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1df526931fe3f2129d63e8dc62bde5101966a2e5	wikidoc	Mepacrine	Mepacrine # Overview Mepacrine (INN; also called quinacrine in the United States and Atabrine (trade name) is a drug with several medical applications. It is related to mefloquine. # Medical uses The main uses of mepacrine are as an antiprotozoal, antirheumatic and an intrapleural sclerosing agent. Antiprotozoal use include targeting giardiasis, where mepacrine is indicated as a primary agent for patients with metronidazole-resistant giardiasis and patients who should not receive or can not tolerate metronidazole. Giardiasis that is very resistant may even require a combination of mepacrine and metronidazole. Mepacrine is also used "off-label" for the treatment of systemic lupus erythematosus, indicated in the treatment of discoid and subcutaneous lupus erythematosus, particularly in patients unable to take chloroquine derivatives. As an intrapleural sclerosing agent, it is used as pneumothorax prophylaxis in patients at high risk of recurrence, e.g., cystic fibrosis patients. Mepacrine is not the drug of choice because side effects are common, including toxic psychosis, and may cause permanent damage. See mefloquine for more information. In addition to medical applications, mepacrine is an effective in vitro research tool for the epifluorescent visualization of cells, especially platelets. Mepacrine is a green fluorescent dye taken up by most cells. Platelets store mepacrine in dense granules. # Mechanism Its mechanism of action against protozoa is uncertain, but it is thought to act against the protozoan's cell membrane. It is known to act as a histamine N-methyltransferase inhibitor. It also inhibits NF-κB and activates p53. # History of uses ## Antiprotozoal Mepacrine was initially approved in the 1930s as an antimalarial drug. It was used extensively during the second World War by US forces fighting in the Far East to prevent malaria. This antiprotozoal is also approved for the treatment of giardiasis (an intestinal parasite), and has been researched as an inhibitor of phospholipase A2. Scientists at Bayer in Germany first synthesised mepacrine in 1931. The product was one of the first synthetic substitutes for quinine although later superseded by chloroquine. ## Anthelmintics In addition it has been used for treating tapeworm infections. ## Creutzfeldt-Jakob disease Mepacrine has been shown to bind to the prion protein and prevent the formation of prion aggregates in vitro, and full clinical trials of its use as a treatment for Creutzfeldt-Jakob disease are under way in the United Kingdom and the United States. Small trials in Japan have reported improvement in the condition of patients with the disease, although other reports have shown no significant effect, and treatment of scrapie in mice and sheep has also shown no effect. Possible reasons for the lack of an in-vivo effect include inefficient penetration of the blood brain barrier, as well as the existence of drug-resistant prion proteins that increase in number when selected for by treatment with mepacrine. ## Non-surgical sterilization for women The use of mepacrine for non-surgical sterilization for women has also been studied. The first report of this method claimed a first year failure rate of 3.1%. However, despite a multitude of clinical studies on the use of mepacrine and female sterilization, no randomized, controlled trials have been reported to date and there is some controversy over its use. Pellets of mepacrine are inserted through the cervix into a woman's uterine cavity using a preloaded inserter device, similar in manner to IUCD insertion. The procedure is undertaken twice, first in the proliferative phase, 6 to 12 days following the first day of the menstrual cycle and again one month later. The sclerosing effects of the drugs at the utero-tubal junctions (where the Fallopian tubes enter the uterus) results in scar tissue forming over a six week interval to close off the tubes permanently. In the United States, this method has undergone Phase I clinical testing. The FDA has waived the necessity for Phase II clinical trials because of the extensive data pertaining to other uses of mepacrine. The next step in the FDA approval process in the United States is a Phase III large multi-center clinical trial. The method is currently used off-label. Many peer reviewed studies suggest that mepacrine sterilization (QS) is potentially safer than surgical sterilization. Nevertheless, in 1998 the Supreme Court of India banned the import or use of the drug, allegedly based on reports that it could cause cancer or ectopic pregnancies.	Mepacrine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Mepacrine (INN; also called quinacrine in the United States and Atabrine (trade name) is a drug with several medical applications. It is related to mefloquine. # Medical uses The main uses of mepacrine are as an antiprotozoal, antirheumatic and an intrapleural sclerosing agent.[1] Antiprotozoal use include targeting giardiasis, where mepacrine is indicated as a primary agent for patients with metronidazole-resistant giardiasis and patients who should not receive or can not tolerate metronidazole. Giardiasis that is very resistant may even require a combination of mepacrine and metronidazole.[1] Mepacrine is also used "off-label" for the treatment of systemic lupus erythematosus,[2] indicated in the treatment of discoid and subcutaneous lupus erythematosus, particularly in patients unable to take chloroquine derivatives.[1] As an intrapleural sclerosing agent, it is used as pneumothorax prophylaxis in patients at high risk of recurrence, e.g., cystic fibrosis patients.[1] Mepacrine is not the drug of choice because side effects are common, including toxic psychosis, and may cause permanent damage. See mefloquine for more information. In addition to medical applications, mepacrine is an effective in vitro research tool for the epifluorescent visualization of cells, especially platelets. Mepacrine is a green fluorescent dye taken up by most cells. Platelets store mepacrine in dense granules.[3] # Mechanism Its mechanism of action against protozoa is uncertain, but it is thought to act against the protozoan's cell membrane. It is known to act as a histamine N-methyltransferase inhibitor. It also inhibits NF-κB and activates p53. # History of uses ## Antiprotozoal Mepacrine was initially approved in the 1930s as an antimalarial drug. It was used extensively during the second World War by US forces fighting in the Far East to prevent malaria.[4] This antiprotozoal is also approved for the treatment of giardiasis (an intestinal parasite),[5] and has been researched as an inhibitor of phospholipase A2. Scientists at Bayer in Germany first synthesised mepacrine in 1931. The product was one of the first synthetic substitutes for quinine although later superseded by chloroquine. ## Anthelmintics In addition it has been used for treating tapeworm infections.[6] ## Creutzfeldt-Jakob disease Mepacrine has been shown to bind to the prion protein and prevent the formation of prion aggregates in vitro,[7] and full clinical trials of its use as a treatment for Creutzfeldt-Jakob disease are under way in the United Kingdom and the United States. Small trials in Japan have reported improvement in the condition of patients with the disease,[8] although other reports have shown no significant effect,[9] and treatment of scrapie in mice and sheep has also shown no effect.[10][11] Possible reasons for the lack of an in-vivo effect include inefficient penetration of the blood brain barrier, as well as the existence of drug-resistant prion proteins that increase in number when selected for by treatment with mepacrine.[12] ## Non-surgical sterilization for women The use of mepacrine for non-surgical sterilization for women has also been studied. The first report of this method claimed a first year failure rate of 3.1%.[13] However, despite a multitude of clinical studies on the use of mepacrine and female sterilization, no randomized, controlled trials have been reported to date and there is some controversy over its use.[1] Pellets of mepacrine are inserted through the cervix into a woman's uterine cavity using a preloaded inserter device, similar in manner to IUCD insertion. The procedure is undertaken twice, first in the proliferative phase, 6 to 12 days following the first day of the menstrual cycle and again one month later. The sclerosing effects of the drugs at the utero-tubal junctions (where the Fallopian tubes enter the uterus) results in scar tissue forming over a six week interval to close off the tubes permanently. In the United States, this method has undergone Phase I clinical testing. The FDA has waived the necessity for Phase II clinical trials because of the extensive data pertaining to other uses of mepacrine. The next step in the FDA approval process in the United States is a Phase III large multi-center clinical trial. The method is currently used off-label. Many peer reviewed studies suggest that[14] mepacrine sterilization (QS) is potentially safer than surgical sterilization.[15][16] Nevertheless, in 1998 the Supreme Court of India banned the import or use of the drug, allegedly based on reports that it could cause cancer or ectopic pregnancies.[17]	https://www.wikidoc.org/index.php/Mepacrine
7089594edb426ebaaf0ecd3bcaaae2f653835bb1	wikidoc	Merbromin	Merbromin # Overview Merbromin (marketed as Mercurochrome, Merbromine, Sodium mercurescein, Asceptichrome, Supercrome, Brocasept and Cinfacromin) is a topical antiseptic used for minor cuts and scrapes. Merbromin is an organomercuric disodium salt compound and a fluorescein. It is readily available in most countries but, because of its mercury content, it is no longer sold in Germany, the United States or France. # Uses Merbromin's best-known use is as a topical antiseptic. When applied on a wound, it stains the skin bright red. In the United States, its use has been superseded by other agents (e.g., povidone iodine, benzalkonium chloride, chloroxylenol). It is still an important antiseptic, particularly in developing nations, due to its “unbelievably low cost.” Merbromin is also used as a biological dye to mark tissue margins and as a metal dye in industrial dye penetrant inspection to detect metal fractures. # Mercurochrome Mercurochrome is a trade name of merbromin. The name is also commonly used for over-the-counter antiseptic solutions consisting of merbromin (typically at 2% concentration) dissolved in either ethyl alcohol (tincture) or water (aqueous). Its antiseptic qualities were discovered by Hugh H. Young in 1918, while working at Johns Hopkins Hospital as a physician. The chemical soon became popular among parents and physicians for everyday antiseptic uses, and it was commonly used for minor injuries in the schoolyard. The United States Food and Drug Administration (FDA) moved it from the “generally recognized as safe” classification into the “untested” classification to effectively halt its distribution in the United States on October 19, 1998 over fears of potential mercury poisoning. Sales were halted in Germany in 2003, and in France in 2006. It is readily available in most other countries. Within the United States, products such as Humco Mercuroclear play on the brand recognition history of Mercurochrome but substitute other ingredients with similar properties (Mercuroclear: "Aqueous solution of benzalkonium chloride and lidocaine hydrochloride").	Merbromin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Merbromin (marketed as Mercurochrome, Merbromine, Sodium mercurescein, Asceptichrome, Supercrome, Brocasept and Cinfacromin) is a topical antiseptic used for minor cuts and scrapes. Merbromin is an organomercuric disodium salt compound and a fluorescein. It is readily available in most countries but, because of its mercury content, it is no longer sold in Germany, the United States or France.[1][2][3] # Uses Merbromin's best-known use is as a topical antiseptic. When applied on a wound, it stains the skin bright red. In the United States, its use has been superseded by other agents (e.g., povidone iodine, benzalkonium chloride, chloroxylenol). It is still an important antiseptic, particularly in developing nations, due to its “unbelievably low cost.”[4] Merbromin is also used as a biological dye to mark tissue margins and as a metal dye in industrial dye penetrant inspection to detect metal fractures. # Mercurochrome Mercurochrome is a trade name of merbromin. The name is also commonly used for over-the-counter antiseptic solutions consisting of merbromin (typically at 2% concentration) dissolved in either ethyl alcohol (tincture) or water (aqueous). Its antiseptic qualities were discovered by Hugh H. Young in 1918, while working at Johns Hopkins Hospital as a physician.[5] The chemical soon became popular among parents and physicians for everyday antiseptic uses, and it was commonly used for minor injuries in the schoolyard. The United States Food and Drug Administration (FDA) moved it from the “generally recognized as safe” classification into the “untested” classification to effectively halt its distribution in the United States on October 19, 1998 over fears of potential mercury poisoning.[1] Sales were halted in Germany in 2003,[2] and in France in 2006.[3] It is readily available in most other countries.[citation needed] Within the United States, products such as Humco Mercuroclear play on the brand recognition history of Mercurochrome but substitute other ingredients with similar properties (Mercuroclear: "Aqueous solution of benzalkonium chloride and lidocaine hydrochloride").[6]	https://www.wikidoc.org/index.php/Merbromin
500c6ef12b79f47b32a0fb05ea13b8fbe5c13d91	wikidoc	Merocrine	Merocrine Merocrine (eccrine) is a classification of exocrine glands in the study of Histology. A cell is classified as merocrine if the secretions of that cell dump directly into the lumen. This is done by vesicles opening onto the surface of the cell, and the secretory product is discharged from the cell - normal exocytosis. Merocrine is the most common manner of secretion. It may be remembered by thinking of “Merry” as in happy. The gland releases its product and no part of the gland is lost. # Examples - Merocrine sweat glands	Merocrine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Phone:617-632-7753 Merocrine (eccrine) is a classification of exocrine glands in the study of Histology. A cell is classified as merocrine if the secretions of that cell dump directly into the lumen. This is done by vesicles opening onto the surface of the cell, and the secretory product is discharged from the cell - normal exocytosis. Merocrine is the most common manner of secretion. It may be remembered by thinking of “Merry” as in happy. The gland releases its product and no part of the gland is lost. # Examples - Merocrine sweat glands	https://www.wikidoc.org/index.php/Merocrine
314468548cebffb3f05514048c3fe9b2a85bbd41	wikidoc	Meropenem	Meropenem # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Meropenem is a Carbapenem that is FDA approved for the treatment of complicated skin and skin structure infections, intra-abdominal infections, bacterial meningitis (pediatric patients).. Common adverse reactions include headache, nausea, constipation, diarrhea, anemia, vomiting, and rash. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Skin and Skin Structure Infections - Dosage: 500 mg IV every 8 hours. Is indicated as a single agent therapy for the treatment of complicated skin and skin structure infections due to: - Staphylococcus aureus (methicillin-susceptible isolates only) - Streptococcus pyogenes - Streptococcus agalactiae - Viridans group streptococci - Enterococcus faecalis (vancomycin-susceptible isolates only) - Pseudomonas aeruginosa - Escherichia coli - Proteus mirabilis - Bacteroides fragilis - Peptostreptococcus species ### Intra-abdominal Infections - 1 g IV every 8 hours Is indicated as a single agent therapy for the treatment of complicated appendicitis and peritonitis caused by: - Viridans group streptococci - Escherichia coli - Klebsiella pneumoniae - Pseudomonas aeruginosa - Bacteroides fragilis - B. thetaiotaomicron - Peptostreptococcus species Meropenem for injection (I.V.) should be administered by intravenous infusion over approximately 15 to 30 minutes. Doses of 1 g may also be administered as an intravenous bolus injection (5 to 20 mL) over approximately 3-5 minutes. ### Use in Adult Patients with Renal Impairment - Dosage should be reduced in patients with creatinine clearance of 50 mL/min or less. - When only serum creatinine is available, the following formula (Cockcroft and Gault equation) may be used to estimate creatinine clearance. There is inadequate information regarding the use of Meropenem for injection (I.V.) in patients on hemodialysis or peritoneal dialysis. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Meropenem in adult patients. ### Non–Guideline-Supported Use ### Cystic Fibrosis - 120 mg/kg IV t.i.d. (maximum 2 g/dose) - In combination with tobramycin ### Nosocomial Pneumonia - 1 g IV t.i.d. - As monotherapy ### Febrile Neutropenia - 1 g t.i.d. - As monotherapy. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ### Skin and Skin Structure Infections (Pediatric Patients ≥ 3 Months only) - 10m/kg IV every 8 hours. - Up to a maximum Dose of 500 mg - Pediatric patients weighing over 50 kg should be administered Meropenem for injection (I.V.) at a dose of 500 mg every 8 hours for complicated skin and skin structure infections. Is indicated as a single agent therapy for the treatment of complicated skin and skin structure infections due to: - Staphylococcus aureus (methicillin-susceptible isolates only) - Streptococcus pyogenes - Streptococcus agalactiae - Viridans group streptococci - Enterococcus faecalis (vancomycin-susceptible isolates only) - Pseudomonas aeruginosa - Escherichia coli - Proteus mirabilis - Bacteroides fragilis - Peptostreptococcus species ### Intra-abdominal Infections (Pediatric Patients ≥ 3 Months only) - 20 mg/kg IV every 8 hours - Up to a maximum dose of 1g - Pediatric patients weighing over 50 kg should be administered Meropenem for injection (I.V.) at a dose of 1 g every 8 hours for intra-abdominal infections. Is indicated as a single agent therapy for the treatment of complicated appendicitis and peritonitis caused by: - Viridans group streptococci - Escherichia coli - Klebsiella pneumoniae - Pseudomonas aeruginosa - Bacteroides fragilis - B. thetaiotaomicron - Peptostreptococcus species ### Bacterial Meningitis (Pediatric Patients ≥ 3 Months only) - 40 mg IV every 8 hours. - Up to a maximum of 2 g. Pediatric patients weighing over 50 kg should be administered Meropenem for injection (I.V.) at a dose of 2 g every 8 hours for meningitis. Meropenem for injection (I.V.) is indicated as a single agent therapy for the treatment of bacterial meningitis caused by: - Streptococcus pneumoniae - Haemophilus influenzae - Neisseria meningitidis Meropenem for injection (I.V.) should be given as intravenous infusion over approximately 15 to 30 minutes or as an intravenous bolus injection (5 to 20 mL) over approximately 3-5 minutes. There is limited safety data available to support the administration of a 40 mg/kg (up to a maximum of 2 g) bolus dose. There is no experience in pediatric patients with renal impairment. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Meropenem in pediatric patients. ### Non–Guideline-Supported Use ### Cystic Fibrosis - 120 mg/kg IV t.i.d. (maximum 2 g/dose) - In combination with tobramycin ### Febrile Neutropenia - 60 mg/kg/day t.i.d. - As monotherapy # Contraindications - Hypersensitivity to any component of this product or to other drugs in the same class - Demonstrated anaphylactic reactions to β-lactams. # Warnings ### Hypersensitivity Reactions - Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving therapy with β-lactams. - These reactions are more likely to occur in individuals with a history of sensitivity to multiple allergens. - There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe hypersensitivity reactions when treated with another β-lactam. - Before initiating therapy with Meropenem for injection (I.V.), careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, other β-lactams, and other allergens. If an allergic reaction to Meropenem for injection (I.V.) occurs, discontinue the drug immediately. - Serious anaphylactic reactions require immediate emergency treatment with epinephrine, oxygen, intravenous steroids, and airway management, including intubation. Other therapy may also be administered as indicated. ### Seizure Potential - Seizures and other adverse CNS experiences have been reported during treatment with Meropenem for injection (I.V.). - These experiences have occurred most commonly in patients with CNS disorders (e.g., brain lesions or history of seizures) or with bacterial meningitis and/or compromised renal function. - During clinical investigations, 2904 immunocompetent adult patients were treated for non-CNS infections with the overall seizure rate being 0.7% (based on 20 patients with this adverse event). - All meropenem-treated patients with seizures had pre-existing contributing factors. - Among these are included prior history of seizures or CNS abnormality and concomitant medications with seizure potential. - Dosage adjustment is recommended in patients with advanced age and/or reduced renal function. - Close adherence to the recommended dosage regimens is urged, especially in patients with known factors that predispose to convulsive activity. - Anti-convulsant therapy should be continued in patients with known seizure disorders. - If focal tremors, myoclonus, or seizures occur, patients should be evaluated neurologically, placed on anti-convulsant therapy if not already instituted, and the dosage of Meropenem for injection (I.V.) re-examined to determine whether it should be decreased or the antibiotic discontinued. ### Interaction with Valproic Acid - Case reports in the literature have shown that co-administration of carbapenems, including meropenem, to patients receiving valproic acid or divalproex sodium results in a reduction in valproic acid concentrations. - The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures. - Increasing the dose of valproic acid or divalproex sodium may not be sufficient to overcome this interaction. - The concomitant use of meropenem and valproic acid or divalproex sodium is generally not recommended. - Antibacterials other than carbapenems should be considered to treat infections in patients whose seizures are well controlled on valproic acid or divalproex sodium. - If administration of Meropenem for injection (I.V.) is necessary, supplemental anti-convulsant therapy should be considered. ### Clostridium difficile–Associated Diarrhea - Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Meropenem for injection (I.V.), and may range in severity from mild diarrhea to fatal colitis. - Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. - C. difficile produces toxins A and B which contribute to the development of CDAD. - Hypertoxin producing isolates of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. - CDAD must be considered in all patients who present with diarrhea following antibiotic use. - Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. - If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. - Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. ### Development of Drug-Resistant Bacteria - Prescribing Meropenem for injection (I.V.) in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. ### Overgrowth of Nonsusceptible Organisms - As with other broad-spectrum antibiotics, prolonged use of meropenem may result in overgrowth of nonsusceptible organisms. - Repeated evaluation of the patient is essential. - If superinfection does occur during therapy, appropriate measures should be taken. ### Laboratory Tests - While Meropenem for injection (I.V.) possesses the characteristic low toxicity of the beta-lactam group of antibiotics, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, is advisable during prolonged therapy. ### Patients with Renal Impairment - In patients with renal impairment, thrombocytopenia has been observed but no clinical bleeding reported. ### Dialysis - There is inadequate information regarding the use of Meropenem for injection (I.V.) in patients on hemodialysis or peritoneal dialysis. ### Potential for Neuromotor Impairment - Patients receiving Meropenem for injection (I.V.) on an outpatient basis may develop adverse events such as seizures, headaches and/or paresthesias that could interfere with mental alertness and/or cause motor impairment. - Until it is reasonably well established that Meropenem for injection (I.V.) is well tolerated, patients should not operate machinery or motorized vehicles. # Adverse Reactions ## Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. ### Adult Patients - During clinical investigations, 2904 immunocompetent adult patients were treated for non-CNS infections with Meropenem for injection (I.V.) (500 mg or 1000 mg every 8 hours). - Deaths in 5 patients were assessed as possibly related to meropenem; 36 (1.2%) patients had meropenem discontinued because of adverse events. - Many patients in these trials were severely ill and had multiple background diseases, physiological impairments and were receiving multiple other drug therapies. - In the seriously ill patient population, it was not possible to determine the relationship between observed adverse events and therapy with Meropenem for injection (I.V.). The following adverse reaction frequencies were derived from the clinical trials in the 2904 patients treated with Meropenem for injection (I.V.) Local adverse reactions that were reported irrespective of the relationship to therapy with Meropenem for injection (I.V.) were as follows: - Inflammation at the injection site 2.4% - Injection site reaction 0.9% - Phlebitis/thrombophlebitis 0.8% Systemic adverse reactions that were reported irrespective of the relationship to Meropenem for injection (I.V.) occurring in greater than 1% of the patients were diarrhea (4.8%), nausea/vomiting (3.6%), headache (2.3%), rash (1.9%), sepsis (1.6%), constipation (1.4%), apnea (1.3%), shock (1.2%), and pruritus (1.2%). Additional systemic adverse reactions that were reported irrespective of relationship to therapy with Meropenem for injection (I.V.) and occurring in less than or equal to 1% but greater than 0.1% of the patients are listed below within each body system in order of decreasing frequency: - Bleeding events were seen as follows: gastrointestinal hemorrhage (0.5%), melena (0.3%), epistaxis (0.2%), hemoperitoneum (0.2%), summing to 1.2%. - Pain - Abdominal pain - Chest pain - Fever - Back pain - Abdominal enlargement - Chills - Pelvic pain - Heart failure - Heart arrest - Tachycardia - Hypertension - Myocardial infarction - Pulmonary embolus - Bradycardia - Hypotension - Syncope - Oral moniliasis - Anorexia - Cholestatic jaundice/jaundice - Flatulence - Ileus - Hepatic failure - Dyspepsia - Intestinal obstruction - Anemia - Hypochromic anemia - Hypervolemia - Peripheral edema - Hypoxia - Insomnia - Agitation/delirium - Confusion - Dizziness - Seizure - Nervousness - Paresthesia - Hallucinations - Somnolence - Anxiety - Depression - Asthenia - Respiratory disorder - Dyspnea - Pleural effusion - Asthma - Cough increased - Lung edema - Urticaria sweating - Skin ulcer - Dysuria - Kidney failure - Vaginal moniliasis - Urinary incontinence Adverse laboratory changes that were reported irrespective of relationship to Meropenem for injection (I.V.) and occurring in greater than 0.2% of the patients were as follows: - Increased SGPT (ALT), SGOT (AST), alkaline phosphatase, LDH, and bilirubin - Increased platelets - Increased eosinophils - Decreased platelets - Decreased hemoglobin - Decreased hematocrit - Decreased WBC - Shortened prothrombin time and shortened partial thromboplastin time - Leukocytosis - Hypokalemia - Increased creatinine - Increased BUN For patients with varying degrees of renal impairment, the incidence of heart failure, kidney failure, seizure and shock reported irrespective of relationship to Meropenem for injection (I.V.), increased in patients with moderately severe renal impairment (creatinine clearance > 10 to 26 mL/min). - Presence of red blood cells - Pain at the injection site 0.4% - Edema at the injection site 0.2% In a study of complicated skin and skin structure infections, the adverse reactions were similar to those listed above. The most common adverse events occurring in > 5% of the patients were: - Headache (7.8%) - Nausea (7.8%) - Constipation (7%) - Diarrhea (7%) - Anemia (5.5%) - Pain (5.1%) Adverse events with an incidence of > 1%, and not listed above, include: - Pharyngitis, - Accidental injury - Gastrointestinal disorder - Hypoglycemia - Peripheral vascular disorder - Pneumonia ### Pediatric Patients Meropenem for injection (I.V.) was studied in 515 pediatric patients (≥ 3 months to < 13 years of age) with serious bacterial infections (excluding meningitisinfections). At dosages of 10 to 20 mg/kg every 8 hours. The types of clinical adverse events seen in these patients are similar to the adults, with the most common adverse events reported as possibly, probably, or definitely related to Meropenem for injection (I.V.) and their rates of occurrence as follows: - Diarrhea 3.5% - Rash 1.6% - Nausea and Vomiting 0.8% Meropenem for injection (I.V.) was studied in 321 pediatric patients (≥ 3 months to < 17 years of age) with meningitis at a dosage of 40 mg/kg every 8 hours. The types of clinical adverse events seen in these patients are similar to the adults, with the most common adverse events reported as possibly, probably, or definitely related to Meropenem for injection (I.V.) and their rates of occurrence as follows: - Diarrhea 4.7% - Rash (mostly diaper area moniliasis) 3.1% - Oral Moniliasis 1.9% - Glossitis 1% In the meningitis studies, the rates of seizure activity during therapy were comparable between patients with no CNS abnormalities who received meropenem and those who received comparator agents (either cefotaxime or ceftriaxone). In the Meropenem for injection (I.V.) treated group, 12/15 patients with seizures had late onset seizures (defined as occurring on day 3 or later) versus 7/20 in the comparator arm. Laboratory changes seen in the pediatric studies, including the meningitis studies, were similar to those reported in the adult studies. There is no experience in pediatric patients with renal impairment. ## Postmarketing Experience The following adverse reactions have been identified during post-approval use of Meropenem for injection (I.V.). