Representative flow cytometric histogram plots including gating of the individual markers are depicted (red: HCV epitope-specific CD8+ T cells; grey: corresponding bulk CD8+ T cells). Bar charts show the median value with interquartile range. Statistical significance was assessed by Kruskal-Wallis with Dunn's multiple comparison test. (*P<0.05; **P<0.01; ***P<0.001; ****P<0.0001.)\n\nFigure 3 TCF1+CD127+PD1+ HCV-specific CD8+ T cells are maintained after cessation of antigen stimulation.\nCD127/PD1 subset distribution of HCV epitope-specific CD8+ T cells after cessation of antigen stimulation by direct acting antiviral (DAA) therapy (n=9–16). (a) Viral loads (HCV RNA) in the sera of DAA-treated HCV patients (n=20) were determined at the indicated time-points. Lower detection limit is indicated by dashed line. (b) Representative dot plots showing CD127/PD1 subset distribution of HCV epitope-specific CD8+ T cells (red) at baseline (left) and at the end of DAA therapy (EOT; right) (grey: corresponding bulk CD8+ T cells). (c–e) Statistical graphs depicting frequencies of the indicated CD127/PD1 subset among HCV epitope-specific CD8+ T cells during DAA-mediated cessation of antigen stimulation. (f,g) Frequencies of CD39+ and Eomeshi HCV epitope-specific CD8+ T cells during DAA-mediated cessation of antigen stimulation. (h) Representative flow cytometric dot plots depict CD127/PD1 co-expression of TCF1+ HCV epitope-specific CD8+ T cells (green; grey: corresponding bulk HCV epitope-specific CD8+ T cells) at baseline (left) and at the end of DAA therapy (EOT, right). Frequencies of TCF1-expressing HCV epitope-specific CD8+ T cells (i) and TCF1-expressing CD127+PD1+ HCV epitope-specific CD8+ T cells (j) during DAA-mediated HCV elimination. Statistical significance was assessed by Friedman and Dunn's multiple comparison tests. (*P<0.05; **P<0.01; ***P<0.001; ****P<0.0001.)\n\nFigure 4 Memory-like and conventional memory HCV-specific CD8+ T cells differ.\nHCV epitope-specific CD8+ T cells from patients (n=9–10) 12 weeks after the end of DAA therapy (cHCV FU12) were compared to HCV epitope-specific CD8+ T cells from patients who spontaneously resolved HCV infection (SpR; n=6). Representative flow cytometric dot plots depict CD127/PD1 co-expression of HCV epitope-specific CD8+ T cells derived from cHCV FU12 (a) and SpR (b) (red: HCV epitope-specific CD8+ T cells, grey: corresponding bulk CD8+ T cell). Frequencies of the indicated CD127/PD1 subset (c,d), Eomeshi (e) and TCF1+ cells (f) among HCV epitope-specific CD8+ T cells present in cHCV FU12 and SpR. Bar charts show the median value with interquartile range. Statistical significance was assessed by Mann—Whitney test. (*P<0.05; ***P<0.001.)\n\nFigure 5 Low cytokine production by memory-like HCV-specific CD8+ T cells.\nVirus-specific CD8+ T cells were stimulated with epitope-specific peptides (10 μg ml−1) for 5 h at 37 °C and analysed for cytokine production (a,b). (a) Flow cytometric dot plots demonstrate stability of peptide/MHCI tetramer staining (upper row) and IFNγ and TNF production (lower row) of HCV epitope-specific CD8+ T cells (red gate). (b) Cytokine production by HCV epitope-specific CD8+ T cells of five patients with HCV infection (HCV; six HCV epitope-specific CD8+ T-cell responses), seven spontaneous resolvers (SpR; ten HCV-epitope-specific CD8+ T-cell responses) and five FLU epitope-specific CD8+ T-cell responses (FLU, n=5). (c–e) In vitro peptide-expanded HCV epitope-specific CD8+ T cells from HCV-infected patients (n=9; 12 HCV epitope-specific CD8+ T-cell responses) or spontaneous resolvers (n=8; 13 HCV epitope-specific CD8+ T-cell responses) were analysed for cytokine production after 5 h of peptide-specific re-stimulation. (c) Representative dot plots showing cytokine production by in vitro HCV peptide-expanded CD8+ T cells after HCV peptide-specific re-stimulation (gated on bulk CD8+ T cells). Percentages of the respective quadrant are depicted. (d) Frequencies of IFNγ- (left) and TNF-producing (right) in vitro peptide-expanded HCV epitope-specific CD8+ T cells are shown in the statistical graphs. (e) TNF production by IFNγ+\nin vitro peptide-expanded CD8+ T cells in per cent. Bar charts show the median value with interquartile range. Statistical significance was assessed by Friedman test (HCV/DAA) and by unpaired Kruskal−Wallis (HCV, SpR, FLU). Multiple comparisons were performed with Dunn's test. (*P<0.05.)\n\nFigure 6 Proliferative capacity of HCV-specific CD8+ T cells correlates with TCF1 expression.\nHCV epitope-specific CD8+ T cells of eight HCV-infected patients (eleven HCV epitope-specific CD8+ T-cell responses) and four spontaneous resolvers (SpR; five HCV epitope-specific CD8+ T-cell responses) were expanded at baseline and at end of therapy (EOT) for 14 days by HCV epitope-specific peptides and proliferative capacity was determined by the expansion factor. The expansion factor is the logarithmic fold-increase in absolute numbers of HCV epitope-specific CD8+ T cells from day 0 to day 14 of in vitro culture. (a) Representative dot plots of HCV epitope-specific CD8+ T cells determined by peptide/MHCI and CD8 staining at day 14 of expansion at baseline (left plot) or at end of therapy (EOT; right plot), respectively. Quantification of proliferative capacity of HCV epitope-specific CD8+ T cells derived from donors at baseline, at EOT and of SpR is depicted on the right. (b,c) Correlation analyses of the expansion factor with the abundance of memory-like CD127+PD1+ (b) or TCF1+ (c) HCV epitope-specific CD8+ T cells at day 0 of the assay, respectively (grey: baseline; black: EOT; open circles: SpR). Bar chart shows the median value with interquartile range. Statistical significance was assessed with Wilcoxon test (HCV/DAA Baseline to EOT), multiple comparisons with Kruskal–Wallis and Dunn's test (SpR to cHCV Baseline/EOT). Pearson correlation in (b,c) was performed. (*P<0.05; **P<0.01; ****P<0.0001.)\n\nFigure 7 Memory-like HCV-specific CD8+ T cells provide recall response after viral relapse.\nLongitudinal analyses of HCV epitope-specific CD8+ T cells of one patient with HCV relapse after DAA-mediated antigen elimination. (a) Viral loads (HCV RNA) in serum samples at the indicated time-points were determined. Lower detection limit is indicated by blue dashed line. (b) Frequencies of NS31073-specific CD8+ T-cell populations at end of therapy (EOT) and after viral relapse at FU12 and FU58 are shown. (c) CD127/PD1 subset distribution and relative expression of CD39 (d), Eomeshi (e) and TCF1 (f) of NS31073-specific CD8+ T cells were assessed at the indicated time-points (red: HCV epitope-specific CD8+ T cells; grey: corresponding CD8+ T cells).\n\nTable 1 Patient characteristics.\nPt\tD\tCohort\tTreatment\tOutcome\tgt\tNS31073\tNS31406\tNS52594\tVL\tAge\tSex\tCIR\t\n1\tcHCV\tDAA\tLedipasvir/Sofosbuvir 8 wk\tSVR\t1a\t \t------V---\t \t0.15\t47\tf\tno\t\n2\tcHCV\tDAA\tLedipasvir/Sofosbuvir 12 wk\tSVR\t1a\t---------\t \t \t0.26\t60\tm\tno\t\n3\tcHCV\tDAA\tLedipasvir/Sofosbuvir 12 wk\tSVR\t1a\t---------\t----------\t \t1.06\t52\tm\tno\t\n4\tcHCV\tDAA\tLedipasvir/Sofosbuvir 12 wk\tSVR\t1a\t \t------V---\t \t3.20\t66\tf\tno\t\n5\tcHCV\tDAA\tLedipasvir/Sofosbuvir 12 wk\tSVR\t1a\t---------\t \t----------\t0.63\t59\tf\tno\t\n6\tcHCV\tDAA\tLedipasvir/Sofosbuvir 12 wk\tSVR\t1a\t \t----------\t----------\t0.68\t64\tf\tno\t\n7\tcHCV\tDAA\tLedipasvir/Sofosbuvir 12 wk\tSVR\t1a\t---------\t \t----------\t2.96\t50\tm\tno\t\n8\tcHCV\tDAA\tLedipasvir/Sofosbuvir 12 wk\tSVR\t1a\t---------\t \t \tND\t49\tm\tno\t\n9\tcHCV\tDAA\tLedipasvir/Sofosbuvir 12 wk\tSVR\t1a\t---------\t \t----------\t15.0\t58\tm\tno\t\n10\tcHCV\tDAA\tLedipasvir/Sofosbuvir 12 wk\tSVR\t1a\t---------\t \t \t0.29\t59\tm\tno\t\n11\tcHCV\tDAA\tLedipasvir/Sofosbuvir 12 wk\tSVR\t1a\t---------\t \t \t1.03\t47\tm\tno\t\n12\tcHCV\tDAA\tLedipasvir/Sofosbuvir/Ribavirin 12 wk\tSVR\t1a\t \t------V---\t \t0.04\t73\tf\tno\t\n13\tcHCV\tDAA\tLedipasvir/Sofosbuvir/Ribavirin 12 wk; untreated after relapse\tRELAPSE\t1a\t---------\t \t \tND\t62\tm\tyes\t\n14\tcHCV\tDAA\tLedipasvir/Sofosbuvir 8 wk\tSVR\t1b\t-I-------\t \t \t0.70\t49\tm\tno\t\n15\tcHCV\tDAA\tLedipasvir/Sofosbuvir 8 wk\tSVR\t1b\t---------\t \t \t0.30\t60\tf\tno\t\n16\tcHCV\tDAA\tLedipasvir/Sofosbuvir 12 wk\tSVR\t1b\t---------\t \t \t5.30\t78\tf\tno\t\n17\tcHCV\tDAA\tLedipasvir/Sofosbuvir 12 wk\tSVR\t1b\t---------\t \t \t1.00\t63\tf\tno\t\n18\tcHCV\tDAA\tOmbitasvir/Paritaprevir/Ritonavir/Dasabuvir 12 wk\tSVR\t1b\t-I-------\t \t \t1.23\t29\tm\tno\t\n19\tcHCV\tDAA\tOmbitasvir/Paritaprevir/Ritonavir/Dasabuvir/Ribavirin 12 wk\tSVR\t1b\t---------\t \t \t0.04\t66\tf\tno\t\n20\tcHCV\tDAA\tLedipasvir/Sofosbuvir/Ribavirin 12 wk\tSVR\t1b\t-I-------\t \t \t0.61\t58\tf\tno\t\n21\tcHCV\tuntreated\t-\t-\t1a\t---------\t \t \t1.36\t41\tm\tno\t\n22\tcHCV\tuntreated\t-\t-\t1a\t---------\t \t \t4.59\t51\tm\tno\t\n23\tcHCV\tuntreated\t-\t-\t1a\t \t----------\t \t0.41\t55\tf\tno\t\n1\tcHCV\tESC\tLedipasvir/Sofosbuvir 8 wk\tSVR\t1a\t--------A\t \t \t0.15\t47\tf\tno\t\n4\tcHCV\tESC\tLedipasvir/Sofosbuvir 12 wk\tSVR\t1a\t--------A\t \t \t3.2\t66\tf\tno\t\n12\tcHCV\tESC\tLedipasvir/Sofosbuvir/Ribavirin12 wk\tSVR\t1a\t--------A\t \t \t0.04\t73\tf\tno\t\n24\tcHCV\tESC\tLedipasvir/Sofosbuvir 12 wk\tSVR\t1b\t--S------\t \t \t2.46\t56\tf\tno\t\n25\tcHCV\tESC\t-\tSVR\t1b\t-------SA\t \t \t0.04\t57\tm\tno\t\nPt\tD\tCohort\tApprox. time after primary HCV infection\tAge\tSex\tCIR\t\n26\tSpR\tSpR\t22 years\t43\tm\tno\t\n27\tSpR\tSpR\tunknown\t39\tf\tno\t\n28\tSpR\tSpR\tunknown\t25\tm\tno\t\n29\tSpR\tSpR\tunknown\t67\tf\tno\t\n30\tSpR\tSpR\tunknown\t38\tf\tno\t\n31\tSpR\tSpR\tunknown\t23\tm\tno\t\n32\tSpR\tSpR\tunknown\t54\tm\tno\t\n33\tSpR\tSpR\tunknown\t57\tf\tno\t\n34\tSpR\tSpR\tunknown\t42\tm\tno\t\n35\tSpR\tSpR\t12 years\t39\tf\tno\t\n36\tSpR\tSpR\t19 years\t37\tm\tno\t\n37\tSpR\tSpR\tunknown\t38\tm\tno\t\n38\tSpR\tSpR\tunknown\t60\tf\tno\t\n39\tSpR\tSpR\tunknown\t54\tf\tno\t\n40\tSpR\tSpR\t13 years\t33\tm\tno\t\nCIR, cirrhosis; D, diagnosis; f, female; gt, HCV genotype; m, male; ND, not defined; Pt, patient; SVR, sustained virological response; VL, baseline viral load (IU ml−1 × 106); wk, week.\n\nPatient characteristics are depicted. 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Med. \n201 , 1741 –1752 (2005 ).15939790\n\n", "fulltext_license": "CC BY", "issn_linking": "2041-1723", "issue": "8()", "journal": "Nature communications", "keywords": null, "medline_ta": "Nat Commun", "mesh_terms": "D000328:Adult; D000368:Aged; D000998:Antiviral Agents; D018414:CD8-Positive T-Lymphocytes; D005260:Female; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D051538:Hepatocyte Nuclear Factor 1-alpha; D006801:Humans; D007156:Immunologic Memory; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D016176:T-Lymphocyte Subsets; D055815:Young Adult", "nlm_unique_id": "101528555", "other_id": null, "pages": "15050", "pmc": null, "pmid": "28466857", "pubdate": "2017-05-03", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": "20644163;23197535;10790425;21943489;21867926;12070280;22623779;26485519;1313893;20483725;25127860;17591857;27487330;11356962;23580520;19043418;27455951;20457902;9858507;25032686;24148617;23142136;20727791;18549878;20200354;15939790;24975498;16382236;23644506;15505208;20548953;21398582;7911534;12370255;25004816;24905492;17420267;12663797;24412289;22875805;17950003;9565631;27533016;19906915;27501245;17000870;22337949;23836236;26513111;27501248;19434929;18809920;17287266", "title": "TCF1+ hepatitis C virus-specific CD8+ T cells are maintained after cessation of chronic antigen stimulation.", "title_normalized": "tcf1 hepatitis c virus specific cd8 t cells are maintained after cessation of chronic antigen stimulation" }

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{ "abstract": "There are no clinical trials involving patients with diffuse large B-cell lymphoma (DLBCL) in sub-Saharan Africa since antiretroviral therapy (ART) for HIV became widely available in this region. We aimed to establish the safety and efficacy of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with DLBCL in Malawi.\n\n\n\nThis prospective, single-arm, non-randomised phase 1/2 clinical trial was done at Kamuzu Central Hospital Cancer Clinic (Lilongwe, Malawi). Eligible patients were adults (aged 18-60 years) with newly diagnosed DLBCL, an Eastern Cooperative Oncology Group performance status of 0-2, a CD4 count of 100 cells per μL or higher (if HIV-positive), measurable disease by physical examination, an absolute neutrophil count of 1000 × 109 cells per L or higher, a platelet count of 100 × 109 platelets per L or higher, a serum creatinine concentration of 132·60 μmol/L or less, a total bilirubin concentration of 34·21 μmol/L or less, a negative urine pregnancy test in women of childbearing potential, and no previous cytotoxic therapy. Pregnant or breastfeeding women, and individuals with CNS involvement from DLBCL, chronic hepatitis B infection (unless they were receiving tenofovir plus lamivudine), or any other comorbidities that would compromise the protocol objectives were excluded. Eligible patients received intravenous rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 (maximum 2 mg/m2), and oral prednisone 100 mg or an equivalent drug every 21 days for up to six cycles. HIV-positive patients received concurrent ART. The primary outcome was the proportion of patients with National Cancer Institute Common Terminology Criteria for Adverse Events grade 3 or 4 non-haematological toxic effects or treatment-related deaths after six cycles of treatment. Secondary efficacy outcomes included the proportion of patients with a complete response after six cycles of treatment, and progression-free survival and overall survival at 12 months and 24 months. This trial is registered with ClinicalTrials.gov, NCT02660710.\n\n\n\nBetween Aug 1, 2016, and July 31, 2019, 76 patients were screened, of whom 37 were eligible for the study and received R-CHOP. The median age of patients was 44 years (IQR 39-49) and 16 (43%) were women. Of all 37 patients, 20 (54%) had stage III or IV DLBCL, and the age-adjusted international prognostic index was 2 or higher in 25 (68%) patients. 27 (73%) patients were HIV-positive, with a median CD4 count of 208 cells per μL (IQR 144-422), and 21 (78%) patients were receiving ART at enrolment. Patients completed a median of six cycles (IQR 4-6). Grade 3 or 4 non-haematological toxic effects were reported in 12 (32% [95% CI 19-49]) patients, the most common of which was infection (nine [24%] patients). Of 16 (43%) deaths, ten were due to progression of DLBCL, four were due to treatment-related complications, and two were due to other causes, yielding a treatment-related mortality of 11% (95% CI 4-26%). Grade 3 or 4 neutropenia was observed in 26 (70%) patients, and grade 3 or 4 anaemia was observed in 11 (29%) patients. A total of 22 (59%) patients had a complete response. Overall survival was 68% (95% CI 50-80) at 12 months and 55% (37-70) at 24 months, and progression-free survival was 59% (42-73) at 12 months and 53% (35-68) at 24 months.\n\n\n\nR-CHOP could be feasible, safe, and efficacious in patients with DLBCL in Malawi. This is the first completed clinical trial on DLBCL focused on sub-Saharan African populations. Given the paucity of data on treatment of DLBCL from this region, these results could inform emerging cancer treatment programmes in sub-Saharan Africa.\n\n\n\nThe University of North Carolina Lineberger Comprehensive Cancer Center.", "affiliations": "Department of Medicine, Division of Hematology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; University of North Carolina Project-Malawi, Lilongwe, Malawi.;Department of Medicine, Division of Hematology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; University of North Carolina Project-Malawi, Lilongwe, Malawi.;University of North Carolina Project-Malawi, Lilongwe, Malawi; University of Malawi, College of Medicine, Lilongwe Campus, Lilongwe, Malawi.;University of North Carolina Project-Malawi, Lilongwe, Malawi.;University of North Carolina Project-Malawi, Lilongwe, Malawi.;Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; University of North Carolina Project-Malawi, Lilongwe, Malawi; University of Malawi, College of Medicine, Lilongwe Campus, Lilongwe, Malawi.;Kamuzu Central Hospital, Malawi Ministry of Health, Lilongwe, Malawi.;Kamuzu Central Hospital, Malawi Ministry of Health, Lilongwe, Malawi.;University of North Carolina Project-Malawi, Lilongwe, Malawi.;University of North Carolina Project-Malawi, Lilongwe, Malawi.;University of North Carolina Project-Malawi, Lilongwe, Malawi.;University of North Carolina Project-Malawi, Lilongwe, Malawi.;University of North Carolina Project-Malawi, Lilongwe, Malawi.;University of North Carolina Project-Malawi, Lilongwe, Malawi.;University of North Carolina Project-Malawi, Lilongwe, Malawi.;University of North Carolina Project-Malawi, Lilongwe, Malawi.;Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.;Department of Pathology, Anatomy and Laboratory Medicine, West Virginia University, Morgantown, WV, USA.;University of North Carolina Project-Malawi, Lilongwe, Malawi.;Department of Medicine, Division of Hematology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; University of North Carolina Project-Malawi, Lilongwe, Malawi.;Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; University of North Carolina Project-Malawi, Lilongwe, Malawi.;Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; University of North Carolina Project-Malawi, Lilongwe, Malawi.;Center for Global Health, National Cancer Institute, Rockville, MD, USA. Electronic address: [email protected].", "authors": "Kimani|Stephen|S|;Painschab|Matthew S|MS|;Kaimila|Bongani|B|;Kasonkanji|Edwards|E|;Zuze|Takondwa|T|;Tomoka|Tamiwe|T|;Mulenga|Maurice|M|;Nyasosela|Richard|R|;Chikasema|Maria|M|;Mtangwanika|Asekanadziwa|A|;Chawinga|Mena|M|;Mhango|Wilberforce|W|;Nicholas|Simon|S|;Chimzimu|Fred|F|;Kampani|Coxcilly|C|;Krysiak|Robert|R|;Lilly|Amy|A|;Randall|Cara|C|;Seguin|Ryan|R|;Westmoreland|Katherine D|KD|;Montgomery|Nathan D|ND|;Fedoriw|Yuri|Y|;Gopal|Satish|S|", "chemical_list": "C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone", "country": "England", "delete": false, "doi": "10.1016/S2214-109X(21)00181-9", "fulltext": "\n==== Front\n101613665\n42402\nLancet Glob Health\nLancet Glob Health\nThe Lancet. Global health\n2214-109X\n\n34022150\n10.1016/S2214-109X(21)00181-9\nnihpa1821306\nArticle\nSafety and efficacy of rituximab in patients with diffuse large B-cell lymphoma in Malawi: a prospective, single-arm, non-randomised phase 1/2 clinical trial\nKimani Stephen *Department of Medicine, Division of Hematology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA\nLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA\nUniversity of North Carolina Project-Malawi, Lilongwe, Malawi\n\nPainschab Matthew S *Department of Medicine, Division of Hematology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA\nLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA\nUniversity of North Carolina Project-Malawi, Lilongwe, Malawi\n\nKaimila Bongani University of North Carolina Project-Malawi, Lilongwe, Malawi\nUniversity of Malawi, College of Medicine, Lilongwe Campus, Lilongwe, Malawi\n\nKasonkanji Edwards University of North Carolina Project-Malawi, Lilongwe, Malawi\n\nZuze Takondwa University of North Carolina Project-Malawi, Lilongwe, Malawi\n\nTomoka Tamiwe Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA\nUniversity of North Carolina Project-Malawi, Lilongwe, Malawi\nUniversity of Malawi, College of Medicine, Lilongwe Campus, Lilongwe, Malawi\n\nMulenga Maurice Kamuzu Central Hospital, Malawi Ministry of Health, Lilongwe, Malawi\n\nNyasosela Richard Kamuzu Central Hospital, Malawi Ministry of Health, Lilongwe, Malawi\n\nChikasema Maria University of North Carolina Project-Malawi, Lilongwe, Malawi\n\nMtangwanika Asekanadziwa University of North Carolina Project-Malawi, Lilongwe, Malawi\n\nChawinga Mena University of North Carolina Project-Malawi, Lilongwe, Malawi\n\nMhango Wilberforce University of North Carolina Project-Malawi, Lilongwe, Malawi\n\nNicholas Simon University of North Carolina Project-Malawi, Lilongwe, Malawi\n\nChimzimu Fred University of North Carolina Project-Malawi, Lilongwe, Malawi\n\nKampani Coxcilly University of North Carolina Project-Malawi, Lilongwe, Malawi\n\nKrysiak Robert University of North Carolina Project-Malawi, Lilongwe, Malawi\n\nLilly Amy Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA\n\nRandall Cara Department of Pathology, Anatomy and Laboratory Medicine, West Virginia University, Morgantown, WV, USA\n\nSeguin Ryan University of North Carolina Project-Malawi, Lilongwe, Malawi\n\nWestmoreland Katherine D Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA\nUniversity of North Carolina Project-Malawi, Lilongwe, Malawi\n\nMontgomery Nathan D Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA\nUniversity of North Carolina Project-Malawi, Lilongwe, Malawi\n\nFedoriw Yuri Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA\nUniversity of North Carolina Project-Malawi, Lilongwe, Malawi\n\nGopal Satish Center for Global Health, National Cancer Institute, Rockville, MD, USA\n\n* Contributed equally\n\nContributors\n\nSG conceptualised the study and supervised the project as the principal investigator. SK, MSP, and SG statistically analysed the data and prepared the first draft of the manuscript. SK, MSP, SG, KDW, and YF reviewed and edited draft versions of the manuscript. SK, MSP, BK, EK, TZ, RN, MaC, AM, MeC, WM, SN, KDW, and SG evaluated and provided treatment to study participants. TT, MM, FC, CK, RK, AL, CR, NDM, and YF processed and analysed laboratory samples. RS provided research support and coordinated the study. All authors reviewed the final draft of the manuscript. SK, MSP, and SG accessed and verified all the data in the study. SG had full access to all of the data in the study and had final responsibility to submit for publication. All authors vouch for the completeness and accuracy of the data and analyses reported, and for the fidelity of the study to the protocol.\n\nCorrespondence to: Dr Satish Gopal, Center for Global Health, National Cancer Institute, Rockville, MD 20892-9760, USA [email protected]\n20 7 2022\n7 2021\n19 5 2021\n30 7 2022\n9 7 e1008e1016\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article under the CC BY 4.0 license.\nSummary\n\nBackground\n\nThere are no clinical trials involving patients with diffuse large B-cell lymphoma (DLBCL) in sub-Saharan Africa since antiretroviral therapy (ART) for HIV became widely available in this region. We aimed to establish the safety and efficacy of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with DLBCL in Malawi.\n\nMethods\n\nThis prospective, single-arm, non-randomised phase 1/2 clinical trial was done at Kamuzu Central Hospital Cancer Clinic (Lilongwe, Malawi). Eligible patients were adults (aged 18–60 years) with newly diagnosed DLBCL, an Eastern Cooperative Oncology Group performance status of 0–2, a CD4 count of 100 cells per μL or higher (if HIV-positive), measurable disease by physical examination, an absolute neutrophil count of 1000×109 cells per L or higher, a platelet count of 100×109 platelets per L or higher, a serum creatinine concentration of 132·60 μmol/L or less, a total bilirubin concentration of 34·21 μmol/L or less, a negative urine pregnancy test in women of childbearing potential, and no previous cytotoxic therapy. Pregnant or breastfeeding women, and individuals with CNS involvement from DLBCL, chronic hepatitis B infection (unless they were receiving tenofovir plus lamivudine), or any other comorbidities that would compromise the protocol objectives were excluded. Eligible patients received intravenous rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 (maximum 2 mg/m2), and oral prednisone 100 mg or an equivalent drug every 21 days for up to six cycles. HIV-positive patients received concurrent ART. The primary outcome was the proportion of patients with National Cancer Institute Common Terminology Criteria for Adverse Events grade 3 or 4 non-haematological toxic effects or treatment-related deaths after six cycles of treatment. Secondary efficacy outcomes included the proportion of patients with a complete response after six cycles of treatment, and progression-free survival and overall survival at 12 months and 24 months. This trial is registered with ClinicalTrials.gov, NCT02660710.\n\nFindings\n\nBetween Aug 1, 2016, and July 31, 2019, 76 patients were screened, of whom 37 were eligible for the study and received R-CHOP. The median age of patients was 44 years (IQR 39–49) and 16 (43%) were women. Of all 37 patients, 20 (54%) had stage III or IV DLBCL, and the age-adjusted international prognostic index was 2 or higher in 25 (68%) patients. 27 (73%) patients were HIV-positive, with a median CD4 count of 208 cells per μL (IQR 144–422), and 21 (78%) patients were receiving ART at enrolment. Patients completed a median of six cycles (IQR 4–6). Grade 3 or 4 non-haematological toxic effects were reported in 12 (32% [95% CI 19–49]) patients, the most common of which was infection (nine [24%] patients). Of 16 (43%) deaths, ten were due to progression of DLBCL, four were due to treatment-related complications, and two were due to other causes, yielding a treatment-related mortality of 11% (95% CI 4–26%). Grade 3 or 4 neutropenia was observed in 26 (70%) patients, and grade 3 or 4 anaemia was observed in 11 (29%) patients. A total of 22 (59%) patients had a complete response. Overall survival was 68% (95% CI 50–80) at 12 months and 55% (37–70) at 24 months, and progression-free survival was 59% (42–73) at 12 months and 53% (35–68) at 24 months.\n\nInterpretation\n\nR-CHOP could be feasible, safe, and efficacious in patients with DLBCL in Malawi. This is the first completed clinical trial on DLBCL focused on sub-Saharan African populations. Given the paucity of data on treatment of DLBCL from this region, these results could inform emerging cancer treatment programmes in sub-Saharan Africa.\n\nFunding\n\nThe University of North Carolina Lineberger Comprehensive Cancer Center.\n==== Body\npmcIntroduction\n\nThe incidence of non-Hodgkin lymphoma is increasing in sub-Saharan Africa, where approximately 50000 new cases were diagnosed in 2019.1 The prevalence of HIV infection in patients with non-Hodgkin lymphoma in this region ranges from 30% to 60%.2,3 Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma worldwide.4 Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the international first-line standard-of-care that cures most patients.4 DLBCL is highly associated with HIV infection,5,6 and is a common, curable lymphoma throughout sub-Saharan Africa, where the global HIV epidemic is concentrated.7,8\n\nAdding rituximab to CHOP has been the primary therapeutic advance for DLBCL in the past two decades, yielding absolute increases in long-term overall survival of 10–20% compared with CHOP alone,4,9,10 and rituximab was approved by the US Food and Drug Administration in 1997. Rituximab also improves outcomes in patients with HIV-associated DLBCL, although this benefit in resource-rich settings is less clear in patients with CD4 cell counts of less than 50 per μL (ie, those with severe immunosuppression) compared with patients who have higher CD4 cell counts due to the increased risk of treatment-related infectious complications.11\n\nRituximab is currently included in the WHO Model List of Essential Medicines, and several biosimilar drugs, with equivalent pharmacokinetic, safety, and efficacy data to the proprietary drug, are commercially available worldwide.12,13 Despite the importance and availability of biosimilar drugs, rituximab remains unavailable in most public sector settings in sub-Saharan Africa because of cost. Additionally, there are no prospective data for rituximab focused on populations in sub-Saharan Africa, where HIV is prevalent, the supportive care infrastructure is weak, haematopoietic growth factors are often unavailable, and the burden of opportunistic infections is high.14 Robust safety, efficacy, and cost-effectiveness data from this region are essential to inform the programmatic implementation of rituximab, and to convince policy makers facing many competing priorities that newer anti-cancer drugs, such as rituximab, can be prudent public health investments.\n\nTo address these gaps, we did a clinical trial of the Indian rituximab biosimilar Reditux (Dr Reddy’s Laboratories, Hyderabad, Telangana, India) plus CHOP in Malawi, a low-income country in sub-Saharan Africa with a gross domestic product of US$411 per person, an annual health expenditure of $38 per person, a human development index rank of 172 of 189 countries, and where the prevalence of HIV is 9%.15–17 We aimed to investigate the safety and efficacy of R-CHOP in HIV-infected and HIV-uninfected patients with DLBCL. We hypothesised that rituximab would be safe and effective for patients with DLBCL, even under routine programmatic conditions.\n\nMethods\n\nStudy design and patients\n\nThis prospective, single-arm, non-randomised phase 1/2 clinical trial was done at the Kamuzu Central Hospital Cancer Clinic in Lilongwe, Malawi.\n\nEligible patients were adults (aged 18–60 years) with newly diagnosed DLBCL, an Eastern Cooperative Oncology Group performance status of 0–2, a CD4 count of 100 cells per μL or higher (if HIV-positive), measurable disease by physical examination, an absolute neutrophil count of 1000×109 cells per L or higher, a platelet count of 100×109 per L or higher, a serum creatinine concentration of 132·60 μmol/L or less, a total bilirubin concentration of 34·21 μmol/L or less, a negative urine pregnancy test in women of childbearing potential, and no previous cytotoxic therapy. Pregnant or breastfeeding women, and individuals with CNS involvement from DLBCL on clinical assessment or by cerebrospinal fluid cytology, chronic hepatitis B infection (unless they were receiving tenofovir plus lamivudine), or any other comorbidities (including cardiac disease) that would compromise the protocol objectives were excluded. For diagnosis of DLBCL, biopsy specimens were evaluated on-site in Lilongwe in real-time by immunohistochemistry and telepathology, with consensus review by 2–4 pathologists in the USA (NDM and YF) and in Malawi (TT and MM). Biopsy tissue specimens from all patients were then transported to the University of North Carolina (Chapel Hill, NC, USA) for delayed repeat immunohistochemical staining and review (by AL and CR).18,19 Baseline staging evaluations were done as described in the appendix (pp 32–33).\n\nAll patients provided written informed consent. The study was approved by the institutional review board at the University of North Carolina at Chapel Hill (Chapel Hill, NC, USA), and the National Health Sciences Research Committee and Pharmacy, Medicines, and Poisons Board (Lilongwe, Malawi).\n\nProcedures\n\nEligible patients received intravenous rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 (maximum 2 mg/m2), and oral prednisone 100 mg or an equivalent drug every 21 days for up to six cycles. Dosing was modelled on the R-CHOP group of the phase 3 Intergroup Trial Alliance/CALGB 50303 study.20 Treatment was administered at the Kamuzu Central Hospital Cancer Clinic and as described in the appendix (pp 9–12). Allopurinol 300 mg twice daily was administered on days 1–5 of cycle one. Haematopoietic growth factors were not routinely available in Malawi during the study period. Between the screening visit and R-CHOP initiation, patients could receive up to 10 days of pre-phase corticosteroids but no cytotoxic treatment. Patients were assessed before treatment; at each treatment visit (ie, every 21 days); and then every 3 months until 24 months after treatment. Assessments by clinicians included clinical history, details of treatment and adverse effects, performance status, and results of blood counts and other relevant tests. Imaging with chest x-ray and abdominal ultrasound were done at baseline and at the end of treatment. A bone marrow biopsy was done at baseline for all patients, but was only repeated at the end of treatment if lymphomatous involvement was present at baseline. Lumbar puncture at baseline was done only in high-risk patients (ie, those with lymphoma, with involvement of two or more extranodal sites and elevated lactate dehydrogenase concentrations, or bone marrow, testicular, epidural, ocular, breast, or paranasal sinus involvement). Lumbar puncture was repeated as clinically indicated (see appendix p 10). In the event of clinical suspicion of relapse, additional evaluation was done as clinically indicated.\n\nProtocol-defined dose adjustments and delays for non-haematological and haematological toxicities are described in the appendix (pp 13–16).\n\nHIV-infected patients received oral co-trimoxazole 960 mg once daily, consistent with Malawi guidelines, plus oral ciprofloxacin 500 mg twice daily during days 8–15 of each chemotherapy cycle, and oral fluconazole 100 mg once daily continuously throughout chemotherapy until recovery of absolute neutrophil counts of 500×109 cells per L or higher after treatment completion. HIV-uninfected patients received oral ciprofloxacin 500 mg twice daily during days 8–15 of each chemotherapy cycle if febrile neutropenia (ie, a neutrophil count of <1×109 cells per L) developed after a previous chemotherapy cycle. For HIV-infected patients, concurrent antiretroviral therapy (ART) was administered to all patients consistent with Malawi guidelines. These guidelines evolved over the study period in accordance with WHO recommendations, with tenofovir, lamivudine, and efavirenz changed to tenofovir, lamivudine, and dolutegravir as the recommended first-line ART for most patients. For patients receiving ritonavir, the dose of vincristine was reduced by 50% with each cycle. Consolidative radiotherapy after R-CHOP was not available in Malawi during the study period for persistent or bulky disease. Patients received transportation reimbursement for all visits, as per Malawi National Health Sciences Research Committee guidelines.\n\nOutcomes\n\nThe primary outcome was the proportion of patients with National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 grade 3 or 4 non-haematological toxic effects or treatment-related deaths after six cycles of treatment. Assigning cause of death in Malawi is often difficult given limited diagnostic capabilities, and some deaths could have occurred outside of health facilities. Therefore, two senior non-study Malawian clinicians were enlisted to review all study data for deceased patients and assign cause of death as probably treatment-related, lymphoma-related, related to another cause, or indeterminable. In the event of discordant conclusions, a third senior clinician made the final decision. Deaths occurring outside Kamuzu Central Hospital Cancer Clinic were adjudicated as related or unrelated to treatment on the basis of known clinical information, including DLBCL status at the time of death, proximity to treatment, a family interview, and review of the most recent cancer clinic records, laboratory data, imaging data, and medical records from peripheral health centres.\n\nThe secondary outcomes were the proportion of patients with grade 3 or 4 non-haematological toxic effects after six cycles of treatment according to HIV status; the dose intensity of R-CHOP in patients with and without HIV infection; treatment efficacy, as assessed by progression-free survival and overall survival at 12 months and 24 months after treatment, and the proportion of patients with a complete response after six cycles, overall and according to HIV status; health-related quality of life, as assessed by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30, overall and according to HIV status; and the cost-effectiveness of R-CHOP administered for six cycles, modelled by use of locally derived clinical trial and cost data. Response was assessed by investigators according to standard international criteria by physical examination, chest radiography, abdominal sonography, and in rare instances CT scan. PET was not available in Malawi during the study period. Progression-free survival was defined as the time from treatment initiation until disease progression or death. Overall survival was defined as the time from treatment initiation until death. A complete response was defined as the disappearance of all evident disease (additional details about treatment response assessments are described in the appendix [pp 32–34]).\n\nPost-hoc exploratory endpoints included the frequency of treatment delays (defined as an interval of 7 days or more between cycles) and the proportion of patients with grade 3 or 4 haematological toxic effects after six cycles of treatment, according to HIV status.\n\nStatistical analysis\n\nGiven the single-arm design of this phase 1/2 study, a sample size of at least 36 patients was calculated on the basis of desired precision of the safety estimates for grade 3 or 4 non-haematological toxicity (maximum allowable 95% CI width of 34%) and treatment-related deaths (maximum allowable 95% CI width of 30%). Primary and safety analyses were done in all patients with measurable disease who had received at least one cycle of R-CHOP.\n\nIn prespecified exploratory post-hoc analyses, differences between HIV-infected and HIV-uninfected patients were assessed with an exact Wilcoxon rank sum test for continuous variables and Fisher’s exact test for categorical variables. All reported p values are two-sided and presented without adjustment for multiple comparisons. Progression-free survival and overall survival were estimated by use of Kaplan-Meier methods, and the log-rank test was used to assess differences between HIV-infected and HIV-uninfected individuals.\n\nStudy data were monitored by the University of North Carolina Lineberger Comprehensive Cancer Center Data and Safety Monitoring Committee. Statistical analyses were done with Stata, version 6.1.\n\nThis trial is registered with ClinicalTrials.gov, NCT02660710.\n\nRole of the funding source\n\nThe funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.\n\nResults\n\nBetween Aug 1, 2016, and July 31, 2019, 76 patients were screened for eligibility (figure 1). The primary reasons for exclusion were non-DLBCL diagnosis (n=17) and having a CD4 count of less than 100 cells per μL (n=11). Of 59 patients with confirmed DLBCL who had completed screening, 39 (66%) were enrolled and received R-CHOP. Of these patients, one (3%) was subsequently diagnosed with Burkitt lymphoma and one (3%) was subsequently diagnosed with follicular lymphoma after pathological review of biopsy specimens in the USA. As such, 37 patients were included in the final analyses. No patients had transformed DLBCL. The median time from screening to initiation of R-CHOP was 10 days (range 2–30).\n\nCharacteristics of the 37 patients with DLBCL who received R-CHOP are shown in table 1. The median age of patients was 44 years (IQR 39–49), and 16 (43%) were women. 20 (54%) patients had stage III or IV disease, 15 (41%) had palpable masses of 10 cm or more in diameter, the median lactate dehydrogenase concentration was 515 IU/L (IQR 373–692; the laboratory upper limit of normal was defined as 250 IU/L), and 25 (68%) patients had an age-adjusted absolute International Prognostic Index of 2 or higher. The median tumour Ki-67 expression score was 80% (IQR 60–90). Epstein-Barr virus (EBV) status, as assessed by EBV-encoded RNA in-situ hybridisation and immunophenotype classification by immunohistochemistry with the Hans classifier,21 was known for 28 (76%) patients. Of these patients, two (7%) were EBV-positive and 16 (57%) had a germinal centre B-cell phenotype. Of all 37 patients, 27 (73%) were HIV-positive, 21 (78%) of whom were receiving ART for 3 months or more before they were diagnosed with DLBCL. Among the 27 HIV-positive patients, the median duration of ART was 36 months (IQR 5–86), the median CD4 count was 208 cells per μL (144–422), and 20 (74%) patients had viral suppression (defined as HIV RNA concentrations of <1000 copies per mL). Baseline characteristics did not differ substantially between HIV-positive and HIV-negative patients.\n\nThe treatment course and proportion of patients with grade 3 or 4 toxic effects are shown in table 2. As of Aug 14, 2020, all patients had completed a median of 6 cycles (IQR 4–6) of R-CHOP. A total of 12 (32% [95% CI 19–49]) patients had grade 3 or 4 non-haematological toxic effects (table 2). The most frequent grade 3 or 4 non-haematological toxic effects were infections (nine [24%] patients), including Escherichia coli bacteraemia (n=2), skin and soft tissue infections (n=2), malaria (n=1), Proteus mirabilis osteomyelitis (n=1), Streptococcus pneumoniae septic arthritis (n=1), Staphylococcus aureus empyema (n=1), and progressive multifocal leukoencephalopathy (n=1). Progressive multifocal leukoencephalopathy associated with John Cunningham virus reactivation occurred in the context of patient nonadherence to ART, and a decline in the CD4 cell count from 145 cells per μL at enrolment to 69 cells per μL at 6 months. After ART was resumed, this patient improved despite persistent neurological impairment. During the initial rituximab infusion, one patient had grade 3 hypersensitivity that resolved with standard measures and did not recur with subsequent R-CHOP cycles. Of note, grade 3 or 4 non-haematological toxic effects in five (42%) of 12 patients were partly attributable to anatomical complications caused by specific sites of bulky disease. These anatomical complications of DLBCL included gram-negative bacteraemia, which was likely to have occurred due to an anal mass with a suspected fistula, intestinal obstruction due to primary intestinal involvement, soft-tissue superinfection of an ulcerated axillary mass, osteomyelitis in a primary bone DLBCL resulting in a non-healing sinus tract, and empyema due to pathologically confirmed pleural involvement of DLBCL.\n\nDisease and vital status were known for all patients, with a median follow-up of 27 months (IQR 19–34). Of 16 total deaths in the study population, ten were due to DLBCL progression, four were due to treatment-related complications, and two were due to other causes, yielding a treatment-related mortality of 11% (95% CI 4–26). Two deaths from treatment-related complications were due to chronic osteomyelitis leading to progressive renal failure and S aureus empyema. Two deaths attributed to treatment-related complications were temporally associated with receipt of treatment, but confirmation of these deaths as treatment-related was not possible, as they occurred at rural health facilities with an inadequate diagnostic infrastructure, such as specialised clinicians, laboratory tests, or imaging. Two deaths from other causes were due to complications of uncontrolled diabetes in patients who responded to R-CHOP, without an alternative infectious or other cause of death identified.\n\nHIV-positive patients had a lower treatment intensity than HIV-negative patients, as reflected by the lower number of treatment cycles, higher frequency of treatment delays, and higher frequency of dose reductions due to the greater severity and duration of neutropenia (table 2). Irrespective of differences in treatment intensity, no significant difference was observed in the overall frequency of grade 3 or 4 neutropenia between HIV-positive and HIV-negative patients. Grade 3 or 4 neutropenia occurred in 26 (70%) of 37 patients overall, and 11 (29%) patients had grade 3 or 4 anaemia. No patients had grade 3 or 4 thrombocytopenia.\n\nOf all 37 patients, 22 (59%) had a protocol-defined complete response. Three additional patients had a protocol-defined partial response with small residual masses, and these patients survived without disease progression for 34 months, 36 months, and 40 months from R-CHOP initiation, suggesting a functional complete response in 25 (68%) patients overall; however, a metabolic complete response could not be confirmed by PET scan in these three patients. Progression-free survival and overall survival in the total cohort are shown in figure 2. Progression-free survival was 59% (95% CI 42–73) at 12 months and 53% (35–68) at 24 months. Overall survival was 68% (50–80) at 12 months and 55% (37–70) at 24 months. No significant differences in progression-free survival (log-rank p=0·43) and overall survival (log-rank p=0·27) according to HIV status were observed.\n\nDiscussion\n\nTo our knowledge, this is the first clinical trial of rituximab for DLBCL focused on sub-Saharan African populations, and the first clinical trial of the treatment of adults with lymphoma in this region in the current era of widespread access to HIV treatment.22 We enrolled patients with DLBCL who had adverse disease characteristics that typically confer poor outcomes (27 [73%] of 37 patients were HIV-positive, 20 [54%] had stage III or IV disease, 15 [41%] had a bulky palpable mass, 25 [68%] had an age-adjusted absolute International Prognostic Index of ≥2, and median lactate dehydrogenase concentrations were more than two times the upper limit of normal). However, relative to cohorts in high-income countries, patients were likely to have been understaged due to absent PET and restricted CT availability in Malawi. No patients were lost to follow-up, and overall survival at 24 months was 55% (95% CI 37–70) under routine programmatic conditions, which is among the best reported outcomes to date in a sub-Saharan African population. We enrolled 39 (66%) of 59 screened patients who presented to the cancer clinic at the national teaching hospital, and who were confirmed to have DLBCL on-site during the study period. We acknowledge that some referral and selection bias might have occurred, given the extreme centralisation of cancer services and multiple barriers patients face in accessing care in Malawi. R-CHOP was initiated a median of 10 days after the initial screening visit. As a reference, 2-year overall survival in patients with HIV-associated DLBCL receiving R-CHOP or infusions of rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin have typically been 60–70%, according to clinical trials done in the USA and Europe.11,23 Additionally, in the USA, long diagnosis-to-treatment intervals of more than 14 days have been independently associated with improved outcomes in patients with DLBCL compared with shorter intervals (ie, ≤14 days).24 These long intervals have been proposed as a reason for better than anticipated outcomes in the control groups of contemporary DLBCL clinical trials, particularly when treatment assignment has required molecular characterisation of tumours.25\n\nA 2020 review by the AIDS Malignancy Consortium, which includes leaders of African clinical trial sites involved in the consortium, found no clinical trials actively enrolling patients with HIV-associated lymphoma in sub-Saharan Africa.26 Additionally, a randomised clinical trial by the same consortium initiated in November, 2016, which aimed to compare an investigational oral regimen with CHOP in patients with HIV-associated DLBCL, was stopped after only seven patients in four sub-Saharan African countries (including Malawi) were enrolled over 2 years.26,27 Before this trial, the only completed clinical trial focused on adults with lymphoma in sub-Saharan Africa evaluated an investigational oral regimen (lomustine, etoposide, cyclophosphamide, and procarbazine) in HIV-infected patients in Kenya and Uganda in 2001–05, before public sector ART was widely available.22 Of 149 screened patients with HIV and lymphoma, 49 (33%) were ultimately given the investigational regimen, among whom median overall survival was 12·3 months. In this previous trial, patients with diverse non-Hodgkin lymphoma histologies were included, with only seven patients having confirmed DLBCL. Therefore, given the extreme paucity of high-grade contemporary clinical trial data from the assessment of a contemporary international standard of care regimen in sub-Saharan Africa, together with the increasing incidence of HIV-associated non-Hodgkin lymphoma throughout the region,6,28,29 our findings can inform emerging efforts to address gaps in cancer treatment. Despite the limitations of our study, including the small sample size, the absence of a control group, and the single-centre design, our data could be informative. For comparison, in a recent report published in 2019, 2-year overall survival was 42% (95% CI 30–53) in an unselected historical cohort of patients (outside a clinical trial) with DLBCL in Malawi who received CHOP without rituximab under similar programmatic conditions to this trial in 2013–17.7 An additional limitation of this study was that quality-of-life data were not collected with sufficient rigour nor completeness. Efforts are underway to translate and validate patient-reported outcome instruments to better capture quality- of-life data in Malawi for future studies.\n\nWe also note the occurrence of frequent grade 3 or 4 toxic effects among patients in our study, including neutropenia (26 [70%] of 37 patients), anaemia (11 [30%]), and infection (nine [24%]). Neutropenia was generally manageable with protocol-specified dose reduction and treatment delay, even in the absence of available routine haematopoietic growth factor during the study period. Recent increases in the availability of haematopoietic growth factor in many sub-Saharan African settings in the past 12 months could help mitigate risk of neutropenia and increase the achievable cumulative dose and dose intensity of R-CHOP in patients with DLBCL. Most treatment-related infectious complications were successfully identified and managed in our study; however, this detection required adverse event monitoring and laboratory diagnostic capacity, which might not be present in many routine programmatic settings across the region. Although increasing haematopoietic growth factor availability in sub-Saharan Africa can help mitigate the risk of infection in future studies, we also excluded patients with a CD4 count of less than 100 cells per μL because of safety concerns for severely immunosuppressed patients, and we mandated concurrent ART in all HIV-infected patients. Therefore, our findings should not be generalised to HIV-positive patients with DLBCL who do not receive concurrent ART or who have low CD4 counts. Treatment-related mortality in our study was 11% (95% CI 4–26), compared with 18% in the unselected historical cohort of patients with DLBCL in Malawi who received CHOP without rituximab in 2013–17 under similar programmatic conditions.7 Of note, two deaths in our study occurred due to uncontrolled diabetes in patients who had a complete response to R-CHOP, without an alternative infectious or other cause of death identified. These outcomes highlight the major challenges we encountered in treating cancer patients with comorbidities other than HIV in Malawi. Robust programmes in sub-Saharan Africa for chronic diseases other than HIV are generally scarce. We diagnosed two patients with new uncontrolled diabetes, one during enrolment and one at R-CHOP initiation, but we did not have the specialised capacity to provide intensive inpatient blood glucose management, as these services were not routinely available in the Malawi public sector.\n\nIn conclusion, R-CHOP could be a feasible treatment option for patients with DLBCL under routine programmatic conditions in Malawi, with a favourable safety and efficacy profile relative to scant existing regional literature. Given the paucity of similar data from this region, our results could inform emerging cancer treatment programmes and priorities in sub-Saharan Africa. Opportunities to participate in oncology clinical trials are scarce throughout the region, which is rightly viewed as an issue of cancer health equity, even if high quality observational data can also inform cancer care policies and practice.30 Large randomised multicentre studies to rigorously test treatments for DLBCL in sub-Saharan Africa are needed, and should include studies evaluating subcutaneous rituximab administration with various chemotherapy platforms and individualised risk-adapted and response-guided strategies to better guide treatment intensification or de-intensification. Finally, in addition to rigorous safety and efficacy evaluation, formal cost-effectiveness analyses of rituximab and other novel drugs in sub-Saharan Africa will be important to provide a strong case for investment to governments and policy makers when they allocate limited resources and consider providing new cancer treatments to the populations they serve.\n\nSupplementary Material\n\n1\n\nAcknowledgments\n\nThis study was funded by a University of North Carolina Lineberger Developmental Research Award awarded to SG. No commercial support was provided for this study. We are exceedingly grateful to the study participants and their families, and for the leadership from Kamuzu Central Hospital, the Malawi Ministry of Health (Lilongwe, Malawi), and the University of North Carolina Project-Malawi (Lilongwe, Malawi) for their support in conducting this study. This Article reflects work done while SG was employed at the University of North Carolina at Chapel Hill (Chapel Hill, NC, USA). The opinions expressed in this Article are the authors own and do not reflect the view of the US National Institutes of Health, the US Department of Health and Human Services, or the US Government.\n\nData sharing\n\nDeidentified individual participant data underlying the reported results will be available with publication of this study. Only approved study proposals with a signed data access agreement will be granted access to these data. A copy of the study protocol is available in the appendix. For all requests, please contact [email protected].\n\nFigure 1: Trial profile\n\nDLBCL=diffuse large B-cell lymphoma. ECOG=Eastern Cooperative Oncology Group. R-CHOP=rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. *Seven patients had plasmablastic lymphoma, six had Burkitt lymphoma, three had T-cell lymphoma, and one had primary effusion lymphoma.\n\nFigure 2: Progression-free (A) and overall (B) survival of patients with DLBCL in Malawi receiving R-CHOP\n\nIn A and B, the blue shaded region shows the 95% CIs. DLBCL=diffuse large B-cell lymphoma. R-CHOP=rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone.\n\nTable 1: Baseline characteristics of patients with diffuse large B-cell lymphoma receiving R-CHOP\n\n\tAll patients (n=37)\tHIV-positive patients (n=27)\tHIV-negative patients (n=10)\tp value\t\n\t\nSex\t..\t..\t..\t0·61\t\n Female\t16 (43%)\t11 (41%)\t5 (50%)\t..\t\n Male\t21 (57%)\t16 (59%)\t5 (50%)\t..\t\nAge, years\t44 (39–49)\t46 (39–50)\t40 (35–49)\t0·37\t\nECOG performance status\t..\t..\t..\t0·055\t\n 0\t13 (35%)\t10 (37%)\t3 (30%)\t..\t\n 1\t13 (35%)\t12 (44%)\t1 (10%)\t..\t\n 2\t11 (30%)\t5 (19%)\t6 (60%)\t..\t\nStage III or IV disease\t20 (54%)\t16 (59%)\t4 (40%)\t0·30\t\nPalpable mass of ≥10 cm\t15 (41%)\t12 (44%)\t3 (30%)\t0·43\t\nLactate dehydrogenase, IU/L*\t515 (373–692)\t504 (309–692)\t577 (432–740)\t0·34\t\nAge-adjusted absolute International Prognostic Index\t..\t..\t..\t0·91\t\n 0\t1 (3%)\t1 (4%)\t0\t..\t\n 1\t11 (30%)\t8 (30%)\t3 (30%)\t..\t\n 2\t20 (54%)\t15 (56%)\t5 (50%)\t..\t\n 3\t5 (14%)\t3 (11%)\t2 (20%)\t..\t\nOn ART for ≥3 months at diagnosis\t..\t21 (78%)\tNA\t..\t\nDuration of ART, months\t..\t36 (5–86)\tNA\t..\t\nCD4 count, cells per μL\t..\t208 (144–422)\tNA\t..\t\nHIV RNA <1000 copies per mL\t..\t20 (74%)\tNA\t..\t\nEBV-positive tumour†\t2/28 (7%)\t1/22 (5%)\t1/6 (17%)\t0·31\t\nTumour with GCB immunophenotype‡\t16/28 (57%)\t13/22 (59%)\t3/6 (50%)\t0·69\t\nKi67 expression score\t80% (60–90)\t83% (60–95)\t75% (55–80)\t0·11\t\nSelf-reported symptom duration of ≤6 months\t25 (68%)\t20 (74%)\t5 (50%)\t0·24\t\nAny history of tuberculosis treatment\t11 (30%)\t11 (41%)\t0\t0·016\t\nTuberculosis treatment prescribed for lymphadenopathy\t5/11 (45%)\t5/11 (45%)\t0\t..\t\nData are n (%), median (IQR), or n/N (%). R-CHOP=rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. ECOG=Eastern Cooperative Oncology Group. ART=antiretroviral therapy. NA=not applicable. EBV=Epstein-Barr virus. GCB=germinal centre B-cell.\n\n* Laboratory upper limit of normal was 250 IU/L.\n\n† Assessed by EBV-encoded RNA in-situ hybridisation.\n\n‡ Assessed by immunohistochemistry with the Hans classifier.\n\nTable 2: Treatment course and toxic effects in patients with diffuse large B-cell lymphoma who received R-CHOP\n\n\tAll patients (n=37)\tHIV-positive patients (n=27)\tHIV-negative patients (n=10)\tp value\t\n\t\nTreatment course\t\t\t\t\t\n Number of R-CHOP cycles, median (IQR)\t6 (4–6)\t5 (4–6)\t6 (6–6)\t0·041\t\n Completed six R-CHOP cycles\t22 (59%)\t13 (48%)\t9 (90%)\t0·021\t\n Any treatment delay of ≥7 days*\t21 (57%)\t18 (67%)\t3 (30%)\t0·046\t\n Any dose reduction\t21 (57%)\t19 (70%)\t2 (20%)\t0·0060\t\n Total number of dose-reduced cycles\t1(0–2)\t1 (0–3)\t0 (0–0)\t0·013\t\n Concentration of cyclophosphamide per cycle, mg/m2\t750 (657–750)\t750 (563–750)\t750 (750–750)\t0·058\t\n Concentration of doxorubicin per cycle, mg/m2\t50 (44–50)\t50 (38–50)\t50 (50–50)\t0·061\t\n Interval between cycles, days\t21 (21–25)\t22 (21–28)\t21 (21–21)\t0·0037\t\nToxic effects\t\t\t\t\t\n Haematological toxicity†‡\t32 (86%)\t23 (85%)\t9 (90%)\t0·70\t\n Neutropenia†\t26 (70%)\t21 (78%)\t5 (50%)\t0·10\t\n Anaemia†\t11 (30%)\t6 (22%)\t5 (50%)\t..\t\n Thrombocytopenia†\t0\t0\t0\t..\t\nNon-haematological toxicity†\t12 (32%)\t10 (37%)\t2 (20%)\t0·33\t\n Infections\t9 (24%)§\t7 (26%)\t2 (20%)\t..\t\n Febrile neutropenia\t4 (11%)\t4 (15%)\t0\t..\t\n Hypersensitivity\t1 (3%)\t1 (4%)\t0\t..\t\n Diarrhoea\t1 (3%)\t1 (4%)\t0\t..\t\n Constipation\t1 (3%)\t1 (4%)\t0\t..\t\n Bowel obstruction\t1 (3%)\t1 (4%)\t0\t..\t\n Anorexia\t1 (3%)\t0\t1 (4%)\t..\t\nData are median (IQR) or n (%). R-CHOP=rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone.\n\n* Treatment was considered as delayed if the interval between cycles was 7 days or more.\n\n† Grade 3 or 4 in severity.\n\n‡ The total number of individual grade 3 or 4 toxicities was greater than the total number of patients, as patients could have more than one event.\n\n§ Included Gram-negative bacteraemia (n=2), malaria (n=1), osteomyelitis (n=1), septic arthritis (n=1), cellulitis (n=2), empyema (n=1), and progressive multifocal leukoencephalopathy (n=1).\n\nResearch in context\n\nEvidence before this study\n\nWe searched PubMed, Embase, and Global Health biomedical research databases on Dec 1, 2020, using the search terms “lymphoma”, “non-hodgkin lymphoma”, “diffuse large B-cell lymphoma”, “outcomes”, “survival”, “treatment”, “HIV”, “chemotherapy”, “rituximab plus chemotherapy”, “CHOP”, and “R-CHOP”. We searched for prospective treatment trials for diffuse large B-cell lymphoma (DLBCL) published in English between Jan 1, 1990, and Nov 30, 2020. Non-English articles were included when an English translation of the abstract was available. We also reviewed references from relevant articles to identify studies that might have been missed by the aforementioned search terms. We found that the integration of rituximab (R) to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) has been the primary therapeutic advance for DLBCL in high-income countries in the past two decades, yielding absolute increases in long-term overall survival of 10–20% compared with CHOP alone. Rituximab also improves outcomes in patients with HIV-associated DLBCL, although this benefit in resource-rich settings is less clear in patients with CD4 cell counts of less than 50 cells per μL (ie, those with severe immunosuppression) due to the increased risk of treatment-related infectious complications. We found no prospective data for R-CHOP in patients with DLBCL in sub-Saharan Africa.\n\nAdded value of this study\n\nTo our knowledge, this is the first clinical trial of rituximab for DLBCL focused on sub-Saharan African populations, and the first clinical trial of the treatment of adults with lymphoma in this region in the current era of widespread access to HIV treatment. We enrolled patients with DLBCL who had adverse disease characteristics (ie, those that typically confer poor outcomes). No patients were lost to follow-up, and overall survival at 24 months was 55% under routine programmatic conditions, which is among the best reported outcomes to date for this population in sub-Saharan Africa.\n\nImplications of all the available evidence\n\nR-CHOP could be feasible, safe, and efficacious for patients with DLBCL under routine programmatic conditions in Malawi and in similar settings.\n\nDeclaration of interests\n\nWe declare no competing interests.\n==== Refs\nReferences\n\n1 International Agency for Research on Cancer.Global Cancer Observatory. 2020. https://gco.iarc.fr/today/online-analysis-table?v=2020&mode=population&mode_population=continents&population=900&populations=903_900_991&key=asr&sex=0&cancer=34&type=0&statistic=5&prevalence=0&population_group=0&ages_group%5B%5D=0&ages_group%5B%5D=17&group_cancer=1&include_nmsc=1&include_nmsc_other=1#collapse-group-1-0-3 (accessed Oct 5, 2020).\n2 Wiggill TM , Mantina H , Willem P , Perner Y , Stevens WS . 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Transfus Apher Sci 2011; 44 : 161–66.21402310\n30 Wells JC , Sharma S , Del Paggio JC , An analysis of contemporary oncology randomized clinical trials from low/middle-income vs high-income countries. JAMA Oncol 2021; 7 : 379–85.33507236\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2214-109X", "issue": "9(7)", "journal": "The Lancet. Global health", "keywords": null, "medline_ta": "Lancet Glob Health", "mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D004317:Doxorubicin; D005260:Female; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008295:Malawi; D008297:Male; D008875:Middle Aged; D011241:Prednisone; D011446:Prospective Studies; D000069283:Rituximab; D016896:Treatment Outcome; D014750:Vincristine", "nlm_unique_id": "101613665", "other_id": null, "pages": "e1008-e1016", "pmc": null, "pmid": "34022150", "pubdate": "2021-07", "publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Safety and efficacy of rituximab in patients with diffuse large B-cell lymphoma in Malawi: a prospective, single-arm, non-randomised phase 1/2 clinical trial.", "title_normalized": "safety and efficacy of rituximab in patients with diffuse large b cell lymphoma in malawi a prospective single arm non randomised phase 1 2 clinical trial" }