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Worldwide post-marketing adverse reactions not otherwise listed in the Adverse Reactions section of this product label and reported as possibly, probably, or definitely drug related are listed within each body system in order of decreasing severity. - Agranulocytosis - Neutropenia - Leukopenia - Positive direct or indirect Coombs test - hemolytic anemia. - Toxic epidermal necrolysis - Stevens-Johnson Syndrome - Angioedema - Erythema multiforme # Drug Interactions ### Probenecid - Probenecid competes with meropenem for active tubular secretion, resulting in increased plasma concentrations of meropenem. - Co-administration of probenecid with meropenem is not recommended. ### Other Antibiotics - In vitro tests show meropenem to act synergistically with aminoglycoside antibiotics against some isolates of Pseudomonas aeruginosa. ### Valproic Acid - Case reports in the literature have shown that co-administration of carbapenems, including meropenem, to patients receiving valproic acid or divalproex sodium results in a reduction in valproic acid concentrations. - The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures. - Although the mechanism of this interaction is unknown, data from in vitro and animal studies suggest that carbapenems may inhibit the hydrolysis of valproic acid’s glucuronide metabolite (VPA-g) back to valproic acid, thus decreasing the serum concentrations of valproic acid. - If administration of Meropenem for injection (I.V.) is necessary, then supplemental anti-convulsant therapy should be considered. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B - Reproductive studies have been performed with meropenem in rats at doses of up to 1000 mg/kg/day, and cynomolgus monkeys at doses of up to 360 mg/kg/day (on the basis of AUC comparisons, approximately 1.8 times and 3.7 times, respectively, to the human exposure at the usual dose of 1 g every 8 hours). These studies revealed no evidence of impaired fertility or harm to the fetus due to meropenem, although there were slight changes in fetal body weight at doses of 250 mg/kg/day (on the basis of AUC comparisons, 0.4 times the human exposure at a dose of 1 g every 8 hours) and above in rats. - There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Pregnancy Category (AUS): B2 There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Meropenem in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Meropenem during labor and delivery. ### Nursing Mothers - It is not known whether this drug is excreted in human milk. - Because many drugs are excreted in human milk, caution should be exercised when Meropenem for injection (I.V.) is administered to a nursing woman. ### Pediatric Use - The safety and effectiveness of Meropenem for injection (I.V.) have been established for pediatric patients ≥ 3 months of age. - Use of Meropenem for injection (I.V.) in pediatric patients with bacterial meningitis is supported by evidence from adequate and well-controlled studies in the pediatric population. - Use of Meropenem for injection (I.V.) in pediatric patients with intra-abdominal infections is supported by evidence from adequate and well-controlled studies with adults with additional data from pediatric pharmacokinetics studies and controlled clinical trials in pediatric patients. - Use of Meropenem for injection (I.V.) in pediatric patients with complicated skin and skin structure infections is supported by evidence from an adequate and well-controlled study with adults and additional data from pediatric pharmacokinetics studies. ### Geriatic Use - Of the total number of subjects in clinical studies of Meropenem for injection (I.V.), approximately 1100 (30%) were 65 years of age and older, while 400 (11%) were 75 years and older. - Additionally, in a study of 511 patients with complicatedskin and skin structure infections, 93 (18%) were 65 years of age and older, while 38 (7%) were 75 years and older. - No overall differences in safety or effectiveness were observed between these subjects and younger subjects; spontaneous reports and other reported clinical experience have not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. - Meropenem is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with renal impairment. - Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. - A pharmacokinetic study with Meropenem for injection (I.V.) in elderly patients has shown a reduction in the plasma clearance of meropenem that correlates with age-associated reduction in creatinine clearance. ### Gender There is no FDA guidance on the use of Meropenem with respect to specific gender populations. ### Race There is no FDA guidance on the use of Meropenem with respect to specific racial populations. ### Renal Impairment - Dosage adjustment is necessary in patients with creatinine clearance 50 mL/min or less. - Pharmacokinetic studies with Meropenem for injection (I.V.) in patients with renal impairment have shown that the plasma clearance of meropenem correlates with creatinine clearance. ### Hepatic Impairment There is no FDA guidance on the use of Meropenem in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Meropenem in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Meropenem in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring While Meropenem for injection (I.V.) possesses the characteristic low toxicity of the beta-lactam group of antibiotics, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, is advisable during prolonged therapy. # IV Compatibility There is limited information regarding the compatibility of Meropenem and IV administrations. # Overdosage - In mice and rats, large intravenous doses of meropenem (2200-4000 mg/kg) have been associated with ataxia, dyspnea, convulsions, and mortalities. - Intentional overdosing of Meropenem for injection (I.V.) is unlikely, although accidental overdosing might occur if large doses are given to patients with reduced renal function. - The largest dose of meropenem administered in clinical trials has been 2 g given intravenously every 8 hours. - At this dosage, no adverse pharmacological effects or increased safety risks have been observed. - Limited post-marketing experience indicates that if adverse events occur following overdosage, they are consistent with the adverse event profile described in the Adverse Reactions section and are generally mild in severity and resolve on withdrawal or dose reduction. - Symptomatic treatments should be considered. - In individuals with normal renal function, rapid renal elimination takes place. - Meropenem and its metabolite are readily dialyzable and effectively removed by hemodialysis; however, no information is available on the use of hemodialysis to treat overdosage. # Pharmacology ## Mechanism of Action - The bactericidal activity of meropenem results from the inhibition of cell wall synthesis. - Meropenem readily penetrates the cell wall of most Gram-positive and Gram-negative bacteria to reach penicillin-binding-protein (PBP) targets. - Its strongest affinities are toward PBPs 2, 3 and 4 of Escherichia coli and Pseudomonas aeruginosa; and PBPs 1, 2, and 4 of Staphylococcus aureus. - Bactericidal concentrations (defined as a 3 log10 reduction in cell counts within 12 to 24 hours) are typically 1-2 times the bacteriostatic concentrations of meropenem, with the exception of Listeria monocytogenes, against which lethal activity is not observed. - Meropenem has significant stability to hydrolysis by β-lactamases, both penicillinases and cephalosporinases produced by Gram-positive and Gram-negative bacteria. - Meropenem should not be used to treat methicillin-resistant Staphylococcus aureus (MRSA) or methicillin-resistant Staphylococcus epidermidis (MRSE). ### Mechanism of Resistance - There are several mechanisms of resistance to carbapenems: - Decreased permeability of the outer membrane of Gram-negative bacteria (due to diminished production of porins) causing reduced bacterial uptake. - Reduced affinity of the target PBPs. - Increased expression of efflux pump components. - Production of antibiotic destroying enzymes (carbapenemases, metallo-β-lactamases). Localized clusters of infections due to carbapenem-resistant bacteria have been reported in some regions. ## Structure - Meropenem for Injection, USP (I.V.) is a sterile, pyrogen-free, synthetic, broad-spectrum, carbapenem antibiotic for intravenous administration. - It is (4R,5S,6S)-3-thio]-6--4-methyl-7-oxo-1-azabicyclohept-2-ene-2-carboxylic acid trihydrate. Its empirical formula is C17H25N3O5S3H2O with a molecular weight of 437.52. - Its structural formula is: - Meropenem for Injection, USP (I.V.) is a white to pale yellow crystalline powder. - The solution varies from colorless to yellow depending on the concentration. The pH of freshly constituted solutions is between 7.3 and 8.3. Meropenem is soluble in 5% monobasic potassium phosphate solution, sparingly soluble in water, very slightly soluble in hydrated ethanol, and practically insoluble in acetone or ether. - When constituted as instructed, each 500 mg Meropenem for Injection, USP (I.V.) vial will deliver 500 mg meropenem and 45.1 mg of sodium as sodium carbonate (1.96 mEq). Each 1 g Meropenem for Injection, USP (I.V.) vial will deliver 1 g of meropenem and 90.2 mg of sodium as sodium carbonate (3.92 mEq). ## Pharmacodynamics There is limited information regarding Meropenem Pharmacodynamics in the drug label. ## Pharmacokinetics At the end of a 30-minute intravenous infusion of a single dose of Meropenem for injection (I.V.) in healthy volunteers, mean peak plasma concentrations of meropenem are approximately 23 mcg/mL (range 14-26) for the 500 mg dose and 49 mcg/mL (range 39-58) for the 1 g dose. A 5-minute intravenous bolus injection of Meropenem for injection (I.V.) in healthy volunteers results in mean peak plasma concentrations of approximately 45 mcg/mL (range 18-65) for the 500 mg dose and 112 mcg/mL (range 83-140) for the 1 g dose. Following intravenous doses of 500 mg, mean plasma concentrations of meropenem usually decline to approximately 1 mcg/mL at 6 hours after administration. No accumulation of meropenem in plasma was observed with regimens using 500 mg administered every 8 hours or 1 g administered every 6 hours in healthy volunteers with normal renal function. The plasma protein binding of meropenem is approximately 2%. Meropenem penetrates well into most body fluids and tissues including cerebrospinal fluid, achieving concentrations matching or exceeding those required to inhibit most susceptible bacteria. After a single intravenous dose of Meropenem for injection (I.V.), the highest mean concentrations of meropenem were found in tissues and fluids at 1 hour (0.5 to 1.5 hours) after the start of infusion, except where indicated in the tissues and fluids listed in the table below. There is one metabolite of meropenem that is microbiologically inactive. In subjects with normal renal function, the elimination half-life of meropenem is approximately 1 hour. Meropenem is primarily excreted unchanged by the kidneys. Approximately 70% (50 – 75%) of the dose is excreted unchanged within 12 hours. A further 28% is recovered as the microbiologically inactive metabolite. Fecal elimination represents only approximately 2% of the dose. The measured renal clearance and the effect of probenecid show that meropenem undergoes both filtration and tubular secretion. ### Specific Populations Pharmacokinetic studies with Meropenem for injection (I.V.) in patients with renal impairment have shown that the plasma clearance of meropenem correlates with creatinine clearance. Dosage adjustments are necessary in subjects with renal impairment (creatinine clearance 50 mL/min or less). Meropenem I.V. is hemodialyzable. However, there is no information on the usefulness of hemodialysis to treat overdosage. A pharmacokinetic study with Meropenem for injection (I.V.) in patients with hepatic impairment has shown no effects of liver disease on the pharmacokinetics of meropenem. A pharmacokinetic study with Meropenem for injection (I.V.) in elderly patients with renal impairment showed a reduction in plasma clearance of meropenem that correlates with age-associated reduction in creatinine clearance. The pharmacokinetics of meropenem in pediatric patients 2 years of age or older are essentially similar to those in adults. The elimination half-life for meropenem was approximately 1.5 hours in pediatric patients of age 3 months to 2 years. The pharmacokinetics are linear over the dose range from 10 to 40 mg/kg. Probenecid competes with meropenem for active tubular secretion and thus inhibits the renal excretion of meropenem. Following administration of probenecid with meropenem, the mean systemic exposure increased 56% and the mean elimination half-life increased 38%. Co-administration of probenecid with meropenem is not recommended. ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, Impairment of Fertility - Carcinogenesis studies have not been performed. - Genetic toxicity studies were performed with meropenem using the bacterial reverse mutation test, the Chinese hamster ovary HGPRT assay, cultured human lymphocytes cytogenic assay, and the mouse micronucleus test. - There was no evidence of mutagenic potential found in any of these tests. - Reproductive studies were performed with meropenem in rats at doses up to 1000 mg/kg/day, and cynomolgus monkeys at doses up to 360 mg/kg/day (on the basis of AUC comparisons, approximately 1.8 times and 3.7 times, respectively, to the human exposure at the usual dose of 1 g every 8 hours). - There was no reproductive toxicity seen. # Clinical Studies ### Complicated Skin and Skin Structure Infections Adult patients with complicated skin and skin structure infections including complicated cellulitis, complex abscesses, perirectal abscesses, and skin infections requiring intravenous antimicrobials, hospitalization, and surgical intervention were enrolled in a randomized, multi-center, international, double-blind trial. The study evaluated meropenem at doses of 500 mg administered intravenously every 8 hours and imipenem-cilastatin at doses of 500 mg administered intravenously every 8 hours. The study compared the clinical response between treatment groups in the clinically evaluable population at the follow-up visit (test-of-cure). The trial was conducted in the United States, South Africa, Canada, and Brazil. At enrollment, approximately 37% of the patients had underlying diabetes, 12% had underlying peripheral vascular disease and 67% had a surgical intervention. The study included 510 patients randomized to meropenem and 527 patients randomized to imipenem-cilastatin. Two hundred and sixty-one (261) patients randomized to meropenem and 287 patients randomized to imipenem-cilastatin were clinically evaluable. The success rates in the clinically evaluable patients at the follow-up visit were 86% (225/261) in the meropenem arm and 83% (238/287) in imipenem-cilastatin arm. The following table provides the results for the overall as well as subgroup comparisons in clinically evaluable population. The following clinical efficacy rates were obtained, per organism. The values represent the number of patients clinically cured/number of clinically evaluable patients at the post-treatment follow-up visit, with the percent cure in parentheses (Fully Evaluable analysis set). The proportion of patients who discontinued study treatment due to an adverse event was similar for both treatment groups (meropenem, 2.5% and imipenem-cilastatin, 2.7%). ### Complicated Intra-Abdominal Infections One controlled clinical study of complicated intra-abdominal infection was performed in the United States where meropenem was compared with clindamycin/tobramycin. Three controlled clinical studies of complicated intra-abdominal infections were performed in Europe; meropenem was compared with imipenem (two trials) and cefotaxime/metronidazole (one trial). Using strict evaluability criteria and microbiologic eradication and clinical cures at follow-up which occurred 7 or more days after completion of therapy, the following presumptive microbiologic eradication/clinical cure rates and statistical findings were obtained: The finding that meropenem was not statistically equivalent to cefotaxime/metronidazole may have been due to uneven assignment of more seriously ill patients to the meropenem arm. Currently there is no additional information available to further interpret this observation. ### Bacterial Meningitis Four hundred forty-six patients (397 pediatric patients ≥ 3 months to < 17 years of age) were enrolled in 4 separate clinical trials and randomized to treatment with meropenem (n = 225) at a dose of 40 mg/kg every 8 hours or a comparator drug, i.e., cefotaxime (n = 187) or ceftriaxone (n = 34), at the approved dosing regimens. A comparable number of patients were found to be clinically evaluable (ranging from 61-68%) and with a similar distribution of pathogens isolated on initial CSF culture. Patients were defined as clinically not cured if any one of the following three criteria were met: At the 5-7 week post-completion of therapy visit, the patient had any one of the following: moderate to severe motor, behavior or development deficits, hearing loss of > 60 decibels in one or both ears, or blindness. During therapy the patient’s clinical status necessitated the addition of other antibiotics. Either during or post-therapy, the patient developed a large subdural effusion needing surgical drainage, or a cerebral abscess, or a bacteriologic relapse. Using the definition, the following efficacy rates were obtained, per organism. The values represent the number of patients clinically cured/number of clinically evaluable patients, with the percent cure in parentheses. Sequelae were the most common reason patients were assessed as clinically not cured. Five patients were found to be bacteriologically not cured, 3 in the comparator group (1 relapse and 2 patients with cerebral abscesses) and 2 in the meropenem group (1 relapse and 1 with continued growth of Pseudomonas aeruginosa). The adverse events seen were comparable between the two treatment groups both in type and frequency. The meropenem group did have a statistically higher number of patients with transient elevation of liver enzymes. Rates of seizure activity during therapy were comparable between patients with no CNS abnormalities who received meropenem and those who received comparator agents. In the Meropenem for injection (I.V.) treated group, 12/15 patients with seizures had late onset seizures (defined as occurring on day 3 or later) versus 7/20 in the comparator arm. With respect to hearing loss, 263 of the 271 evaluable patients had at least one hearing test performed post-therapy. The following table shows the degree of hearing loss between the meropenem-treated patients and the comparator-treated patients. # How Supplied - Meropenem for Injection, USP (I.V.) is supplied in 20 mL and 30 mL injection vials containing sufficient meropenem to deliver 500 mg or 1 g for intravenous administration, respectively. ## Storage - The dry powder should be stored at controlled room temperature 20-25ºC (68-77ºF) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be counseled that antibacterial drugs including Meropenem for injection (I.V.) should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Meropenem for injection (I.V.) is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. - Skipping doses or not completing the full course of therapy may - (1) Decrease the effectiveness of the immediate treatment and - (2) Increase the likelihood that bacteria will develop resistance and will not be treatable by Meropenem for injection (I.V.) or other antibacterial drugs in the future. - Patients should be counseled that diarrhea is a common problem caused by ntibiotics which usually ends when the antibiotic is discontinued. - Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible - Patients should be counseled to inform their physician if they are taking valproic acid or divalproex sodium. Valproic acid concentrations in the blood may drop below the therapeutic range upon co-administration with Meropenem for injection (I.V.). - If treatment with Meropenem for injection (I.V.) is necessary and continued, alternative or supplemental anti-convulsant medication to prevent and/or treat seizures may be needed. - Patients receiving Meropenem for injection (I.V.) on an outpatient basis may develop adverse events such as seizures, headaches and/or paresthesias that could interfere with mental alertness and/or cause motor impairment. Until it is reasonably well established that Meropenem for injection (I.V.) is well tolerated, patients should not operate machinery or motorized vehicles. # Precautions with Alcohol Alcohol-Meropenem interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Merrem IV # Look-Alike Drug Names There is limited information regarding Meropenem Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Meropenem Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Stefano Giannoni [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Meropenem is a Carbapenem that is FDA approved for the treatment of complicated skin and skin structure infections, intra-abdominal infections, bacterial meningitis (pediatric patients).. Common adverse reactions include headache, nausea, constipation, diarrhea, anemia, vomiting, and rash. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Skin and Skin Structure Infections - Dosage: 500 mg IV every 8 hours. Is indicated as a single agent therapy for the treatment of complicated skin and skin structure infections due to: - Staphylococcus aureus (methicillin-susceptible isolates only) - Streptococcus pyogenes - Streptococcus agalactiae - Viridans group streptococci - Enterococcus faecalis (vancomycin-susceptible isolates only) - Pseudomonas aeruginosa - Escherichia coli - Proteus mirabilis - Bacteroides fragilis - Peptostreptococcus species ### Intra-abdominal Infections - 1 g IV every 8 hours Is indicated as a single agent therapy for the treatment of complicated appendicitis and peritonitis caused by: - Viridans group streptococci - Escherichia coli - Klebsiella pneumoniae - Pseudomonas aeruginosa - Bacteroides fragilis - B. thetaiotaomicron - Peptostreptococcus species Meropenem for injection (I.V.) should be administered by intravenous infusion over approximately 15 to 30 minutes. Doses of 1 g may also be administered as an intravenous bolus injection (5 to 20 mL) over approximately 3-5 minutes. ### Use in Adult Patients with Renal Impairment - Dosage should be reduced in patients with creatinine clearance of 50 mL/min or less. - When only serum creatinine is available, the following formula (Cockcroft and Gault equation) may be used to estimate creatinine clearance. There is inadequate information regarding the use of Meropenem for injection (I.V.) in patients on hemodialysis or peritoneal dialysis. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Meropenem in adult patients. ### Non–Guideline-Supported Use ### Cystic Fibrosis - 120 mg/kg IV t.i.d. (maximum 2 g/dose)[1] - In combination with tobramycin ### Nosocomial Pneumonia - 1 g IV t.i.d.[2] - As monotherapy ### Febrile Neutropenia - 1 g t.i.d.[3] - As monotherapy. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ### Skin and Skin Structure Infections (Pediatric Patients ≥ 3 Months only) - 10m/kg IV every 8 hours. - Up to a maximum Dose of 500 mg - Pediatric patients weighing over 50 kg should be administered Meropenem for injection (I.V.) at a dose of 500 mg every 8 hours for complicated skin and skin structure infections. Is indicated as a single agent therapy for the treatment of complicated skin and skin structure infections due to: - Staphylococcus aureus (methicillin-susceptible isolates only) - Streptococcus pyogenes - Streptococcus agalactiae - Viridans group streptococci - Enterococcus faecalis (vancomycin-susceptible isolates only) - Pseudomonas aeruginosa - Escherichia coli - Proteus mirabilis - Bacteroides fragilis - Peptostreptococcus species ### Intra-abdominal Infections (Pediatric Patients ≥ 3 Months only) - 20 mg/kg IV every 8 hours - Up to a maximum dose of 1g - Pediatric patients weighing over 50 kg should be administered Meropenem for injection (I.V.) at a dose of 1 g every 8 hours for intra-abdominal infections. Is indicated as a single agent therapy for the treatment of complicated appendicitis and peritonitis caused by: - Viridans group streptococci - Escherichia coli - Klebsiella pneumoniae - Pseudomonas aeruginosa - Bacteroides fragilis - B. thetaiotaomicron - Peptostreptococcus species ### Bacterial Meningitis (Pediatric Patients ≥ 3 Months only) - 40 mg IV every 8 hours. - Up to a maximum of 2 g. Pediatric patients weighing over 50 kg should be administered Meropenem for injection (I.V.) at a dose of 2 g every 8 hours for meningitis. Meropenem for injection (I.V.) is indicated as a single agent therapy for the treatment of bacterial meningitis caused by: - Streptococcus pneumoniae - Haemophilus influenzae - Neisseria meningitidis Meropenem for injection (I.V.) should be given as intravenous infusion over approximately 15 to 30 minutes or as an intravenous bolus injection (5 to 20 mL) over approximately 3-5 minutes. There is limited safety data available to support the administration of a 40 mg/kg (up to a maximum of 2 g) bolus dose. There is no experience in pediatric patients with renal impairment. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Meropenem in pediatric patients. ### Non–Guideline-Supported Use ### Cystic Fibrosis - 120 mg/kg IV t.i.d. (maximum 2 g/dose)[1] - In combination with tobramycin ### Febrile Neutropenia - 60 mg/kg/day t.i.d.[4] - As monotherapy # Contraindications - Hypersensitivity to any component of this product or to other drugs in the same class - Demonstrated anaphylactic reactions to β-lactams. # Warnings ### Hypersensitivity Reactions - Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving therapy with β-lactams. - These reactions are more likely to occur in individuals with a history of sensitivity to multiple allergens. - There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe hypersensitivity reactions when treated with another β-lactam. - Before initiating therapy with Meropenem for injection (I.V.), careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, other β-lactams, and other allergens. If an allergic reaction to Meropenem for injection (I.V.) occurs, discontinue the drug immediately. - Serious anaphylactic reactions require immediate emergency treatment with epinephrine, oxygen, intravenous steroids, and airway management, including intubation. Other therapy may also be administered as indicated. ### Seizure Potential - Seizures and other adverse CNS experiences have been reported during treatment with Meropenem for injection (I.V.). - These experiences have occurred most commonly in patients with CNS disorders (e.g., brain lesions or history of seizures) or with bacterial meningitis and/or compromised renal function. - During clinical investigations, 2904 immunocompetent adult patients were treated for non-CNS infections with the overall seizure rate being 0.7% (based on 20 patients with this adverse event). - All meropenem-treated patients with seizures had pre-existing contributing factors. - Among these are included prior history of seizures or CNS abnormality and concomitant medications with seizure potential. - Dosage adjustment is recommended in patients with advanced age and/or reduced renal function. - Close adherence to the recommended dosage regimens is urged, especially in patients with known factors that predispose to convulsive activity. - Anti-convulsant therapy should be continued in patients with known seizure disorders. - If focal tremors, myoclonus, or seizures occur, patients should be evaluated neurologically, placed on anti-convulsant therapy if not already instituted, and the dosage of Meropenem for injection (I.V.) re-examined to determine whether it should be decreased or the antibiotic discontinued. ### Interaction with Valproic Acid - Case reports in the literature have shown that co-administration of carbapenems, including meropenem, to patients receiving valproic acid or divalproex sodium results in a reduction in valproic acid concentrations. - The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures. - Increasing the dose of valproic acid or divalproex sodium may not be sufficient to overcome this interaction. - The concomitant use of meropenem and valproic acid or divalproex sodium is generally not recommended. - Antibacterials other than carbapenems should be considered to treat infections in patients whose seizures are well controlled on valproic acid or divalproex sodium. - If administration of Meropenem for injection (I.V.) is necessary, supplemental anti-convulsant therapy should be considered. ### Clostridium difficile–Associated Diarrhea - Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Meropenem for injection (I.V.), and may range in severity from mild diarrhea to fatal colitis. - Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. - C. difficile produces toxins A and B which contribute to the development of CDAD. - Hypertoxin producing isolates of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. - CDAD must be considered in all patients who present with diarrhea following antibiotic use. - Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. - If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. - Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. ### Development of Drug-Resistant Bacteria - Prescribing Meropenem for injection (I.V.) in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. ### Overgrowth of Nonsusceptible Organisms - As with other broad-spectrum antibiotics, prolonged use of meropenem may result in overgrowth of nonsusceptible organisms. - Repeated evaluation of the patient is essential. - If superinfection does occur during therapy, appropriate measures should be taken. ### Laboratory Tests - While Meropenem for injection (I.V.) possesses the characteristic low toxicity of the beta-lactam group of antibiotics, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, is advisable during prolonged therapy. ### Patients with Renal Impairment - In patients with renal impairment, thrombocytopenia has been observed but no clinical bleeding reported. ### Dialysis - There is inadequate information regarding the use of Meropenem for injection (I.V.) in patients on hemodialysis or peritoneal dialysis. ### Potential for Neuromotor Impairment - Patients receiving Meropenem for injection (I.V.) on an outpatient basis may develop adverse events such as seizures, headaches and/or paresthesias that could interfere with mental alertness and/or cause motor impairment. - Until it is reasonably well established that Meropenem for injection (I.V.) is well tolerated, patients should not operate machinery or motorized vehicles. # Adverse Reactions ## Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. ### Adult Patients - During clinical investigations, 2904 immunocompetent adult patients were treated for non-CNS infections with Meropenem for injection (I.V.) (500 mg or 1000 mg every 8 hours). - Deaths in 5 patients were assessed as possibly related to meropenem; 36 (1.2%) patients had meropenem discontinued because of adverse events. - Many patients in these trials were severely ill and had multiple background diseases, physiological impairments and were receiving multiple other drug therapies. - In the seriously ill patient population, it was not possible to determine the relationship between observed adverse events and therapy with Meropenem for injection (I.V.). The following adverse reaction frequencies were derived from the clinical trials in the 2904 patients treated with Meropenem for injection (I.V.) Local adverse reactions that were reported irrespective of the relationship to therapy with Meropenem for injection (I.V.) were as follows: - Inflammation at the injection site 2.4% - Injection site reaction 0.9% - Phlebitis/thrombophlebitis 0.8% Systemic adverse reactions that were reported irrespective of the relationship to Meropenem for injection (I.V.) occurring in greater than 1% of the patients were diarrhea (4.8%), nausea/vomiting (3.6%), headache (2.3%), rash (1.9%), sepsis (1.6%), constipation (1.4%), apnea (1.3%), shock (1.2%), and pruritus (1.2%). Additional systemic adverse reactions that were reported irrespective of relationship to therapy with Meropenem for injection (I.V.) and occurring in less than or equal to 1% but greater than 0.1% of the patients are listed below within each body system in order of decreasing frequency: - Bleeding events were seen as follows: gastrointestinal hemorrhage (0.5%), melena (0.3%), epistaxis (0.2%), hemoperitoneum (0.2%), summing to 1.2%. - Pain - Abdominal pain - Chest pain - Fever - Back pain - Abdominal enlargement - Chills - Pelvic pain - Heart failure - Heart arrest - Tachycardia - Hypertension - Myocardial infarction - Pulmonary embolus - Bradycardia - Hypotension - Syncope - Oral moniliasis - Anorexia - Cholestatic jaundice/jaundice - Flatulence - Ileus - Hepatic failure - Dyspepsia - Intestinal obstruction - Anemia - Hypochromic anemia - Hypervolemia - Peripheral edema - Hypoxia - Insomnia - Agitation/delirium - Confusion - Dizziness - Seizure - Nervousness - Paresthesia - Hallucinations - Somnolence - Anxiety - Depression - Asthenia - Respiratory disorder - Dyspnea - Pleural effusion - Asthma - Cough increased - Lung edema - Urticaria sweating - Skin ulcer - Dysuria - Kidney failure - Vaginal moniliasis - Urinary incontinence Adverse laboratory changes that were reported irrespective of relationship to Meropenem for injection (I.V.) and occurring in greater than 0.2% of the patients were as follows: - Increased SGPT (ALT), SGOT (AST), alkaline phosphatase, LDH, and bilirubin - Increased platelets - Increased eosinophils - Decreased platelets - Decreased hemoglobin - Decreased hematocrit - Decreased WBC - Shortened prothrombin time and shortened partial thromboplastin time - Leukocytosis - Hypokalemia - Increased creatinine - Increased BUN For patients with varying degrees of renal impairment, the incidence of heart failure, kidney failure, seizure and shock reported irrespective of relationship to Meropenem for injection (I.V.), increased in patients with moderately severe renal impairment (creatinine clearance > 10 to 26 mL/min). - Presence of red blood cells - Pain at the injection site 0.4% - Edema at the injection site 0.2% In a study of complicated skin and skin structure infections, the adverse reactions were similar to those listed above. The most common adverse events occurring in > 5% of the patients were: - Headache (7.8%) - Nausea (7.8%) - Constipation (7%) - Diarrhea (7%) - Anemia (5.5%) - Pain (5.1%) Adverse events with an incidence of > 1%, and not listed above, include: - Pharyngitis, - Accidental injury - Gastrointestinal disorder - Hypoglycemia - Peripheral vascular disorder - Pneumonia ### Pediatric Patients Meropenem for injection (I.V.) was studied in 515 pediatric patients (≥ 3 months to < 13 years of age) with serious bacterial infections (excluding meningitisinfections). At dosages of 10 to 20 mg/kg every 8 hours. The types of clinical adverse events seen in these patients are similar to the adults, with the most common adverse events reported as possibly, probably, or definitely related to Meropenem for injection (I.V.) and their rates of occurrence as follows: - Diarrhea 3.5% - Rash 1.6% - Nausea and Vomiting 0.8% Meropenem for injection (I.V.) was studied in 321 pediatric patients (≥ 3 months to < 17 years of age) with meningitis at a dosage of 40 mg/kg every 8 hours. The types of clinical adverse events seen in these patients are similar to the adults, with the most common adverse events reported as possibly, probably, or definitely related to Meropenem for injection (I.V.) and their rates of occurrence as follows: - Diarrhea 4.7% - Rash (mostly diaper area moniliasis) 3.1% - Oral Moniliasis 1.9% - Glossitis 1% In the meningitis studies, the rates of seizure activity during therapy were comparable between patients with no CNS abnormalities who received meropenem and those who received comparator agents (either cefotaxime or ceftriaxone). In the Meropenem for injection (I.V.) treated group, 12/15 patients with seizures had late onset seizures (defined as occurring on day 3 or later) versus 7/20 in the comparator arm. Laboratory changes seen in the pediatric studies, including the meningitis studies, were similar to those reported in the adult studies. There is no experience in pediatric patients with renal impairment. ## Postmarketing Experience The following adverse reactions have been identified during post-approval use of Meropenem for injection (I.V.). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Worldwide post-marketing adverse reactions not otherwise listed in the Adverse Reactions section of this product label and reported as possibly, probably, or definitely drug related are listed within each body system in order of decreasing severity. - Agranulocytosis - Neutropenia - Leukopenia - Positive direct or indirect Coombs test - hemolytic anemia. - Toxic epidermal necrolysis - Stevens-Johnson Syndrome - Angioedema - Erythema multiforme # Drug Interactions ### Probenecid - Probenecid competes with meropenem for active tubular secretion, resulting in increased plasma concentrations of meropenem. - Co-administration of probenecid with meropenem is not recommended. ### Other Antibiotics - In vitro tests show meropenem to act synergistically with aminoglycoside antibiotics against some isolates of Pseudomonas aeruginosa. ### Valproic Acid - Case reports in the literature have shown that co-administration of carbapenems, including meropenem, to patients receiving valproic acid or divalproex sodium results in a reduction in valproic acid concentrations. - The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures. - Although the mechanism of this interaction is unknown, data from in vitro and animal studies suggest that carbapenems may inhibit the hydrolysis of valproic acid’s glucuronide metabolite (VPA-g) back to valproic acid, thus decreasing the serum concentrations of valproic acid. - If administration of Meropenem for injection (I.V.) is necessary, then supplemental anti-convulsant therapy should be considered. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B - Reproductive studies have been performed with meropenem in rats at doses of up to 1000 mg/kg/day, and cynomolgus monkeys at doses of up to 360 mg/kg/day (on the basis of AUC comparisons, approximately 1.8 times and 3.7 times, respectively, to the human exposure at the usual dose of 1 g every 8 hours). These studies revealed no evidence of impaired fertility or harm to the fetus due to meropenem, although there were slight changes in fetal body weight at doses of 250 mg/kg/day (on the basis of AUC comparisons, 0.4 times the human exposure at a dose of 1 g every 8 hours) and above in rats. - There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Pregnancy Category (AUS): B2 There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Meropenem in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Meropenem during labor and delivery. ### Nursing Mothers - It is not known whether this drug is excreted in human milk. - Because many drugs are excreted in human milk, caution should be exercised when Meropenem for injection (I.V.) is administered to a nursing woman. ### Pediatric Use - The safety and effectiveness of Meropenem for injection (I.V.) have been established for pediatric patients ≥ 3 months of age. - Use of Meropenem for injection (I.V.) in pediatric patients with bacterial meningitis is supported by evidence from adequate and well-controlled studies in the pediatric population. - Use of Meropenem for injection (I.V.) in pediatric patients with intra-abdominal infections is supported by evidence from adequate and well-controlled studies with adults with additional data from pediatric pharmacokinetics studies and controlled clinical trials in pediatric patients. - Use of Meropenem for injection (I.V.) in pediatric patients with complicated skin and skin structure infections is supported by evidence from an adequate and well-controlled study with adults and additional data from pediatric pharmacokinetics studies. ### Geriatic Use - Of the total number of subjects in clinical studies of Meropenem for injection (I.V.), approximately 1100 (30%) were 65 years of age and older, while 400 (11%) were 75 years and older. - Additionally, in a study of 511 patients with complicatedskin and skin structure infections, 93 (18%) were 65 years of age and older, while 38 (7%) were 75 years and older. - No overall differences in safety or effectiveness were observed between these subjects and younger subjects; spontaneous reports and other reported clinical experience have not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. - Meropenem is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with renal impairment. - Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. - A pharmacokinetic study with Meropenem for injection (I.V.) in elderly patients has shown a reduction in the plasma clearance of meropenem that correlates with age-associated reduction in creatinine clearance. ### Gender There is no FDA guidance on the use of Meropenem with respect to specific gender populations. ### Race There is no FDA guidance on the use of Meropenem with respect to specific racial populations. ### Renal Impairment - Dosage adjustment is necessary in patients with creatinine clearance 50 mL/min or less. - Pharmacokinetic studies with Meropenem for injection (I.V.) in patients with renal impairment have shown that the plasma clearance of meropenem correlates with creatinine clearance. ### Hepatic Impairment There is no FDA guidance on the use of Meropenem in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Meropenem in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Meropenem in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring While Meropenem for injection (I.V.) possesses the characteristic low toxicity of the beta-lactam group of antibiotics, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, is advisable during prolonged therapy. # IV Compatibility There is limited information regarding the compatibility of Meropenem and IV administrations. # Overdosage - In mice and rats, large intravenous doses of meropenem (2200-4000 mg/kg) have been associated with ataxia, dyspnea, convulsions, and mortalities. - Intentional overdosing of Meropenem for injection (I.V.) is unlikely, although accidental overdosing might occur if large doses are given to patients with reduced renal function. - The largest dose of meropenem administered in clinical trials has been 2 g given intravenously every 8 hours. - At this dosage, no adverse pharmacological effects or increased safety risks have been observed. - Limited post-marketing experience indicates that if adverse events occur following overdosage, they are consistent with the adverse event profile described in the Adverse Reactions section and are generally mild in severity and resolve on withdrawal or dose reduction. - Symptomatic treatments should be considered. - In individuals with normal renal function, rapid renal elimination takes place. - Meropenem and its metabolite are readily dialyzable and effectively removed by hemodialysis; however, no information is available on the use of hemodialysis to treat overdosage. # Pharmacology ## Mechanism of Action - The bactericidal activity of meropenem results from the inhibition of cell wall synthesis. - Meropenem readily penetrates the cell wall of most Gram-positive and Gram-negative bacteria to reach penicillin-binding-protein (PBP) targets. - Its strongest affinities are toward PBPs 2, 3 and 4 of Escherichia coli and Pseudomonas aeruginosa; and PBPs 1, 2, and 4 of Staphylococcus aureus. - Bactericidal concentrations (defined as a 3 log10 reduction in cell counts within 12 to 24 hours) are typically 1-2 times the bacteriostatic concentrations of meropenem, with the exception of Listeria monocytogenes, against which lethal activity is not observed. - Meropenem has significant stability to hydrolysis by β-lactamases, both penicillinases and cephalosporinases produced by Gram-positive and Gram-negative bacteria. - Meropenem should not be used to treat methicillin-resistant Staphylococcus aureus (MRSA) or methicillin-resistant Staphylococcus epidermidis (MRSE). ### Mechanism of Resistance - There are several mechanisms of resistance to carbapenems: - Decreased permeability of the outer membrane of Gram-negative bacteria (due to diminished production of porins) causing reduced bacterial uptake. - Reduced affinity of the target PBPs. - Increased expression of efflux pump components. - Production of antibiotic destroying enzymes (carbapenemases, metallo-β-lactamases). Localized clusters of infections due to carbapenem-resistant bacteria have been reported in some regions. ## Structure - Meropenem for Injection, USP (I.V.) is a sterile, pyrogen-free, synthetic, broad-spectrum, carbapenem antibiotic for intravenous administration. - It is (4R,5S,6S)-3-[(3S,5S)-5-(Dimethylcarbamoyl)-3-pyrrolidinyl]thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid trihydrate. Its empirical formula is C17H25N3O5S•3H2O with a molecular weight of 437.52. - Its structural formula is: - Meropenem for Injection, USP (I.V.) is a white to pale yellow crystalline powder. - The solution varies from colorless to yellow depending on the concentration. The pH of freshly constituted solutions is between 7.3 and 8.3. Meropenem is soluble in 5% monobasic potassium phosphate solution, sparingly soluble in water, very slightly soluble in hydrated ethanol, and practically insoluble in acetone or ether. - When constituted as instructed, each 500 mg Meropenem for Injection, USP (I.V.) vial will deliver 500 mg meropenem and 45.1 mg of sodium as sodium carbonate (1.96 mEq). Each 1 g Meropenem for Injection, USP (I.V.) vial will deliver 1 g of meropenem and 90.2 mg of sodium as sodium carbonate (3.92 mEq). ## Pharmacodynamics There is limited information regarding Meropenem Pharmacodynamics in the drug label. ## Pharmacokinetics At the end of a 30-minute intravenous infusion of a single dose of Meropenem for injection (I.V.) in healthy volunteers, mean peak plasma concentrations of meropenem are approximately 23 mcg/mL (range 14-26) for the 500 mg dose and 49 mcg/mL (range 39-58) for the 1 g dose. A 5-minute intravenous bolus injection of Meropenem for injection (I.V.) in healthy volunteers results in mean peak plasma concentrations of approximately 45 mcg/mL (range 18-65) for the 500 mg dose and 112 mcg/mL (range 83-140) for the 1 g dose. Following intravenous doses of 500 mg, mean plasma concentrations of meropenem usually decline to approximately 1 mcg/mL at 6 hours after administration. No accumulation of meropenem in plasma was observed with regimens using 500 mg administered every 8 hours or 1 g administered every 6 hours in healthy volunteers with normal renal function. The plasma protein binding of meropenem is approximately 2%. Meropenem penetrates well into most body fluids and tissues including cerebrospinal fluid, achieving concentrations matching or exceeding those required to inhibit most susceptible bacteria. After a single intravenous dose of Meropenem for injection (I.V.), the highest mean concentrations of meropenem were found in tissues and fluids at 1 hour (0.5 to 1.5 hours) after the start of infusion, except where indicated in the tissues and fluids listed in the table below. There is one metabolite of meropenem that is microbiologically inactive. In subjects with normal renal function, the elimination half-life of meropenem is approximately 1 hour. Meropenem is primarily excreted unchanged by the kidneys. Approximately 70% (50 – 75%) of the dose is excreted unchanged within 12 hours. A further 28% is recovered as the microbiologically inactive metabolite. Fecal elimination represents only approximately 2% of the dose. The measured renal clearance and the effect of probenecid show that meropenem undergoes both filtration and tubular secretion. ### Specific Populations Pharmacokinetic studies with Meropenem for injection (I.V.) in patients with renal impairment have shown that the plasma clearance of meropenem correlates with creatinine clearance. Dosage adjustments are necessary in subjects with renal impairment (creatinine clearance 50 mL/min or less). Meropenem I.V. is hemodialyzable. However, there is no information on the usefulness of hemodialysis to treat overdosage. A pharmacokinetic study with Meropenem for injection (I.V.) in patients with hepatic impairment has shown no effects of liver disease on the pharmacokinetics of meropenem. A pharmacokinetic study with Meropenem for injection (I.V.) in elderly patients with renal impairment showed a reduction in plasma clearance of meropenem that correlates with age-associated reduction in creatinine clearance. The pharmacokinetics of meropenem in pediatric patients 2 years of age or older are essentially similar to those in adults. The elimination half-life for meropenem was approximately 1.5 hours in pediatric patients of age 3 months to 2 years. The pharmacokinetics are linear over the dose range from 10 to 40 mg/kg. Probenecid competes with meropenem for active tubular secretion and thus inhibits the renal excretion of meropenem. Following administration of probenecid with meropenem, the mean systemic exposure increased 56% and the mean elimination half-life increased 38%. Co-administration of probenecid with meropenem is not recommended. ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, Impairment of Fertility - Carcinogenesis studies have not been performed. - Genetic toxicity studies were performed with meropenem using the bacterial reverse mutation test, the Chinese hamster ovary HGPRT assay, cultured human lymphocytes cytogenic assay, and the mouse micronucleus test. - There was no evidence of mutagenic potential found in any of these tests. - Reproductive studies were performed with meropenem in rats at doses up to 1000 mg/kg/day, and cynomolgus monkeys at doses up to 360 mg/kg/day (on the basis of AUC comparisons, approximately 1.8 times and 3.7 times, respectively, to the human exposure at the usual dose of 1 g every 8 hours). - There was no reproductive toxicity seen. # Clinical Studies ### Complicated Skin and Skin Structure Infections Adult patients with complicated skin and skin structure infections including complicated cellulitis, complex abscesses, perirectal abscesses, and skin infections requiring intravenous antimicrobials, hospitalization, and surgical intervention were enrolled in a randomized, multi-center, international, double-blind trial. The study evaluated meropenem at doses of 500 mg administered intravenously every 8 hours and imipenem-cilastatin at doses of 500 mg administered intravenously every 8 hours. The study compared the clinical response between treatment groups in the clinically evaluable population at the follow-up visit (test-of-cure). The trial was conducted in the United States, South Africa, Canada, and Brazil. At enrollment, approximately 37% of the patients had underlying diabetes, 12% had underlying peripheral vascular disease and 67% had a surgical intervention. The study included 510 patients randomized to meropenem and 527 patients randomized to imipenem-cilastatin. Two hundred and sixty-one (261) patients randomized to meropenem and 287 patients randomized to imipenem-cilastatin were clinically evaluable. The success rates in the clinically evaluable patients at the follow-up visit were 86% (225/261) in the meropenem arm and 83% (238/287) in imipenem-cilastatin arm. The following table provides the results for the overall as well as subgroup comparisons in clinically evaluable population. The following clinical efficacy rates were obtained, per organism. The values represent the number of patients clinically cured/number of clinically evaluable patients at the post-treatment follow-up visit, with the percent cure in parentheses (Fully Evaluable analysis set). The proportion of patients who discontinued study treatment due to an adverse event was similar for both treatment groups (meropenem, 2.5% and imipenem-cilastatin, 2.7%). ### Complicated Intra-Abdominal Infections One controlled clinical study of complicated intra-abdominal infection was performed in the United States where meropenem was compared with clindamycin/tobramycin. Three controlled clinical studies of complicated intra-abdominal infections were performed in Europe; meropenem was compared with imipenem (two trials) and cefotaxime/metronidazole (one trial). Using strict evaluability criteria and microbiologic eradication and clinical cures at follow-up which occurred 7 or more days after completion of therapy, the following presumptive microbiologic eradication/clinical cure rates and statistical findings were obtained: The finding that meropenem was not statistically equivalent to cefotaxime/metronidazole may have been due to uneven assignment of more seriously ill patients to the meropenem arm. Currently there is no additional information available to further interpret this observation. ### Bacterial Meningitis Four hundred forty-six patients (397 pediatric patients ≥ 3 months to < 17 years of age) were enrolled in 4 separate clinical trials and randomized to treatment with meropenem (n = 225) at a dose of 40 mg/kg every 8 hours or a comparator drug, i.e., cefotaxime (n = 187) or ceftriaxone (n = 34), at the approved dosing regimens. A comparable number of patients were found to be clinically evaluable (ranging from 61-68%) and with a similar distribution of pathogens isolated on initial CSF culture. Patients were defined as clinically not cured if any one of the following three criteria were met: At the 5-7 week post-completion of therapy visit, the patient had any one of the following: moderate to severe motor, behavior or development deficits, hearing loss of > 60 decibels in one or both ears, or blindness. During therapy the patient’s clinical status necessitated the addition of other antibiotics. Either during or post-therapy, the patient developed a large subdural effusion needing surgical drainage, or a cerebral abscess, or a bacteriologic relapse. Using the definition, the following efficacy rates were obtained, per organism. The values represent the number of patients clinically cured/number of clinically evaluable patients, with the percent cure in parentheses. Sequelae were the most common reason patients were assessed as clinically not cured. Five patients were found to be bacteriologically not cured, 3 in the comparator group (1 relapse and 2 patients with cerebral abscesses) and 2 in the meropenem group (1 relapse and 1 with continued growth of Pseudomonas aeruginosa). The adverse events seen were comparable between the two treatment groups both in type and frequency. The meropenem group did have a statistically higher number of patients with transient elevation of liver enzymes. Rates of seizure activity during therapy were comparable between patients with no CNS abnormalities who received meropenem and those who received comparator agents. In the Meropenem for injection (I.V.) treated group, 12/15 patients with seizures had late onset seizures (defined as occurring on day 3 or later) versus 7/20 in the comparator arm. With respect to hearing loss, 263 of the 271 evaluable patients had at least one hearing test performed post-therapy. The following table shows the degree of hearing loss between the meropenem-treated patients and the comparator-treated patients. # How Supplied - Meropenem for Injection, USP (I.V.) is supplied in 20 mL and 30 mL injection vials containing sufficient meropenem to deliver 500 mg or 1 g for intravenous administration, respectively. ## Storage - The dry powder should be stored at controlled room temperature 20-25ºC (68-77ºF) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be counseled that antibacterial drugs including Meropenem for injection (I.V.) should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Meropenem for injection (I.V.) is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. - Skipping doses or not completing the full course of therapy may - (1) Decrease the effectiveness of the immediate treatment and - (2) Increase the likelihood that bacteria will develop resistance and will not be treatable by Meropenem for injection (I.V.) or other antibacterial drugs in the future. - Patients should be counseled that diarrhea is a common problem caused by ntibiotics which usually ends when the antibiotic is discontinued. - Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible - Patients should be counseled to inform their physician if they are taking valproic acid or divalproex sodium. Valproic acid concentrations in the blood may drop below the therapeutic range upon co-administration with Meropenem for injection (I.V.). - If treatment with Meropenem for injection (I.V.) is necessary and continued, alternative or supplemental anti-convulsant medication to prevent and/or treat seizures may be needed. - Patients receiving Meropenem for injection (I.V.) on an outpatient basis may develop adverse events such as seizures, headaches and/or paresthesias that could interfere with mental alertness and/or cause motor impairment. Until it is reasonably well established that Meropenem for injection (I.V.) is well tolerated, patients should not operate machinery or motorized vehicles. # Precautions with Alcohol Alcohol-Meropenem interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Merrem IV [5] # Look-Alike Drug Names There is limited information regarding Meropenem Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Meropenem