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null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomyelitis chronic", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Renal failure", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Staphylococcal infection", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "Kimani, S.. 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{ "abstract": "OBJECTIVE\nDespite successful primary treatment of nasopharyngeal carcinoma (NPC), the incidence of distant metastasis remains 25-34 %. Treatment options are limited, and survival is poor. Intratumoural Epstein-Barr virus (EBV) was used as treatment target. In NPC, EBV is present in a latent state, expressing only few non-immunogenic viral products. Gemcitabine and valproic acid can trigger EBV to the lytic state, wherein viral kinases are expressed, making EBV-positive tumour cells susceptible for antiviral therapy with, i.e. valganciclovir, and inducing an EBV-specific immune response.\n\n\nMETHODS\nThis drug combination was applied in eight patients with EBV-positive NPC, refractory to conventional treatment. The primary endpoints were safety, tolerability and clinical response. Secondary endpoint was to get proof of concept based on biomarkers, i.e. pharmacokinetics, EBV-DNA load in whole blood and nasopharyngeal brushes, EBV-RNA profiling for proof of lytic induction, EBV-IgG and EBV-IgA levels and diversity and EBV-specific T cell response.\n\n\nRESULTS\nThe best observed clinical response was partial in two patients (25 %) and stable disease in three patients (37.5 %). The median survival was 9 months (95 % confidence interval 7-17 months). Effective dose levels were reached. Peaking of EBV-DNA loads in blood and brush proved the biological effect on EBV during most treatment cycles. In one patient, RNA profiling confirmed lytic EBV induction. EBV-IgG and EBV-IgA antibody levels were already high before treatment and did not change during treatment. No changes in EBV-specific T cell response were detected.\n\n\nCONCLUSIONS\nThe treatment was safe with manageable side effects, clinical response was observed, and viral activation corroborated.", "affiliations": "Department of Head and Neck Surgery and Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands, [email protected].", "authors": "Stoker|Sharon D|SD|;Novalić|Zlata|Z|;Wildeman|Maarten A|MA|;Huitema|Alwin D R|AD|;Verkuijlen|Sandra A W M|SA|;Juwana|Hedy|H|;Greijer|Astrid E|AE|;Tan|I Bing|IB|;Middeldorp|Jaap M|JM|;de Boer|Jan Paul|JP|", "chemical_list": "D000914:Antibodies, Viral; D004279:DNA, Viral; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D003841:Deoxycytidine; D014635:Valproic Acid; C056507:gemcitabine", "country": "Germany", "delete": false, "doi": "10.1007/s00432-015-1969-3", "fulltext": null, "fulltext_license": null, "issn_linking": "0171-5216", "issue": "141(10)", "journal": "Journal of cancer research and clinical oncology", "keywords": null, "medline_ta": "J Cancer Res Clin Oncol", "mesh_terms": "D000328:Adult; D000914:Antibodies, Viral; D000971:Antineoplastic Combined Chemotherapy Protocols; D002277:Carcinoma; D004279:DNA, Viral; D003841:Deoxycytidine; D005260:Female; D004854:Herpesvirus 4, Human; D006801:Humans; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D008297:Male; D008875:Middle Aged; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms; D013601:T-Lymphocytes; D014635:Valproic Acid; D017735:Virus Latency", "nlm_unique_id": "7902060", "other_id": null, "pages": "1845-57", "pmc": null, "pmid": "25920375", "pubdate": "2015-10", "publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": "20948438;11408227;21177151;25019625;17117372;12450734;17156439;24213277;23675501;22160379;18087217;17378764;23346186;24638904;23459720;19220831;25228810;14747554;17577879;16145162;21336546;25232180;23089459;16002393;17119113;24297049;16597877;20657553;15507698;15950718;24206918;21586688;25687508;17987110;12482570;16951192;19013244;18256216;22687948;12036863;24351754;11555713;22498709;22761471;16933315;20103659;10203511;10918205;25024604;22500168;2846609;23493345;16572427;21540588;17135642", "title": "Epstein-Barr virus-targeted therapy in nasopharyngeal carcinoma.", "title_normalized": "epstein barr virus targeted therapy in nasopharyngeal carcinoma" }

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EPSTEIN-BARR VIRUS-TARGETED THERAPY IN NASOPHARYNGEAL CARCINOMA. 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EPSTEIN-BARR VIRUS-TARGETED THERAPY IN NASOPHARYNGEAL CARCINOMA. 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EPSTEIN-BARR VIRUS-TARGETED THERAPY IN NASOPHARYNGEAL CARCINOMA. 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EPSTEIN-BARR VIRUS-TARGETED THERAPY IN NASOPHARYNGEAL CARCINOMA. 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"drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALPROIC ACID." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VALPROIC ACID" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "12.5 MG/KG FROM DAY 1 TILL DAY 14 EACH CYCLE FOR 2 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "NASOPHARYNGEAL CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "12.5", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALPROIC ACID." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "078759", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTASIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pneumonia", "reactionmeddraversionpt": "18.1", "reactionoutcome": null }, { "reactionmeddrapt": "Disease progression", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "18.1", "reactionoutcome": null }, { "reactionmeddrapt": "Pulmonary oedema", "reactionmeddraversionpt": "18.1", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "STOKER S, BOER J, NOVALIC Z, WILDEMAN M, HUITEMA A, VERKUIJLEN S, JUWANA H, GREIJER A ET AL... EPSTEIN-BARR VIRUS-TARGETED THERAPY IN NASOPHARYNGEAL CARCINOMA. J CANCER RES CLIN ONCOL. 2015?141:1845-1857", "literaturereference_normalized": "epstein barr virus targeted therapy in nasopharyngeal carcinoma", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20151016", "receivedate": "20151016", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11635381, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160304" }, { "companynumb": "NL-CIPLA LTD.-2015NL07911", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "VALPROIC ACID" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "12.5 MG/KG, QD, DAY 1 TILL DAY 14", "drugenddate": null, "drugenddateformat": null, "drugindication": "NASOPHARYNGEAL CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "12.5", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALPROIC ACID." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "GANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "450 MG, TID FROM DAY 8 TILL 21", "drugenddate": null, "drugenddateformat": null, "drugindication": "NASOPHARYNGEAL CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "450", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GANCICLOVIR." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "078759", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "1250 MG/KG2 AT DAY 1 AND 8", "drugenddate": null, "drugenddateformat": null, "drugindication": "NASOPHARYNGEAL CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatic enzyme increased", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Disease progression", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "STOKER S, BOER J, NOVALIC Z, WILDEMAN M, HUITEMA A, VERKUIJLEN S, JUWANA H, GREIJER A ET AL... EPSTEIN-BARR VIRUS-TARGETED THERAPY IN NASOPHARYNGEAL CARCINOMA. J CANCER RES CLIN ONCOL. 2015?141:1845-1857", "literaturereference_normalized": "epstein barr virus targeted therapy in nasopharyngeal carcinoma", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20151016", "receivedate": "20151016", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11635393, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" } ]

{ "abstract": "Toxic epidermal necrolysis (TEN) is a potentially life-threatening muco-cutaneous disease, largely caused by an idiosyncratic reaction to medication or infectious disease, and is characterised by acute necrosis of the epidermis. No definitive consensus regarding the treatment of TEN has been agreed. A 60-year-old woman, diagnosed with multiple myeloma three months prior, was admitted with signs of TEN to the intensive care burns unit. She had been given ciprofloxacin to treat a urinary tract infection. She complained of malaise and pain, with maculopapular and bullous eruptions over her whole body on the third day of ciprofloxacin administration. Her supportive cares included intravenous immunoglobulins, pain control with analgesics, wound care, nutrition, and fluid support. Hyperbaric oxygen treatment (HBOT) was added on the second day of admission. The patient underwent 5 sessions of HBOT at 243.1 kPa (2.4 atmospheres absolute). Desquamation was noted to stop after the first session of HBOT and re-epithelisation commenced rapidly. The patient was discharged from the burn unit after 14 days of hospital admission. Improvement in this case was temporally related to the initiation of HBOT.", "affiliations": "University of Health Sciences, Hamidiye Medical Faculty, Department of Underwater and Hyperbaric Medicine, Istanbul, Turkey.;University of Health Sciences, Kartal Dr Lütfi Kirdar City Hospital, Department of Anesthesiology and Reanimation, Istanbul, Turkey.;University of Health Sciences, Kartal Dr Lütfi Kirdar City Hospital, Department of Underwater and Hyperbaric Medicine, Istanbul, Turkey.;University of Health Sciences, Kartal Dr Lütfi Kirdar City Hospital, Department of Infectious Diseases and Clinical Microbiology, Istanbul, Turkey.", "authors": "Gamze Sümen|Selin|S|;Yakupoğlu|Sezer|S|;Gümüş|Tuna|T|;Benzonana|Nur|N|", "chemical_list": "D010100:Oxygen", "country": "Australia", "delete": false, "doi": "10.28920/dhm51.2.216-219", "fulltext": null, "fulltext_license": null, "issn_linking": "1833-3516", "issue": "51(2)", "journal": "Diving and hyperbaric medicine", "keywords": "Case reports; Drugs; Hyperbaric medicine; Outcome; Side effects; Skin; Toxicity", "medline_ta": "Diving Hyperb Med", "mesh_terms": "D003422:Critical Care; D005260:Female; D006801:Humans; D006931:Hyperbaric Oxygenation; D008875:Middle Aged; D010100:Oxygen; D013262:Stevens-Johnson Syndrome", "nlm_unique_id": "101282742", "other_id": null, "pages": "216-219", "pmc": null, "pmid": "34157739", "pubdate": "2021-06-30", "publication_types": "D002363:Case Reports", "references": "17973540;19766401;28724844;3780308;27400826;27999358;11724089;28301358;16908399;15115708;10850900;23756299;9310730;31481319;13374196;8305780;20879700;28439852", "title": "Hyperbaric oxygen treatment for toxic epidermal necrolysis: A case report.", "title_normalized": "hyperbaric oxygen treatment for toxic epidermal necrolysis a case report" }

[ { "companynumb": "TR-TELIGENT, INC-20210700063", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "076754", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "URINARY TRACT INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN UNSPECIFIED" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Malaise", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Dermatitis bullous", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Pain", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SEZER YAKUPOLU. HYPERBARIC OXYGEN TREATMENT FOR TOXIC EPIDERMAL NECROLYSIS: A CASE REPORT. DIVING HYPERB MED. 2021?51(2):216?219", "literaturereference_normalized": "hyperbaric oxygen treatment for toxic epidermal necrolysis a case report", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "TR", "receiptdate": "20210719", "receivedate": "20210719", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19575478, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "TR-FRESENIUS KABI-FK202109150", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "GENTAMICIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "062356", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ENDOCARDITIS BACTERIAL", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GENTAMICIN (MANUFACTURER UNKNOWN)" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "URINARY TRACT INFECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VANCOMYCIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "062663", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ENDOCARDITIS BACTERIAL", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VANCOMYCIN (MANUFACTURER UNKNOWN)" } ], "patientagegroup": null, "patientonsetage": "60", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Klebsiella infection", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxic epidermal necrolysis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Acinetobacter infection", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "GAMZE SUMEN S, YAKUPOGLU S, GUMUS T, BENZONANA N. HYPERBARIC OXYGEN TREATMENT FOR TOXIC EPIDERMAL NECROLYSIS: A CASE REPORT. DIVING AND HYPERBARIC MEDICINE. 2021 JUN 30?51 (2):216?219.", "literaturereference_normalized": "hyperbaric oxygen treatment for toxic epidermal necrolysis a case report", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20210827", "receivedate": "20210827", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19761942, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "TR-FDC LIMITED-2118481", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "077568", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "URINARY TRACT INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN." } ], "patientagegroup": null, "patientonsetage": "60", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxic epidermal necrolysis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SUMEN SG, YAKUPOGLU S, GUMUS T, BENZONANA. HYPERBARIC OXYGEN TREATMENT FOR TOXIC EPIDERMAL NECROLYSIS: A CASE REPORT. DIVING AND HYPERBARIC MEDICINE 51: 216?219, NO. 2, 30 JUN 2021.URL: HTTP://DOI.ORG/10.28920/DHM51.2.216?219.", "literaturereference_normalized": "hyperbaric oxygen treatment for toxic epidermal necrolysis a case report", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20210917", "receivedate": "20210917", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 19843361, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20211014" } ]

{ "abstract": "A 17-year-old boy developed prominent mediastinal and subcutaneous emphysema while receiving treatment with 5-aminosalicylic acid (5-ASA) and oral corticosteroids for severe ulcerative colitis. We ruled out infection and initiated oral administration of tacrolimus, after which both the underlying disease and mediastinal and subcutaneous emphysema improved. However, he continued to experience repeated bouts of ulcerative colitis, so we ultimately opted for surgical intervention. Although mediastinal and subcutaneous emphysema is rare, it is one of the known extra-intestinal complications and can be particularly concerning. In this patient, mediastinal and subcutaneous emphysema might have been caused by the vulnerability of pulmonary alveolar walls to steroid medication and the increase of pulmonary alveolar pressure with abdominal pain and breath holding. Here, we report a case of inflammatory bowel disease with mediastinal and subcutaneous emphysema, along with a review of the literature.", "affiliations": "Department of Gastroenterology, Japanese Red Cross Kyoto Daiichi Hospital.", "authors": "Terasaki|Kei|K|;Okuyama|Yusuke|Y|;Ueda|Tomohiro|T|;Matsuyama|Kiichi|K|;Urata|Yoji|Y|;Yoshida|Norimasa|N|", "chemical_list": null, "country": "Japan", "delete": false, "doi": "10.11405/nisshoshi.113.457", "fulltext": null, "fulltext_license": null, "issn_linking": "0446-6586", "issue": "113(3)", "journal": "Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology", "keywords": null, "medline_ta": "Nihon Shokakibyo Gakkai Zasshi", "mesh_terms": "D000293:Adolescent; D003093:Colitis, Ulcerative; D006801:Humans; D008297:Male; D008478:Mediastinal Emphysema; D013352:Subcutaneous Emphysema", "nlm_unique_id": "2984683R", "other_id": null, "pages": "457-63", "pmc": null, "pmid": "26947047", "pubdate": "2016-03", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "A case report of severe ulcerative colitis with mediastinal and subcutaneous emphysema.", "title_normalized": "a case report of severe ulcerative colitis with mediastinal and subcutaneous emphysema" }

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A CASE REPORT OF SEVERE ULCERATIVE COLITIS WITH MEDIASTINAL AND SUBCUTANEOUS EMPHYSEMA. NIHON-SHOKAKIBYO-GAKKAI-ZASSHI 2016;113(3):457-63.", "literaturereference_normalized": "a case report of severe ulcerative colitis with mediastinal and subcutaneous emphysema", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20161101", "receivedate": "20160906", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12716490, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "JP-SHIRE-JP202033197", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MESALAMINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "022000", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK, UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "COLITIS ULCERATIVE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "476 (MESALAZINE/MESALAMINE)" } ], "patientagegroup": null, "patientonsetage": "17", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "39.91", "reaction": [ { "reactionmeddrapt": "Pneumomediastinum", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Subcutaneous emphysema", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "TERASAKI, K.? OKUYAMA ET AL. A CASE REPORT OF SEVERE ULCERATIVE COLITIS WITH MEDIASTINAL AND SUBCUTANEOUS EMPHYSEMA. 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A CASE REPORT OF SEVERE ULCERATIVE COLITIS WITH MEDIASTINAL AND SUBCUTANEOUS EMPHYSEMA. NIHON-SHOKAKIBYO-GAKKAI-ZASSHI 2016;113(3):457-63.", "literaturereference_normalized": "a case report of severe ulcerative colitis with mediastinal and subcutaneous emphysema", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20161118", "receivedate": "20160824", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12681133, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" } ]