5d0949ef69ea37283180c0dec791510af9203c3e	wikidoc	Mesentery	Mesentery # Overview Mesentery is, in anatomy, the double layer of peritoneum that connects a part of the small intestine to the posterior wall of the abdomen. Its meaning, however, is frequently extended to include double layers of peritoneum connecting various components of the abdominal cavity. # Mesentery (proper) The mesentery proper (i.e. the original definition) refers to the peritoneum responsible for connecting the jejunum and ileum, parts of the small intestine, to the back wall of the abdomen. Between the two sheets of peritoneum are blood vessels, lymph vessels, and nerves. This allows these parts of the small intestine to move relatively freely within the abdominal cavity. The brain, however, cannot map sensation accurately, so sensation is usually referred to the midline, an example of referred pain. # Development The mesentery is derived from what is known in the embryo as the dorsal mesentery. The dorsal mesentery is larger than the ventral mesentery, which gradually becomes other parts of the peritoneum. Most parts of the ventral mesentery are associated with the liver. # Mesentery (general) Mesenteries are composed of two layers of peritoneum. The peritoneum that lies on the walls of the abdominopelvic cavity (parietal peritoneum) invaginates at certain parts, with an organ inside this invagination. This invaginated peritoneum (visceral peritoneum) will often surround all but a part of the organ ("bare area"), through which the organ transmits blood vessels and nerves. If this organ is invaginated far enough into the peritoneum, the visceral peritoneum will come in contact with itself, forming the organ's mesentery. Mesenteries in the body: - Mesentery (proper) - surrounds parts of the small intestine (the jejunum and the ileum) - Mesocolon - surrounds parts of the colon Meso-appendix - peritoneum of the vermiform appendix Transverse mesocolon - peritoneum of the transverse colon Sigmoid mesocolon - peritoneum of the sigmoid colon - Meso-appendix - peritoneum of the vermiform appendix - Transverse mesocolon - peritoneum of the transverse colon - Sigmoid mesocolon - peritoneum of the sigmoid colon - Broad ligament of the uterus - peritoneum of the uterus, uterine tubes, and ovaries The fetal pig is a good reference for this subject # Invertebrate anatomy In invertebrate animals, the term mesentery is used for any tissue that divides the body cavity (coelom) into partitions. # Additional images - Figure obtained by combining several successive sections of a human embryo of about the fourth week. - Abdominal part of digestive tube and its attachment to the primitive or common mesentery. Human embryo of six weeks.	Mesentery # Overview Template:Infobox Anatomy Mesentery is, in anatomy, the double layer of peritoneum that connects a part of the small intestine to the posterior wall of the abdomen. Its meaning, however, is frequently extended to include double layers of peritoneum connecting various components of the abdominal cavity. # Mesentery (proper) The mesentery proper (i.e. the original definition) refers to the peritoneum responsible for connecting the jejunum and ileum, parts of the small intestine, to the back wall of the abdomen. Between the two sheets of peritoneum are blood vessels, lymph vessels, and nerves. This allows these parts of the small intestine to move relatively freely within the abdominal cavity. The brain, however, cannot map sensation accurately, so sensation is usually referred to the midline, an example of referred pain. # Development The mesentery is derived from what is known in the embryo as the dorsal mesentery. The dorsal mesentery is larger than the ventral mesentery, which gradually becomes other parts of the peritoneum. Most parts of the ventral mesentery are associated with the liver. # Mesentery (general) Mesenteries are composed of two layers of peritoneum. The peritoneum that lies on the walls of the abdominopelvic cavity (parietal peritoneum) invaginates at certain parts, with an organ inside this invagination. This invaginated peritoneum (visceral peritoneum) will often surround all but a part of the organ ("bare area"), through which the organ transmits blood vessels and nerves. If this organ is invaginated far enough into the peritoneum, the visceral peritoneum will come in contact with itself, forming the organ's mesentery. Mesenteries in the body: - Mesentery (proper) - surrounds parts of the small intestine (the jejunum and the ileum) - Mesocolon - surrounds parts of the colon Meso-appendix - peritoneum of the vermiform appendix Transverse mesocolon - peritoneum of the transverse colon Sigmoid mesocolon - peritoneum of the sigmoid colon - Meso-appendix - peritoneum of the vermiform appendix - Transverse mesocolon - peritoneum of the transverse colon - Sigmoid mesocolon - peritoneum of the sigmoid colon - Broad ligament of the uterus - peritoneum of the uterus, uterine tubes, and ovaries The fetal pig is a good reference for this subject # Invertebrate anatomy In invertebrate animals, the term mesentery is used for any tissue that divides the body cavity (coelom) into partitions. # Additional images - Figure obtained by combining several successive sections of a human embryo of about the fourth week. - Abdominal part of digestive tube and its attachment to the primitive or common mesentery. Human embryo of six weeks. # External links - Template:SUNYAnatomyLabs - Template:NormanAnatomy - McGill - Template:GPNotebook Template:Peritoneum Template:Development of digestive system ca:Transcavitat dels epiplons de:Gekröse it:Mesentere Template:WH Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Mesenteric
013973d9f2167c848825673b8849ac0209869db7	wikidoc	Metalloid	Metalloid Metalloid is a term used in chemistry when classifying the chemical elements. On the basis of their general physical and chemical properties, nearly every element in the periodic table can be termed either a metal or a nonmetal - however a few elements with intermediate properties are referred to as metalloids. (In Greek metallon = metal and eidos = sort) There is no rigorous definition of the term, however the following properties are usually considered characteristic of metalloids: - metalloids often form amphoteric oxides. - metalloids often behave as semiconductors (B,Si,Ge) to semimetals (eg. Sb). The concepts of metalloid and semiconductor should not be confused. Metalloid refers to the properties of certain elements in relation to the periodic table. Semiconductor refers to the physical properties of materials (including alloys, compounds) and there is only partial overlap between the two. The following elements are generally considered metalloids: - Boron (B) - Silicon (Si) - Germanium (Ge) - Arsenic (As) - Antimony (Sb) - Tellurium (Te) - Polonium (Po) Some allotropes of elements exhibit more pronounced metal, metalloid or non-metal behavior than others. For example, for the element carbon, its diamond allotrope is clearly non-metallic, however the graphite allotrope displays limited electric conductivity more characteristic of a metalloid. Phosphorus, tin, selenium and bismuth also have allotropes which display borderline behavior. In the standard layout of the periodic table, metalloids occur along the diagonal line through the p block from boron to astatine. Elements to the upper right of this line display increasing nonmetallic behaviour; elements to the lower left display increasing metallic behaviour. This line is called the "stair-step" or "staircase." The poor metals are to the left and down and the nonmetals are to the right and up. In addition, the halogens are found at the right.	Metalloid Metalloid is a term used in chemistry when classifying the chemical elements. On the basis of their general physical and chemical properties, nearly every element in the periodic table can be termed either a metal or a nonmetal - however a few elements with intermediate properties are referred to as metalloids. (In Greek metallon = metal and eidos = sort) There is no rigorous definition of the term, however the following properties are usually considered characteristic of metalloids: - metalloids often form amphoteric oxides. - metalloids often behave as semiconductors (B,Si,Ge) to semimetals (eg. Sb). The concepts of metalloid and semiconductor should not be confused. Metalloid refers to the properties of certain elements in relation to the periodic table. Semiconductor refers to the physical properties of materials (including alloys, compounds) and there is only partial overlap between the two. The following elements are generally considered metalloids:[1] - Boron (B) - Silicon (Si) - Germanium (Ge) - Arsenic (As) - Antimony (Sb) - Tellurium (Te) - Polonium (Po) Some allotropes of elements exhibit more pronounced metal, metalloid or non-metal behavior than others. For example, for the element carbon, its diamond allotrope is clearly non-metallic, however the graphite allotrope displays limited electric conductivity more characteristic of a metalloid. Phosphorus, tin, selenium and bismuth also have allotropes which display borderline behavior. In the standard layout of the periodic table, metalloids occur along the diagonal line through the p block from boron to astatine. Elements to the upper right of this line display increasing nonmetallic behaviour; elements to the lower left display increasing metallic behaviour. This line is called the "stair-step" or "staircase." The poor metals are to the left and down and the nonmetals are to the right and up. In addition, the halogens are found at the right.	https://www.wikidoc.org/index.php/Metalloid
8e4784a898b609f5cb89c7f69095e12120e300c8	wikidoc	Methoxide	Methoxide Methoxide is an organic salt, and the simplest alkoxide. In Organic chemistry, the methoxide ion has a formula of CH3O- and is the conjugate base of methanol. Sodium methoxide, also referred to as Sodium methylate, is a white powder when pure. It is used as an initiator of an anionic addition polymerization with ethylene oxide, forming a polyether with high molecular weight. The main application of sodium methoxide today is in the production of biodiesel. In this process, vegetable oils or animal fats, which chemically are fatty acid triglycerides, are transesterified with methanol to give fatty acid methyl esters (FAMEs). Sodium methoxide is produced on an industrial scale and available from a number of chemical companies. The major suppliers today are BASF, Degussa, and Interstate Chemical Company. Sodium methoxide in methanol is a liquid that kills human nerve cells before any pain can be felt. In the event of contact with methoxide, rinse the contacted area with water, seek medical attention immediately. Making sodium methoxide is dangerous, involving H2 and lots of heat. In addition, the resultant chemical is highly toxic. For this reason, the safety of the design of equipment and workspace should be carefully considered before use, and protective clothing and a respirator should be worn during handling. Only as much as is intended to be used immediately should be created. it:Metossido	Methoxide Methoxide is an organic salt, and the simplest alkoxide. In Organic chemistry, the methoxide ion has a formula of CH3O- and is the conjugate base of methanol. Sodium methoxide, also referred to as Sodium methylate, is a white powder when pure. It is used as an initiator of an anionic addition polymerization with ethylene oxide, forming a polyether with high molecular weight. The main application[citation needed] of sodium methoxide today is in the production of biodiesel. In this process, vegetable oils or animal fats, which chemically are fatty acid triglycerides, are transesterified with methanol to give fatty acid methyl esters (FAMEs). Sodium methoxide is produced on an industrial scale and available from a number of chemical companies. The major suppliers today are BASF, Degussa, and Interstate Chemical Company. Sodium methoxide in methanol is a liquid that kills human nerve cells before any pain can be felt. In the event of contact with methoxide, rinse the contacted area with water, seek medical attention immediately. Making sodium methoxide is dangerous, involving H2 and lots of heat. In addition, the resultant chemical is highly toxic. For this reason, the safety of the design of equipment and workspace should be carefully considered before use, and protective clothing and a respirator should be worn during handling. Only as much as is intended to be used immediately should be created. it:Metossido Template:WH Template:WS	https://www.wikidoc.org/index.php/Methoxide
7bfc5bcbcd9fe624616ed599ffc0005044ba31cd	wikidoc	Parathion	Parathion Parathion, or diethyl parathion, is an organophosphate compound. Like many other organophosphate insecticides, it is a very potent insecticide and acaricide. It was originally developed by IG Farben in the 1940s. It is highly toxic to non-target organisms. Its use is banned or restricted in many countries, and there are proposals to ban it from all use. # History Parathion was developed by the German trust IG Farben in the 1940s. Dr. Gerhard Schrader was the inventor. After the war the Western allies seized the according patent and Parathion was thereafter marketed worldwide by different companies and under different brand names. The most common German brand was E605 (banned in Germany after 2002); this was not an E number (not a food additive). "E" stands for Entwicklungsnummer (German for "development number"), not for "European". # Properties In its purest form, parathion consists of white crystals; however more commonly distributed forms take the form of a brown liquid which smells of rotting eggs or garlic. The insecticide is more or less stable, though it darkens when exposed to sunlight. # Applications As a pesticide, parathion is generally applied by spraying, and often used on cotton, rice and fruit trees. The usual concentrations of ready-to-use solutions are 0.05 to 0.1%. The chemical is banned for use on many food crops. # Safety Parathion is a cholinesterase inhibitor. It generally disrupts neural function by inhibiting the essential enzyme acetylcholinesterase. It is absorbed via skin, mucous membranes, and orally. Absorbed Parathion is rapidly metabolized to Paraoxon in which the sulfur atom is replaced by oxygen. Paraoxon exposure can result in headaches, convulsions, poor vision, vomiting, abdominal pain, severe diarrhea, unconsciousness, tremor, dyspnea and finally lung-edema as well as respiratory arrest. Symptoms of poisoning are known to last for extended periods of time, sometimes months. The most common and very specific antidote is atropine in doses of up to 100 mg daily. Because atropine may also be toxic, it is now recommended to use small doses which are frequently repeated. If human poisoning is detected early and the treatment is prompt (antidote and artificial respiration), fatalities are infrequent. Insufficient respiration may lead to cerebral hypoxia and permanent brain damage. Additionally, peripheral neuropathy including paralysis is noticed as late sequelae after recovery from acute intoxication. Parathion has been extensively used for committing suicide and deliberately killing other persons. For the latter reason most formulations contain a blue dye providing warning. Based on animal studies, Parathion is considered by the US EPA to be a possible human carcinogen. Studies show that Parathion is toxic to fetuses, but does not cause birth defects. Parathion is very toxic to bees, fish, birds, and other forms of wildlife. Parathion can be replaced by many safer and less toxic alternatives (less toxic organophosphates, carbamates, or synthetic pyrethroids). ## Protection against poisoning To assure human protection the end user must wear protective gloves, clean protective clothing, and a respirator of the organic-vapour type when handling this material. He/she should bathe immediately after work. Industrial safety during the production process requires special ventilation and continuous measurement of air contamination in order not to exceed PEL levels as well as keeping personal hygiene. Frequent determination of workers' serum acetylcholinesterase activity is also helpful in regards of occupational safety, because the action of Parathion is cumulative. If an area of the body is contaminated with parathion, if possible, it should be removed immediately. Also, atropine may be used as a specific antidote. # Proposals to ban According to the non-governmental organisation Pesticide Action Network, parathion is one of the most dangerous pesticides. This organization lists used. PAN lists Parathion also as 'bad actor chemical'. In the US alone more than 650 agricultural workers have been poisoned since 1966, of which 100 died. In underdeveloped countries many more people have suffered fatal and nonfatal intoxications. The World Health Organization, PAN and numerous environmental organisations propose a general and global ban. Its use is banned or restricted in 23 countries and its import is illegal in a total of 50 countries.	Parathion Template:Chembox new Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Parathion, or diethyl parathion, is an organophosphate compound. Like many other organophosphate insecticides, it is a very potent insecticide and acaricide. It was originally developed by IG Farben in the 1940s. It is highly toxic to non-target organisms. Its use is banned or restricted in many countries, and there are proposals to ban it from all use. # History Parathion was developed by the German trust IG Farben in the 1940s. Dr. Gerhard Schrader was the inventor. After the war the Western allies seized the according patent and Parathion was thereafter marketed worldwide by different companies and under different brand names. The most common German brand was E605 (banned in Germany after 2002); this was not an E number (not a food additive). "E" stands for Entwicklungsnummer (German for "development number"), not for "European". # Properties In its purest form, parathion consists of white crystals; however more commonly distributed forms take the form of a brown liquid which smells of rotting eggs or garlic. The insecticide is more or less stable, though it darkens when exposed to sunlight. # Applications As a pesticide, parathion is generally applied by spraying, and often used on cotton, rice and fruit trees. The usual concentrations of ready-to-use solutions are 0.05 to 0.1%. The chemical is banned for use on many food crops.[citation needed] # Safety Parathion is a cholinesterase inhibitor. It generally disrupts neural function by inhibiting the essential enzyme acetylcholinesterase. It is absorbed via skin, mucous membranes, and orally. Absorbed Parathion is rapidly metabolized to Paraoxon in which the sulfur atom is replaced by oxygen. Paraoxon exposure can result in headaches, convulsions, poor vision, vomiting, abdominal pain, severe diarrhea, unconsciousness, tremor, dyspnea and finally lung-edema as well as respiratory arrest.[citation needed] Symptoms of poisoning are known to last for extended periods of time, sometimes months. The most common and very specific antidote is atropine in doses of up to 100 mg daily. Because atropine may also be toxic, it is now recommended to use small doses which are frequently repeated. If human poisoning is detected early and the treatment is prompt (antidote and artificial respiration), fatalities are infrequent. Insufficient respiration may lead to cerebral hypoxia and permanent brain damage. Additionally, peripheral neuropathy including paralysis is noticed as late sequelae after recovery from acute intoxication.[citation needed] Parathion has been extensively used for committing suicide and deliberately killing other persons.[citation needed] For the latter reason most formulations contain a blue dye providing warning. Based on animal studies, Parathion is considered by the US EPA to be a possible human carcinogen.[1] Studies show that Parathion is toxic to fetuses, but does not cause birth defects.[2] Parathion is very toxic to bees, fish, birds, and other forms of wildlife.[2] Parathion can be replaced by many safer and less toxic alternatives (less toxic organophosphates, carbamates, or synthetic pyrethroids).[citation needed] ## Protection against poisoning To assure human protection the end user must wear protective gloves, clean protective clothing, and a respirator of the organic-vapour type when handling this material. He/she should bathe immediately after work. Industrial safety during the production process requires special ventilation and continuous measurement of air contamination in order not to exceed PEL levels as well as keeping personal hygiene. Frequent determination of workers' serum acetylcholinesterase activity is also helpful in regards of occupational safety, because the action of Parathion is cumulative. If an area of the body is contaminated with parathion, if possible, it should be removed immediately. Also, atropine may be used as a specific antidote.[citation needed] # Proposals to ban According to the non-governmental organisation Pesticide Action Network, parathion is one of the most dangerous pesticides. This organization lists used. PAN lists Parathion also as 'bad actor chemical'.[3] In the US alone more than 650 agricultural workers have been poisoned since 1966, of which 100 died.[citation needed] In underdeveloped countries many more people have suffered fatal and nonfatal intoxications. The World Health Organization, PAN and numerous environmental organisations propose a general and global ban.[citation needed] Its use is banned or restricted in 23 countries and its import is illegal in a total of 50 countries.[3]	https://www.wikidoc.org/index.php/Methyl_parathion
63cc54be3321070132a92776035c9eb24162d77f	wikidoc	Metiamide	Metiamide Metiamide is an H2-receptor antagonist developed from another H2 antagonist, burimamide. It was an intermediate compound in the development of the successful anti-ulcer drug cimetidine (Tagamet®). # Development of metiamide from burimamide After discovering that burimamide is largely inactive at physiological pH, due to the presence of its electron donating side chain, the following steps were undertaken to stabilse burimamide: - addition of a sulfide group close to the imidazole ring, giving thiaburimamide - addition of methyl group to the 4- position on the imidazole ring to favour the tautomer of thiaburimamide which binds better to the H2-receptor Metiamide - is 10 times more potent than burimamide - inhibited histamine-stimulated release of gastric acid - increased healing rate of peptic ulcers - provided symptomatic relief for ulcerous patients. However, - in clinical trials, an unacceptable number of patients dosed with metiamide developed agranulocytosis (decreased white blood cell count) - clinical trials aborted, as patients were left susceptible to infection # Modification of metiamide to cimetidine It was determined that the thiourea group was the cause of the agranulocytosis. Therefore replacement of the =S in the thiourea group was suggested: - with =O or =NH resulted in a compound with much less activity (20 times less than metiamide) - however, the NH form (the guanidine analogue of metiamide) did not show agonistic effects - to prevent the guanidine group being protonated at physiological pH, electron-withdrawing groups were added - adding a -C≡N or -NO2 group prevented the guanidine group being protonated and did not cause agranulocytosis The nitro and cyano groups are sufficiently electronegative to reduce the pKa of the neighbouring nitrogens to the same acidity of the thiourea group, hence preserving the activity of the drug in a physiological environment. - the -C≡N group (part of a cyanoguanidine moiety) was a little more effective - it was developed and marketed as cimetidine,	Metiamide Template:Chembox new Metiamide is an H2-receptor antagonist developed from another H2 antagonist, burimamide. It was an intermediate compound in the development of the successful anti-ulcer drug cimetidine (Tagamet®). # Development of metiamide from burimamide After discovering that burimamide is largely inactive at physiological pH, due to the presence of its electron donating side chain, the following steps were undertaken to stabilse burimamide: - addition of a sulfide group close to the imidazole ring, giving thiaburimamide - addition of methyl group to the 4- position on the imidazole ring to favour the tautomer of thiaburimamide which binds better to the H2-receptor Metiamide - is 10 times more potent than burimamide - inhibited histamine-stimulated release of gastric acid - increased healing rate of peptic ulcers - provided symptomatic relief for ulcerous patients. However, - in clinical trials, an unacceptable number of patients dosed with metiamide developed agranulocytosis (decreased white blood cell count) - clinical trials aborted, as patients were left susceptible to infection # Modification of metiamide to cimetidine It was determined that the thiourea group was the cause of the agranulocytosis. Therefore replacement of the =S in the thiourea group was suggested: - with =O or =NH resulted in a compound with much less activity (20 times less than metiamide) - however, the NH form (the guanidine analogue of metiamide) did not show agonistic effects - to prevent the guanidine group being protonated at physiological pH, electron-withdrawing groups were added - adding a -C≡N or -NO2 group prevented the guanidine group being protonated and did not cause agranulocytosis The nitro and cyano groups are sufficiently electronegative to reduce the pKa of the neighbouring nitrogens to the same acidity of the thiourea group, hence preserving the activity of the drug in a physiological environment. - the -C≡N group (part of a cyanoguanidine moiety) was a little more effective - it was developed and marketed as cimetidine,	https://www.wikidoc.org/index.php/Metiamide
02690b5b448b7a77bde5663005577e49245cb233	wikidoc	Mianserin	Mianserin Mianserin (brand names: Depnon (IN), Lantanon (ZA), Lerivon (AR, BE, CZ, PL, RU, SK), Lumin (AU), Norval (UK), Tolvon (AU, HK†, IE†, NZ, SG†), Tolmin (DK); where † indicates discontinued products) is a psychoactive drug of the tetracyclic antidepressant (TeCA) therapeutic family. It is classified as a noradrenergic and specific serotonergic antidepressant (NaSSA) and has antidepressant, anxiolytic (anti-anxiety), hypnotic (sedating), antiemetic (nausea and vomiting-attenuating), orexigenic (appetite-stimulating), and antihistamine effects. It is not approved for use in the US, but its analogue, mirtazapine, is. Mianserin was the first antidepressant to reach the UK market that was less dangerous than the tricyclic antidepressants in overdose. # Medical uses When used for the treatment of depression, its efficacy appears comparable to that of amitriptyline, citalopram, clomipramine, dothiepin, doxepin, fluoxetine, flupenthixol, fluvoxamine, imipramine, moclobemide, nortriptyline, paroxetine, and trazodone. Mianserin received TGA approval in May 1996. Similarly to its analogue, mirtazapine, mianserin has been tried as an augmentation strategy in treatment-resistant depression with some success. Mianserin has been tried, similarly to mirtazapine, as an adjunct in schizophrenia and has been found to reduce negative and cognitive symptoms. Mianserin has demonstrated efficacy as a monotherapy for the treatment of Parkinson's disease psychosis in an open-label clinical trial. # Adverse effects ## Side effects Information sources: - Constipation - Dry mouth - Somnolence/drowsiness (transiently at the beginning of therapy) - Somnolence/drowsiness (during maintenance therapy, that is, in some patients this side effect persists) - Tremor - Headache - Dizziness - Vertigo - Dry mouth - Weakness - Weight gain — likely related to its potent antihistamine and 5-HT2C receptor-antagonist effects. - Oedema — the swelling of the body's tissues due to fluid draining into said tissues. - Arthralgia (joint pain) - Arthritis - Rash - Akathisia — a sense of inner restlessness that is often distressing for patients. - Orthostatic hypotension — the dropping of blood pressure upon standing up leading to light-headedness, dizziness and even fainting - Hypomania — an excessively elated/irritable mood that can be dangerous. - Bradycardia — low heart rate. - Disturbances of liver function (including jaundice) — the Australian Medicines Handbook recommends that patients with a history of liver disease undergo regular liver function tests and that treatment is ceased at the first sign of jaundice. - Exanthema - Seizures - Blood dyscrasias (particularly neutropaenia — a drop in the neutrophils which are part of the body's immune system that is particularly tailored to destroying bacteria — and agranulocytosis — a potentially life-threatening drop in the white blood cells of the immune system leaving the patient open to potentially fatal infections.) — for this reason in the Australian Medicines Handbook 2013 and the British National Formulary 65 it is recommended that the prescribing physician checks the patient's complete blood counts (CBCs) at the initiation of treatment and then every four weeks until 3 months have passed. Some cases of mianserin-induced blood dyscrasias have been fatal. - Neuroleptic malignant syndrome — an often life-threatening drug reaction that is characterised by: - Restless legs - Cardiac arrest - Cardiac failure - Nasal congestion - Paraesthesia - Vision abnormality - Diplopia — seeing double. - Gynaecomastia — abnormal breast enlargement in males. - Impotence - Myalgia — muscle aches. - Pruritus — itchiness - Hypertension - Tachycardia - Tinnitus — hearing ringing in the ears in the absence of an actual sound. - Confusion - Agitation ## Interactions CYP2D6 inhibitors such as the selective serotonin reuptake inhibitors (SSRIs), quinidine, ritonavir, etc. would likely raise plasma levels of mianserin and hence could lead to mianserin toxicity. Conversely, CYP2D6 inducers would likely lead to reduced mianserin plasma concentrations and hence potentially diminish the therapeutic effects of mianserin. ## Withdrawal Abrupt or rapid discontinuation of mianserin may provoke a withdrawal, the effects of which may include depression, anxiety, panic attacks, decreased appetite or anorexia, insomnia, diarrhea, nausea and vomiting, and flu-like symptoms, such as allergies or pruritus, among others. ## Overdose Overdose of mianserin is known to produce the following symptoms: - Sedation - Coma - Hypotension - Hypertension - Tachycardia - QT interval prolongation and is relatively safe in overdose similarly to its successor mirtazapine. # Pharmacology Mianserin is an antagonist/inverse agonist of the H1, 5-HT1D, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT6, 5-HT7, α1-adrenergic, and α2-adrenergic receptors, and also inhibits the reuptake of norepinephrine. As a high affinity H1 receptor inverse agonist, mianserin has strong antihistamine effects (sedation, weight gain, etc.). Contrarily, it has negligible affinity for the mACh receptors, and thus lacks anticholinergic properties. It was recently found to be a weak (Ki = 1.7 μM, EC50 = 0.53 μM) κ-opioid receptor partial agonist. In addition, mianserin also appears to be a potent antagonist of the neuronal octopamine receptor. What implications this may have on mood are currently unknown, however octopamine has been implicated in the regulation of sleep, appetite and insulin production and therefore may theoretically contribute to the overall side effect profile of mianserin. Blockade of the H1 and α1-adrenergic receptors has sedative effects, and also antagonism of the 5-HT2A and α1-adrenergic receptors inhibits activation of intracellular phospholipase C (PLC), which seems to be a common target for several different classes of antidepressants. By antagonizing the somatodendritic and presynaptic α2-adrenergic receptors which function predominantly as inhibitory autoreceptors and heteroreceptors, mianserin disinhibits the release of norepinephrine, dopamine, serotonin, and acetylcholine in various areas of the brain and body. ## Enantioselectivity (S)-(+)-Mianserin is approximately 200–300 times more active than its antipode (R)-(−)-mianserin. ## Binding profile	Mianserin Mianserin (brand names: Depnon (IN), Lantanon (ZA), Lerivon (AR, BE, CZ, PL, RU, SK), Lumin (AU), Norval (UK), Tolvon (AU, HK†, IE†, NZ, SG†), Tolmin (DK); where † indicates discontinued products) is a psychoactive drug of the tetracyclic antidepressant (TeCA) therapeutic family. It is classified as a noradrenergic and specific serotonergic antidepressant (NaSSA) and has antidepressant, anxiolytic (anti-anxiety), hypnotic (sedating), antiemetic (nausea and vomiting-attenuating), orexigenic (appetite-stimulating), and antihistamine effects. It is not approved for use in the US, but its analogue, mirtazapine, is. Mianserin was the first antidepressant to reach the UK market that was less dangerous than the tricyclic antidepressants in overdose.