{ "abstract": "Acute respiratory distress syndrome (ARDS) is the leading cause of mortality in hospitalized patients with coronavirus disease 2019 (COVID-19) because of limited effective therapies. During infection, the accumulation and activation of macrophages and monocytes in the lungs induce inflammatory mediators and contribute to tissue injury, leading to ARDS. However, therapeutic strategies that directly target activated macrophage and monocytes have not been reported. Combination treatment with etoposide (a cytotoxic agent) and a corticosteroid has been widely used for treating hemophagocytic lymphohistiocytosis characterized by the systemic activation of macrophages with overwhelming inflammation. Herein, we present five cases of COVID-19-associated ARDS treated with etoposide and corticosteroids. Three of the five patients were over 65 years of age and had various underlying diseases, including multiple myeloma. Four patients required invasive mechanical ventilation (MV), and one patient refused to be placed on MV due to underlying diseases. All patients were pre-treated with antiviral and/or other anti-inflammatory agents, but their condition deteriorated and hyperinflammation was noted. All five patients responded well to treatment and had an immediate response, as reflected by improvement in their respiratory condition and inflammatory marker levels and rapid resolution of fever after etoposide administration; however, some patients required a second dose of etoposide and longer course of steroids. All patients recovered, and there were no severe adverse events related to the drugs. Following successful treatment in these five patients, we plan to conduct a clinical trial to evaluate the efficacy and safety of combination therapy with etoposide and corticosteroid for treating COVID-19 patients in Japan.", "affiliations": "Department of Infectious Diseases, Internal Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.;Department of Infectious Diseases, Internal Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.;Department of Intelligent Network for Infection Control, Tohoku University Graduate School of Medicine, Sendai, Japan.;Department of Intensive Care Unit, Tohoku University Hospital, Sendai, Japan.;Department of Infectious Diseases, Internal Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.;Department of Infectious Diseases, Internal Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.;Department of Infectious Diseases, Internal Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.;Department of Intensive Care Unit, Tohoku University Hospital, Sendai, Japan.;Department of Infectious Diseases, Internal Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.;Department of Infectious Diseases, Internal Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.;Department of Infectious Diseases, Internal Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.;Department of Intensive Care Unit, Tohoku University Hospital, Sendai, Japan.;Department of Infectious Diseases, Internal Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.;Department of Infectious Diseases, Internal Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.", "authors": "Aoyagi|Tetsuji|T|;Sato|Yukio|Y|;Baba|Hiroaki|H|;Shiga|Takuya|T|;Seike|Issei|I|;Niitsuma Sugaya|Ikumi|I|;Takei|Kentarou|K|;Iwasaki|Yudai|Y|;Oshima|Kengo|K|;Kanamori|Hajime|H|;Yoshida|Makiko|M|;Saito|Koji|K|;Tokuda|Koichi|K|;Kaku|Mitsuo|M|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.3389/fmed.2021.718641", "fulltext": "\n==== Front\nFront Med (Lausanne)\nFront Med (Lausanne)\nFront. Med.\nFrontiers in Medicine\n2296-858X\nFrontiers Media S.A.\n\n10.3389/fmed.2021.718641\nMedicine\nCase Report\nCase Report: Successful Treatment of Five Critically Ill Coronavirus Disease 2019 Patients Using Combination Therapy With Etoposide and Corticosteroids\nAoyagi Tetsuji 1 2 *\n\nSato Yukio 1\nBaba Hiroaki 2\nShiga Takuya 3\n\nSeike Issei 1\nNiitsuma Sugaya Ikumi 1\nTakei Kentarou 1\nIwasaki Yudai 3 4\n\nOshima Kengo 1 2\nKanamori Hajime 1 2\nYoshida Makiko 1 2\nSaito Koji 3\nTokuda Koichi 1 2\nKaku Mitsuo 1 5\n1Department of Infectious Diseases, Internal Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan\n2Department of Intelligent Network for Infection Control, Tohoku University Graduate School of Medicine, Sendai, Japan\n3Department of Intensive Care Unit, Tohoku University Hospital, Sendai, Japan\n4Department of Anaesthesiology and Perioperative Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan\n5Division of Infectious Diseases and Infection Control, Tohoku Medical and Pharmaceutical University, Sendai, Japan\nEdited by: Yimin Zhang, Zhejiang University, China\n\nReviewed by: Mohamed Gomaa Kamel, Minia University, Egypt; Ning Zhou, Central South University, China\n\n*Correspondence: Tetsuji Aoyagi [email protected]\nThis article was submitted to Infectious Diseases - Surveillance, Prevention and Treatment, a section of the journal Frontiers in Medicine\n\n23 9 2021\n2021\n23 9 2021\n8 71864101 6 2021\n30 8 2021\nCopyright © 2021 Aoyagi, Sato, Baba, Shiga, Seike, Niitsuma Sugaya, Takei, Iwasaki, Oshima, Kanamori, Yoshida, Saito, Tokuda and Kaku.\n2021\nAoyagi, Sato, Baba, Shiga, Seike, Niitsuma Sugaya, Takei, Iwasaki, Oshima, Kanamori, Yoshida, Saito, Tokuda and Kaku\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nAcute respiratory distress syndrome (ARDS) is the leading cause of mortality in hospitalized patients with coronavirus disease 2019 (COVID-19) because of limited effective therapies. During infection, the accumulation and activation of macrophages and monocytes in the lungs induce inflammatory mediators and contribute to tissue injury, leading to ARDS. However, therapeutic strategies that directly target activated macrophage and monocytes have not been reported. Combination treatment with etoposide (a cytotoxic agent) and a corticosteroid has been widely used for treating hemophagocytic lymphohistiocytosis characterized by the systemic activation of macrophages with overwhelming inflammation. Herein, we present five cases of COVID-19-associated ARDS treated with etoposide and corticosteroids. Three of the five patients were over 65 years of age and had various underlying diseases, including multiple myeloma. Four patients required invasive mechanical ventilation (MV), and one patient refused to be placed on MV due to underlying diseases. All patients were pre-treated with antiviral and/or other anti-inflammatory agents, but their condition deteriorated and hyperinflammation was noted. All five patients responded well to treatment and had an immediate response, as reflected by improvement in their respiratory condition and inflammatory marker levels and rapid resolution of fever after etoposide administration; however, some patients required a second dose of etoposide and longer course of steroids. All patients recovered, and there were no severe adverse events related to the drugs. Following successful treatment in these five patients, we plan to conduct a clinical trial to evaluate the efficacy and safety of combination therapy with etoposide and corticosteroid for treating COVID-19 patients in Japan.\n\nCOVID-19\nSARS-CoV-2\netoposide\ncorticosteroid\ncase series\nacute respiratory distress (ARDS)\nJapan Society for the Promotion of Science 10.13039/501100001691 Japan Agency for Medical Research and Development 10.13039/100009619\n==== Body\npmcIntroduction\n\nAcute respiratory distress syndrome (ARDS) is the leading cause of mortality among critically ill coronavirus disease 2019 (COVID-19) patients (1). Disease severity or mortality in COVID-19 patients is associated with elevated levels of pro-inflammatory cytokines and chemokines. Corticosteroid therapy is widely used to suppress inflammatory mediators in COVID-19 and has been reported to improve survival, especially in critically ill patients requiring invasive mechanical ventilation (MV) (2, 3). However, the associated mortality rate remains as high as 30% (2, 3).\n\nHemophagocytic lymphohistiocytosis (HLH) is a potentially life-threatening hyperinflammatory syndrome characterized by sustained activation of macrophages and elevated cytokine levels. Histologic evidence of secondary HLH (sHLH) has been observed in fatal respiratory infection with severe acute respiratory syndrome coronavirus 1, H5N1, and 2009H1N1pdm influenza virus (4–6). Recently, post-mortem analysis of COVID-19 patients with ARDS showed diffuse alveolar damage and hemophagocytosis with pulmonary hilar or mediastinal lymphadenopathy (7). Clinical data of severe COVID-19 patients revealed lymphopenia, hyperferritinemia, and elevated pro-inflammatory cytokine levels (8). Thus, macrophage-mediated inflammation might be involved in the pathogenesis of ARDS caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.\n\nHistorically, the HLH-94 protocol, etoposide (a cytotoxic agent), and a corticosteroid have been used to treat primary or secondary HLH (9). Etoposide is a chemotherapeutic drug that inhibits topoisomerase II, resulting in DNA synthesis errors that lead to apoptosis in rapidly dividing or activated cells. In this process of etoposide-induced cell death, etoposide can reduce the number of macrophages and monocytes in blood. We previously demonstrated that a combination therapy using etoposide and a low-dose corticosteroid, but not etoposide or a corticosteroid alone, reduced the mortality rate and lung injury in a fatal ARDS murine model, in which hypercytokinemia and highly activated macrophages with hemophagocytic activity were observed (10). Moreover, successful treatment with a combination of etoposide and corticosteroid has been reported in severe ARDS caused by H1N1/09 influenza virus (11). Recently, in a study of 11 patients with COVID-19 without invasive MV treated with etoposide as salvage therapy (12), all patients received methylprednisolone plus Tocilizmab (IL-6 inhibitor) or Ankinra (IL-1 inhibitor) before treatment with etoposide. Herein, we report the disease course of five critically ill COVID-19 patients on invasive MV who were treated with a combination of etoposide and corticosteroids.\n\nCase Description\n\nThe off-label use of etoposide and corticosteroid was approved by the Ethics Committee of Tohoku University Hospital. All patients received heparin (10,000–20,000 U/day) to prevent thrombosis. In patients undergoing invasive MV, prone positioning was performed. Figure 1; Table 1 show the clinical progress and clinical characteristics of five critically ill patients infected with SARS-CoV-2, respectively. We evaluated clinical indicators for activation of macrophages and monocytes using H-Score and COVID-19-associated hyperinflammatory syndrome (cHIS) score (Table 1). The median value of H-Score, excluding histological findings of bone marrow, was 54 (range: 33–97) on administration of etoposide and corticosteroid. All patients met 2–4 items of the cHIS criteria at the time of etoposide administration. The median sequential organ failure assessment (SOFA) score at the time of etoposide administration was 5.5 (range: 3–8), which improved by 0.5 (0–2) after a combination treatment with etoposide and prednisolone (PSL). Figure 2 shows the changes in white blood cell count before and after treatment with etoposide and corticosteroid.\n\nFigure 1 Timeline of clinical progress of COVID-19 patients after hospitalization and that after treatment with etoposide and corticosteroid. An 7 point ordinal clinical scale was used to assess pulmonary status consisting of the following values: 7, Ventilation in addition to extracorporeal membrane oxygen (ECMO); 6, Ventilation in addition to need for vasopressors (noradrenaline ≥ 0.1 μg/kg/min); 5, Intubation and mechanical ventilation; 4, Oxygen by mask or nasal prongs; 3, Hospitalization without oxygen supplementation; 2, Discharged from hospital either to home or to inpatient rehabilitation facility with supplemental oxygen; 1, Discharged to home without supplemental oxygen.\n\nTable 1 Patient background, laboratory parameter, time-course of admission, and assessment of clinical outcome after etoposide and corticosteroid.\n\n\tPatient 1\tPatient 2\tPatient 3\tPatient 4\tPatient 5\t\nAge\t58\t88\t71\t45\t69\t\nCo-morbidity\tNone\tMultiple myeloma, CKD, DM, HT\tBrain infarction, hemiplegia, atrial fibrillation, CHF, HT, DM\tChildhood asthma\tPost-CABG, stent graft for abdominal aortic aneurysm, brain infarction, HL, HT, DM\t\nCurrent or Ex-smoker\tYES\tNO\tYES\tNO\tYES\t\nSex\tFemale\tFemale\tMale\tMale\tMale\t\nFever (>38°C)\tYES\tYES\tYES*\tYES**\tYES\tYES\t\nPaO2/FiO2 (mmHg)\t134\t250\t90\t183\t150\t104\t\nFerritin (ng/ml)\t1,507\t538.6\t323.6\t855\t588.1\t580.3\t\nsoluble IL-2R (U/ml)\t630\t954\t1262\t1205\t883\t1,453\t\nCRP (mg/dl)\t3.91\t3.14\t15.93\t20.88\t19.16\t10.46\t\nLDH (U/L)\t509\t349\t306\t317\t288\t193\t\nD-dimer (μg/ml)\t1.7\t3.1\t1.3\t2.8\t1.1\t4.7\t\nCK (U/L)\t797\t55\t58\t62\t27\t144\t\nNeutrophils (/μl)\t6,240\t2,470\t10,490\t9,340\t10,390\t13,450\t\nLymphocytes (/μl)\t620\t1,530\t1,520\t1,480\t660\t760\t\nCytopenia > 2 Lines\tNO\tNO\tNO\tNO\tNO\tNO\t\nHepatomegaly or Splenomegaly\tNO\tNO\tNO\tNO\tSplenomegaly\tNO\t\nH-Score (without histological evidence of hemophagocytosis)\t96\t97\t33\t52\t56\t33\t\ncHIS score\t4/6\t3/6\t2/6\t3/6\t3/6\t3/6\t\nMechanical ventilation\tYES\tNO\tYES\tYES\tYES\tYES (ECMO)\t\nEtoposide (doses and times)\t80 mg/m2 × 1\t50 mg/m2 × 1\t80 mg/m2 × 1\t80 mg/m2 × 1\t80 mg/m2 × 2\t80 mg/m2 × 2\t\nPrednisolone (dose and duration)\t20 mg for 1 week → 10 mg for 1 week\t20 mg for 1 week → 10 mg for 1 week\t20 mg for 1 week → 10 mg for 1 week\t20 mg for 1 week → 10 mg for 1 week\t20 mg for 2 week → 15 mg for 3 days → 10 mg for 6 days\t20 mg for 1 week → 10 mg for 1 week\t\nPost etoposide and prednisolone PaO2/FiO2 (mmHg)\t480\t450\t396\t397\t450\t250\t\nA change in SOFA score (before and after etoposide and prednisolone)\t7 to 0\t4 to 0\t8 to 1\t7 to 1\t3 to 0\t4 to 2\t\nOutcome\tDischarge\tDischarge\tDischarge\tDischarge\tContinue rehabilitation\t\nInfection\tNO\tNO\tNO\tNO\tNO\tYES (perianal abscess)\t\n* First course,\n\n** Second course.\n\nH-Score; (20).\n\ncHIS; (24).\n\nCKD, chronic kidney disease; DM, diabetes mellitus; HT, hypertension; CHF, chronic heart failure; HL, hyperlipidemia; CABG, Coronary artery bypass grafting; ECMO, extracorporeal membrane oxygenation; SOFA, sequential organ failure assessment.\n\nFigure 2 Changes in white blood cell count before and after treatment with etoposide and corticosteroid.\n\nPatient 1\n\nIn April 2020, a 58-year-old woman was transferred to our hospital with severe hypoxia (SpO2 90% on 8 L/min oxygen) 7 days after the onset of COVID-19 symptoms, which included general fatigue and cough. She was immediately transferred to our intensive care unit (ICU) and underwent endotracheal intubation and MV. Chest computed tomography (CT) showed bilateral ground-glass opacities and peripheral condensation. Partial pressure of oxygen in arterial blood (PaO2) was 80 mmHg while receiving FiO2 of 60%, which yielded a PaO2 to FiO2 ratio (P/F ratio) of 134 mmHg. She was treated with favipiravir (3,600 mg on day 1, followed by 1,800 mg from days 2 to 14). On day 2, noradrenaline was administered to maintain a mean blood pressure of >70 mmHg. On day 3, she still had fever (>38°C); her general condition deteriorated, with decreased urine output, and an increased dose of noradrenaline was required. Moreover, her laboratory data showed increased levels of soluble interleukin-2 receptor (sIL-2R), C-reactive protein (CRP), and creatine kinase (CK). We decided to treat her with etoposide (80 mg/m2) and PSL (20 mg/day) (instead of dexamethasone as PSL is the preferred corticosteroid in Japan). On the day following treatment with etoposide and corticosteroids, her respiratory and hemodynamic conditions improved dramatically, and the P/F ratio (312 mmHg) increased significantly. On day 7, 4 days after starting treatment, she was extubated. Because her general condition continued to be good and laboratory data showed decreased inflammatory marker levels, including sIL-2R and CRP, the PSL dose was tapered after 7 days of treatment. The patient was discharged home without supplemental oxygen after real-time polymerase chain reaction (RT-PCR) tests for SARS-CoV-2 on days 18 and 20 were confirmed to be negative.\n\nPatient 2\n\nAn 88-year-old woman with a history of recently diagnosed multiple myeloma (Bence-Jones protein λ, R-ISS III), diabetes mellitus, and chronic kidney failure (serum creatinine, 2.15 mg/dl) presented with low-grade fever and exertional dyspnea owing to COVID-19 pneumonia, with SpO2 of 95% on room air at presentation. Chest CT revealed bilateral multiple ground-glass opacities. Her renal function prevented the use of antiviral agents, including remdesivir. A single dose of 500 mg tocilizumab was administered on the day of admission. However, on day 4 of hospitalization, she developed fever (>38°C), and her respiratory condition progressively worsened (P/F ratio: 252 mmHg), but her family did not agree to MV. The patient was treated with etoposide and PSL (20 mg/day). The dose of etoposide was reduced from 80 to 50 mg/m2, considering her kidney failure and old age. After this treatment, her fever subsided and her respiratory condition gradually improved (P/F ratio: 452 mmHg). However, she still had exertional dyspnea, and CT showed progressive consolidation and parenchymal changes with pulmonary fibrosis. On day 28, she was discharged home with supplemental oxygen therapy. She was followed up in the outpatient clinic for 3 months with no evidence of exacerbation. However, she could not be weaned from home oxygen therapy.\n\nPatient 3\n\nA 71-year-old man with a history of hemiplegia owing to a stroke, atrial fibrillation, hypertension, chronic heart failure, and untreated diabetes mellitus was intubated and transferred to our hospital because of severe hypoxia and fever (>38°C) at 10 days after the laboratory diagnosis of asymptomatic SARS-CoV-2 infection following close contact with another patient. CT showed lung consolidation with bronchial distribution in multiple lobes and segments and thrombus formation in the left atrial appendage. He was immediately admitted to our ICU and required invasive MV for severe ARDS with a P/F ratio of 90 mmHg; noradrenalin was administered to maintain his blood pressure. Treatment with remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 4 additional days), etoposide (80 mg/m2), and PSL (20 mg/day) was started. On the day after etoposide administration, his fever subsided, respiratory and hemodynamic conditions improved dramatically, and P/F ratio increased to 152 mmHg. Noradrenalin was discontinued 5 days after treatment initiation. His general condition and laboratory data, including lactate dehydrogenase, CK, sIL-2R, and CRP levels, remarkably improved. The PSL dose was tapered after 7 days of treatment. RT-PCR tests for SARS-CoV-2 on days 10 and 11 were confirmed to be negative. However, on day 12, he developed high fever (>39°C), and circulatory agents, including noradrenalin and dobutamine, were required to maintain his hemodynamic condition because he had a history of atrial fibrillation and chronic heart failure; tracheostomy was performed. There was no evidence of superinfection. Several blood and sputum cultures were negative, and CT showed improved lung consolidation with no new infectious sites. There were clinical and biochemical features of cytokine-releasing syndrome, with increased levels of aspartate transaminase, lactate dehydrogenase, sIL-2R, ferritin, D-dimer, and CRP levels and increased peripheral monocytes. Thus, a second course of etoposide and PSL was administered for macrophage activation syndrome on day 18. The day after starting the second treatment course, his fever subsided and general and hemodynamic conditions improved immediately; the PSL dose was tapered 7 days after second course of etoposide. He was weaned from the MV 10 days post-second treatment course (on day 29) and discharged to an inpatient rehabilitation hospital with supplemental oxygen therapy on day 35. Four months later, he was discharged home without oxygen support.\n\nPatient 4\n\nA 45-year-old man with a history of childhood asthma presented with fever (>39°C), cough, and dyspnea 10 days after the onset of symptoms. His SpO2 was 90% on 10 L/min oxygen via a mask. Chest CT showed consolidation with a bronchial distribution in multiple lobes. SARS-CoV-2 infection was confirmed on a respiratory viral multiplex PCR test using a nasal swab sample. Dexamethasone (6.6 mg/day) and favipiravir were started immediately after diagnosis. On the day after treatment initiation, his respiratory condition deteriorated owing to ARDS and fever remained high (>39°C). He was transferred to our hospital for further management. He was intubated and admitted to the ICU, and favipiravir was replaced with remdesivir. On day 2, his respiratory condition had not improved (P/F ratio: 150 mmHg) and high fever persisted; thus, etoposide (80 mg/m2) and PSL (20 mg/day) were administered. His P/F ratio improved to 220 mmHg and fever subsided 2 days after combination treatment initiation. On day 6, he developed high fever (>39°C), and his P/F ratio worsened to 152 mmHg with no evidence of superinfection (negative blood and sputum cultures). On day 9, CT revealed worsening pulmonary consolidation, mediastinal lymphadenopathy, and splenomegaly. Laboratory test results showed increased sIL-2R (1506 U/ml), ferritin (991.3 ng/ml), CRP (24.4 mg/dl), and D-dimer (2.9 g/ml) levels in contrast to the levels before combination treatment initiation. Thus, we decided to administer a second dose of etoposide and continue the same dose of PSL for another week. His fever eventually subsided and P/F ratio improved to 220 mmHg 2 days after the second dose of etoposide; he was extubated on day 13. RT-PCR tests for SARS-CoV-2 on days 14 and 15 were confirmed to be negative. Because his general condition continued to be good and laboratory data showed decreased inflammatory marker levels, the PSL dose was gradually tapered after 14 days of treatment and stopped on day 20.\n\nHe was discharged home without supplemental oxygen on day 24.\n\nPatient 5\n\nA 68-year-old man with a history of coronary artery bypass surgery, endovascular aortic repair for an abdominal aortic aneurysm, stroke, diabetes mellitus, hypertension, and hyperlipidemia presented with general fatigue and dyspnea 5 days after the onset of symptoms including low-grade fever, cough, and rhinorrhea. His SpO2 was 94% on 1 L/min oxygen via a nasal tube. Chest CT showed bilateral multiple ground-glass opacities. Laboratory data showed an elevated D-dimer level (4.7 g/ml). Treatment with dexamethasone (6.6 mg/day), favipiravir, and heparin (10,000 U/day) was immediately started after SARS-CoV-2 infection was confirmed by respiratory viral multiplex PCR. However, his respiratory condition (SpO2 90–95% on 5 L/min oxygen via a mask) deteriorated 3 days after treatment initiation. He was transferred to our hospital for further management, and favipiravir was replaced with remdesivir. On day 2, he developed high fever (>39°C) and his SpO2 decreased to <90% on 10 L/min oxygen via a mask. Chest CT revealed progression of the pulmonary lesions in extent and density. He was transferred to our ICU and required invasive MV for severe ARDS with a P/F ratio of 105 mmHg. On day 3, his respiratory condition and laboratory data, including inflammatory marker levels, had not improved despite dexamethasone was being administered for 5 days; hence, etoposide (80 mg/m2) and PSL (20 mg/day) were administered. His P/F ratio improved to 237.5 mmHg and fever subsided 2 days after combination therapy initiation. On day 10, he developed high fever again, and laboratory data showed increased inflammatory marker levels, including sIL-2R (1741 U/ml), CRP (11.39 mg/dl), and D-dimer (5.1 g/ml), but no evidence of secondary infection or change in respiratory condition was noted. Thus, we administered a second dose of etoposide and tapered the PSL dose to 10 mg. After the second dose of etoposide, his fever subsided immediately; he was extubated on day 15. SARS-CoV-2 PCR tests were confirmed to be negative on days 16 and 17. On day 18, he developed septic shock and was re-intubated, and noradrenaline was administered. Blood and central catheter line samples were positive for Enterobacter aerogenes. On day 21, his respiratory condition worsened (P/F ratio: 100 mmHg) even though carbapenem and an aminoglycoside were administered, necessitating venovenous extracorporeal membrane oxygenation (ECMO). E. aerogenes was isolated several times from the blood culture, despite effective antimicrobial therapy and catheter replacement. Eventually, CT showed a perianal abscess. Drainage of the abscess and administration of antimicrobial agents improved his condition, and he was weaned off ECMO on day 40. Three months later, he was weaned off the mechanical ventilator and transferred to an inpatient rehabilitation hospital.\n\nDiscussion\n\nExpanding the treatment options for critically ill COVID-19 patients on MV will improve individual outcomes and reduce the burden on medical practitioners and healthcare staff leading to more effective use of medical resources. The COVID-19 mortality rate is particularly high in elderly patients requiring invasive MV (13). Combination treatment with etoposide and low-dose corticosteroid showed favorable outcomes in five cases of severe COVID-19, including four patients on invasive MV. Three of the five patients who received etoposide and corticosteroid were over 65 years of age and had various underlying diseases, but all of them recovered. The 88-year-old patient with multiple myeloma was not placed on invasive MV during treatment.\n\nPeripheral blood in patients with severe COVID-19 shows lymphopenia with increased CD14-positive monocyte and inflammatory cytokine levels, such as tumor necrosis factor (TNF)-α and interferon (IFN)-γ (14, 15). In severe COVID-19 pneumonia, TNF-α and IFN-γ induce nitric oxide synthase (iNOS), which produces cytotoxic nitric oxide in macrophages and plays a central role in tissue injury and mortality (16). Thus, macrophages and monocytes are implicated as potential therapeutic targets to reduce hyperinflammation and tissue injury. Using a lethal ARDS model, we demonstrated that combination therapy with etoposide and low-dose corticosteroids improved mortality and lung injury associated with suppressed macrophage/monocyte accumulation and high iNOS expression levels in the lungs rather than suppressed inflammatory cytokines (10). In our COVID-19 cases, treatment with etoposide and corticosteroid rapidly reduced the number of circulating monocytes (Figure 2) and improved the respiratory condition.\n\nEtoposide is an anti-cancer agent; thus, clinicians should be aware of its dose-dependent side effects. When the HLH-94 protocol is applied to adults with HLH, reducing the etoposide dose from 150 mg/m2 to 50–100 mg/m2 is recommended (9). Thus, we administered etoposide at a dose of 80 mg/m2 in all patients, except the one with impaired renal function. Secondary leukemia is one of the most serious side effects of etoposide, occurring in up to 18.4% of patients treated with cumulative doses ranging from 5,200 to 19,200 mg/m2 (17). We treated five COVID-19 patients with 50–80 mg/m2 of etoposide as one or two doses. This dose is much lower than the treatment dose for small lung cancer and that in the HLH-94 protocol. Reactive cytopenia and hepatotoxicity are other potential adverse events following etoposide administration. However, these potential side effects were not observed in any of our patients. We believe that etoposide can be used safely to treat patients with severe COVID-19 who are on invasive MV; however, a clinical trial is needed to validate the efficacy and safety of this regimen.\n\nDexamethasone is effective in severe COVID-19. The recommended dose of dexamethasone (6 mg/day) is equivalent to 40 mg/day of PSL. High-dose corticosteroid (>20 mg/day PSL) increases the risk of steroid toxicity, including diabetes mellitus and secondary infection (18). Further, the administration of high-dose corticosteroids to COVID-19 patients increases the risk of secondary infections, including bacteremia and pulmonary aspergillosis (3, 19). Therefore, we decided to administer low-dose corticosteroids (20 mg/day for 1 week, subsequently reduced to 10 mg/day for 1 week) based on animal experiment findings (10). One patient had perianal abscess-associated bacteremia, but the corticosteroid dose could be reduced by combining it with etoposide. Moreover, corticosteroids affect glycemic control in individuals with diabetes or hyperglycemia due to COVID-19 (3, 19). Three patients had underlying diabetes mellitus, and their glucose levels increased after combination treatment with etoposide and corticosteroids that could be controlled with insulin administration. The other two patients did not show abnormal glucoses levels during the therapy.\n\nPrevious studies demonstrated that ICU admission and corticosteroid treatment significantly delayed viral clearance (20, 21). All the four ICU patients had negative SARS-CoV-2 RT-PCR tests on days 10–18 after hospital admission (Figure 1). Among COVID-19 ICU patients, the median time to a negative SARS-CoV-2 RT-PCR test was 19–26 days post-ICU admission (22). Thus, it is unlikely that our combination therapy delayed viral clearance when compared with other immunosuppressive therapies.\n\nThe H-Score has been widely used to support the diagnosis of sHLH (23). However, none of our patients met the sHLH criterion using the H-Score upon etoposide and corticosteroid administration (Table 1). In a study of autopsy cases of H1N1/09 influenza, <50% with histological evidence of hemophagocytosis met the criteria for sHLH based on the H-S score (6). Moreover, the H-Score was low in COVID-19 patients with hemophagocytosis (7). These discrepancies may be explained by the fact that the lung is the initial site of hyperinflammation following respiratory virus infection, thus HLH occurs in the lung, but not always throughout the body as is observed in malignancies and autoimmune diseases. Recently, Webb et al. proposed a set of six clinical criteria for cHIS: fever, macrophage activation (hyperferritinemia), hematological dysfunction (neutrophil-to-lymphocyte ratio), hepatic injury (lactate dehydrogenase or aspartate aminotransferase), coagulopathy (D-dimer), and cytokinemia (C-reactive protein, interleukin-6, or triglycerides). Meeting two or more of the six cHIS items is generally associated with severe disease and high fatality rate (24). All our patients met more than two of the cHIS items at the time of etoposide administration. Although these criteria need to be validated, they may serve as an indicator for clinicians to consider life-saving immunotherapy, including etoposide and corticosteroid, in severe COVID-19.\n\nIn conclusion, in this preliminary experience, combination treatment with etoposide and low-dose corticosteroids resulted in an overall favorable outcome in patients with SARS-CoV-2 infection-associated ARDS. Recently, etoposide has been described as an effective treatment for severe COVID-19 patients who do not require MV (12, 25). We plan to conduct a clinical trial to evaluate the efficacy and safety of combination therapy with etoposide and low-dose corticosteroids in critically ill COVID-19 patients who are on invasive MV in Japan (jRCT2021210012).\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.\n\nEthics Statement\n\nThe off-label use of etoposide and corticosteroid was approved by the Ethics Committee of Tohoku University Hospital. Written informed consent was obtained from patients. If the patients with ARDS received mechanical ventilation under the sedation, and they were not able to make their decision by themselves, we obtained written informed consent from their legal proxy for medical decision making before treatment. Written informed consent was obtained from the individual(s) for publication of any potentially identifiable images or data included in this articles.\n\nAuthor Contributions\n\nTA, YS, and MK designed the study. TA and YS wrote the initial draft. HB, TS, IS, IN, KTa, YI, KO, HK, MY, KS, and KTo provided patient care and collected the data. This paper has been reviewed, edited, and approved by all authors.\n\nFunding\n\nThis study has been supported in part by Japanese Society for the Promotion of Science Grant-in-Aid for Scientific Research 18K08424 (TA). Department of Intelligent Network for Infection Control, Tohoku University Graduate School of Medicine (TA, HB, KO, HK, MY, KTo) is an endowment department, supported with an unrestricted grant from Kyosei Igaku Laboratory Co., Ltd. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nPublisher's Note\n\nAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.\n\nThe authors thank all of the medical staff members involved in treating this patient.\n\nSupplementary Material\n\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fmed.2021.718641/full#supplementary-material\n\nClick here for additional data file.\n==== Refs\nReferences\n\n1. Huang C Wang Y Li X Ren L Zhao J Hu Y . Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. (2020) 395:497-506. 10.1016/S0140-6736(20)30183-5 32502551\n2. Group RC Horby P Lim WS Emberson JR Mafham M Bell JL . Dexamethasone in hospitalized patients with Covid-19. N Engl J Med. (2021) 384:693-704. 10.1056/NEJMoa2021436 32678530\n3. Sterne JAC Murthy S Diaz JV Slutsky AS Villar J Angus DC . Association between administration of systemic corticosteroids and mortality among critically Ill patients with COVID-19 a meta-analysis. JAMA. (2020) 324:1330-41. 10.1001/jama.2020.17023 32876694\n4. Nicholls JM Poon LL Lee KC Ng WF Lai ST Leung CY . Lung pathology of fatal severe acute respiratory syndrome. Lancet. (2003) 361:1773-8. 10.1016/s0140-6736(03)13413-7 12781536\n5. de Jong MD Simmons CP Thanh TT Hien VM Smith GJD Chau TNB . Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nat Med. (2006) 12:1203-7. 10.1038/nm1477 16964257\n6. Schulert GS Zhang M Fall N Husami A Kissell D Hanosh A . Whole-Exome sequencing reveals mutations in genes linked to hemophagocytic lymphohistiocytosis and macrophage activation syndrome in fatal cases of H1N1 influenza. J Infect Dis. (2016) 213:1180-8. 10.1093/infdis/jiv550 26597256\n7. Prilutskiy A Kritselis M Shevtsov A Yambayev I Vadlamudi C Zhao Q . 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(2010) 376 :2116. 10.1016/S0140-6736(10)61345-1 21168053\n12. M MB L B I A P D E I F C . Etoposide treatment adjunctive to immunosuppressants for critically ill COVID-19 patients. J Infect. (2020) 81:452-82. 10.1016/j.jinf.2020.06.006 32579985\n13. Lim ZJ Subramaniam A Ponnapa Reddy M Blecher G Kadam U Afroz A . Case fatality rates for patients with COVID-19 requiring invasive mechanical ventilation. A meta-analysis. Am J Respir Crit Care Med. (2021) 203:54-66. 10.1164/rccm.202006-2405OC 33119402\n14. Wen W Su W Tang H Le W Zhang X Zheng Y . Immune cell profiling of COVID-19 patients in the recovery stage by single-cell sequencing. Cell Discov. (2020) 6 :31. 10.1038/s41421-020-0168-9 33941770\n15. Lucas C Wong P Klein J Castro TBR Silva J Sundaram M . Longitudinal analyses reveal immunological misfiring in severe COVID-19. Nature. (2020) 584:463-9. 10.1038/s41586-020-2588-y 32717743\n16. Karki R Sharma BR Tuladhar S Williams EP Zalduondo L Samir P . Synergism of TNF-alpha and IFN-gamma triggers inflammatory cell death, tissue damage, and mortality in SARS-CoV-2 infection and cytokine shock syndromes. Cell. (2021) 184:149-+. 10.1016/j.cell.2020.11.025 33278357\n17. Ezoe S . Secondary leukemia associated with the anti-cancer agent, etoposide, a topoisomerase II inhibitor. Int J Environ Res Public Health. (2012) 9:2444-53. 10.3390/ijerph9072444 22851953\n18. Youssef J Novosad SA Winthrop KL . Infection risk and safety of corticosteroid use. Rheum Dis Clin North Am. (2016) 42:157-76, ix-x. 10.1016/j.rdc.2015.08.004 26611557\n19. Cano EJ Fonseca Fuentes X Corsini Campioli C O'Horo JC Abu Saleh O Odeyemi Y . Impact of corticosteroids in coronavirus disease 2019 outcomes: systematic review and meta-analysis. Chest. (2021) 159:1019-40. 10.1016/j.chest.2020.10.054 33129791\n20. Wang J Yang W Chen P Guo J Liu R Wen P . 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Webb BJ Peltan ID Jensen P Hoda D Hunter B Silver A . Clinical criteria for COVID-19-associated hyperinflammatory syndrome: a cohort study. Lancet Rheumatol. (2020) 2:e754-63. 10.1016/S2665-9913(20)30343-X 33015645\n25. Patel M Dominguez E Sacher D Desai P Chandar A Bromberg M . Etoposide as salvage therapy for cytokine storm due to coronavirus disease 2019. Chest. (2021) 159:e7-11. 10.1016/j.chest.2020.09.077 32931823\n\n", "fulltext_license": "CC BY", "issn_linking": "2296-858X", "issue": "8()", "journal": "Frontiers in medicine", "keywords": "COVID-19; SARS-CoV-2; acute respiratory distress (ARDS); case series; corticosteroid; etoposide", "medline_ta": "Front Med (Lausanne)", "mesh_terms": null, "nlm_unique_id": "101648047", "other_id": null, "pages": "718641", "pmc": null, "pmid": "34631741", "pubdate": "2021", "publication_types": "D002363:Case Reports", "references": "21168053;26611557;33119402;32931823;32876694;32681166;16964257;33301059;32717743;24782338;32007143;33278357;32678530;33015645;33882090;33129791;22851953;32579985;30028782;33639375;31986264;30992265;12781536;26597256", "title": "Case Report: Successful Treatment of Five Critically Ill Coronavirus Disease 2019 Patients Using Combination Therapy With Etoposide and Corticosteroids.", "title_normalized": "case report successful treatment of five critically ill coronavirus disease 2019 patients using combination therapy with etoposide and corticosteroids" }