[3] # Medical uses When used for the treatment of depression, its efficacy appears comparable to that of amitriptyline, citalopram, clomipramine, dothiepin, doxepin, fluoxetine, flupenthixol, fluvoxamine, imipramine, moclobemide, nortriptyline, paroxetine, and trazodone.[1][4] Mianserin received TGA approval in May 1996.[5] Similarly to its analogue, mirtazapine, mianserin has been tried as an augmentation strategy in treatment-resistant depression with some success.[6] Mianserin has been tried, similarly to mirtazapine, as an adjunct in schizophrenia and has been found to reduce negative and cognitive symptoms.[7][8][9] Mianserin has demonstrated efficacy as a monotherapy for the treatment of Parkinson's disease psychosis in an open-label clinical trial.[10] # Adverse effects ## Side effects Information sources:[1][2][5][11][12] - Constipation - Dry mouth - Somnolence/drowsiness (transiently at the beginning of therapy) - Somnolence/drowsiness (during maintenance therapy, that is, in some patients this side effect persists) - Tremor - Headache - Dizziness - Vertigo - Dry mouth - Weakness - Weight gain — likely related to its potent antihistamine and 5-HT2C receptor-antagonist effects. - Oedema — the swelling of the body's tissues due to fluid draining into said tissues. - Arthralgia (joint pain) - Arthritis - Rash - Akathisia — a sense of inner restlessness that is often distressing for patients. - Orthostatic hypotension — the dropping of blood pressure upon standing up leading to light-headedness, dizziness and even fainting - Hypomania — an excessively elated/irritable mood that can be dangerous. - Bradycardia — low heart rate. - Disturbances of liver function (including jaundice) — the Australian Medicines Handbook recommends that patients with a history of liver disease undergo regular liver function tests and that treatment is ceased at the first sign of jaundice. - Exanthema - Seizures - Blood dyscrasias (particularly neutropaenia — a drop in the neutrophils which are part of the body's immune system that is particularly tailored to destroying bacteria — and agranulocytosis — a potentially life-threatening drop in the white blood cells of the immune system leaving the patient open to potentially fatal infections.) — for this reason in the Australian Medicines Handbook 2013 and the British National Formulary 65 it is recommended that the prescribing physician checks the patient's complete blood counts (CBCs) at the initiation of treatment and then every four weeks until 3 months have passed.[11][12] Some cases of mianserin-induced blood dyscrasias have been fatal.[13] - Neuroleptic malignant syndrome — an often life-threatening drug reaction that is characterised by: - Restless legs - Cardiac arrest - Cardiac failure - Nasal congestion - Paraesthesia - Vision abnormality - Diplopia — seeing double. - Gynaecomastia — abnormal breast enlargement in males. - Impotence - Myalgia — muscle aches. - Pruritus — itchiness - Hypertension - Tachycardia - Tinnitus — hearing ringing in the ears in the absence of an actual sound. - Confusion - Agitation ## Interactions CYP2D6 inhibitors such as the selective serotonin reuptake inhibitors (SSRIs), quinidine, ritonavir, etc. would likely raise plasma levels of mianserin and hence could lead to mianserin toxicity. Conversely, CYP2D6 inducers would likely lead to reduced mianserin plasma concentrations and hence potentially diminish the therapeutic effects of mianserin.[1] ## Withdrawal Abrupt or rapid discontinuation of mianserin may provoke a withdrawal, the effects of which may include depression, anxiety, panic attacks,[14] decreased appetite or anorexia, insomnia, diarrhea, nausea and vomiting, and flu-like symptoms, such as allergies or pruritus, among others. ## Overdose Overdose of mianserin is known to produce the following symptoms:[15] - Sedation - Coma - Hypotension - Hypertension - Tachycardia - QT interval prolongation and is relatively safe in overdose similarly to its successor mirtazapine.[15] # Pharmacology Mianserin is an antagonist/inverse agonist of the H1, 5-HT1D, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT6, 5-HT7, α1-adrenergic, and α2-adrenergic receptors, and also inhibits the reuptake of norepinephrine.[16][17] As a high affinity H1 receptor inverse agonist, mianserin has strong antihistamine effects (sedation, weight gain, etc.). Contrarily, it has negligible affinity for the mACh receptors, and thus lacks anticholinergic properties. It was recently found to be a weak (Ki = 1.7 μM, EC50 = 0.53 μM) κ-opioid receptor partial agonist.[18] In addition, mianserin also appears to be a potent antagonist of the neuronal octopamine receptor.[19] What implications this may have on mood are currently unknown, however octopamine has been implicated in the regulation of sleep, appetite and insulin production and therefore may theoretically contribute to the overall side effect profile of mianserin.[20][21] Blockade of the H1 and α1-adrenergic receptors has sedative effects,[2] and also antagonism of the 5-HT2A and α1-adrenergic receptors inhibits activation of intracellular phospholipase C (PLC), which seems to be a common target for several different classes of antidepressants.[22] By antagonizing the somatodendritic and presynaptic α2-adrenergic receptors which function predominantly as inhibitory autoreceptors and heteroreceptors, mianserin disinhibits the release of norepinephrine, dopamine, serotonin, and acetylcholine in various areas of the brain and body. ## Enantioselectivity (S)-(+)-Mianserin is approximately 200–300 times more active than its antipode (R)-(−)-mianserin.[citation needed] ## Binding profile	https://www.wikidoc.org/index.php/Mianserin
38a7638e07f9ef966ebb2a8d71a575028f0f39f4	wikidoc	Microglia	Microglia Microglia are a type of glial cell that act as the immune cells of the Central nervous system (CNS). Microglia, the smallest of the glial cells, can act as phagocytes, cleaning up CNS debris. Most serve as representatives of the immune system in the brain and spinal cord. Microglia are close cousins of other phagocytic cells including macrophages and dendritic cells. Microglia are thought to be highly mobile cells that play numerous important roles in protecting the nervous system. # Origin Microglia are derived from myeloid progenitor cells (as are macrophages and dendritic cells) which come from the bone marrow. During embryonic development, however, they migrate to the CNS to differentiate into microglia. ## Further development After phagocytosis of lipid droplets and other debris (usually from tissue necrosis), microglia are termed gitter cells. A gitter cell is globular and swollen and can also be called a compound granule cell or compound granular corpuscle. # Clinical significance Microglia are also thought to play a role in neurodegenerative disorders such as Alzheimer's disease, dementia, multiple sclerosis and Amyotrophic lateral sclerosis. They are responsible for producing an inflammatory reaction to brain trauma and are the main HIV-1 target cells in the central nervous system.. # History Babes described activation of microglia in a rabies case in 1897, but did not know what the clusters of microglia he saw were (Streit et al., 2004). Franz Nissl and F. Robertson first described microglial cells, and Pio del Rio-Hortega, a student of Santiago Ramón y Cajal, first called the cells "microglia" around 1920 . Cell staining techniques in the 1980s showed that microglia are related to macrophages.	Microglia Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Microglia are a type of glial cell that act as the immune cells of the Central nervous system (CNS). Microglia, the smallest of the glial cells, can act as phagocytes, cleaning up CNS debris. Most serve as representatives of the immune system in the brain and spinal cord. Microglia are close cousins of other phagocytic cells including macrophages and dendritic cells. Microglia are thought to be highly mobile cells that play numerous important roles in protecting the nervous system. # Origin Microglia are derived from myeloid progenitor cells (as are macrophages and dendritic cells) which come from the bone marrow. During embryonic development, however, they migrate to the CNS to differentiate into microglia. ## Further development After phagocytosis of lipid droplets and other debris (usually from tissue necrosis), microglia are termed gitter cells. A gitter cell is globular and swollen and can also be called a compound granule cell or compound granular corpuscle. # Clinical significance Microglia are also thought to play a role in neurodegenerative disorders such as Alzheimer's disease, dementia, multiple sclerosis and Amyotrophic lateral sclerosis. They are responsible for producing an inflammatory reaction to brain trauma [1] and are the main HIV-1 target cells in the central nervous system.[2]. # History Babes described activation of microglia in a rabies case in 1897, but did not know what the clusters of microglia he saw were (Streit et al., 2004). Franz Nissl and F. Robertson first described microglial cells, and Pio del Rio-Hortega, a student of Santiago Ramón y Cajal, first called the cells "microglia" around 1920 [2]. Cell staining techniques in the 1980s showed that microglia are related to macrophages.	https://www.wikidoc.org/index.php/Microglia
f79d9a222e91978edb67c9c9d056c4a752d356fc	wikidoc	Micropipe	Micropipe A micropipe is a defect in a single crystal substrate. Today this is of great interest to makers of silicon carbide (SiC) substrates which are used in a variety of industries such as power devices for vehicles and high frequency communication devices. However, during the production of these materials, the crystal undergoes internal and external stresses causing growth of defects, or dislocations, within the atomic lattice. A screw dislocation is a common dislocation that transforms successive atomic planes within a crystal lattice into the shape of a helix. Once a screw dislocation propagates through the bulk of a sample during the wafer growth process, a micropipe is formed. The presence of a high density of micropipes within a wafer will result in a loss of yield in the device manufacturing process. Micropipes and screw dislocations in epitaxial layers are normally derived from the substrates on which the epitaxy is performed. Micropipes are considered to be empty-core screw dislocations with large strain energy (i.e. they have large Burgers vector); they follow the growth direction (c-axis) in silicon carbide boules and substrates propagating into the deposited epitaxial layers. Factors which influence formation of micropipes (and other defects) are such growth parameters as temperature, supersaturation, vapor phase stoichiometry, impurities and the polarity of the seed surface. Many laboratories in universities and companies are striving to perfect the micropipe-free substrate. One of the pioneers of the commercialization of SiC materials and devices is Cree Inc. which in May 2007, announced that it had achieved 100-mm (4-inch), Zero-Micropipe, n-type SiC substrates. It is therefore possible to eliminate these defects in large-area wafers as well as smaller fragments and should open up the commercialization of this area of microelectronic devices.	Micropipe A micropipe is a defect in a single crystal substrate. Today this is of great interest to makers of silicon carbide (SiC) substrates which are used in a variety of industries such as power devices for vehicles and high frequency communication devices. However, during the production of these materials, the crystal undergoes internal and external stresses causing growth of defects, or dislocations, within the atomic lattice. A screw dislocation is a common dislocation that transforms successive atomic planes within a crystal lattice into the shape of a helix. Once a screw dislocation propagates through the bulk of a sample during the wafer growth process, a micropipe is formed. The presence of a high density of micropipes within a wafer will result in a loss of yield in the device manufacturing process. Micropipes and screw dislocations in epitaxial layers are normally derived from the substrates on which the epitaxy is performed. Micropipes are considered to be empty-core screw dislocations with large strain energy (i.e. they have large Burgers vector); they follow the growth direction (c-axis) in silicon carbide boules and substrates propagating into the deposited epitaxial layers. Factors which influence formation of micropipes (and other defects) are such growth parameters as temperature, supersaturation, vapor phase stoichiometry, impurities and the polarity of the seed surface. Many laboratories in universities and companies are striving to perfect the micropipe-free substrate. One of the pioneers of the commercialization of SiC materials and devices is Cree Inc. which in May 2007, announced that it had achieved 100-mm (4-inch), Zero-Micropipe, n-type SiC substrates. It is therefore possible to eliminate these defects in large-area wafers as well as smaller fragments and should open up the commercialization of this area of microelectronic devices.	https://www.wikidoc.org/index.php/Micropipe
f68430827edfdde0b9ed977809645ea8194a1c18	wikidoc	Microwave	Microwave Microwaves are electromagnetic waves with wavelengths shorter than one meter and longer than one millimeter, or frequencies between 300 megahertz and 300 gigahertz. (UHF, SHF, EHF) Apparatuses and techniques may be described qualitatively as "microwave" when the wavelengths of signals are roughly the same as the dimensions of the equipment, so that lumped-element circuit theory is inaccurate. As a consequence, practical microwave technique tends to move away from the discrete resistors, capacitors, and inductors used with lower frequency radio waves. Instead, distributed circuit elements and transmission-line theory are more useful methods for design, analysis, and construction of microwave circuits. Open-wire and coaxial transmission lines give way to waveguides, and lumped-element tuned circuits are replaced by cavity resonators or resonant lines. Effects of reflection, polarization, scattering, diffraction, and atmospheric absorption usually associated with visible light are of practical significance in the study of microwave propagation. The same equations of electromagnetic theory apply at all frequencies. While the name suggests a micrometer wavelength, it is better understood as indicating wavelengths very much smaller than those used in radio broadcasting. The boundaries between far infrared light, terahertz radiation, microwaves, and ultra-high-frequency radio waves are fairly arbitrary and are used variously between different fields of study. The term microwave generally refers to "alternating current signals with frequencies between 300 MHz (3×108 Hz) and 300 GHz (3×1011 Hz)." (UHF, SHF, EHF)Both IEC standard 60050 and IEEE standard 100 define "microwave" frequencies starting at 1 GHz (30 cm wavelength). Electromagnetic waves longer (lower frequency) than microwaves are called "radio waves". Electromagnetic radiation with shorter wavelengths may be called "millimeter waves", terahertz radiation or even T-rays. Definitions differ for millimeter wave band, which the IEEE defines as 110GHz to 300GHz while military radar definitions use 30-300GHz. # Discovery The existence of electromagnetic waves, of which microwaves are part of the frequency spectrum, was predicted by James Clerk Maxwell in 1864 from his equations. In 1888, Heinrich Hertz was the first to demonstrate the existence of electromagnetic waves by building an apparatus that produced and detected microwaves in the UHF region. The design necessarily used horse-and-buggy materials, including a horse trough, a wrought iron point spark, Leyden jars, and a length of zinc gutter whose parabolic cross-section worked as a reflection antenna. In 1894 J. C. Bose publicly demonstrated radio control of a bell using millimetre wavelengths, and conducted research into the propagation of microwaves. # Frequency range The microwave range includes ultra-high frequency (UHF) (0.3–3 GHz), super high frequency (SHF) (3–30 GHz), and extremely high frequency (EHF) (30–300 GHz) signals. Above 300 GHz, the absorption of electromagnetic radiation by Earth's atmosphere is so great that it is effectively opaque, until the atmosphere becomes transparent again in the so-called infrared and optical window frequency ranges. # Microwave Sources Vacuum tube based devices operate on the ballistic motion of electrons in a vacuum under the influence of controlling electric or magnetic fields, and include the magnetron, klystron, travelling wave tube (TWT), and gyrotron. These devices work in the density modulated mode, rather than the current modulated mode. This means that they work on the basis of clumps of electrons flying ballistically through them, rather than using a continuous stream. A maser is a device similar to a laser, except that it works at microwave frequencies. # Uses ## Communication - Before the advent of fiber optic transmission, most long distance telephone calls were carried via microwave point-to-point links through sites like the AT&T Long Lines. Starting in the early 1950's, frequency division multiplex was used to send up to 5,400 telephone channels on each microwave radio channel, with as many as ten radio channels combined into one antenna for the hop to the next site, up to 70 km away. - Wireless LAN protocols, such as Bluetooth and the IEEE 802.11 specifications, also use microwaves in the 2.4 GHz ISM band, although 802.11a uses ISM band and U-NII frequencies in the 5 GHz range. Licensed long-range (up to about 25 km) Wireless Internet Access services can be found in many countries (but not the USA) in the 3.5–4.0 GHz range. - Metropolitan Area Networks: MAN protocols, such as WiMAX (Worldwide Interoperability for Microwave Access) based in the IEEE 802.16 specification. The IEEE 802.16 specification was designed to operate between 2 to 11 GHz. The commercial implementations are in the 2.5 GHz, 3.5 GHz and 5.8 GHz ranges. - Wide Area Mobile Broadband Wireless Access: MBWA protocols based on standards specifications such as IEEE 802.20 or ATIS/ANSI HC-SDMA (e.g. iBurst) are designed to operate between 1.6 and 2.3 GHz to give mobility and in-building penetration characteristics similar to mobile phones but with vastly greater spectral efficiency. - Cable TV and Internet access on coax cable as well as broadcast television use some of the lower microwave frequencies. Some mobile phone networks, like GSM, also use the lower microwave frequencies. - Microwave radio is used in broadcasting and telecommunication transmissions because, due to their short wavelength, highly directive antennas are smaller and therefore more practical than they would be at longer wavelengths (lower frequencies). There is also more bandwidth in the microwave spectrum than in the rest of the radio spectrum; the usable bandwidth below 300 MHz is less than 300 MHz while many GHz can be used above 300 MHz. Typically, microwaves are used in television news to transmit a signal from a remote location to a television station from a specially equipped van. ## Remote Sensing - Radar uses microwave radiation to detect the range, speed, and other characteristics of remote objects. Development of radar was accelerated during World War II due to its great military utility. Now radar is widely used for applications such as air traffic control, navigation of ships, and speed limit enforcement. - Most radio astronomy uses microwaves. - Microwave imaging; see Photoacoustic imaging in biomedicine ## Navigation - Global Navigation Satellite Systems (GNSS) including the American Global Positioning System (GPS) and the Russian ГЛОбальная НАвигационная Спутниковая Система (GLONASS) broadcast navigational signals in various bands between about 1.2 GHz and 1.6 GHz. ## Power - A microwave oven passes (non-ionizing) microwave radiation (at a frequency near 2.45 GHz) through food, causing dielectric heating by absorption of energy in the water, fats and sugar contained in the food. Microwave ovens became common kitchen appliances in Western countries in the late 1970s, following development of inexpensive cavity magnetrons. - Microwave heating is used in industrial processes for drying and curing products. - Many semiconductor processing techniques use microwaves to generate plasma for such purposes as reactive ion etching and plasma-enhanced chemical vapor deposition (PECVD). - Microwaves can be used to transmit power over long distances, and post-World War II research was done to examine possibilities. NASA worked in the 1970s and early 1980s to research the possibilities of using Solar power satellite (SPS) systems with large solar arrays that would beam power down to the Earth's surface via microwaves. - Less-than-lethal weaponry exists that uses millimeter waves to heat a thin layer of human skin to an intolerable temperature so as to make the targeted person move away. A two-second burst of the 95 GHz focused beam heats the skin to a temperature of 130 F (54 C) at a depth of 1/64th of an inch (0.4 mm). The United States Air Force and Marines are currently using this type of Active Denial System. # Microwave frequency bands The microwave spectrum is usually defined as electromagnetic energy ranging from approximately 1 GHz to 1000 GHz in frequency, but older usage includes lower frequencies. Most common applications are within the 1 to 40 GHz range. Microwave frequency bands, as defined by the Radio Society of Great Britain (RSGB), are shown in the table below: The term P band is sometimes used for Ku Band. For other definitions see Letter Designations of Microwave Bands # Health effects Microwaves contain insufficient energy to directly chemically change substances by ionization, and so are an example of nonionizing radiation. The word "radiation" refers to the fact that energy can radiate, and not to the different nature and effects of different kinds of energy. A great number of studies have been undertaken in the last two decades, most concluding they are safe. It is understood that microwave radiation at a level that causes heating of living tissue is hazardous (due to the possibility of overheating and burns) and most countries have standards limiting exposure, such as the Federal Communications Commission RF safety regulations. Synthetic reviews of literature indicate the predominance of their safety of use. # History and research Perhaps the first, documented, formal use of the term microwave occurred in 1931: Perhaps the first use of the word microwave in an astronomical context occurred in 1946 in an article "Microwave Radiation from the Sun and Moon" by Robert Dicke and Robert Beringer. For some of the history in the development of electromagnetic theory applicable to modern microwave applications see the following figures: - Hans Christian Ørsted. - Michael Faraday. - James Clerk Maxwell. - Heinrich Hertz. - Nikola Tesla. - Guglielmo Marconi. - Samuel Morse. - Sir William Thomson, later Lord Kelvin. - Oliver Heaviside. - Lord Rayleigh. - Oliver Lodge. - Jagadish Chandra Bose. - Julius Lange. Specific significant areas of research and work developing microwaves and their applications:	Microwave Microwaves are electromagnetic waves with wavelengths shorter than one meter and longer than one millimeter, or frequencies between 300 megahertz and 300 gigahertz. (UHF, SHF, EHF) Apparatuses and techniques may be described qualitatively as "microwave" when the wavelengths of signals are roughly the same as the dimensions of the equipment, so that lumped-element circuit theory is inaccurate. As a consequence, practical microwave technique tends to move away from the discrete resistors, capacitors, and inductors used with lower frequency radio waves. Instead, distributed circuit elements and transmission-line theory are more useful methods for design, analysis, and construction of microwave circuits. Open-wire and coaxial transmission lines give way to waveguides, and lumped-element tuned circuits are replaced by cavity resonators or resonant lines. Effects of reflection, polarization, scattering, diffraction, and atmospheric absorption usually associated with visible light are of practical significance in the study of microwave propagation. The same equations of electromagnetic theory apply at all frequencies. While the name suggests a micrometer wavelength, it is better understood as indicating wavelengths very much smaller than those used in radio broadcasting. The boundaries between far infrared light, terahertz radiation, microwaves, and ultra-high-frequency radio waves are fairly arbitrary and are used variously between different fields of study. The term microwave generally refers to "alternating current signals with frequencies between 300 MHz (3×108 Hz) and 300 GHz (3×1011 Hz)."