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Case Report: Successful Treatment of Five Critically Ill Coronavirus Disease 2019 Patients Using Combination Therapy With Etoposide and Corticosteroids. 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Case Report: Successful Treatment of Five Critically Ill Coronavirus Disease 2019 Patients Using Combination Therapy With Etoposide and Corticosteroids. 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"2" }, { "reactionmeddrapt": "Blood glucose increased", "reactionmeddraversionpt": "24.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Enterobacter infection", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Aoyagi T, Sato Y, Baba H, Shiga T, Seike I, Niitsuma Sugaya I, et al. Case Report: Successful Treatment of Five Critically Ill Coronavirus Disease 2019 Patients Using Combination Therapy With Etoposide and Corticosteroids. 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FOR 1 WEEK", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19 pneumonia", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": "2", "drugtreatmentdurationunit": "803", "medicinalproduct": "PREDNISOLONE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": "080354", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM DAILY; FOR 1 WEEK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": "2", "drugtreatmentdurationunit": "803", "medicinalproduct": "PREDNISOLONE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "TOCILIZUMAB" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "SINGLE DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19 pneumonia", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOCILIZUMAB" } ], "patientagegroup": "6", "patientonsetage": "88", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Blood glucose increased", "reactionmeddraversionpt": "24.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Aoyagi T, Sato Y, Baba H, Shiga T, Seike I, Niitsuma Sugaya I, et al. Case Report: Successful Treatment of Five Critically Ill Coronavirus Disease 2019 Patients Using Combination Therapy With Etoposide and Corticosteroids. 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METER", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19 pneumonia", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TOCILIZUMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MILLIGRAM, SINGLE DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19 pneumonia", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOCILIZUMAB" } ], "patientagegroup": null, "patientonsetage": "88", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Blood glucose increased", "reactionmeddraversionpt": "24.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Aoyagi T, Sato Y, Baba H, Shiga T, Seike I, Niitsuma Sugaya I, et al. Case Report: Successful Treatment of Five Critically Ill Coronavirus Disease 2019 Patients Using Combination Therapy With Etoposide and Corticosteroids. Front-Med 2021;null:null.. 2021", "literaturereference_normalized": "case report successful treatment of five critically ill coronavirus disease 2019 patients using combination therapy with etoposide and corticosteroids", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20211124", "receivedate": "20211124", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 20110163, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220303" }, { "companynumb": "JP-TEVA-2021-JP-1982425", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": "74284", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MILLIGRAM DAILY; 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{ "abstract": "PML should be considered in patients with neurological symptoms following MM and in those who are immunosuppressed. Symptoms are diverse and often rapidly progressing. Prompt referral and early involvement of the multidisciplinary team are crucial.", "affiliations": "Department of Neurology NHS Lothian Western General Hospital Edinburgh UK.;Department of Haematology NHS Lothian Western General Hospital Edinburgh UK.;Department of Haematology NHS Lothian Western General Hospital Edinburgh UK.;Centre for Clinical Brain Sciences University of Edinburgh Edinburgh UK.", "authors": "Bennett|Karina M|KM|https://orcid.org/0000-0001-9828-5558;Storrar|Neill|N|;Johnson|Peter|P|;Fernandes|Peter M|PM|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1002/ccr3.2612", "fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904 John Wiley and Sons Inc. Hoboken \n\n10.1002/ccr3.2612\nCCR32612\nCase Report\nCase Reports\nProgressive multifocal leukoencephalopathy (PML) following autologous peripheral blood stem cell transplantation for multiple myeloma\nBENNETT et al.Bennett Karina M. https://orcid.org/0000-0001-9828-5558\n1\[email protected] Storrar Neill \n2\n Johnson Peter \n2\n Fernandes Peter M. \n3\n \n1 \nDepartment of Neurology\nNHS Lothian\nWestern General Hospital\nEdinburgh\nUK\n\n\n2 \nDepartment of Haematology\nNHS Lothian\nWestern General Hospital\nEdinburgh\nUK\n\n\n3 \nCentre for Clinical Brain Sciences\nUniversity of Edinburgh\nEdinburgh\nUK\n\n* Correspondence\n\nKarina Bennett, Department of Neurology, NHS Lothian, Western General Hospital, Flat 4, 18 Royal Circus, Edinburgh. EH3 6SS, UK.\n\nEmail: [email protected]\n\n20 3 2020 \n6 2020 \n8 6 10.1002/ccr3.v8.6938 943\n12 7 2019 19 10 2019 29 10 2019 © 2020 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nPML should be considered in patients with neurological symptoms following MM and in those who are immunosuppressed. Symptoms are diverse and often rapidly progressing. Prompt referral and early involvement of the multidisciplinary team are crucial.\n\nPML should be considered in patients with neurological symptoms following MM and in those who are immunosuppressed. Symptoms are diverse and often rapidly progressing. Prompt referral and early involvement of the multidisciplinary team are crucial.\n\n\nautologous peripheral blood stem cell transplantationmultiple myelomaprogressive multifocal leukoencephalopathy source-schema-version-number2.0cover-dateJune 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.8.4 mode:remove_FC converted:19.06.2020\n\n\nBennett \nKM \n, \nStorrar \nN \n, \nJohnson \nP \n, \nFernandes \nPM \n. Progressive multifocal leukoencephalopathy (PML) following autologous peripheral blood stem cell transplantation for multiple myeloma\n. Clin Case Rep . 2020 ;8 :938 –943\n. 10.1002/ccr3.2612\n==== Body\n1 INTRODUCTION\nA 67‐year‐old man presented with left‐sided weakness and reduced left‐hand dexterity four months after autologous stem cell transplant (ASCT) for multiple myeloma (MM). Clinical neurological examination was felt to be normal. Three months later, he reported progressive worsening of this weakness; neurological examination showed mild left‐sided facial asymmetry.\n\nHe was diagnosed with IgG lambda MM in March 2016 during follow‐up of lytic lesions on a chest radiograph performed because of recurrent chest infections. His past medical history included chronic obstructive pulmonary disease and controlled hypertension. He was human immunodeficiency virus (HIV) negative. He underwent induction treatment with four cycles of bortezomib, thalidomide, and dexamethasone starting in April 2016, complicated by neutropenic sepsis requiring intensive care for high‐flow oxygen and granulocyte‐colony stimulating factor. He also developed thrombosis of his peripherally inserted central catheter, treated with low molecular weight heparin. ASCT with melphalan conditioning (200 mg/m2) was carried out in January 2017. On day 7 following ASCT, he developed neutropenic sepsis from urinary Escherichia coli. He took routine post‐transplant Pneumocystis jirovecii prophylaxis trimethoprim/sulfamethoxazole, which was switched to pentamidine in April 2017 because of slow platelet count recovery. This stopped in July 2017. In March 2017, he had an episode of herpes zoster affecting the left trunk.\n\nGeneral weakness is common in the months following transplant as the patient recovers from the intensive treatment, complications and hospital admission. The focal progressive symptoms and new findings on neurological examination are much more concerning. There is a wide differential diagnosis, including cerebrovascular disease, demyelinating illness and space occupying lesions.\n\nComputerized tomography (CT) scan of the head was performed which showed multiple areas of low attenuation (Figure 1).\n\nFigure 1 Computerized tomography (CT) scan of the head was performed which showed multiple areas of low attenuation, as shown by the white arrow\n\nThe radiological findings were thought to represent multiple areas of infarction, likely embolic in nature. The progressive nature of the weakness could represent multiple infarcts over time. The patient had several risk factors for stroke: smoking history, hypertension, malignancy, and treatment with chemotherapy. 1 The complication of peripherally inserted central catheter thrombosis could also point toward a predisposition for thrombosis.\n\nMagnetic Resonance Imaging (MRI) of the brain showed numerous hyper‐intense T2 lesions within the subcortical white matter of both cerebral hemispheres (Figure 2). The MRI was repeated one month later and showed interval progression in lesion size (Figure 3).\n\nFigure 2 Magnetic resonance imaging of the brain showed numerous hyper‐intense T2 lesions within the subcortical white matter of both cerebral hemispheres\n\nFigure 3 Magnetic resonance imaging (MRI) repeated one month after the MRI shown in Figure 1 shows interval progression in lesion size\n\nThe MRI head showed multiple areas T2 high signal in the white matter, in keeping with demyelination. This is a feature of several neurological conditions, including hypoxic/ ischemic insults, inflammation (multiple sclerosis, acute disseminated encephalomyelitis, vasculitis, and sarcoidosis), metabolic/toxic causes (carbon monoxide poisoning, vitamin B12 deficiency, central pontine myelinolysis, inherited leukodystrophies), and infections (HIV, syphilis, lyme disease, and progressive multifocal leukoencephalopathy (PML)).\n\nHis clinical symptoms continued to progress, and by September 2017, he was unable to walk 2 m unaided. He developed emotional lability and motion sickness. There was no alteration in sensation, sphincter or bulbar symptoms, and he had no weight loss, night sweats or fevers.\n\nExamination showed normal tone bilaterally. There was mild left‐sided weakness of the face and left‐sided hemiparesis, worse than previous. Reflexes in the legs were brisk with some spreading, and the left plantar response was up‐going. Gait was narrow‐based, stiff and hemiplegic. There were no cerebellar signs. Sensation was intact. Assessment of cognitive function with Addenbrooke's Cognitive Examination III‐revised (ACE III‐R) showed mild cognitive impairment with a score of 84/100 (attention 17/18, memory 21/26, fluency 7/14, language 26/26, and visuospatial 13/16).\n\nInterpretation of ACE III‐R scores is difficult, and repeated tests at different points in time are the best way to show cognitive decline. A score of less than 88 gives a significant likelihood of dementia 2; thus, in our patient, a score of 84 demonstrates probable cognitive impairment.\n\nFurther investigations were performed to determine the cause of the demyelination. A CT chest, abdomen, and pelvis showed no evidence of systemic disease, such as solid malignancy. Serum serology was negative for HIV, syphilis, and lyme disease. Connective tissue autoimmune screen was negative, with no evidence of systemic vasculitis, and vitamin B12 levels were normal. A lumbar puncture showed normal cell count (red blood cell 0 × 1012/L, white blood cell 2 × 109/L), protein (0.37 mg/dL), glucose (3.4 mg/dL), and no oligoclonal bands in serum or cerebrospinal fluid (CSF). Viral polymerase chain reaction was negative for enteroviruses, herpes simplex virus 1 & 2, parechovirus, and varicella zoster virus, and there were no abnormal cells on microscopy. John Cunningham polyomavirus virus (JCPyV), the causative agent of PML, was positive in serum (1.55 index value); CSF testing for JCPyV was strongly positive at a value of 830 000 copies/ml.\n\nSeropositivity for JCPyV in this patient was not unexpected as between 38% and 82% of the normal population have positive serology, but the virus should not be present in the CSF.3, 4 The positive CSF for JCPyV with compatible clinical and radiological findings fulfill the diagnostic criteria for PML,5 and there was no diagnostic need to perform a brain biopsy. This diagnosis was unexpected as the patient did not appear to be significantly immunocompromised following ASCT and PML is rare in this patient group.\n\nKey blood results before and after ASCT are shown in Table 1, and further measures of immune functioning were taken after the diagnosis of PML to evaluate scope for optimization of immune function (Table 2).\n\nTable 1 Table showing key blood results before, immediately after and 1, 2, and 3 months after ASCT\n\nTime\t\nIgG lambda paraprotein\n\n\n(g/L)\n\n\n\tIgA (g/L)\tIgM (g/L)\t\nHb\n\n\n(135‐180 g/L)\n\n\n\t\nWCC\n\n\n(4.0‐11 109/L)\n\n\n\t\nLymphocytes\n\n\n(1.5‐4\n\n\n109/L)\n\n\n\t\nNeutrophils\n\n\n(2.0‐7.5 109/L)\n\n\n\t\nPlatelets\n\n\n(150‐400 109/L)\n\n\n\t\nDiagnosed MM (March 2016)\t24\t0.36\t0.14\t‐\t‐\t‐\t‐\t‐\t\nBefore chemotherapy (April 2016)\t16\t \t \t130\t14.6\t0.23\t14.09\t143\t\nImmediately post ASCT (January 2017)\t<1\t1.25\t0.20\t117\t5.2\t0.13\t4.85\t141\t\n1 month (February 2017)\t<1\t \t \t95\t5.2\t0.85\t3.19\t39\t\n2 months (March 2017)\t<1\t \t \t92\t6.7\t0.52\t5.47\t100\t\n3 months (April 2017)\t<1\t0.87\t0.13\t98\t5.6\t0.67\t4.3\t57\t\nJohn Wiley & Sons, LtdTable 2 Measures of immune functioning at the time of diagnosis of PML\n\nImmune measure\tResult\t\nLymphocytes (1.5‐4 cells 109/L)\t0.41\t\nB cells (10%‐16%)\t43\t\nT‐cells (67%‐76%)\t40\t\nCD4 absolute (500‐1500 cells u/L)\t72\t\nCD4% (29%‐61%)\t18\t\nCD8 absolute (250‐750 cells u/L)\t90\t\nCD8% (14%‐44%)\t22\t\nCD4/CD8 ratio (0.9‐3.5)\t0.8\t\nNatural killer cells (10%‐15%)\t16\t\nC3 (0.81‐1.57 g/L)\t1.44\t\nC4 (0.13‐1.39 g/L)\t0.34\t\nIgA (6‐15 g/L)\t0.58\t\nIgG (0.8‐4.5 g/L)\t6.82\t\nIgM (0.35‐2.9 g/L)\t0.29\t\nJohn Wiley & Sons, LtdASCT improves the duration of remission and overall survival in patients with MM although most patients develop relapse of MM after a period of remission. 6, 7, 8 The recovery of different immune cells occurs at different time points post‐transplant. The reconstitution of innate immunity occurs rapidly, within 20‐30 days, while reconstitution of adaptive immunity can take 1 year. 9 Early recovery of absolute lymphocyte count (ALC) can be used as a prognostic indicator of overall survival and progression free survival. 10 The patient followed the usual pace of immune reconstitution, with neutrophil recovery at day + 12; implying good immune functioning. Reactivation of varicella zoster virus is common after ASCT 11 and does not suggest unusual immunodeficiency for this patient group. The CD4 count is low; in cases of HIV‐associated PML, there appears to be an association between CD4 count and PML. 5\n\n\nTreatment for JCPyV was commenced with mirtazapine 30mg once daily and intensive physiotherapy.\n\nTreatment for PML can be tackled in two ways: restoring the immune function and attacking the virus. Restoring the immune functioning in the patient was problematic as he did not appear to have reversible immune suppression beyond normal recovery post‐ASCT. No methods to restore immune function were thought feasible except for the possibility of performing a second ASCT using remaining stem cells cryopreserved prior to the first ASCT. Several experimental antiviral therapies were considered, including mirtazapine, which is thought to block virus entry into glial cells via 5HT2a serotonin receptors. 12 Recently, three groups have reported favorably on the use of immune‐checkpoint inhibitors to treat PML; immunotherapy appears promising but requires further study. 13, 14, 15\n\n\nDuring admission, his condition continued to worsen. He developed hospital acquired pneumonia (HAP) and deteriorated rapidly, dying 5 days later. His death was 18 months after diagnosis of MM, 10 months after ASCT, 14 days after diagnosis of PML and 10 days after mirtazapine had started. His death was before the second ASCT could be attempted.\n\nIt was very difficult to give a prognosis to the patient due to lack of comparable cases. His rapid deterioration from HAP was unexpected. This could reflect a weaker immune function than suggested by his blood test results. It was unlikely that a second stem cell infusion (without conditioning chemotherapy) would have promoted immune reconstitution, but equally seemed unlikely to cause harm.\n\n2 DISCUSSION\nPML is a rare demyelinating disorder of the central nervous system caused by reactivation of JCPyV virus, a neurotropic polyomavirus.16 The clinical presentation depends on the extent of demyelination and brain structures involved. Symptoms include muscle weakness, sensory deficit, hemianopia, cognitive dysfunction, aphasia, and coordination and gait difficulties. 17 JCPyV virus is present in 38%‐82% of the population 3, 4 but is usually well‐controlled by the immune system, resulting in asymptomatic latent infection. The kidney and bone marrow are the likely sites of latent infection,18 and there should be no JCPyV virus detectable in the CSF. PML primarily affects those with chronic and severely suppressed immune systems. 19 Three associations account for 90% of cases: (1) HIV; (2) immunosuppressing hematological malignancies, and (3) Multiple sclerosis patients treated with natalizumab, a monoclonal antibody to alpha‐4 integrin that prevents immune cells accessing the central nervous system. 20 PML is rarely associated with organ transplantation, solid malignancies, sarcoidosis, and autoimmune disorders.20\n\n\nTreatment for PML is via restoring immune function and/or attacking the virus. Restoring immune function can be achieved by reversal of the immunosuppression caused by a disease, for example antiretroviral drugs in HIV 21; removal of immunosuppressive treatment for example stopping Natalizumab 22 or speeding drug clearance through plasma exchange. 23 The second option is to attack the virus. Pavlovic et al 20 conducted a review of treatment options and divided them into 3 main groups: (1) antiviral agents (JCPyV cell entry inhibitors, retrograde transport inhibitors, inhibitors of DNA replication, antimalarials, poly‐ADP‐ribose polymerase‐1 inhibitors and tyrosine kinase inhibitors), (2) immune response modulators (cytokines and inflammation inhibitors), and (3) immunisation strategies (passive and active immunisation). Research supporting these options is limited to case studies and retrospective studies with no strong consensus. Identification of successful treatment is difficult due to lack of an adequate animal model, small patient numbers, and rapid disease progression.20\n\n\nPrognosis in PML is poor. In HIV, 70% are alive at one year and 50% at 2 years. In those with MS treated with Natalizumab, 77% are alive at three years, and in those with active immunosuppressing hematological malignancies, 10% are alive at 2 months. 20 A younger age at diagnosis, lower viral load of JCPyV, milder functional disability prior to PML diagnosis and more localized MRI brain involvement all appear to predict survival. 24\n\n\nDeveloping PML after MM is rare with 11 case reports in the literature. 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 Presentations varied in these patients depending on the location of the lesion and included: hemiparesis and hemiplegia, 25, 28, 29, 32, 35 numbness and tingling of the legs,29 rapid cognitive decline, 25, 27, 33 homonymous hemianopia, 27 ataxia, 27 speech difficulties, 26, 30, 31, 32, 35 incontinence, 26 apathy, 29 and memory impairment. 32, 33, 34\n. Trying to identify if an individual aspect of the MM treatment was responsible for the development of PML is difficult from these isolated case studies. Thalidomide has indirectly been related in this case and two others 29, 30 and lenalidomide in four cases. 25, 26, 27, 28 ASCT was used in all of the cases except two in which lenalidomide was used alone. 25, 28 Lenalidomide is an immunomodulatory drug with antiangiogenetic, anti‐inflammatory, and antiproliferative effects. Ying (2017) completed a systematic review and meta‐analysis of the risk of serious infection in patients with MM receiving lenalidomide and found that the overall incidence of high‐grade infection was 14.32%. Treatment for the PML varied in these case reports. Mirtazepine was used as a single agent in this case and 2 others; 26, 27 in these cases, the patients died within 2‐4 months. Yokokawa (2016) used mirtazepine in combination with mefloquine. In this case, the patient survived for more than one year from PML onset. Ripelino (2011) used mirtazapine in combination with cidofovir and the patient survived for more than two years after onset of PML. It is not possible to recommend the most appropriate therapy from these reports; however, the use of combined treatments may improve outcome. Treatment outcome may also be improved with early diagnosis.\n\nThere are difficult ethical questions about exposing patients to potentially harmful treatments when there is a lack of evidence of efficacy, even when prognosis is poor. Furthermore, any drug which is used must be able to cross the blood brain barrier and have acceptable side effects. There also needs to be consensus on how to measure outcome. Some possible measures include: survival, neurological examination, radiological lesion load and changes in JCPyV in the CSF. Until randomized control trials become available, the treatment of PML relies on case descriptions, retrospective studies, and informed discussions with patients.\n\nPML is a rare complication of MM therapy and is associated with high mortality and morbidity. Clinicians should consider this diagnosis when assessing patients with neurological symptoms and signs following treatment for MM. It is important that referrals are made promptly, and there is involvement of the multidisciplinary team with haematologists, neurologists, radiologists, virologists, and therapists.\n\nCONFLICT OF INTEREST\nNone declared.\n\nAUTHOR CONTRIBUTION\nKB, NS, PJ, and PMF: substantially contributed to conception and design, acquisition of data, or analysis and interpretation of data; drafted the article or revised it critically for important intellectual content; and finally approved the version to be published. Karina Bennett will act as guarantor for the content.\n==== Refs\nREFERENCES\n1 \n\nKristinsson \nSY \n, \nPfeiffer \nRM \n, \nBjörkholm \nM \n, et al. Arterial and venous thrombosis in monoclonal gammopathy of undetermined significance and multiple myeloma: a population‐based study\n. 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Oncotarget . 2017 ;8 :46593 ‐46600\n.28423741\n\n", "fulltext_license": "CC BY", "issn_linking": "2050-0904", "issue": "8(6)", "journal": "Clinical case reports", "keywords": "autologous peripheral blood stem cell transplantation; multiple myeloma; progressive multifocal leukoencephalopathy", "medline_ta": "Clin Case Rep", "mesh_terms": null, "nlm_unique_id": "101620385", "other_id": null, "pages": "938-943", "pmc": null, "pmid": "32577238", "pubdate": "2020-06", "publication_types": "D002363:Case Reports", "references": "24492738;26600871;30969507;25227934;29507502;24834205;12031917;23568998;22701032;11468153;30969503;12424695;19741228;16956822;20299513;28423741;27909435;19434930;20506049;25771865;16977673;29690814;20298966;19188571;22890289;20190843;17005670;17674313;30969500;28278713;30704932;28039754;27538654;10025799", "title": "Progressive multifocal leukoencephalopathy (PML) following autologous peripheral blood stem cell transplantation for multiple myeloma.", "title_normalized": "progressive multifocal leukoencephalopathy pml following autologous peripheral blood stem cell transplantation for multiple myeloma" }

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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SULFAMETHOXAZOLE, TRIMETHOPRIM" } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Progressive multifocal leukoencephalopathy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutropenic sepsis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BENNETT K.M.. PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) FOLLOWING AUTOLOGOUS PERIPHERAL BLOOD STEM CELL TRANSPLANTATION FOR MULTIPLE MYELOMA. CLINICAL CASE REPORTS. 2020?8:6:938?943", "literaturereference_normalized": "progressive multifocal leukoencephalopathy pml following autologous peripheral blood stem cell transplantation for multiple myeloma", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20200717", "receivedate": "20200717", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18036994, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "GB-TEVA-2020-GB-1809828", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BORTEZOMIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201604", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BORTEZOMIB." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "087668", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201604", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "THALIDOMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201604", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "THALIDOMIDE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PENTAMIDINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "201707", "drugenddateformat": "610", "drugindication": "ANTIFUNGAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201704", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PENTAMIDINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "201704", "drugenddateformat": "610", "drugindication": "ANTIFUNGAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRIMETHOPRIM/SULFAMETHOXAZOLE" } ], "patientagegroup": "6", "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Gait spastic", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dementia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hemiparesis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutropenic sepsis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cognitive disorder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Motion sickness", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Herpes zoster", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Progressive multifocal leukoencephalopathy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fine motor skill dysfunction", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Affect lability", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gait disturbance", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Escherichia infection", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "JC virus infection", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gait inability", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2017" } }, "primarysource": { "literaturereference": "BENNETT KM, STORRAR N, JOHNSON P, FERNANDES PM. PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) FOLLOWING AUTOLOGOUS PERIPHERAL BLOOD STEM CELL TRANSPLANTATION FOR MULTIPLE MYELOMA. CLIN?CASE?REP 2020?8(6):938?943.", "literaturereference_normalized": "progressive multifocal leukoencephalopathy pml following autologous peripheral blood stem cell transplantation for multiple myeloma", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20210628", "receivedate": "20200803", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18103917, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "GB-MYLANLABS-2020M1066945", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "040802", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK UNK, CYCLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PENTAMIDINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIFUNGAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PENTAMIDINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "THALIDOMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201604", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "THALIDOMIDE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200 MILLIGRAM/SQ. METER", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "201704", "drugenddateformat": "610", "drugindication": "ANTIFUNGAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRIMETHOPRIM SULFAMETHOXAZOLE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "BORTEZOMIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BORTEZOMIB." } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Progressive multifocal leukoencephalopathy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hemiparesis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gait spastic", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cognitive disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "JC virus infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Affect lability", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gait inability", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Escherichia infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gait disturbance", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dementia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Herpes zoster", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fine motor skill dysfunction", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutropenic sepsis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Motion sickness", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2017" } }, "primarysource": { "literaturereference": "BENNETT KM, STORRAR N, JOHNSON P, FERNANDES PM. PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) FOLLOWING AUTOLOGOUS PERIPHERAL BLOOD STEM CELL TRANSPLANTATION FOR MULTIPLE MYELOMA. CLIN?CASE?REP 2020?8(6):938?943.", "literaturereference_normalized": "progressive multifocal leukoencephalopathy pml following autologous peripheral blood stem cell transplantation for multiple myeloma", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20200727", "receivedate": "20200727", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18073280, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "GB-ASPEN-GLO2020GB007185", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "THALIDOMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "4 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201604", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "THALIDOMIDE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "4 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201604", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BORTEZOMIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201604", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BORTEZOMIB." } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neutropenic sepsis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2016" } }, "primarysource": { "literaturereference": "BENNETT KM, STORRAR N, JOHNSON P, FERNANDES PM.. PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) FOLLOWING AUTOLOGOUS PERIPHERAL BLOOD STEM CELL TRANSPLANTATION FOR MULTIPLE MYELOMA.. CLINICAL CASE REPORTS. 2020?8(6):938?943", "literaturereference_normalized": "progressive multifocal leukoencephalopathy pml following autologous peripheral blood stem cell transplantation for multiple myeloma", "qualification": "1", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20200728", "receivedate": "20200728", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 18079625, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "GB-FRESENIUS KABI-FK202007446", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "BORTEZOMIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201604", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BORTEZOMIB." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201701", "drugstartdateformat": "610", "drugstructuredosagenumb": "200", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "THALIDOMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201604", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "THALIDOMIDE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "084916", "drugbatchnumb": "UNKNOWN,UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201604", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE INJECTION (MANUFACTURER UNKNOWN)" } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Herpes zoster", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Device related thrombosis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Escherichia sepsis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "JC virus infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutropenic sepsis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Progressive multifocal leukoencephalopathy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201703" } }, "primarysource": { "literaturereference": "BENNETT K, STORRAR N, JOHNSON P, FERNANDES P. PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) FOLLOWING AUTOLOGOUS PERIPHERAL BLOOD STEM CELL TRANSPLANTATION FOR MULTIPLE MYELOMA. CLINICAL CASE REPORTS. 2020?8 (6):938?943.", "literaturereference_normalized": "progressive multifocal leukoencephalopathy pml following autologous peripheral blood stem cell transplantation for multiple myeloma", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20200722", "receivedate": "20200722", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18055433, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" } ]