[1] (UHF, SHF, EHF)Both IEC standard 60050 and IEEE standard 100 define "microwave" frequencies starting at 1 GHz (30 cm wavelength). Electromagnetic waves longer (lower frequency) than microwaves are called "radio waves". Electromagnetic radiation with shorter wavelengths may be called "millimeter waves", terahertz radiation or even T-rays. Definitions differ for millimeter wave band, which the IEEE defines as 110GHz to 300GHz while military radar definitions use 30-300GHz. # Discovery The existence of electromagnetic waves, of which microwaves are part of the frequency spectrum, was predicted by James Clerk Maxwell in 1864 from his equations. In 1888, Heinrich Hertz was the first to demonstrate the existence of electromagnetic waves by building an apparatus that produced and detected microwaves in the UHF region. The design necessarily used horse-and-buggy materials, including a horse trough, a wrought iron point spark, Leyden jars, and a length of zinc gutter whose parabolic cross-section worked as a reflection antenna. In 1894 J. C. Bose publicly demonstrated radio control of a bell using millimetre wavelengths, and conducted research into the propagation of microwaves. # Frequency range The microwave range includes ultra-high frequency (UHF) (0.3–3 GHz), super high frequency (SHF) (3–30 GHz), and extremely high frequency (EHF) (30–300 GHz) signals. Above 300 GHz, the absorption of electromagnetic radiation by Earth's atmosphere is so great that it is effectively opaque, until the atmosphere becomes transparent again in the so-called infrared and optical window frequency ranges. # Microwave Sources Vacuum tube based devices operate on the ballistic motion of electrons in a vacuum under the influence of controlling electric or magnetic fields, and include the magnetron, klystron, travelling wave tube (TWT), and gyrotron. These devices work in the density modulated mode, rather than the current modulated mode. This means that they work on the basis of clumps of electrons flying ballistically through them, rather than using a continuous stream. A maser is a device similar to a laser, except that it works at microwave frequencies. # Uses ## Communication - Before the advent of fiber optic transmission, most long distance telephone calls were carried via microwave point-to-point links through sites like the AT&T Long Lines. Starting in the early 1950's, frequency division multiplex was used to send up to 5,400 telephone channels on each microwave radio channel, with as many as ten radio channels combined into one antenna for the hop to the next site, up to 70 km away. - Wireless LAN protocols, such as Bluetooth and the IEEE 802.11 specifications, also use microwaves in the 2.4 GHz ISM band, although 802.11a uses ISM band and U-NII frequencies in the 5 GHz range. Licensed long-range (up to about 25 km) Wireless Internet Access services can be found in many countries (but not the USA) in the 3.5–4.0 GHz range. - Metropolitan Area Networks: MAN protocols, such as WiMAX (Worldwide Interoperability for Microwave Access) based in the IEEE 802.16 specification. The IEEE 802.16 specification was designed to operate between 2 to 11 GHz. The commercial implementations are in the 2.5 GHz, 3.5 GHz and 5.8 GHz ranges. - Wide Area Mobile Broadband Wireless Access: MBWA protocols based on standards specifications such as IEEE 802.20 or ATIS/ANSI HC-SDMA (e.g. iBurst) are designed to operate between 1.6 and 2.3 GHz to give mobility and in-building penetration characteristics similar to mobile phones but with vastly greater spectral efficiency. - Cable TV and Internet access on coax cable as well as broadcast television use some of the lower microwave frequencies. Some mobile phone networks, like GSM, also use the lower microwave frequencies. - Microwave radio is used in broadcasting and telecommunication transmissions because, due to their short wavelength, highly directive antennas are smaller and therefore more practical than they would be at longer wavelengths (lower frequencies). There is also more bandwidth in the microwave spectrum than in the rest of the radio spectrum; the usable bandwidth below 300 MHz is less than 300 MHz while many GHz can be used above 300 MHz. Typically, microwaves are used in television news to transmit a signal from a remote location to a television station from a specially equipped van. ## Remote Sensing - Radar uses microwave radiation to detect the range, speed, and other characteristics of remote objects. Development of radar was accelerated during World War II due to its great military utility. Now radar is widely used for applications such as air traffic control, navigation of ships, and speed limit enforcement. - Most radio astronomy uses microwaves. - Microwave imaging; see Photoacoustic imaging in biomedicine ## Navigation - Global Navigation Satellite Systems (GNSS) including the American Global Positioning System (GPS) and the Russian ГЛОбальная НАвигационная Спутниковая Система (GLONASS) broadcast navigational signals in various bands between about 1.2 GHz and 1.6 GHz. ## Power - A microwave oven passes (non-ionizing) microwave radiation (at a frequency near 2.45 GHz) through food, causing dielectric heating by absorption of energy in the water, fats and sugar contained in the food. Microwave ovens became common kitchen appliances in Western countries in the late 1970s, following development of inexpensive cavity magnetrons. - Microwave heating is used in industrial processes for drying and curing products. - Many semiconductor processing techniques use microwaves to generate plasma for such purposes as reactive ion etching and plasma-enhanced chemical vapor deposition (PECVD). - Microwaves can be used to transmit power over long distances, and post-World War II research was done to examine possibilities. NASA worked in the 1970s and early 1980s to research the possibilities of using Solar power satellite (SPS) systems with large solar arrays that would beam power down to the Earth's surface via microwaves. - Less-than-lethal weaponry exists that uses millimeter waves to heat a thin layer of human skin to an intolerable temperature so as to make the targeted person move away. A two-second burst of the 95 GHz focused beam heats the skin to a temperature of 130 F (54 C) at a depth of 1/64th of an inch (0.4 mm). The United States Air Force and Marines are currently using this type of Active Denial System.[2] # Microwave frequency bands The microwave spectrum is usually defined as electromagnetic energy ranging from approximately 1 GHz to 1000 GHz in frequency, but older usage includes lower frequencies. Most common applications are within the 1 to 40 GHz range. Microwave frequency bands, as defined by the Radio Society of Great Britain (RSGB), are shown in the table below: Template:MWband The term P band is sometimes used for Ku Band. For other definitions see Letter Designations of Microwave Bands # Health effects Microwaves contain insufficient energy to directly chemically change substances by ionization, and so are an example of nonionizing radiation. The word "radiation" refers to the fact that energy can radiate, and not to the different nature and effects of different kinds of energy. A great number of studies have been undertaken in the last two decades, most concluding they are safe. It is understood that microwave radiation at a level that causes heating of living tissue is hazardous (due to the possibility of overheating and burns) and most countries have standards limiting exposure, such as the Federal Communications Commission RF safety regulations. Synthetic reviews of literature indicate the predominance of their safety of use. [3] [4] # History and research Perhaps the first, documented, formal use of the term microwave occurred in 1931: Perhaps the first use of the word microwave in an astronomical context occurred in 1946 in an article "Microwave Radiation from the Sun and Moon" by Robert Dicke and Robert Beringer. For some of the history in the development of electromagnetic theory applicable to modern microwave applications see the following figures: - Hans Christian Ørsted. - Michael Faraday. - James Clerk Maxwell. - Heinrich Hertz. - Nikola Tesla. - Guglielmo Marconi. - Samuel Morse. - Sir William Thomson, later Lord Kelvin. - Oliver Heaviside. - Lord Rayleigh. - Oliver Lodge. - Jagadish Chandra Bose. - Julius Lange. Specific significant areas of research and work developing microwaves and their applications:	https://www.wikidoc.org/index.php/Microwave
762e03514f781395f5dbf306b38b5bead95a349d	wikidoc	Urination	Urination Steven C. Campbell, M.D., Ph.D. # Overview Urination, known by physiologists as micturition, or more simply as voiding, is the process of disposing urine from the urinary bladder through the urethra to the outside of the body. In healthy adults, the process of urination is under voluntary control; in infants and individuals with neurological injury, urination may occur as an involuntary reflex. # Terms Urination is often referred to as "peeing", a euphemism for "piss" which is considered more vulgar. It is also referred to as "weeing" in the UK. "To whiz" or "whizzing" is common in the U.S. Others of note are "tinkle" and "potty" - both of which are often used with children. # Anatomy of the bladder and outlet The main organs involved in urination are the bladder and the urethra. The smooth muscle of the bladder, known as the detrusor, is innervated by sympathetic nervous system fibers from the lumbar spinal cord and parasympathetic fibers from the sacral spinal cord. Fibers in the pelvic nerves constitute the main afferent limb of the voiding reflex; the parasympathetic fibers to the bladder that constitute the excitatory efferent limb also travel in these nerves. Part of the urethra is surrounded by the external urinary sphincter, which is innervated by somatic fibers originating in the sacral cord, in an area termed Onuf's nucleus. Muscle bundles pass on either side of the urethra, and these fibers are sometimes called the internal urethral sphincter, although they do not encircle the urethra. Farther along the urethra is a sphincter of skeletal muscle, the sphincter of the membranous urethra (external urethral sphincter). The bladder epithelium is made up of a superficial layer of flat cells and a deep layer of cuboidal cells. # Physiology of urination The physiology of micturition and the physiologic basis of its disorders are subjects about which there is much confusion, especially at the supraspinal level. Micturition is fundamentally a spinobulbospinal reflex facilitated and inhibited by higher brain centers and, like defecation, subject to voluntary facilitation and inhibition. In healthy individuals, the lower urinary tract has two discrete phases of activity: the storage phase, when urine is stored in the bladder; and the voiding phase, when urine is released through the urethra. The state of the reflex system is dependent on both a conscious signal from the brain and the firing rate of sensory fibers from the bladder and urethra. At low bladder volumes, afferent firing is low, resulting in excitation of the outlet (the sphincter and urethra), and relaxation of the bladder. At high bladder volumes, afferent firing increases, causing a conscious sensation of urinary urge. When the individual is ready to urinate, he or she consciously initiates voiding, causing the bladder to contract and the outlet to relax. Voiding continues until the bladder empties completely, at which point the bladder relaxes and the outlet contracts to re-initiate storage. In infants, voiding occurs involuntarily (as a reflex). The ability to voluntarily inhibit micturition develops at the age of 2-3 years, as control at higher levels of the central nervous system develops. In the adult, the volume of urine in the bladder that normally initiates a reflex contraction is about 300-400 mL. ## Storage phase During storage, bladder pressure stays low, because of the bladder's highly compliant nature. A plot of bladder (intravesical) pressure against the volume of fluid in the bladder (called a cystometrogram) will show a very slight rise as the bladder is filled. This phenomenon is a manifestation of the law of Laplace, which states that the pressure in a spherical viscus is equal to twice the wall tension divided by the radius. In the case of the bladder, the tension increases as the organ fills, but so does the radius. Therefore, the pressure increase is slight until the organ is relatively full. The bladder smooth muscle has some inherent contractile activity; however, when its nerve supply is intact, stretch receptors in the bladder wall initiate a reflex contraction that has a lower threshold than the inherent contractile response of the muscle. Action potentials carried by sensory neurons from stretch receptors in the urinary bladder wall travel to the sacral segments of the spinal cord through the pelvic nerves. Since bladder wall stretch is low during the storage phase, these afferent neurons fire at low frequencies. Low-frequency afferent signals cause relaxation of the bladder by inhibiting sacral preganglionic neurons and exciting lumbar sympathetic preganglionic neurons. Conversely, afferent input causes contraction of the sphincter through excitation of Onuf's nucleus, and contraction of the bladder neck and urethra through excitation of the sympathetic preganglionic neurons. As the bladder becomes full, afferent firing increases, yet the micturition reflex can be voluntarily inhibited until it is appropriate to begin voiding (e.g. a bathroom is reached). ## Voiding phase Voiding begins when a voluntary signal is sent from the brain to begin urination, and continues until the bladder is empty. Bladder afferent signals ascend the spinal cord to the periaqueductal gray, where they project both to the pontine micturition center and to the cerebrum . At a certain level of afferent activity, the conscious urge to void becomes difficult to ignore. Once the voluntary signal to begin voiding has been issued, neurons in pontine micturition center fire maximally, causing excitation of sacral preganglionic neurons. The firing of these neurons causes the wall of the bladder to contract; as a result, a sudden, sharp rise in pressure in intravesical pressure occurs. The pontine micturition center also causes inhibition of Onuf's nucleus, resulting in relaxation of the external urinary sphincter. When the external urinary sphincter is relaxed urine flows from the urinary bladder when the pressure there is great enough to force urine to flow through the urethra. The micturition reflex normally produces a series of contractions of the urinary bladder. The flow of urine through the urethra has an overall excitatory role in micturition, which helps sustain voiding until the bladder is empty. After urination, the female urethra empties by gravity. Urine remaining in the urethra of the male is expelled by several contractions of the bulbospongiosus muscle. ## Voluntary control The mechanism by which voluntary urination is initiated remains unsettled. One possibility is that the voluntary relaxation of the muscles of the pelvic floor causes a sufficient downward tug on the detrusor muscle to initiate its contraction. Another possibility is the excitation or disinhibition of neurons in the pontine micturition center, which causes concurrent contraction of the bladder and relaxation of the sphincter. There is an inhibitory area for micturition in the midbrain. After transection of the brain stem just above the pons, the threshold is lowered and less bladder filling is required to trigger it, whereas after transection at the top of the midbrain, the threshold for the reflex is essentially normal. There is another facilitatory area in the posterior hypothalamus. In humans with lesions in the superior frontal gyrus, the desire to urinate is reduced and there is also difficulty in stopping micturition once it has commenced. However, stimulation experiments in animals indicate that other cortical areas also affect the process. The bladder can be made to contract by voluntary facilitation of the spinal voiding reflex when it contains only a few milliliters of urine. Voluntary contraction of the abdominal muscles aids the expulsion of urine by increasing the pressure applied to the urinary bladder wall, but voiding can be initiated without straining even when the bladder is nearly empty. Voiding can also be consciously interrupted once it has begun, through a contraction of the perineal muscles and external sphincter can be contracted voluntarily, which will prevent urine from passing down the urethra. ## Experience of urination Need to urinate is experienced as an uncomfortable, full, feeling. It is highly correlated with the fullness of the bladder. In males the feeling of the need to urinate can be sensed at the end of the penis, even though the neural activity associated with a full bladder comes from the bladder itself. Release of urine is experienced as a lessening of the uncomfortable, full, feeling. Post-micturition convulsion syndrome, the feeling of a shiver running down the spine following urination, occurs in more than 80% of men, but also occurs in more than 55% of women. Its explanation is unknown. # Disorders of urination ## Experimentally induced disorders There are three major types of bladder dysfunction due to neural lesions: (1) the type due to interruption of the afferent nerves from the bladder; (2) the type due to interruption of both afferent and efferent nerves; and (3) the type due to interruption of facilitatory and inhibitory pathways descending from the brain. In all three types the bladder contracts, but the contractions are generally not sufficient to empty the viscus completely, and residual urine is left in the bladder. Paruresis, also known as shy bladder syndrome, is an example of a bladder interruption from the brain that often causes total interruption until the person has left a public area. ### Effects of deafferentation When the sacral dorsal roots are cut in experimental animals or interrupted by diseases of the dorsal roots such as tabes dorsalis in humans, all reflex contractions of the bladder are abolished. The bladder becomes distended, thin-walled, and hypotonic, but there are some contractions because of the intrinsic response of the smooth muscle to stretch. ### Effects of denervation When the afferent and efferent nerves are both destroyed, as they may be by tumors of the cauda equina or filum terminale, the bladder is flaccid and distended for a while. Gradually, however, the muscle of the "decentralized bladder" becomes active, with many contraction waves that expel dribbles of urine out of the urethra. The bladder becomes shrunken and the bladder wall hypertrophied. The reason for the difference between the small, hypertrophic bladder seen in this condition and the distended, hypotonic bladder seen when only the afferent nerves are interrupted is not known. The hyperactive state in the former condition suggests the development of denervation hypersensitization even though the neurons interrupted are preganglionic rather than postganglionic. ### Effects of spinal cord transection During spinal shock, the bladder is flaccid and unresponsive. It becomes overfilled, and urine dribbles through the sphincters (overflow incontinence). After spinal shock has passed, the voiding reflex returns, although there is, of course, no voluntary control and no inhibition or facilitation from higher centers when the spinal cord is transected. Some paraplegic patients train themselves to initiate voiding by pinching or stroking their thighs, provoking a mild mass reflex. In some instances, the voiding reflex becomes hyperactive. Bladder capacity is reduced, and the wall becomes hypertrophied. This type of bladder is sometimes called the spastic neurogenic bladder. The reflex hyperactivity is made worse by, and may be caused by, infection in the bladder wall. ## Clinical conditions Many clinical conditions can cause disturbances to normal urination. Here is a partial list: - Urinary incontinence, or the inability to hold urine Stress urinary incontinence, incontinence that occurs as a result of external mechanical disturbances Urge urinary incontinence, incontinence that occurs as a result of the uncontrollable urge to urinate Mixed urinary incontinence, a combination of the two types of incontinence - Stress urinary incontinence, incontinence that occurs as a result of external mechanical disturbances - Urge urinary incontinence, incontinence that occurs as a result of the uncontrollable urge to urinate - Mixed urinary incontinence, a combination of the two types of incontinence - Urinary retention, the inability to initiate urination - Overactive bladder, a strong urge to urinate, usually accompanied by detrusor overactivity - Interstitial cystitis, a condition characterized by urinary frequency, urgency, and pain - Prostatitis, a supposed inflammation of the prostate gland that can cause urinary frequency, urgency, and pain - Benign prostatic hyperplasia, an enlargement of the prostate that can cause urinary frequency, urgency, retention, and the dribbling of urine - Urinary tract infection, which can cause urinary frequency and dysuria - Oliguria refers to a low urine output, usually due to a problem with the upper urinary tract - Anuria refers to absent or almost absent urine output. # Urination techniques Due to the differences in where the urethra ends, men and women use different techniques for urination. ## Male urination Due to the flexible and protruding nature of the penis, it is easy to control the direction of the urine stream. This makes it easy to urinate standing up, and most men urinate this way. The foreskin, if left in place during urination, may block the direct path of the outgoing stream by causing turbulence, resulting in a slower, but thicker stream of urine that may also dribble. Men who choose to retract their foreskin, or who have been circumcised, may have a more focused stream of urine that travels at the same speed it exits the urethra. When a man is done urinating, he will usually shake and/or gently squeeze his penis to expel the excess urine trapped in the opening of the foreskin or on the glans. This is known as "milking" the urethra. A common trick in expelling excess urine is gently pushing on the area behind the testicles (perineum). Trousers usually have a fly allowing men to urinate without lowering the whole trousers. The fly has buttons or a zipper. Either just the fly is opened or also the fastening at the waist. Additionally, the fly of the underpants is used or their front-side is lowered. All combinations are possible. Trousers without fly, like some jogging trousers, have usually an elastic waist band allowing lowering the front side like underpants. It is also possible for men to urinate sitting down. This is normally done when defecation has to take place as well. Some men also prefer to urinate this way. ## Female urination In women, the urethra opens straight into the vulva. Because of this, the urine does not exit at a distance from her body and is, therefore, hard to control. Because of surface tension in the urine, the easiest method is to just rely on gravity to take over once the urine has exited her body. This can easily be achieved if the woman is sitting down, although some women choose to squat or hover. Those alternative choices are sometimes made due to the perceived or actual unsanitary conditions at the location where the woman is urinating. When sitting, it helps if the woman leans forward and keeps her legs together, as this helps direct her stream downwards. When not urinating into a toilet, squatting is the easiest way for a woman to direct her urine stream. Some women use one or both hands to focus the direction of the urine stream, which is more easily achieved while in the squatting position. Women who wear pants/trousers/shorts will need to lower the garment to facilitate urination. Women wearing skirts or dresses only need to raise them to their waists to urinate, just lowering the underpants. While urinating in the squatting position, pants are often just lowered to the midst of the thighs, and some women lift the midst of the lowered underpants up. Some women hold the midst of their underpants or bikinipants to the side, so that they do not have to lower them. It is also possible for many women to urinate standing up by spreading their legs and pushing hard to avoid urine running down their legs. This technique for urinating while standing can be common when women often wear a sarong, skirt, or other such open bottomed garments, and either wear no underwear, or remove it. It is considered normal for women to urinate like this in many parts of Africa, whereas in contrast, it is not completely accepted in countries such as India where it also occurs in some areas. In Africa, even signs which forbid public urination often show a picture of a woman urinating while standing. . It is mostly in West Africa, like Ghana and Nigeria, that it is considered normal for a female to urinate standing up. In many other parts it is mostly occurring in the countryside or not at all. Though uncommon, it is possible for women to urinate standing up in a way similar to that of men. This may be done by spreading the labia minora open in a certain way and orienting the pelvis at an angle and rapidly forcing the urine stream out. An alternative method is to use a tool to assist. ## Urination after injury Occasionally, if a male's penis is damaged or removed, or a female's genitals/urinary tract is damaged, other urination techniques must be used. Most often in such cases, doctors will reposition the urethra to a location where urination can still be accomplished, usually in a position that would only promote urination while seated/squatting, though a permanent urinary catheter may rarely be used in some cases. # Social factors ## Toilet training Babies have no socialized control over urination within societies that do not practise elimination communication and instead use diapers. Toilet training is the process of learning to restrict urination to socially approved times and situations. Many young children suffer from nocturnal enuresis. ## Toilets It is socially more accepted and more hygienic for adults and older children to urinate in a toilet. Public toilets are often separate for men and women, and may be partitioned for reasons of cultural modesty. ## Urinals Public restrooms may have urinals for men. The etiquette associated with two or more males using adjoining urinals varies, however . Urinals for women, though rare, allow females to urinate while standing through the use of a special tool or through the finger-assist method . Urinals for either sex may have partitions between them in order to increase privacy. People with a mild form of paruresis, or "shy bladder syndrome," may have difficulty urinating in the presence of others and will consequently avoid using urinals directly adjacent to another person. Alternatively, they may opt for the privacy of a stall or simply avoid public restrooms altogether. ## Social transgressions A common transgression is urinating in the street (except at a public urinal). Often this is done after consumption of alcoholic beverage: the alcohol causes production of additional urine as well as a reduction of inhibitions. In New Orleans, urination on the street is sometimes referred to as a "New Orleans Piss". In most places, public urination is punishable by fine. Urination can also be seen as a sign of disrespect or contempt for someone or something. In popular culture, signs of a cartoon figure (sometimes Calvin) urinating on another object (usually a car brand) are common. In many countries and in many social classes even mentioning the need to urinate is seen as a social transgression, although the need is universal. Until recently in the UK many children were taught to say "I need a tidy" or "I need attention" when they needed to be taken to urinate. The abbreviations "tidy" or "tenny" were often used. Other euphemisms, such as 'Spending a penny" (a reference to coin-operated pay toilets); 'Going to see my aunt'; or 'Going to see a man about a dog' were used by adults. Even today adults may avoid stating that they need to urinate. Urination in art can be seen as controversial. ## Alternatives to toilets Sometimes urination is done in a container such as a bottle, urinal, bedpan or chamber pot, e.g. in case of lying sick in bed, in the case that the urine has to be examined (for medical reasons, or for a drug test), or in the case that there is no toilet or it is inconvenient to go there, and no other possibility to dispose of the urine right away. See also Bedpan use and output measurement. For the latter application a more expensive solution (hence for special occasions while traveling etc.) is a special disposable bag containing absorbent material that solidifies the urine in 5 to 10 seconds, making it convenient and safe to keep. It can also be used for vomiting. As well, it is not uncommon for people who do not have access to toilets to simply urinate on the ground. The local flora such as a tree or bush can be used for added privacy. ## Urination fetishes Some pornography depicts urination.	Urination Template:Search infobox Steven C. Campbell, M.D., Ph.D. # Overview Urination, known by physiologists as micturition, or more simply as voiding, is the process of disposing urine from the urinary bladder through the urethra to the outside of the body. In healthy adults, the process of urination is under voluntary control; in infants and individuals with neurological injury, urination may occur as an involuntary reflex. # Terms Urination is often referred to as "peeing", a euphemism for "piss" which is considered more vulgar. It is also referred to as "weeing" in the UK. "To whiz" or "whizzing" is common in the U.S. Others of note are "tinkle" and "potty" - both of which are often used with children. # Anatomy of the bladder and outlet The main organs involved in urination are the bladder and the urethra. The smooth muscle of the bladder, known as the detrusor, is innervated by sympathetic nervous system fibers from the lumbar spinal cord and parasympathetic fibers from the sacral spinal cord. [1] Fibers in the pelvic nerves constitute the main afferent limb of the voiding reflex; the parasympathetic fibers to the bladder that constitute the excitatory efferent limb also travel in these nerves. Part of the urethra is surrounded by the external urinary sphincter, which is innervated by somatic fibers originating in the sacral cord, in an area termed Onuf's nucleus[2]. Muscle bundles pass on either side of the urethra, and these fibers are sometimes called the internal urethral sphincter, although they do not encircle the urethra. Farther along the urethra is a sphincter of skeletal muscle, the sphincter of the membranous urethra (external urethral sphincter). The bladder epithelium is made up of a superficial layer of flat cells and a deep layer of cuboidal cells. # Physiology of urination The physiology of micturition and the physiologic basis of its disorders are subjects about which there is much confusion, especially at the supraspinal level. Micturition is fundamentally a spinobulbospinal reflex facilitated and inhibited by higher brain centers and, like defecation, subject to voluntary facilitation and inhibition.[3] In healthy individuals, the lower urinary tract has two discrete phases of activity: the storage phase, when urine is stored in the bladder; and the voiding phase, when urine is released through the urethra. The state of the reflex system is dependent on both a conscious signal from the brain and the firing rate of sensory fibers from the bladder and urethra.[3] At low bladder volumes, afferent firing is low, resulting in excitation of the outlet (the sphincter and urethra), and relaxation of the bladder.[4] At high bladder volumes, afferent firing increases, causing a conscious sensation of urinary urge. When the individual is ready to urinate, he or she consciously initiates voiding, causing the bladder to contract and the outlet to relax. Voiding continues until the bladder empties completely, at which point the bladder relaxes and the outlet contracts to re-initiate storage.[3] In infants, voiding occurs involuntarily (as a reflex). The ability to voluntarily inhibit micturition develops at the age of 2-3 years, as control at higher levels of the central nervous system develops. In the adult, the volume of urine in the bladder that normally initiates a reflex contraction is about 300-400 mL. ## Storage phase During storage, bladder pressure stays low, because of the bladder's highly compliant nature. A plot of bladder (intravesical) pressure against the volume of fluid in the bladder (called a cystometrogram) will show a very slight rise as the bladder is filled. This phenomenon is a manifestation of the law of Laplace, which states that the pressure in a spherical viscus is equal to twice the wall tension divided by the radius. In the case of the bladder, the tension increases as the organ fills, but so does the radius. Therefore, the pressure increase is slight until the organ is relatively full. The bladder smooth muscle has some inherent contractile activity; however, when its nerve supply is intact, stretch receptors in the bladder wall initiate a reflex contraction that has a lower threshold than the inherent contractile response of the muscle. Action potentials carried by sensory neurons from stretch receptors in the urinary bladder wall travel to the sacral segments of the spinal cord through the pelvic nerves.[3] Since bladder wall stretch is low during the storage phase, these afferent neurons fire at low frequencies. Low-frequency afferent signals cause relaxation of the bladder by inhibiting sacral preganglionic neurons and exciting lumbar sympathetic preganglionic neurons. Conversely, afferent input causes contraction of the sphincter through excitation of Onuf's nucleus, and contraction of the bladder neck and urethra through excitation of the sympathetic preganglionic neurons. As the bladder becomes full, afferent firing increases, yet the micturition reflex can be voluntarily inhibited until it is appropriate to begin voiding (e.g. a bathroom is reached). ## Voiding phase Voiding begins when a voluntary signal is sent from the brain to begin urination, and continues until the bladder is empty. Bladder afferent signals ascend the spinal cord to the periaqueductal gray, where they project both to the pontine micturition center and to the cerebrum [5]. At a certain level of afferent activity, the conscious urge to void becomes difficult to ignore. Once the voluntary signal to begin voiding has been issued, neurons in pontine micturition center fire maximally, causing excitation of sacral preganglionic neurons. The firing of these neurons causes the wall of the bladder to contract; as a result, a sudden, sharp rise in pressure in intravesical pressure occurs. The pontine micturition center also causes inhibition of Onuf's nucleus, resulting in relaxation of the external urinary sphincter.[6] When the external urinary sphincter is relaxed urine flows from the urinary bladder when the pressure there is great enough to force urine to flow through the urethra. The micturition reflex normally produces a series of contractions of the urinary bladder. The flow of urine through the urethra has an overall excitatory role in micturition, which helps sustain voiding until the bladder is empty.[7] After urination, the female urethra empties by gravity. Urine remaining in the urethra of the male is expelled by several contractions of the bulbospongiosus muscle. ## Voluntary control The mechanism by which voluntary urination is initiated remains unsettled.[8] One possibility is that the voluntary relaxation of the muscles of the pelvic floor causes a sufficient downward tug on the detrusor muscle to initiate its contraction.[9] Another possibility is the excitation or disinhibition of neurons in the pontine micturition center, which causes concurrent contraction of the bladder and relaxation of the sphincter.[3] There is an inhibitory area for micturition in the midbrain. After transection of the brain stem just above the pons, the threshold is lowered and less bladder filling is required to trigger it, whereas after transection at the top of the midbrain, the threshold for the reflex is essentially normal. There is another facilitatory area in the posterior hypothalamus. In humans with lesions in the superior frontal gyrus, the desire to urinate is reduced and there is also difficulty in stopping micturition once it has commenced. However, stimulation experiments in animals indicate that other cortical areas also affect the process. The bladder can be made to contract by voluntary facilitation of the spinal voiding reflex when it contains only a few milliliters of urine. Voluntary contraction of the abdominal muscles aids the expulsion of urine by increasing the pressure applied to the urinary bladder wall, but voiding can be initiated without straining even when the bladder is nearly empty. Voiding can also be consciously interrupted once it has begun, through a contraction of the perineal muscles and external sphincter can be contracted voluntarily, which will prevent urine from passing down the urethra. ## Experience of urination Need to urinate is experienced as an uncomfortable, full, feeling. It is highly correlated with the fullness of the bladder.[10] In males the feeling of the need to urinate can be sensed at the end of the penis, even though the neural activity associated with a full bladder comes from the bladder itself. Release of urine is experienced as a lessening of the uncomfortable, full, feeling. Post-micturition convulsion syndrome, the feeling of a shiver running down the spine following urination, occurs in more than 80% of men, but also occurs in more than 55% of women[11]. Its explanation is unknown. # Disorders of urination ## Experimentally induced disorders There are three major types of bladder dysfunction due to neural lesions: (1) the type due to interruption of the afferent nerves from the bladder; (2) the type due to interruption of both afferent and efferent nerves; and (3) the type due to interruption of facilitatory and inhibitory pathways descending from the brain. In all three types the bladder contracts, but the contractions are generally not sufficient to empty the viscus completely, and residual urine is left in the bladder. Paruresis, also known as shy bladder syndrome, is an example of a bladder interruption from the brain that often causes total interruption until the person has left a public area. ### Effects of deafferentation When the sacral dorsal roots are cut in experimental animals or interrupted by diseases of the dorsal roots such as tabes dorsalis in humans, all reflex contractions of the bladder are abolished. The bladder becomes distended, thin-walled, and hypotonic, but there are some contractions because of the intrinsic response of the smooth muscle to stretch. ### Effects of denervation When the afferent and efferent nerves are both destroyed, as they may be by tumors of the cauda equina or filum terminale, the bladder is flaccid and distended for a while. Gradually, however, the muscle of the "decentralized bladder" becomes active, with many contraction waves that expel dribbles of urine out of the urethra. The bladder becomes shrunken and the bladder wall hypertrophied. The reason for the difference between the small, hypertrophic bladder seen in this condition and the distended, hypotonic bladder seen when only the afferent nerves are interrupted is not known. The hyperactive state in the former condition suggests the development of denervation hypersensitization even though the neurons interrupted are preganglionic rather than postganglionic. ### Effects of spinal cord transection During spinal shock, the bladder is flaccid and unresponsive. It becomes overfilled, and urine dribbles through the sphincters (overflow incontinence). After spinal shock has passed, the voiding reflex returns, although there is, of course, no voluntary control and no inhibition or facilitation from higher centers when the spinal cord is transected. Some paraplegic patients train themselves to initiate voiding by pinching or stroking their thighs, provoking a mild mass reflex. In some instances, the voiding reflex becomes hyperactive. Bladder capacity is reduced, and the wall becomes hypertrophied. This type of bladder is sometimes called the spastic neurogenic bladder. The reflex hyperactivity is made worse by, and may be caused by, infection in the bladder wall. ## Clinical conditions Many clinical conditions can cause disturbances to normal urination. Here is a partial list: - Urinary incontinence, or the inability to hold urine Stress urinary incontinence, incontinence that occurs as a result of external mechanical disturbances Urge urinary incontinence, incontinence that occurs as a result of the uncontrollable urge to urinate Mixed urinary incontinence, a combination of the two types of incontinence - Stress urinary incontinence, incontinence that occurs as a result of external mechanical disturbances - Urge urinary incontinence, incontinence that occurs as a result of the uncontrollable urge to urinate - Mixed urinary incontinence, a combination of the two types of incontinence - Urinary retention, the inability to initiate urination - Overactive bladder, a strong urge to urinate, usually accompanied by detrusor overactivity - Interstitial cystitis, a condition characterized by urinary frequency, urgency, and pain - Prostatitis, a supposed inflammation of the prostate gland that can cause urinary frequency, urgency, and pain - Benign prostatic hyperplasia, an enlargement of the prostate that can cause urinary frequency, urgency, retention, and the dribbling of urine - Urinary tract infection, which can cause urinary frequency and dysuria - Oliguria refers to a low urine output, usually due to a problem with the upper urinary tract - Anuria refers to absent or almost absent urine output. # Urination techniques Due to the differences in where the urethra ends, men and women use different techniques for urination. ## Male urination Due to the flexible and protruding nature of the penis, it is easy to control the direction of the urine stream. This makes it easy to urinate standing up, and most men urinate this way. The foreskin, if left in place during urination, may block the direct path of the outgoing stream by causing turbulence, resulting in a slower, but thicker stream of urine that may also dribble. Men who choose to retract their foreskin, or who have been circumcised, may have a more focused stream of urine that travels at the same speed it exits the urethra. When a man is done urinating, he will usually shake and/or gently squeeze his penis to expel the excess urine trapped in the opening of the foreskin or on the glans. This is known as "milking" the urethra. A common trick in expelling excess urine is gently pushing on the area behind the testicles (perineum). Trousers usually have a fly allowing men to urinate without lowering the whole trousers. The fly has buttons or a zipper. Either just the fly is opened or also the fastening at the waist. Additionally, the fly of the underpants is used or their front-side is lowered. All combinations are possible. Trousers without fly, like some jogging trousers, have usually an elastic waist band allowing lowering the front side like underpants. It is also possible for men to urinate sitting down. This is normally done when defecation has to take place as well. Some men also prefer to urinate this way. ## Female urination In women, the urethra opens straight into the vulva. Because of this, the urine does not exit at a distance from her body and is, therefore, hard to control. Because of surface tension in the urine, the easiest method is to just rely on gravity to take over once the urine has exited her body. This can easily be achieved if the woman is sitting down, although some women choose to squat or hover. Those alternative choices are sometimes made due to the perceived or actual unsanitary conditions at the location where the woman is urinating. When sitting, it helps if the woman leans forward and keeps her legs together, as this helps direct her stream downwards. When not urinating into a toilet, squatting is the easiest way for a woman to direct her urine stream. Some women use one or both hands to focus the direction of the urine stream, which is more easily achieved while in the squatting position. Women who wear pants/trousers/shorts will need to lower the garment to facilitate urination. Women wearing skirts or dresses only need to raise them to their waists to urinate, just lowering the underpants. While urinating in the squatting position, pants are often just lowered to the midst of the thighs, and some women lift the midst of the lowered underpants up. Some women hold the midst of their underpants or bikinipants to the side, so that they do not have to lower them. It is also possible for many women to urinate standing up by spreading their legs and pushing hard to avoid urine running down their legs. This technique for urinating while standing can be common when women often wear a sarong, skirt, or other such open bottomed garments, and either wear no underwear, or remove it. It is considered normal for women to urinate like this in many parts of Africa, whereas in contrast, it is not completely accepted in countries such as India where it also occurs in some areas. In Africa, even signs which forbid public urination often show a picture of a woman urinating while standing. [12]. It is mostly in West Africa, like Ghana and Nigeria, that it is considered normal for a female to urinate standing up. In many other parts it is mostly occurring in the countryside or not at all. Though uncommon, it is possible for women to urinate standing up in a way similar to that of men. This may be done by spreading the labia minora open in a certain way and orienting the pelvis at an angle and rapidly forcing the urine stream out. [13] An alternative method is to use a tool to assist.[14] ## Urination after injury Occasionally, if a male's penis is damaged or removed, or a female's genitals/urinary tract is damaged, other urination techniques must be used. Most often in such cases, doctors will reposition the urethra to a location where urination can still be accomplished, usually in a position that would only promote urination while seated/squatting, though a permanent urinary catheter may rarely be used in some cases. # Social factors ## Toilet training Babies have no socialized control over urination within societies that do not practise elimination communication and instead use diapers. Toilet training is the process of learning to restrict urination to socially approved times and situations. Many young children suffer from nocturnal enuresis.[15] ## Toilets It is socially more accepted and more hygienic for adults and older children to urinate in a toilet. Public toilets are often separate for men and women, and may be partitioned for reasons of cultural modesty. ## Urinals Public restrooms may have urinals for men. The etiquette associated with two or more males using adjoining urinals varies, however [16][17]. Urinals for women, though rare, allow females to urinate while standing through the use of a special tool [18] or through the finger-assist method [19]. Urinals for either sex may have partitions between them in order to increase privacy. People with a mild form of paruresis, or "shy bladder syndrome," may have difficulty urinating in the presence of others and will consequently avoid using urinals directly adjacent to another person. Alternatively, they may opt for the privacy of a stall or simply avoid public restrooms altogether. ## Social transgressions A common transgression is urinating in the street (except at a public urinal). Often this is done after consumption of alcoholic beverage: the alcohol causes production of additional urine as well as a reduction of inhibitions. In New Orleans, urination on the street is sometimes referred to as a "New Orleans Piss". In most places, public urination is punishable by fine. Urination can also be seen as a sign of disrespect or contempt for someone or something. In popular culture, signs of a cartoon figure (sometimes Calvin) urinating on another object (usually a car brand) are common. In many countries and in many social classes even mentioning the need to urinate is seen as a social transgression, although the need is universal. Until recently in the UK many children were taught to say "I need a tidy" or "I need attention" when they needed to be taken to urinate. The abbreviations "tidy" or "tenny" were often used. Other euphemisms, such as 'Spending a penny" (a reference to coin-operated pay toilets); 'Going to see my aunt'; or 'Going to see a man about a dog' were used by adults. Even today adults may avoid stating that they need to urinate. Urination in art can be seen as controversial. ## Alternatives to toilets Sometimes urination is done in a container such as a bottle, urinal, bedpan or chamber pot, e.g. in case of lying sick in bed, in the case that the urine has to be examined (for medical reasons, or for a drug test), or in the case that there is no toilet or it is inconvenient to go there, and no other possibility to dispose of the urine right away. See also Bedpan use and output measurement. For the latter application a more expensive solution (hence for special occasions while traveling etc.) is a special disposable bag containing absorbent material that solidifies the urine in 5 to 10 seconds, making it convenient and safe to keep. It can also be used for vomiting. As well, it is not uncommon for people who do not have access to toilets to simply urinate on the ground. The local flora such as a tree or bush can be used for added privacy. ## Urination fetishes Some pornography depicts urination.	https://www.wikidoc.org/index.php/Micturition
44811cf52c91665208be2550a46b11e218d261fc	wikidoc	Ovulation	Ovulation # Overview Ovulation is the process in the menstrual cycle by which a mature ovarian follicle ruptures and discharges an ovum (also known as an oocyte, female gamete, or casually, an egg) that participates in reproduction. Ovulation also occurs in the estrous cycle of other animals, which differs in many fundamental ways from the menstrual cycle. The process of ovulation is controlled by the hypothalamus of the brain and through the release of hormones secreted in the anterior lobe of the pituitary gland, (Luteinizing hormone (LH) and Follicle-stimulating hormone (FSH)). In the follicular (pre-ovulatory) phase of the menstrual cycle, the ovarian follicle will undergo a series of transformations called cumulus expansion, this is stimulated by the secretion of FSH. After this is done, a hole called the stigma will form in the follicle, and the ovum will leave the follicle through this hole. Ovulation is triggered by a spike in the amount of FSH and LH released from the pituitary gland. During the luteal (post-ovulatory) phase, the ovum will travel through the fallopian tubes toward the uterus. If fertilized by a sperm, it may perform implantation there 6-12 days later. If not fertilized, it will be degraded in the fallopian tubes within 24 hours. In humans, the few days near ovulation constitute the fertile phase. The average time of ovulation is the fourteenth day of an average length (twenty-eight day) menstrual cycle. It is normal for the day of ovulation to vary from the average, with ovulation anywhere between the tenth and nineteenth day being common. Cycle length alone is not a reliable indicator of the day of ovulation. While in general an earlier ovulation will result in a shorter menstrual cycle, and vice versa, the luteal (post-ovulatory) phase of the menstrual cycle may vary by up to a week between women. # A closer look at the process Strictly defined, the ovulatory phase spans the period of hormonal elevation in the menstrual cycle. The process requires a maximum of thirty-six hours to complete, and it is arbitrarily separated into three phases: periovulatory, ovulatory, and postovulatory. # Prerequisite events Through a process that takes approximately 375 days, or thirteen menstrual cycles, a large group of undeveloped primordial follicles dormant in the ovary is grown and progressively weaned into one preovulatory follicle. Histologically, the preovulatory follicle (also called a mature Graffian follicle or mature tertiary follicle) contains an oocyte arrested in prophase of meiosis I surrounded by a layer corona radiata granulosa cells, a layer of mural granulosa cells, a protective basal lamina, and a network of blood-carrying capillary vessels sandwiched between a layer of theca interna and theca externa cells. A large sac of fluid called the antrum predominates in the follicle. A "bridge" of cumulus oophorous granulosa cells (or simply cumulus cells) connects the corona-ovum complex to the mural granulosa cells. The granulosa cells engage in bidirectional messaging with the theca cells and the oocyte to facilitate follicular function. Research is clarifying the specific factors used in follicular messaging at a rapid pace, but such discussion is beyond the scope of this article. By the action of luteinizing hormone (LH), the preovulatory follicle's theca cells secrete androstenedione that is aromatized by mural granulosa cells into estradiol, a type of estrogen. In contrast to the other phases of the menstrual cycle, estrogen release in late follicular phase has a stimulatory effect on hypothalamus gonadotropin-releasing hormone (GnRH) that in turn stimulates the expression of pituitary LH and follicle stimulating hormone (FSH). The building concentrations of LH and FSH marks the beginning of the periovulatory phase. ## Periovulatory phase For ovulation to be successful, the ovum must be supported by both the corona radiata and cumulus oophorous granulosa cells. The latter undergo a period of proliferation and mucification known as cumulus expansion. Mucification is the secretion of a hyaluronic acid-rich cocktail that disperses and suspends the cumulus cell network in a sticky matrix around the ovum. This network stays with the ovum after ovulation and have been shown to be necessary for fertilization. An increase in cumulus cell number causes a concomitant increase in antrum fluid volume that can swell the follicle to over 20 mm in diameter. It forms a pronounced bulge at the surface of the ovary called the blister. ## Ovulatory phase Through a signal transduction cascade initiated by LH, proteolytic enzymes are secreted by the follicle that degrade the follicular tissue at the site of the blister, forming a hole called the stigma. The ovum-cumulus complex leaves the ruptured follicle and moves out into the peritoneal cavity through the stigma, where it is caught by the fimbriae at the end of the fallopian tube (also called the oviduct). After entering the oviduct, the ovum-cumulus complex is pushed along by cilia, beginning its journey toward the uterus. By this time, the oocyte has completed meiosis I, yielding two cells: the larger secondary oocyte that contains all of the cytoplasmic material and a smaller, inactive first polar body. Meiosis II follows at once but will be arrested in the metaphase and will so remain until fertilization. The spindle apparatus of the second meiotic division appears at the time of ovulation. If no fertilization occurs, the oocyte will degenerate approximately twenty-four hours after ovulation. The mucous membrane of the uterus, termed the functionalis, has reached its maximum size, and so have the endometrial glands, although they are still non-secretory. ## Postovulatory phase The follicle proper has met the end of its lifespan. Without the ovum, the follicle folds inward on itself, transforming into the corpus luteum (pl. corpus lutea), a steriodogenic cluster of cells that produces estrogen and progesterone. These hormones induce the endometrial glands to begin production of the proliferative endometrium and later into secretory endometrium, the site of embryonic growth if fertilization occurs. The action of progesterone increases basal body temperature by one-quarter to one-half degree Celsius (one-half to one degree Fahrenheit). The corpus luteum continues this paracrine action for the remainder of the menstrual cycle, maintaining the endometrium, before disintegrating into scar tissue during menses. # Clinical presentation The start of ovulation can be detected by various signs. Because the signs are not readily discernable by people other than the woman herself, humans are said to have a concealed ovulation. Women near ovulation experience changes in the cervix, in mucus produced by the cervix, and in their basal body temperature. Furthermore, many women also experience secondary fertility signs including Mittelschmerz (pain associated with ovulation) and a heightened sense of smell. Many women experience heightened sexual desire in the several days immediately before ovulation. One study concluded that women subtly improve their facial attractiveness during ovulation and period. # Follicular waves Research spearheaded by Baerwald et al. suggests that the menstrual cycle may not regulate follicular growth as strictly as previously thought. In particular, the majority of women during an average twenty-eight day cycle experience two or three "waves" of follicular development, with only the final wave being ovulatory. The remainder of the waves are anovulatory, characterized by the developed preovulatory follicle falling into atresia (a major anovulatory cycle) or no preovulatory follicle being chosen at all (a minor anovulatory cycle). The phenomenon is similar to the follicular waves seen in cows and horses. In these animals, a large cohort of early tertiary follicles develop consistently during the follicular phase of the menstrual cycle, suggesting that the endocrine system does not regulate folliculogenesis stringently. While seen as a revelation by some in the medical community, researchers of fertility awareness or natural family planning methods discovered follicular waves in the 1950s. These methods of family planning have always taken multiple follicular waves into account, and this research does not challenge their effectiveness. # Induction and suppression ## Induced ovulation Follicle stimulating hormone, gonadotropin releasing hormone (GnRH), and estradiol have been purified in the laboratory. Chemical analogues of estradiol and progesterone have also been synthesized. Recall that GnRH is an upstream inducer of both FSH and LH secretion. Generally, administered FSH or GnRH can induce ovulation by rapidly accelerating the pace of folliculogenesis, allowing for conception. Ovulation induction is a promising assisted reproductive technology for patients with conditions such as polycystic ovary syndrome (PCOS) and oligomenorrhea. Medications that are commonly prescribed to induce ovulation include Clomid, Gonal-F/Follistim AQ, Metformin, Bravelle, Menopur and Repronex. ### Risks All ovulation-inducing medications carry the risk of side effects. A recent study has raised the possibility of a link between ovulation-inducing agents and an increased risk of ovarian carcinoma. ## Suppressed ovulation Contraception can be achieved by suppressing the ovulation. The majority of hormonal contraceptives and conception boosters focus on the ovulatory phase of the menstrual cycle because it is the most important determinant of fertility. Hormone therapy can positively or negatively interfere with ovulation and can give a sense of cycle control to the woman. Estradiol and progesterone, taken in various forms including combined oral contraceptive pills, mimics the hormonal levels of the menstrual cycle and engage in negative feedback of folliculogenesis and ovulation. # Ovulation in animals - Ovulation in camels is induced by male pheromones. In caravans without bulls female camels don't have an oestrus. - In cats and rabbits ovulation is induced mechanically by the male through copulation. - Chickens have an ovulation almost every day. - The embryos of some Marsupial species enter embryonic diapause (or delayed implantation) after fertilization.	