{ "abstract": "BACKGROUND\nCytomegalovirus (CMV) infection is common in thoracic organ transplant recipients. Valganciclovir and ganciclovir are used for both prophylaxis and treatment of this infection, but intolerance and treatment failure are common. Letermovir has been demonstrated to reduce the risk of CMV infection when used for prophylaxis in allogeneic hematopoietic cell transplantation. However, there are no data on its efficacy in thoracic organ transplantation.\n\n\nMETHODS\nWe examined the use of letermovir for either CMV prophylaxis (primary and secondary) or treatment in heart and lung transplant recipients at our institution from February 1, 2018, through December 31, 2018.\n\n\nRESULTS\nNine total patients received letermovir at our institution (8 lung transplant, 1 heart transplant) during the study period. Letermovir was prescribed for CMV prophylaxis in eight patients (primary prophylaxis in two patients and secondary prophylaxis in 6 patients), and for treatment of CMV DNAemia in two cases. One patient received letermovir for both secondary prophylaxis and treatment on separate occasions. Three out of 8 (37.5%) patients receiving letermovir for prophylaxis developed CMV DNAemia during prophylaxis. One patient treated for CMV disease had clinical failure with a sharp rise in serum CMV DNA PCR. The other patient treated for low-grade CMV DNAemia initially had a slight rise in CMV DNA PCR, but has since had a sustained response. No major side effects were experienced, and 2 patients reported minor side effects.\n\n\nCONCLUSIONS\nLetermovir was well tolerated with only minor side effects reported; however, the rate of development of CMV DNAemia on prophylaxis was considerable. Further study of the dosing and efficacy of letermovir for CMV prophylaxis or treatment in thoracic organ transplant recipients is warranted.", "affiliations": "Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, Falls Church, Virginia.;Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, Falls Church, Virginia.;Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, Falls Church, Virginia.;Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, Falls Church, Virginia.;Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, Falls Church, Virginia.;Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, Falls Church, Virginia.;Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, Falls Church, Virginia.;Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, Falls Church, Virginia.;Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, Falls Church, Virginia.;Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, Falls Church, Virginia.;Advanced Heart Failure and Cardiac Transplant Program, Inova Fairfax Hospital, Falls Church, Virginia.;Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, Falls Church, Virginia.", "authors": "Aryal|Shambhu|S|https://orcid.org/0000-0002-3753-4378;Katugaha|Shalika B|SB|;Cochrane|Adam|A|;Brown|Anne Whitney|AW|;Nathan|Steven D|SD|;Shlobin|Oksana A|OA|;Ahmad|Kareem|K|;Marinak|Lauren|L|;Chun|Jessica|J|;Fregoso|Margaret|M|;Desai|Shashank|S|;King|Christopher|C|", "chemical_list": "D000085:Acetates; D000998:Antiviral Agents; D004279:DNA, Viral; D007166:Immunosuppressive Agents; D011799:Quinazolines; C000588473:letermovir", "country": "Denmark", "delete": false, "doi": "10.1111/tid.13166", "fulltext": null, "fulltext_license": null, "issn_linking": "1398-2273", "issue": "21(6)", "journal": "Transplant infectious disease : an official journal of the Transplantation Society", "keywords": "cytomegalovirus; heart transplantation; letermovir; lung transplantation", "medline_ta": "Transpl Infect Dis", "mesh_terms": "D000085:Acetates; D000328:Adult; D000368:Aged; D019072:Antibiotic Prophylaxis; D000998:Antiviral Agents; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D004279:DNA, Viral; D005260:Female; D006084:Graft Rejection; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D011799:Quinazolines; D055502:Secondary Prevention; D066027:Transplant Recipients; D016896:Treatment Outcome", "nlm_unique_id": "100883688", "other_id": null, "pages": "e13166", "pmc": null, "pmid": "31487755", "pubdate": "2019-12", "publication_types": "D016428:Journal Article", "references": null, "title": "Single-center experience with use of letermovir for CMV prophylaxis or treatment in thoracic organ transplant recipients.", "title_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients" }

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SINGLE-CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS. TRANSPLANT INFECTIOUS DISEASE. 2019 DEC?21(6):1-6. 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SINGLE-CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS. TRANSPLANT INFECTIOUS DISEASE. 2019 DEC?21(6):1-6. DOI:10.1111/TID.13166", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200313", "receivedate": "20200313", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17537434, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "US-APOTEX-2020AP008352", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "LETERMOVIR" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "240 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "240", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETERMOVIR" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "LETERMOVIR" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETERMOVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "065040", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, 100-150", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOSPORINE." } ], "patientagegroup": null, "patientonsetage": "60", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cytomegalovirus viraemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA S.B, COCHRANE A, BROWN A.W, NATHAN S.D. ET AL.. SINGLE-CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS. DOI:10.1111/TID.13166.. TRANSPLANT INFECTIOUS DISEASE. 2019?21:E13166:1-6", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200304", "receivedate": "20200304", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17491434, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "US-009507513-1904USA002788", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MILLIGRAM, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LETERMOVIR" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "209939", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK", "drugenddate": "2018", "drugenddateformat": "602", "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2018", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREVYMIS" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10?12, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2018" } }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA SB, COCHRANE A, BROWN AW, NATHAN SD, SHLOBIN OA, ET AL. SINGLE CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS.. TRANSPL INFECT DIS. 2019?21", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210629", "receivedate": "20190408", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16167277, "safetyreportversion": 4, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210716" }, { "companynumb": "NVSC2020US057315", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LETERMOVIR" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "480 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "480", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETERMOVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "65461", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "80336", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." } ], "patientagegroup": null, "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cytomegalovirus viraemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA SB, COCHRANE A, BROWN AW, NATHAN SD, SHLOBIN OA ET AL.. SINGLE-CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS. TRANSPLANT INFECTIOUS DISEASE. 2019?21(6):E13166", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200302", "receivedate": "20200302", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17485857, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "NVSC2020US057316", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "65461", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LETERMOVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETERMOVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "80336", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "7.5 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "7.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cytomegalovirus viraemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Oedema", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA SB, COCHRANE A, BROWN AW, NATHAN SD, SHLOBIN OA ET AL.. SINGLE-CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS.. TRANSPLANT INFECTIOUS DISEASE. 2019?21(6):E13166", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200303", "receivedate": "20200303", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17488397, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "US-TEVA-2020-US-1196956", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "GOAL TROUGH: 10-12", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "080356", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LETERMOVIR" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "480 MILLIGRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "480", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETERMOVIR" } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cytomegalovirus infection", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA SB, COCHRANE A, BROWN AW, NATHAN SD, SHLOBIN OA, ET AL. SINGLE-CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS. TRANSPL-INFECT-DIS 2019?21:NO. 6.", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200310", "receivedate": "20200310", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17524127, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200409" }, { "companynumb": "US-DRREDDYS-USA/USA/20/0120797", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "090509", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "203511", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS VIRAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." } ], "patientagegroup": null, "patientonsetage": "69", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Leukopenia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cytomegalovirus viraemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA S, COCHRANE A, BROWN A, NATHAN S, SHLOBIN O, AHMAD K, MARINAK L, CHUN J, FREGOSO M, DESAI S, KING C. SINGLE-CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS. TRANSPLANT INFECTIOUS DISEASE. 2019 DEC?21(6):1-6. DOI:10.1111/TID.13166", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200313", "receivedate": "20200313", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17537578, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "US-STRIDES ARCOLAB LIMITED-2020SP003571", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, 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SINGLE?CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS. TRANSPLANT INFECTIOUS DISEASE. 2019?21(6)", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200914", "receivedate": "20200914", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18261238, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20201103" }, { "companynumb": "PHHY2019US219908", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, 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null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": "48", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cytomegalovirus infection", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA BS, COCHRANE A, BROWN AW, NATHAN SD, SHLOBIN OA ET AL.. SINGLE-CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS. TRANSPLANT INFECTIOUS DISEASE. 2019?1-6", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190923", "receivedate": "20190923", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16840398, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191005" }, { "companynumb": "US-STRIDES ARCOLAB LIMITED-2020SP003579", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "LETERMOVIR" 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null, "medicinalproduct": "VALGANCICLOVIR." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "90687", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cytomegalovirus viraemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA SB, COCHRANE A, BROWN AW, NATHAN SD, SHLOBIN OA, ET AL. SINGLE?CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS. TRANSPLANT INFECTIOUS DISEASE. 2019?21(6)", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200914", "receivedate": "20200914", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18263208, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20201103" }, { "companynumb": "US-TEVA-2020-US-1196955", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LETERMOVIR" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "480 MILLIGRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "480", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETERMOVIR" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "205220", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "080356", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "7.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "GOAL TROUGH: 10", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cytomegalovirus infection", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukopenia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Oedema", "reactionmeddraversionpt": "22.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA SB, COCHRANE A, BROWN AW, NATHAN SD, SHLOBIN OA, ET AL. SINGLE-CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS. TRANSPL-INFECT-DIS 2019?21:NO. 6.", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200310", "receivedate": "20200310", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17524126, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "US-009507513-1904USA002789", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LETERMOVIR" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "209939", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK", "drugenddate": "2018", "drugenddateformat": "602", "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2018", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREVYMIS" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "7.5 MILLIGRAM, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "7.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Oedema", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2018" } }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA SB, COCHRANE A, BROWN AW, NATHAN SD, SHLOBIN OA, ET AL. SINGLE CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS.. TRANSPL INFECT DIS. 2019?21 (6):E13166", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210607", "receivedate": "20190408", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16167276, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210716" }, { "companynumb": "US-DRREDDYS-USA/USA/20/0120812", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "090509", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "203511", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS VIRAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." } ], "patientagegroup": null, "patientonsetage": "33", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cytomegalovirus viraemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Gene mutation", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA S, COCHRANE A, BROWN A, NATHAN S, SHLOBIN O, AHMAD K, MARINAK L, CHUN J, FREGOSO M, DESAI S, KING C. SINGLE-CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS. TRANSPLANT INFECTIOUS DISEASE. 2019 DEC?21(6):1-6. DOI:10.1111/TID.13166", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200313", "receivedate": "20200313", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17537986, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "US-STRIDES ARCOLAB LIMITED-2020SP003574", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, 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SINGLE?CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS. TRANSPLANT INFECTIOUS DISEASE. 2019?21(6)", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200728", "receivedate": "20200728", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18079966, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20201103" }, { "companynumb": "US-MYLANLABS-2020M1023904", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "GOAL TROUGH: 10-12", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "080292", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cytomegalovirus infection", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA SB, COCHRANE A, BROWN AW, NATHAN SD, SHLOBIN OA, ET AL. SINGLE-CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS. TRANSPL-INFECT-DIS 2019?21:NO. 6.", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200305", "receivedate": "20200305", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17501169, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200409" }, { "companynumb": "US-TEVA-2020-US-1196954", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "205220", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "GOAL TROUGH:10-12", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LETERMOVIR" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "480 MILLIGRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "480", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETERMOVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "080356", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Leukopenia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cytomegalovirus infection", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA SB, COCHRANE A, BROWN AW, NATHAN SD, SHLOBIN OA, ET AL. SINGLE-CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS. TRANSPL-INFECT-DIS 2019?21:NO. 6.", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200311", "receivedate": "20200311", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17524609, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "US-DRREDDYS-USA/USA/20/0120801", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090509", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "12.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "203511", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." } ], "patientagegroup": null, "patientonsetage": "48", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Leukopenia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA S, COCHRANE A, BROWN A, NATHAN S, SHLOBIN O, AHMAD K, MARINAK L, CHUN J, FREGOSO M, DESAI S, KING C. SINGLE-CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS. TRANSPLANT INFECTIOUS DISEASE. 2019 DEC?21(6):1-6. DOI:10.1111/TID.13166", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200313", "receivedate": "20200313", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17537469, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "US-009507513-1904USA002791", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5-9, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LETERMOVIR" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "209939", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK", "drugenddate": "2018", "drugenddateformat": "602", "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2018", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREVYMIS" } ], "patientagegroup": null, "patientonsetage": "33", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2018" } }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA SB, COCHRANE A, WHITNEY BROWN A, NATHAN SD, SHLOBIN OA, ET AL. SINGLE CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS.. TRANSPL INFECT DIS. 2019", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20191016", "receivedate": "20190408", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16167269, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200122" }, { "companynumb": "US-STRIDES ARCOLAB LIMITED-2020SP003577", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "90687", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LETERMOVIR" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "480 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "480", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETERMOVIR" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MILLIGRAM, UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA SB, COCHRANE A, BROWN AW, NATHAN SD, SHLOBIN OA, ET AL. SINGLE?CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS. TRANSPLANT INFECTIOUS DISEASE. 2019?21(6)", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200914", "receivedate": "20200914", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18263209, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20201103" }, { "companynumb": "US-STRIDES ARCOLAB LIMITED-2020SP003580", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "90687", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEART TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "90687", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." } ], "patientagegroup": null, "patientonsetage": "33", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cytomegalovirus viraemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA SB, COCHRANE A, BROWN AW, NATHAN SD, SHLOBIN OA, ET AL. SINGLE?CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS. TRANSPLANT INFECTIOUS DISEASE. 2019?21(6)", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200914", "receivedate": "20200914", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18263202, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "US-009507513-2105USA006239", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LETERMOVIR" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "209939", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "480 MILLIGRAM, ONCE DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2018", "drugstartdateformat": "602", "drugstructuredosagenumb": "480", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREVYMIS" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": "69", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2018" } }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA SB, COCHRANE A, BROWN AW, NATHAN SD, SHLOBIN OA, ET AL.. SINGLE CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS.. TRANSPL INFECT DIS. 2019?21:E13166", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210527", "receivedate": "20210527", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19317362, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210717" }, { "companynumb": "US-DRREDDYS-USA/USA/20/0120800", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "180", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "203511", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS VIRAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "090509", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": "6", "patientonsetage": "68", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cytomegalovirus viraemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukopenia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA S, COCHRANE A, BROWN A, NATHAN S, SHLOBIN O, AHMAD K, MARINAK L, CHUN J, FREGOSO M, DESAI S, KING C. SINGLE-CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS. TRANSPLANT INFECTIOUS DISEASE. 2019 DEC?21(6):1-6. DOI:10.1111/TID.13166", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200317", "receivedate": "20200317", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17548410, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "US-009507513-2105USA005653", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MILLIGRAM, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10?14, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LETERMOVIR" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "209939", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "480 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2018", "drugstartdateformat": "602", "drugstructuredosagenumb": "480", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREVYMIS" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "39", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2018" } }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA SB, COCHRANE A, BROWN AW, NATHAN SD, SHLOBIN OA, ET AL.. SINGLE CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS.. TRANSPL INFECT DIS. 2019?21", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210527", "receivedate": "20210527", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19313830, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210717" }, { "companynumb": "US-DRREDDYS-USA/USA/20/0120809", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "7.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "203511", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS VIRAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090509", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cytomegalovirus infection", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Gene mutation", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA S, COCHRANE A, BROWN A, NATHAN S, SHLOBIN O, AHMAD K, MARINAK L, CHUN J, FREGOSO M, DESAI S, KING C. SINGLE-CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS. TRANSPLANT INFECTIOUS DISEASE. 2019 DEC?21(6):1-6. DOI:10.1111/TID.13166", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200313", "receivedate": "20200313", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17537510, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "US-DRREDDYS-USA/USA/20/0120802", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "090509", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "203511", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS VIRAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." } ], "patientagegroup": null, "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Leukopenia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cytomegalovirus viraemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA S, COCHRANE A, BROWN A, NATHAN S, SHLOBIN O, AHMAD K, MARINAK L, CHUN J, FREGOSO M, DESAI S, KING C. SINGLE-CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS. TRANSPLANT INFECTIOUS DISEASE. 2019 DEC?21(6):1-6. DOI:10.1111/TID.13166", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200313", "receivedate": "20200313", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17537515, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "US-009507513-2105USA006240", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "180 MILLIGRAM, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "180", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LETERMOVIR" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "209939", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "480 MILLIGRAM, ONCE DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2018", "drugstartdateformat": "602", "drugstructuredosagenumb": "480", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREVYMIS" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "68", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2018" } }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA SB, COCHRANE A, BROWN AW, NATHAN SD, SHLOBIN OA, ET AL.. SINGLE CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS.. TRANSPL INFECT DIS. 2019?21:E13166", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210527", "receivedate": "20210527", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19317185, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210717" }, { "companynumb": "US-009507513-1903USA012574", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "LETERMOVIR" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "209939", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "120 MILLIGRAM, UNK", "drugenddate": "2018", "drugenddateformat": "602", "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2018", "drugstartdateformat": "602", "drugstructuredosagenumb": "120", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREVYMIS" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100?150, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CICLOSPORIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "LETERMOVIR" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "209939", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK", "drugenddate": "2018", "drugenddateformat": "602", "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2018", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREVYMIS" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "LETERMOVIR" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "209939", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "240 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "240", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREVYMIS" } ], "patientagegroup": null, "patientonsetage": "60", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Fatigue", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2018" } }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA SB, COCHRANE A, BROWN AW, NATHAN SD, SHLOBIN OA, ET AL.. SINGLE CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS.. TRANSPL INFECT DIS. 2019?21", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210604", "receivedate": "20190408", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16167275, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210716" }, { "companynumb": "NVSC2020US057317", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LETERMOVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETERMOVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "65461", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "80336", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cytomegalovirus viraemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA SB, COCHRANE A, BROWN AW, NATHAN SD, SHLOBIN OA ET AL.. SINGLE-CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS. TRANSPLANT INFECTIOUS DISEASE. 2019?21(6):E13166", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200302", "receivedate": "20200302", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17484765, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "US-009507513-1904USA002790", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LETERMOVIR" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "209939", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK", "drugenddate": "2018", "drugenddateformat": "602", "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2018", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREVYMIS" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LETERMOVIR" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "209939", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK", "drugenddate": "2018", "drugenddateformat": "602", "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2018", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREVYMIS" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10?12, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2018" } }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA SB, COCHRANE A, BROWN AW, NATHAN SD, SHLOBIN OA, ET AL. SINGLE CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS.. TRANSPL INFECT DIS. 2019?21", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210604", "receivedate": "20190408", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16167265, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210716" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-285332", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10, GOAL TROUGH", "drugenddate": null, "drugenddateformat": null, "drugindication": "Immunosuppression", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "089247", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "7.5 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "Immunosuppression", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE" } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cytomegalovirus infection", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Aryal S, Katugaha S B, Cochrane A, Brown A W, Nathan A D, Shlobin O A. et al. Single-center experience with use of letermovir for CMV prophylaxis or treatment in thoracic organ transplant recipients. Transpl Infect Dis. 2019;Aug 21:e13166:1-6", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220215", "receivedate": "20210316", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19011595, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "US-STRIDES ARCOLAB LIMITED-2020SP003576", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "90055", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "90055", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MILLIGRAM, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": 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"drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "480 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "480", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETERMOVIR" } ], "patientagegroup": null, "patientonsetage": "48", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ARYAL S, KATUGAHA SB, COCHRANE A, BROWN AW, NATHAN SD, SHLOBIN OA, ET AL. SINGLE?CENTER EXPERIENCE WITH USE OF LETERMOVIR FOR CMV PROPHYLAXIS OR TREATMENT IN THORACIC ORGAN TRANSPLANT RECIPIENTS. TRANSPLANT INFECTIOUS DISEASE. 2019?21(6)", "literaturereference_normalized": "single center experience with use of letermovir for cmv prophylaxis or treatment in thoracic organ transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200728", "receivedate": "20200728", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18079951, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20201103" }, { "companynumb": "US-STRIDES ARCOLAB LIMITED-2020SP003575", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": 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{ "abstract": "The aim of this study is to investigate the effective therapeutic combination of recombinant VIIa(Novoseven) and factor eight inhibitor bypass activity(FEIBA) drugs for the bleedings of adult hemophiliac patients with inhibitors.19 bleeding episodes of 5 hemophilia A patients who were using bypassing agents and followed-up between 2008 and 2016 in Hacettepe Hematology Department were analyzed retrospectively. In 11, 5 and 3 bleeding episodes, FEIBA, recombinant factor VIIa and FEIBA+recombinant factor VIIa were given to the patients, respectively. The treatment durations differed between 1 and 14 days depending on the bleeding and clinical course of the patients. Generally the treatment with bypassing agents was successful, and only in one patient who had elbow hematoma encountered serious bleeding which was taken under control by switching the bypass agent. We offer a different approach because of three reasons. Firstly, in our protocol we start the treatment with recombinant factor VIIa for the first three days. Secondly, our protocol is adjusted to consider health economics. Thirdly, we extended the time interval between doses of both bypassing agents without increasing bleeding risks because the half-life of both agents enables us to modify the protocol with more flexibility. To conclude, we have evaluated our clinic's data about hemophilia A patients with inhibitors and we offer a different protocol in the management of bleeding episodes for these patients.", "affiliations": "Hacettepe University, School of Medicine, Department of Hematology, Hacettepe Üniversitesi Tıp Fakültesi İç Hastalıkları ABD Hematoloji BD TR-06100 ANKARA-TURKEY, Postal Code: TR-06100, Ankara, Turkey.;Hacettepe University, School of Medicine, Department of Hematology, TR-06100, Ankara, Turkey.", "authors": "Malkan|Umit Yavuz|UY|;Aksu|Salih|S|", "chemical_list": null, "country": "Poland", "delete": false, "doi": "10.1515/med-2018-0090", "fulltext": "\n==== Front\nOpen Med (Wars)Open Med (Wars)medmedOpen Medicine2391-5463De Gruyter med-2018-009010.1515/med-2018-0090Regular ArticlesCombination of Novoseven and Feiba in Hemophiliac Patients with Inhibitors Malkan Umit Yavuz 1*Aksu Salih 21 Hacettepe University, School of Medicine, Department of Hematology, Hacettepe Üniversitesi Tıp Fakültesi İç Hastalıkları ABD Hematoloji BD TR-06100 ANKARA-TURKEY, Postal Code: TR-06100, Ankara, Turkey2 Hacettepe University, School of Medicine, Department of Hematology, TR-06100, Ankara, Turkey* Tel: +90-532-7780087, Fax: +90-312-3051614 [email protected] 12 2018 2018 13 618 621 08 6 2016 14 11 2018 © 2018 Umit Yavuz Malkan, Salih Aksu published by De Gruyter2018Umit Yavuz Malkan, Salih Aksu published by De GruyterThis work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License.Abstract\nThe aim of this study is to investigate the effective therapeutic combination of recombinant VIIa(Novoseven) and factor eight inhibitor bypass activity(FEIBA) drugs for the bleedings of adult hemophiliac patients with inhibitors.19 bleeding episodes of 5 hemophilia A patients who were using bypassing agents and followed-up between 2008 and 2016 in Hacettepe Hematology Department were analyzed retrospectively. In 11, 5 and 3 bleeding episodes, FEIBA, recombinant factor VIIa and FEIBA+recombinant factor VIIa were given to the patients, respectively. The treatment durations differed between 1 and 14 days depending on the bleeding and clinical course of the patients. Generally the treatment with bypassing agents was successful, and only in one patient who had elbow hematoma encountered serious bleeding which was taken under control by switching the bypass agent. We offer a different approach because of three reasons. Firstly, in our protocol we start the treatment with recombinant factor VIIa for the first three days. Secondly, our protocol is adjusted to consider health economics. Thirdly, we extended the time interval between doses of both bypassing agents without increasing bleeding risks because the half-life of both agents enables us to modify the protocol with more flexibility. To conclude, we have evaluated our clinic’s data about hemophilia A patients with inhibitors and we offer a different protocol in the management of bleeding episodes for these patients.\n\nKeywords\nHemophiliaInhibitorsFEIBARecombinant VIIA\n==== Body\n1 Introduction\nThe hemophilias are a group of associated bleeding disorders that are inherited most commonly. Hemophilia A refers to factor VIII deficiency. Cases with hemophilia encounter bleeding incidents that are treated with replacement of the absent factor. Development of an inhibitor is one of the complications of hemophilia treatment. It usually follows the initiation of replacement therapy. Actually, the inhibitors are antibodies (primarily IgG) directed against the specific absent factor. The development of inhibitors is more frequent in cases with hemophilia A than in those with hemophilia B. The inhibitors are more likely to develop in cases with severe disease. The degree of inhibitor response is detected in Bethesda units (BU). High responder patients generally have five or more Bethesda units and these inhibitor levels can persist for a long time even when there is no re-exposure [1,2]. On the other hand, low responder patients always have inhibitor levels less than 5 BU [3]. High responder patients generally need bypassing agents, whereas low responder cases usually have treatment answer to factor VIII replacement therapy [4]. In approximately 25 to 30 percent of cases with severe hemophilia A, Factor VIII inhibitors were detected [5,6]. Factor VIII inhibitors are not frequently encountered in moderate or mild hemophilia A cases [7]. The aim of this study is to investigate the effective therapeutic combination of recombinant VIIa (Novoseven) and factor eight inhibitor bypass activity (FEIBA) drugs for the bleedings of adult hemophiliac patients with inhibitors.\n\n2 Methods\n19 bleeding episodes of 5 hemophilia A patients who were using bypassing agents and followed-up between 2008 and 2016 in Hacettepe Hematology Department were analyzed retrospectively. All of the ethical considerations were strictly handled in accordance with the Helsinki Declaration. As a standard of care/action of the hospitals of Hacettepe Medical School, it was confirmed based on patient records that all of the study participants gave informed consent at the time of hospitalization and relevant diagnostic/therapeutic standards of care. All data were taken from Hacettepe University Medical School Hospital database. Patient records/information was anonymized prior to analysis. Parameters of age, bleeding site, bleeding complications, inhibitor levels, medication type and duration, bleeding complications were noted. In the study patients, evaluation of response to treatment depended upon the patients’ clinical condition. Physical examination was performed in every patient and depending on clinical condition X-ray or magnetic resonance imaging were performed in some patients also.\n\n3 Results\nA total of 19 bleeding episodes of 5 patients were analyzed. The median age of the patient group was 40 (28-78). All of the patients had diagnosis of hemophilia A and all patients were high responders. The median factor level was 1% (0-6%). Only one patient had mild hemophilia A, whereas other patients had severe hemophilia A. The median inhibitor level was 15.1 BU (9.3-56.0 BU). The characteristics of bleeding episodes and the treatment approaches are given in Table 1. There were 4 knee hematoma, 3 tooth extraction, 3 elbow hematoma, 2 prophylaxis, 2 major surgery, 1 psoas hematoma, 1 maxillary hematoma, 1 inguinal hematoma, 1 leg graft operation and 1 gastrointestinal bleeding episodes of hemophilia A patients with inhibitors. In 11, 5 and 3 bleeding episodes, FEIBA, recombinant factor VIIa and FEIBA + recombinant factor VIIa were given to the patients, respectively. The treatment durations differed between 1 and 14 days depending on the bleeding and clinical course of the patients. Generally the treatment with bypassing agents was successful, and only in one patient who had elbow hematoma encountered serious bleeding which was taken under control by switching the bypass agent.\n\nTable 1 The characteristics and treatment approaches of the bleeding episodes in adult hemophiliac patients with inhibitors\n\nClinical Condition\tNumber of patient\tBypassing Agents and Doses\tDays of dose given\t\nBleeds (n:11)\t3\tRecombinant factor VIIa, 3-4 x 90 μg.kg-1\t1-3\t\n\t7\tActivated prothrombin complex concentrate (FEIBA), 1-3 x 50-100 IU.kg-1\t1-5\t\n\t1\tFEIBA, 2 x 100 IU.kg-1 switched to Recombinant factor VIIa, 6 x 90 μg.kg-1\t14\t\nMinor Surgery (n:4)\t2\tRecombinant factor VIIa, 3-6 x 90 μg.kg-1\t3-7\t\n\t2\tFEIBA, 2 x 70 IU.kg-1\t14\t\nMajor Surgery\t2\t(Our proposed protocol) First 3 days Recombinant factor VIIa, 6 x 90 μg.kg-1and then FEIBA, 2 x 50 IU.kg-1\t14\t\nProphylaxis\t2\tFEIBA, 2 x 70 IU.kg-1\t2\t\n4 Discussion\nThe preparation of hemophilia A patients with inhibitors is compelling compared to patients without inhibitors. Two decades ago, elective surgery in hemophilia A patients with inhibitors is contraindicated because of the bleeding risks. However at the present time, with the help of new bypassing agents surgical operations are performed with success. Unlike hemophilia A patients without inhibitors, the factor 8 concentrates are ineffective because of circulating antibodies in patients with inhibitors. The two main bypassing agents are recombinant factor VIIa and activated prothrombin complex concentrate (FEIBA) which also contains vitamin K dependent factors (Factor 2, 7, 9, 10). In the literature the dosing of these agents are described (Table 2) [8]. In this paper, we offer a different approach to hemophilia A patients with inhibitors who will undergo surgical operation (Table 2). Bypassing agents eliminate the need of intrinsic pathway originated “tenase” complex which activates factor X. Recombinant factor VIIa directly activates factor X whereas FEIBA provides precursors for factor X, thus both agents bypass the pathways. FEIBA is considered to be an effective bypassing agent that controls bleeding episodes [9]. However since the activated proteases that provide the pro-coagulant activity of FEIBA have short half-life, initial hemostasis could be followed by breakthrough bleeding between doses that could lead to problems in maintaining hemostasis [10]. Moreover, FEIBA comes with a risk of thrombosis\n\nTable 2 The preparing methods for surgery in hemophilia A patients with inhibitors\n\n\tBypassing Agent\tPre-operative dosing\tPost-operative dosing\t\nIn the literature*\tRecombinant factor VIIa\tBolus 90-120 μg.kg-1\t0-48 hours: 90 μg.kg-1/for each 2 hours,\n\n\n3-4 days: 90 μg.kg-1/for each 3 hours,\n\n\n5-7 days: 90 μg.kg-1/for each 4 hours,\n\n\n8th day-end of treatment: 90 μg.kg-1/for each 6 hours\n\n\n\t\nIn the literature*\tActivated pro-thrombin complex concentrate\tBolus 75-100 IU.kg-1\t0-3 days: 70 IU.kg-1/for each 8 hours (for maximum dose of 200 IU.kg-1/per day).\n\n\n4th day-end of treatment: 50 IU.kg-1/for each 8 hours\n\n\t\nOur Method\tRecombinant factor VIIa+ Activated pro-thrombin complex concentrate\tBolus 90 μg.kg-1\tIn the post-operative 2, 4, 6, 8, 12, 16, 22, 30, 38, 46, 54, 62, 70 hours:\n\n\nRecombinant factor VIIa with dose of 90 μg.kg-1\n\n\n4th day-end of treatment: 2x50 IU.kg-1 Activated prothrombin complex concentrate (FEIBA).\n\n\nTreatment should stop in 7 or 14 days depending on patient’s clinical condition.\n\n\n\t\n*Reference number 8.\n\nthat is likely to occur with large doses [11]. Another problem about FEIBA is the absence of an in vitro assay that would confirm in vivo hemostatic efficacy. Thus, the treatment answer in bleeding episodes in each patient could be different [4]. The treatment approach for each patient should be personalized and it is accepted that if there is no treatment answer for any bypassing agent the other agent should be tried [4]. In the literature the optimal dose for FEIBA treatment was given as 50 to 100 units/kg and doses above 200 units/kg is not recommended because of the risk of disseminated intravascular coagulation development [4]. The optimal dosing frequency of FEIBA is every 8 to 12 hours; more frequent dosing is associated with increased thrombotic risk [4]. The usage of FEIBA for prophylaxis is also stated in the literature [12]. In our study FEIBA was effective for controlling the bleeding episodes in hemophilia A patients with inhibitors. On the other hand, in the literature it was stated that recombinant factor VIIa has excellent treatment response in majority of hemophilia A patients with inhibitors [13]. The difference of recombinant factor VIIa from FEIBA is that tissue factor is essential for factor VIIa to be effective therefore with recombinant factor VIIa treatment coagulation occurs only at local sites of hemostasis thus avoiding the risk of systemic coagulation that could happen with FEIBA treatment [11]. In the literature, the optimal dose for recombinant factor VIIa was given as 90 to 120 mcg/kg at two- to three-hour intervals until the bleeding was controlled [4]. The usage of recombinant factor VIIa for prophylaxis is stated in the literature [14]. The efficiency of recombinant factor VIIa and FEIBA was compared in the literature; both agents had 80-90% efficacy rate and neither agent shown to be superior in efficacy [15]. The usage of both agents together is shown to be very effective. However because of increased thrombotic risk, combination treatment is only recommended in serious life-threathening bleedings [16]. So, the risk of systemic coagulation is lower in rFVII than FEIBA. Although the bypassing agents provide a safe management of patients with inhibitors, the efficacy of these agents always remains lower than pure factor concentrates which are given to patients without inhibitors. As a result, hemophilia A patients with inhibitors have always a higher risk of bleeding than patients without inhibitors even in the presence of bypassing agents.\n\nAnother major concern about the management of hemophilia A patients with inhibitors is the cost of the treatment. Especially in the lower or middle income countries, the cost of bypassing agents is a great problem. In Turkey, the average cost for surgery preparation of a 70 kg hemophilia A patient with inhibitor is $267000, $114000 and $108000 with recombinant factor VIIa, FEIBA and our protocol, respectively. So, if there is a systemic coagulation risk generally rFVII should be preferred. The regular usage of both products at the same time is not recommended because of thrombosis risk. What we offer is to use rFVII in first 3 days and then switching to FEIBA with a different dosing protocol, which offers us a safer, cheaper and flexible control of the bleeding. We offer a different approach from the literature because of three main reasons. Firstly, in our protocol we start the treatment with recombinant factor VIIa for the first three days. The main reason for this choice is the short procoagulant half-life of bypassing agents and the need of frequent infusions to cover all hours of a day in order to quickly and safely achieve hemostasis. In our protocol we do not prefer FEIBA in the beginning because there is a risk of thrombosis if it is used more frequently than every 8 hour and there is a limit dose of 200 units/kg/day. In our protocol after safely achieving the initial hemostasis with recombinant factor VIIa ,we prefer to continue treatment with FEIBA till 7th or 14th days after bleeding. Secondly, our protocol is adjusted to consider health economics. Cost of recombinant factor VIIa is more than twice the cost of FEIBA. Therefore we prefer to use recombinant factor VIIa in first 3 days, the time interval where the bleeding risk is maximum and the homeostasis is the primary target. After achieving the initial hemostasis we set our preference to health economics first since the bleeding risk is decreased and the less frequent doses are sufficient to stabilize the clinical course of patient. Thirdly, we extended the time interval between doses of both bypassing agents without increasing bleeding risks because the half-life of both agents enables us to modify the protocol with more flexibility. This modification let us to control the drug costs without facing extra complications or bleeding risks. To conclude, in this paper we have evaluated our clinic’s data about hemophilia A patients with inhibitors and we offer a different protocol in the management of bleeding episodes for these patients.\n\nAcknowledgments\nUYM and SA designed the study, UYM collected and analyzed the data, UYM write the paper, UYM and SA approved the final version of the paper.\n\nConflict of interest\n\nConflict of interest statement: The authors of this paper have no conflicts of interest, including specific financial interests, relationships, and/or affiliations relevant to the subject matter or materials included.\n==== Refs\nReferences\n[1] White GC 2nd Rosendaal F Aledort LM Definitions in hemophilia. Recommendation of the scientific subcommittee on factor VIII and factor IX of the scientific and standardization committee of the International Society on Thrombosis and Haemostasis Thromb Haemost 2001 85 560 11307831 \n[2] Allain JP Frommel D Antibodies to factor VIII. V. Patterns of immune response to factor VIII in hemophilia A. Blood 1976 47 973 1276479 \n[3] Caram C de Souza RG de Sousa JC The long-term course of factor VIII inhibitors in patients with congenital haemophilia A without immune tolerance induction Thromb Haemost 2011 105 59 21057702 \n[4] Kempton CL White GC 2nd How we treat a hemophilia A patient with a factor VIII inhibitor Blood 2009 113 11 18820129 \n[5] Hoyer LW Scandella D Factor VIII inhibitors: structure and function in autoantibody and hemophilia A patients Semin Hematol 1994 31 1 \n[6] Lusher JM Arkin S Abildgaard CF Schwartz RS Recombinant factor VIII for the treatment of previously untreated patients with hemophilia A. Safety, efficacy, and development of inhibitors. Kogenate Previously Untreated Patient Study Group N Engl J Med 1993 328 453 8421474 \n[7] Fijnvandraat K Turenhout EA van den Brink EN The missense mutation Arg593 --> Cys is related to antibody formation in a patient with mild hemophilia A. Blood 1997 89 4371 \n[8] Mensah PK Gooding R Surgery in patients with inherited bleeding disorders. Anaesthesia 2015 Jan;70 Suppl 1 112 20 e39 40 10.1111/anae.12899 \n[9] Negrier C Goudemand J Sultan Y Multicenter retrospective study on the utilization of FEIBA in France in patients with factor VIII and factor IX inhibitors French FEIBA Study Group. Factor Eight Bypassing Activity. Thromb Haemost 1997 77 1113 \n[10] Lusher JM Use of prothrombin complex concentrates in management of bleeding in hemophiliacs with inhibitors-benefits and limitations Semin Hematol 1994 31 49 7939776 \n[11] Hough RE Hampton KK Preston FE Recombinant VIIa concentrate in the management of bleeding following prothrombin complex concentrate-related myocardial infarction in patients with haemophilia and inhibitors Br J Haematol 2000 111 974 11122162 \n[12] Leissinger C Gringeri A Antmen B Anti-inhibitor coagulant complex prophylaxis in hemophilia with inhibitors N Engl J Med 2011 365 1684 22047559 \n[13] O’Connell N Mc Mahon C Smith J Recombinant factor VIIa in the management of surgery and acute bleeding episodes in children with haemophilia and high responding inhibitors Br J Haematol 2002 116 632 11849223 \n[14] Konkle BA Ebbesen LS Erhardtsen E Randomized, prospective clinical trial of recombinant factor VIIa for secondary prophylaxis in hemophilia patients with inhibitors J Thromb Haemost 2007 5 1904 17723130 \n[15] Astermark J Donfield SM DiMichele DM A randomized comparison of bypassing agents in hemophilia complicated by an inhibitor: the FEIBA NovoSeven Comparative (FENOC) Study. Blood 2007 109 546 16990605 \n[16] Teitel J Berntorp E Collins P A systematic approach to controlling problem bleeds in patients with severe congenital haemophilia A and high-titre inhibitors Haemophilia 2007 13 256 17498074\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": null, "issue": "13()", "journal": "Open medicine (Warsaw, Poland)", "keywords": "FEIBA; Hemophilia; Inhibitors; Recombinant VIIA", "medline_ta": "Open Med (Wars)", "mesh_terms": null, "nlm_unique_id": "101672167", "other_id": null, "pages": "618-621", "pmc": null, "pmid": "30613789", "pubdate": "2018", "publication_types": "D016428:Journal Article", "references": "11122162;11307831;11849223;1276479;16990605;17498074;17723130;18820129;21057702;22047559;25440405;7524160;7939776;8421474;9192760;9241742", "title": "Combination of Novoseven and Feiba in Hemophiliac Patients with Inhibitors.", "title_normalized": "combination of novoseven and feiba in hemophiliac patients with inhibitors" }

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AKSU, S.. COMBINATION OF NOVOSEVEN AND FEIBA IN HEMOPHILIAC PATIENTS WITH INHIBITORS. DE GRUYTER. 2018?13:618-621", "literaturereference_normalized": "combination of novoseven and feiba in hemophiliac patients with inhibitors", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20190215", "receivedate": "20190129", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15886373, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" } ]

{ "abstract": "Literature on the outcome of pregnancy after exposure to capecitabine and temozolomide during the first trimester is scarce. Chemotherapy administration in the first trimester is generally not recommended due the potential risks to the fetus including fetal death and major congenital malformations. Capecitabine and temozolomide are oral chemotherapy agents and pregnancy category D medications, thus the use of these agents in pregnancy is not recommended. We present the case of a 17-year-old female who while receiving cancer treatment, had unintentional exposure to capecitabine and temozolomide during the first trimester of pregnancy, and subsequently delivered a healthy infant.", "affiliations": "Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, United States. Electronic address: [email protected].;Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, GA, 30322, United States. Electronic address: [email protected].;Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX, 77030, United States. Electronic address: [email protected].;Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, United States. Electronic address: [email protected].", "authors": "Castellanos|Maria I|MI|;Childress|Krista J|KJ|;Ramirez|Mildred|M|;Venkatramani|Rajkumar|R|", "chemical_list": null, "country": "France", "delete": false, "doi": "10.1016/j.jogoh.2020.101881", "fulltext": null, "fulltext_license": null, "issn_linking": "2468-7847", "issue": null, "journal": "Journal of gynecology obstetrics and human reproduction", "keywords": "Cancer; Capecitabine; Chemotherapy; Fetus; Pregnancy; Temozolomide", "medline_ta": "J Gynecol Obstet Hum Reprod", "mesh_terms": null, "nlm_unique_id": "101701588", "other_id": null, "pages": "101881", "pmc": null, "pmid": "32712180", "pubdate": "2020-07-23", "publication_types": "D002363:Case Reports", "references": null, "title": "Fetal exposure to capecitabine and temozolomide during the first trimester: A case report.", "title_normalized": "fetal exposure to capecitabine and temozolomide during the first trimester a case report" }

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FETAL EXPOSURE TO CAPECITABINE AND TEMOZOLOMIDE DURING THE FIRST TRIMESTER: A CASE REPORT. 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FETAL EXPOSURE TO CAPECITABINE AND TEMOZOLOMIDE DURING THE FIRST TRIMESTER: A CASE REPORT. 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FETAL EXPOSURE TO CAPECITABINE AND TEMOZOLOMIDE DURING THE FIRST TRIMESTER: A CASE REPORT. 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SHE RECEIVED TOTAL 6 C", "drugenddate": null, "drugenddateformat": null, "drugindication": "NEUROENDOCRINE CARCINOMA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CAPECITABINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "77269", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "STARTED THERAPY AT 24 WEEKS OF GESTATION ; 400 MG/M2/DOSE (TARGET AUC 6) EVERY 21 DAYS; SHE RECEI...", "drugenddate": null, "drugenddateformat": null, "drugindication": "OVARIAN SERTOLI-LEYDIG CELL TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "OVARIAN CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "74656", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "OVARIAN CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "TEMOZOLOMIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "78879", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MILLIGRAM DAILY; 250 MG TWICE DAILY FOR 5DAYS, EACH CYCLE OF 28 DAYS. 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175 MG/M2/DOSE EVERY 21 DAYS; SHE RECEIVED TOTAL 4 CYC...", "drugenddate": null, "drugenddateformat": null, "drugindication": "OVARIAN SERTOLI-LEYDIG CELL TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "175", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PACLITAXEL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "74656", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "SHE UNDERWENT TWO CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "NEUROENDOCRINE CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "TEMOZOLOMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "78879", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "OVARIAN CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TEMOZOLOMIDE." } ], "patientagegroup": "4", "patientonsetage": "17", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Contraindicated product administered", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Maternal exposure during pregnancy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ototoxicity", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Normal newborn", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CASTELLANOS MI, CHILDRESS KJ, RAMIREZ M, VENKATRAMANI R. FETAL EXPOSURE TO CAPECITABINE AND TEMOZOLOMIDE DURING THE FIRST TRIMESTER: A CASE REPORT. 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FETAL EXPOSURE TO CAPECITABINE AND TEMOZOLOMIDE DURING THE FIRST TRIMESTER: A CASE REPORT. 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FETAL EXPOSURE TO CAPECITABINE AND TEMOZOLOMIDE DURING THE FIRST TRIMESTER: A CASE REPORT. J GYNECOL OBSTET HUM REPROD. 2020?101881:ONLINE AHEAD OF PRINT", "literaturereference_normalized": "fetal exposure to capecitabine and temozolomide during the first trimester a case report", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200812", "receivedate": "20200812", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18143761, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" } ]

{ "abstract": "BACKGROUND\nMusculoskeletal disorders are one of the most common reasons military servicemen seek medical care during their line of duty. This study aims to review the clinical profile and outcomes of military personnel with inflammatory arthritis (IA) referred to a specialist rheumatology center in Singapore.\n\n\nMETHODS\nConsecutive new case referrals from the Singapore Armed Forces medical centers during the study period January 1, 2010, to December 31, 2019, were retrospectively studied.\n\n\nRESULTS\nThere were 123 referrals, comprising 112 (91.1%) males, with the majority being Chinese (110, 89.4%). The mean age was 25.5 ± 11.1 years. The most common diagnoses were gout (including chronic tophaceous gout; 34, 27.6%), spondyloarthritis (18, 14.6%), palindromic rheumatism (8, 6.5%), rheumatoid arthritis (4, 3.3%), and juvenile idiopathic arthritis (4, 3.3%). Among servicemen with gout, all were male, the majority (31, 91.3%) were Chinese, and mean age was 34.1 ± 8.8 years. Mean body mass index (BMI) was 27.5 ± 3.9 kg/m2, of which 41.2% had moderate-risk and 47.1% high-risk BMI for cardiovascular disease and diabetes mellitus (DM). Comorbidities included hyperlipidemia (14), hypertension (6), and type 2 DM (3). Urate lowering therapy was initiated in 27 (79.4%) patients, comprising allopurinol (85.2%), probenecid (11.1%), and their combination (3.7%). One patient developed allopurinol-induced hepatitis; none had severe cutaneous adverse reactions. Among the remaining patients with IA, conventional synthetic disease-modifying antirheumatic drugs (DMARDs) used were sulfasalazine (8), methotrexate (4), hydroxychloroquine (4), and leflunomide (2). Biologic DMARDs used in five patients comprised adalimumab (3) and golimumab (2).\n\n\nCONCLUSIONS\nServicemen with IA and good functional status can still be physically fit and deployable into certain combat and service support vocations. This will optimize manpower resources in military organizations with a shrinking young workforce.", "affiliations": "Department of Rheumatology, Allergy and Immunology, Tan Tock Seng Hospital, 308433, Singapore.;Department of Rheumatology, Allergy and Immunology, Tan Tock Seng Hospital, 308433, Singapore.", "authors": "Chua|Choon-Guan|CG|0000-0001-6166-4351;Thong|Bernard Yu-Hor|BY|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1093/milmed/usab246", "fulltext": null, "fulltext_license": null, "issn_linking": "0026-4075", "issue": null, "journal": "Military medicine", "keywords": null, "medline_ta": "Mil Med", "mesh_terms": null, "nlm_unique_id": "2984771R", "other_id": null, "pages": null, "pmc": null, "pmid": "34190324", "pubdate": "2021-06-30", "publication_types": "D016428:Journal Article", "references": null, "title": "Inflammatory Arthritis Among Military Servicemen From a Rheumatology Center in Singapore.", "title_normalized": "inflammatory arthritis among military servicemen from a rheumatology center in singapore" }

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