Ovulation Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Ovulation is the process in the menstrual cycle by which a mature ovarian follicle ruptures and discharges an ovum (also known as an oocyte, female gamete, or casually, an egg) that participates in reproduction. Ovulation also occurs in the estrous cycle of other animals, which differs in many fundamental ways from the menstrual cycle. The process of ovulation is controlled by the hypothalamus of the brain and through the release of hormones secreted in the anterior lobe of the pituitary gland, (Luteinizing hormone (LH) and Follicle-stimulating hormone (FSH)). In the follicular (pre-ovulatory) phase of the menstrual cycle, the ovarian follicle will undergo a series of transformations called cumulus expansion, this is stimulated by the secretion of FSH. After this is done, a hole called the stigma will form in the follicle, and the ovum will leave the follicle through this hole. Ovulation is triggered by a spike in the amount of FSH and LH released from the pituitary gland. During the luteal (post-ovulatory) phase, the ovum will travel through the fallopian tubes toward the uterus. If fertilized by a sperm, it may perform implantation there 6-12 days later. If not fertilized, it will be degraded in the fallopian tubes within 24 hours. In humans, the few days near ovulation constitute the fertile phase. The average time of ovulation is the fourteenth day of an average length (twenty-eight day) menstrual cycle. It is normal for the day of ovulation to vary from the average, with ovulation anywhere between the tenth and nineteenth day being common. Cycle length alone is not a reliable indicator of the day of ovulation. While in general an earlier ovulation will result in a shorter menstrual cycle, and vice versa, the luteal (post-ovulatory) phase of the menstrual cycle may vary by up to a week between women. # A closer look at the process Strictly defined, the ovulatory phase spans the period of hormonal elevation in the menstrual cycle. The process requires a maximum of thirty-six hours to complete, and it is arbitrarily separated into three phases: periovulatory, ovulatory, and postovulatory. # Prerequisite events Through a process that takes approximately 375 days, or thirteen menstrual cycles, a large group of undeveloped primordial follicles dormant in the ovary is grown and progressively weaned into one preovulatory follicle. Histologically, the preovulatory follicle (also called a mature Graffian follicle or mature tertiary follicle) contains an oocyte arrested in prophase of meiosis I surrounded by a layer corona radiata granulosa cells, a layer of mural granulosa cells, a protective basal lamina, and a network of blood-carrying capillary vessels sandwiched between a layer of theca interna and theca externa cells. A large sac of fluid called the antrum predominates in the follicle. A "bridge" of cumulus oophorous granulosa cells (or simply cumulus cells) connects the corona-ovum complex to the mural granulosa cells. The granulosa cells engage in bidirectional messaging with the theca cells and the oocyte to facilitate follicular function. Research is clarifying the specific factors used in follicular messaging at a rapid pace, but such discussion is beyond the scope of this article. By the action of luteinizing hormone (LH), the preovulatory follicle's theca cells secrete androstenedione that is aromatized by mural granulosa cells into estradiol, a type of estrogen. In contrast to the other phases of the menstrual cycle, estrogen release in late follicular phase has a stimulatory effect on hypothalamus gonadotropin-releasing hormone (GnRH) that in turn stimulates the expression of pituitary LH and follicle stimulating hormone (FSH). The building concentrations of LH and FSH marks the beginning of the periovulatory phase. ## Periovulatory phase For ovulation to be successful, the ovum must be supported by both the corona radiata and cumulus oophorous granulosa cells. The latter undergo a period of proliferation and mucification known as cumulus expansion. Mucification is the secretion of a hyaluronic acid-rich cocktail that disperses and suspends the cumulus cell network in a sticky matrix around the ovum. This network stays with the ovum after ovulation and have been shown to be necessary for fertilization. An increase in cumulus cell number causes a concomitant increase in antrum fluid volume that can swell the follicle to over 20 mm in diameter. It forms a pronounced bulge at the surface of the ovary called the blister. ## Ovulatory phase Through a signal transduction cascade initiated by LH, proteolytic enzymes are secreted by the follicle that degrade the follicular tissue at the site of the blister, forming a hole called the stigma. The ovum-cumulus complex leaves the ruptured follicle and moves out into the peritoneal cavity through the stigma, where it is caught by the fimbriae at the end of the fallopian tube (also called the oviduct). After entering the oviduct, the ovum-cumulus complex is pushed along by cilia, beginning its journey toward the uterus. By this time, the oocyte has completed meiosis I, yielding two cells: the larger secondary oocyte that contains all of the cytoplasmic material and a smaller, inactive first polar body. Meiosis II follows at once but will be arrested in the metaphase and will so remain until fertilization. The spindle apparatus of the second meiotic division appears at the time of ovulation. If no fertilization occurs, the oocyte will degenerate approximately twenty-four hours after ovulation. The mucous membrane of the uterus, termed the functionalis, has reached its maximum size, and so have the endometrial glands, although they are still non-secretory. ## Postovulatory phase The follicle proper has met the end of its lifespan. Without the ovum, the follicle folds inward on itself, transforming into the corpus luteum (pl. corpus lutea), a steriodogenic cluster of cells that produces estrogen and progesterone. These hormones induce the endometrial glands to begin production of the proliferative endometrium and later into secretory endometrium, the site of embryonic growth if fertilization occurs. The action of progesterone increases basal body temperature by one-quarter to one-half degree Celsius (one-half to one degree Fahrenheit). The corpus luteum continues this paracrine action for the remainder of the menstrual cycle, maintaining the endometrium, before disintegrating into scar tissue during menses. # Clinical presentation The start of ovulation can be detected by various signs. Because the signs are not readily discernable by people other than the woman herself, humans are said to have a concealed ovulation. Women near ovulation experience changes in the cervix, in mucus produced by the cervix, and in their basal body temperature. Furthermore, many women also experience secondary fertility signs including Mittelschmerz (pain associated with ovulation) and a heightened sense of smell.[1] Many women experience heightened sexual desire in the several days immediately before ovulation.[2] One study concluded that women subtly improve their facial attractiveness during ovulation and period.[3] # Follicular waves Research spearheaded by Baerwald et al. suggests that the menstrual cycle may not regulate follicular growth as strictly as previously thought. In particular, the majority of women during an average twenty-eight day cycle experience two or three "waves" of follicular development, with only the final wave being ovulatory. The remainder of the waves are anovulatory, characterized by the developed preovulatory follicle falling into atresia (a major anovulatory cycle) or no preovulatory follicle being chosen at all (a minor anovulatory cycle). The phenomenon is similar to the follicular waves seen in cows and horses. In these animals, a large cohort of early tertiary follicles develop consistently during the follicular phase of the menstrual cycle, suggesting that the endocrine system does not regulate folliculogenesis stringently. While seen as a revelation by some in the medical community, researchers of fertility awareness or natural family planning methods discovered follicular waves in the 1950s. These methods of family planning have always taken multiple follicular waves into account, and this research does not challenge their effectiveness. # Induction and suppression ## Induced ovulation Follicle stimulating hormone, gonadotropin releasing hormone (GnRH), and estradiol have been purified in the laboratory. Chemical analogues of estradiol and progesterone have also been synthesized. Recall that GnRH is an upstream inducer of both FSH and LH secretion. Generally, administered FSH or GnRH can induce ovulation by rapidly accelerating the pace of folliculogenesis, allowing for conception. Ovulation induction is a promising assisted reproductive technology for patients with conditions such as polycystic ovary syndrome (PCOS) and oligomenorrhea. Medications that are commonly prescribed to induce ovulation include Clomid, Gonal-F/Follistim AQ, Metformin, Bravelle, Menopur and Repronex. ### Risks All ovulation-inducing medications carry the risk of side effects. A recent study has raised the possibility of a link between ovulation-inducing agents and an increased risk of ovarian carcinoma. [4] ## Suppressed ovulation Contraception can be achieved by suppressing the ovulation. The majority of hormonal contraceptives and conception boosters focus on the ovulatory phase of the menstrual cycle because it is the most important determinant of fertility. Hormone therapy can positively or negatively interfere with ovulation and can give a sense of cycle control to the woman. Estradiol and progesterone, taken in various forms including combined oral contraceptive pills, mimics the hormonal levels of the menstrual cycle and engage in negative feedback of folliculogenesis and ovulation. # Ovulation in animals - Ovulation in camels is induced by male pheromones. In caravans without bulls female camels don't have an oestrus. - In cats and rabbits ovulation is induced mechanically by the male through copulation. - Chickens have an ovulation almost every day. - The embryos of some Marsupial species enter embryonic diapause (or delayed implantation) after fertilization.	https://www.wikidoc.org/index.php/Midcycle_ovulation
cd117a682cf90352de9d898040b0d8c593a7ccd5	wikidoc	Midodrine	Midodrine # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Midodrine is an alpha-adrenergic agonist that is FDA approved for the {{{indicationType}}} of symptomatic orthostatic hypotension. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hypertension, piloerection, pruritus, shivering, paresthesia, dysuria, urinary retention, and urinary frequency. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Midodrine hydrochloride tablets are indicated for the treatment of symptomatic orthostatic hypotension (OH). Because midodrine hydrochloride tablets can cause marked elevation of supine blood pressure (BP>200 mmHg systolic), it should be used in patients whose lives are considerably impaired despite standard clinical care, including non-pharmacologic treatment (such as support stockings), fluid expansion and lifestyle alterations. The indication is based on midodrine hydrochloride tablet's effect on increases in 1-minute standing systolic blood pressure, a surrogate marker considered likely to correspond to a clinical benefit. At present, however, clinical benefits of midodrine hydrochloride tablets, principally improved ability to perform life activities, have not been established. Further clinical trials are underway to verify and describe the clinical benefits of midodrine hydrochloride tablets. - After initiation of treatment, midodrine hydrochloride tablets should be continued only for patients who report significant symptomatic improvement. - Dosing Information - The recommended dose of midodrine hydrochloride tablets is 10 mg, 3 times daily. - Dosing should take place during the daytime hours when the patient needs to be upright, pursuing the activities of daily living. A suggested dosing schedule of approximately 4-hour intervals is as follows: shortly before or upon arising in the morning, midday and late afternoon (not later than 6 P.M.). Doses may be given in 3-hour intervals, if required, to control symptoms, but not more frequently. - Single doses as high as 20 mg have been given to patients, but severe and persistent systolic supine hypertension occurs at a high rate (about 45%) at this dose. In order to reduce the potential for supine hypertension during sleep, midodrine hydrochloride tablets should not be given after the evening meal or less than 4 hours before bedtime. Total daily doses greater than 30 mg have been tolerated by some patients, but their safety and usefulness have not been studied systematically or established. Because of the risk of supine hypertension, midodrine hydrochloride tablets should be continued only in patients who appear to attain symptomatic improvement during initial treatment. - The supine and standing blood pressure should be monitored regularly and the administration of midodrine hydrochloride tablets should be stopped if supine blood pressure increases excessively. - Because desglymidodrine is excreted renally, dosing in patients with abnormal renal function should be cautious; although this has not been systematically studied, it is recommended that treatment of these patients be initiated using 2.5 mg doses. - Blood levels of midodrine and desglymidodrine were similar when comparing levels in patients 65 or older vs. younger than 65 and when comparing males vs. females, suggesting dose modifications for these groups are not necessary. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Midodrine in adult patients. ### Non–Guideline-Supported Use - Dosing Information - Midodrine up to 15 mg 3 times daily was used to treat severely symptomatic neurocardiogenic syncope. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Safety and effectiveness in pediatric patients have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Midodrine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Midodrine in pediatric patients. # Contraindications - Severe organic heart disease - Acute renal disease - Urinary retention - Pheochromocytoma - Thyrotoxicosis - Persistent and excessive supine hypertension # Warnings - Supine Hypertension - The most potentially serious adverse reaction associated with midodrine hydrochloride therapy is marked elevation of supine arterial blood pressure (supine hypertension). Systolic pressure of about 200 mmHg was seen overall in about 13.4% of patients given 10 mg of midodrine hydrochloride. Systolic elevations of this degree were most likely to be observed in patients with relatively elevated pre-treatment systolic blood pressures (mean 170 mmHg). There is no experience in patients with initial supine systolic pressure above 180 mmHg, as those patients were excluded from the clinical trials. Use of midodrine hydrochloride in such patients is not recommended. Sitting blood pressures were also elevated by midodrine hydrochloride therapy. It is essential to monitor supine and sitting blood pressures in patients maintained on midodrine hydrochloride. ### Precautions - The potential for supine and sitting hypertension should be evaluated at the beginning of midodrine hydrochloride therapy. Supine hypertension can often be controlled by preventing the patient from becoming fully supine, i.e., sleeping with the head of the bed elevated. The patient should be cautioned to report symptoms of supine hypertension immediately. Symptoms may include cardiac awareness, pounding in the ears, headache, blurred vision, etc. - The patient should be advised to discontinue the medication immediately if supine hypertension persists. Blood pressure should be monitored carefully when midodrine hydrochloride is used concomitantly with other agents that cause vasoconstriction, such as phenylephrine, ephedrine, dihydroergotamine, phenylpropanolamine or pseudoephedrine. - A slight slowing of the heart rate may occur after administration of midodrine hydrochloride, primarily due to vagal reflex. Caution should be exercised when midodrine hydrochloride is used concomitantly with cardiac glycosides (such as digitalis), psychopharmacologic agents, beta blockers or other agents that directly or indirectly reduce heart rate. Patients who experience any signs or symptoms suggesting bradycardia (pulse slowing, increased dizziness, syncope, cardiac awareness) should be advised to discontinue midodrine hydrochloride and should be re-evaluated. - Midodrine hydrochloride should be used cautiously in patients with urinary retention problems, as desglymidodrine acts on the alpha-adrenergic receptors of the bladder neck. - Midodrine hydrochloride should be used with caution in orthostatic hypotensive patients who are also diabetic, as well as those with a history of visual problems who are also taking fludrocortisone acetate, which is known to cause an increase in intraocular pressure and glaucoma. - Midodrine hydrochloride use has not been studied in patients with renal impairment. Because desglymidodrine is eliminated via the kidneys and higher blood levels would be expected in such patients, midodrine hydrochloride should be used with caution in patients with renal impairment, with a starting dose of 2.5 mg. Renal function should be assessed prior to initial use of midodrine hydrochloride. - Midodrine hydrochloride use has not been studied in patients with hepatic impairment. Midodrine hydrochloride should be used with caution in patients with hepatic impairment, as the liver has a role in the metabolism of midodrine. - Laboratory Tests - Since desglymidodrine is eliminated by the kidneys and the liver has a role in its metabolism, evaluation of the patient should include assessment of renal and hepatic function prior to initiating therapy and subsequently, as appropriate. # Adverse Reactions ## Clinical Trials Experience - The most frequent adverse reactions seen in controlled trials were supine and sitting hypertension; paresthesia and pruritus, mainly of the scalp; goosebumps; chills; urinary urge; urinary retention and urinary frequency. - The frequency of these events in a 3-week placebo-controlled trial is shown in the following table: - Less frequent adverse reactions were headache; feeling of pressure/fullness in the head; vasodilation/flushing face; confusion/thinking abnormality; dry mouth; nervousness/anxiety and rash. Other adverse reactions that occurred rarely were visual field defect; dizziness; skin hyperesthesia; insomnia; somnolence; erythema multiforme; canker sore; dry skin; dysuria; impaired urination; asthenia; backache; pyrosis; nausea; gastrointestinal distress; flatulence; and leg cramps. - The most potentially serious adverse reaction associated with midodrine hydrochloride therapy is supine hypertension. The feelings of paresthesia, pruritus, piloerection and chills are pilomotor reactions associated with the action of midodrine on the alpha-adrenergic receptors of the hair follicles. Feelings of urinary urgency, urinary retention and urinary frequency are associated with the action of midodrine on the alpha-receptors of the bladder neck. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Midodrine in the drug label. # Drug Interactions - When administered concomitantly with midodrine hydrochloride, cardiac glycosides may enhance or precipitate bradycardia, AV block or arrhythmia. - The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of midodrine hydrochloride. Therefore, caution should be used when midodrine hydrochloride is administered concomitantly with agents that cause vasoconstriction. - Midodrine hydrochloride has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with midodrine hydrochloride. Alpha-adrenergic blocking agents, such as prazosin, terazosin and doxazosin, can antagonize the effects of midodrine hydrochloride. - It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interaction with these drugs. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Midodrine hydrochloride increased the rate of embryo resorption, reduced fetal body weight in rats and rabbits and decreased fetal survival in rabbits when given in doses 13 (rat) and 7 (rabbit) times the maximum human dose based on body surface area (mg/m2). There are no adequate and well-controlled studies in pregnant women. Midodrine hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. No teratogenic effects have been observed in studies in rats and rabbits. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Midodrine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Midodrine during labor and delivery. ### Nursing Mothers - It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when midodrine hydrochloride is administered to a nursing woman. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use There is no FDA guidance on the use of Midodrine with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Midodrine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Midodrine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Midodrine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Midodrine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Midodrine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Midodrine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring - The supine and standing blood pressure should be monitored regularly and the administration of midodrine hydrochloride tablets should be stopped if supine blood pressure increases excessively. # IV Compatibility There is limited information regarding IV Compatibility of Midodrine in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - Symptoms of overdose could include hypertension, piloerection (goosebumps), a sensation of coldness and urinary retention. There are 2 reported cases of overdosage with midodrine hydrochloride, both in young males. One patient ingested midodrine hydrochloride drops, 250 mg, experienced systolic blood pressure greater than 200 mmHg, was treated with an IV injection of 20 mg of phentolamine and was discharged the same night without any complaints. - The other patient ingested 205 mg of midodrine hydrochloride (41 5-mg tablets) and was found lethargic and unable to talk, unresponsive to voice but responsive to painful stimuli, hypertensive and bradycardic. Gastric lavage was performed and the patient recovered fully by the next day without sequelae. The single doses that would be associated with symptoms of overdosage or would be potentially life-threatening are unknown. The oral LD50 is approximately 30 mg/kg to 50 mg/kg in rats, 675 mg/kg in mice and 125 mg/kg to 160 mg/kg in dogs. ### Management - Desglymidodrine is dialyzable. - Recommended general treatment, based on the pharmacology of the drug, includes induced emesis and administration of alpha-sympatholytic drugs (e.g., phentolamine). ## Chronic Overdose There is limited information regarding Chronic Overdose of Midodrine in the drug label. # Pharmacology ## Mechanism of Action - Midodrine hydrochloride forms an active metabolite, desglymidodrine, that is an alpha1-agonist and exerts its actions via activation of the alpha-adrenergic receptors of the arteriolar and venous vasculature, producing an increase in vascular tone and elevation of blood pressure. Desglymidodrine does not stimulate cardiac beta-adrenergic receptors. Desglymidodrine diffuses poorly across the blood-brain barrier and is therefore not associated with effects on the central nervous system. - Administration of midodrine hydrochloride results in a rise in standing, sitting and supine systolic and diastolic blood pressure in patients with orthostatic hypotension of various etiologies. Standing systolic blood pressure is elevated by approximately 15 mmHg to 30 mmHg at 1 hour after a 10 mg dose of midodrine, with some effect persisting for 2 to 3 hours. Midodrine hydrochloride has no clinically significant effect on standing or supine pulse rates in patients with autonomic failure. ## Structure - Midodrine hydrochloride is a vasopressor/antihypotensive agent. Midodrine hydrochloride is an odorless, white, crystalline powder, soluble in water and sparingly soluble in methanol having a pKa of 7.8 (0.3% aqueous solution), a pH of 3.5 to 5.5 (5% aqueous solution) and a melting range of 200°C to 203°C. It is chemically described as: (1) Acetamide, 2-amino-N--monohydrochloride, (±)-; or (2) (±)-2-amino-N-(ß-hydroxy-2,5-dimethoxyphenethyl)acetamide monohydrochloride. Midodrine Hydrochloride’s molecular formula is C12H18N2O4HCl, its molecular weight is 290.7 and its structural formula is: - Each tablet for oral administration contains 2.5 mg, 5 mg or 10 mg of midodrine hydrochloride and the following inactive ingredients: pregelatinized starch (corn starch), microcrystalline cellulose, colloidal silicon dioxide, magnesium stearate. In addition, the 5 mg tablets contain FD&C yellow No. 6 aluminum lake and FD&C red No. 40 aluminum lake and the 10 mg tablets contain FD&C blue No. 2 aluminum lake. ## Pharmacodynamics - Thorough metabolic studies have not been conducted, but it appears that deglycination of midodrine to desglymidodrine takes place in many tissues and both compounds are metabolized in part by the liver. Neither midodrine nor desglymidodrine is a substrate for monoamine oxidase. Renal elimination of midodrine is insignificant. The renal clearance of desglymidodrine is of the order of 385 mL/minute, most, about 80%, by active renal secretion. The actual mechanism of active secretion has not been studied, but it is possible that it occurs by the base-secreting pathway responsible for the secretion of several other drugs that are bases ## Pharmacokinetics - Midodrine hydrochloride is a prodrug, i.e., the therapeutic effect of orally administered midodrine is due to the major metabolite desglymidodrine, formed by deglycination of midodrine. After oral administration, midodrine hydrochloride is rapidly absorbed. The plasma levels of the prodrug peak after about half an hour and decline with a half-life of approximately 25 minutes, while the metabolite reaches peak blood concentrations about 1 to 2 hours after a dose of midodrine and has a half-life of about 3 to 4 hours. The absolute bioavailability of midodrine (measured as desglymidodrine) is 93%. The bioavailability of desglymidodrine is not affected by food. Approximately the same amount of desglymidodrine is formed after intravenous and oral administration of midodrine. Neither midodrine nor desglymidodrine is bound to plasma proteins to any significant extent. ## Nonclinical Toxicology - Carcinogenesis, Mutagenesis, Impairment of Fertility - Long-term studies have been conducted in rats and mice at dosages of 3 to 4 times the maximum recommended daily human dose on a mg/m2 basis, with no indication of carcinogenic effects related to midodrine hydrochloride. Studies investigating the mutagenic potential of midodrine hydrochloride revealed no evidence of mutagenicity. Other than the dominant lethal assay in male mice, where no impairment of fertility was observed, there have been no studies on the effects of midodrine hydrochloride on fertility. # Clinical Studies - Midodrine has been studied in 3 principal controlled trials, one of 3-weeks duration and 2 of 1 to 2 days duration. All studies were randomized, double-blind and parallel-design trials in patients with orthostatic hypotension of any etiology and supine-to-standing fall of systolic blood pressure of at least 15 mmHg accompanied by at least moderate dizziness/lightheadedness. - Patients with pre-existing sustained supine hypertension above 180/110 mmHg were routinely excluded. In a 3-week study in 170 patients, most previously untreated with midodrine, the midodrine-treated patients (10 mg t.i.d., with the last dose not later than 6 P.M.) had significantly higher (by about 20 mmHg) 1-minute standing systolic pressure 1 hour after dosing (blood pressures were not measured at other times) for all 3 weeks. After week 1, midodrine-treated patients had small improvements in dizziness/ lightheadedness/unsteadiness scores and global evaluations, but these effects were made difficult to interpret by a high early drop-out rate (about 25% vs 5% on placebo). Supine and sitting blood pressure rose 16/8 mmHg and 20/10 mmHg, respectively, on average. - In a 2-day study, after open-label midodrine, known midodrine responders received midodrine 10 mg or placebo at 0, 3 and 6 hours. One-minute standing systolic blood pressures were increased 1 hour after each dose by about 15 mmHg and 3 hours after each dose by about 12 mmHg; 3-minute standing pressures were increased also at 1, but not 3, hours after dosing. There were increases in standing time seen intermittently 1 hour after dosing, but not at 3 hours. - In a 1-day, dose-response trial, single doses of 0 mg, 2.5 mg, 10 mg and 20 mg of midodrine were given to 25 patients. The 10 mg and 20 mg doses produced increases in standing 1-minute systolic pressure of about 30 mmHg at 1 hour; the increase was sustained in part for 2 hours after 10 mg and 4 hours after 20 mg. Supine systolic pressure was ≥200 mmHg in 22% of patients on 10 mg and 45% of patients on 20 mg; elevated pressures often lasted 6 hours or more. # How Supplied - Midodrine Hydrochloride Tablets, for oral administration, are available as: - 2.5 mg: White, round, flat-faced, bevelled edge, debossed “E“ over “40” on one side and bisected on the other side and supplied as: - 5 mg: Reddish-orange, round, flat-faced, bevelled edge, debossed “E“ over “43” on one side and bisected on the other side and supplied as: - 10 mg: Blue-grey, round, flat-faced, bevelled edge, debossed, “E“ over “149” on one side and bisected on the other side and supplied as: - Store at 20° to 25°C (68° to 77°F) . - Dispense contents in a tight, light-resistant container as defined in the USP with a child-resistant closure, as required. ## Storage There is limited information regarding Midodrine Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be told that certain agents in over-the-counter products, such as cold remedies and diet aids, can elevate blood pressure and therefore, should be used cautiously with midodrine hydrochloride, as they may enhance or potentiate the pressor effects of midodrine hydrochloride. Patients should also be made aware of the possibility of supine hypertension. They should be told to avoid taking their dose if they are to be supine for any length of time, i.e., they should take their last daily dose of midodrine hydrochloride 3 to 4 hours before bedtime to minimize nighttime supine hypertension. # Precautions with Alcohol - Alcohol-Midodrine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Proamatine® - Orvaten® # Look-Alike Drug Names - Midodrine — Midrin® # Drug Shortage Status # Price	Midodrine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gerald Chi # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Midodrine is an alpha-adrenergic agonist that is FDA approved for the {{{indicationType}}} of symptomatic orthostatic hypotension. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hypertension, piloerection, pruritus, shivering, paresthesia, dysuria, urinary retention, and urinary frequency. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Midodrine hydrochloride tablets are indicated for the treatment of symptomatic orthostatic hypotension (OH). Because midodrine hydrochloride tablets can cause marked elevation of supine blood pressure (BP>200 mmHg systolic), it should be used in patients whose lives are considerably impaired despite standard clinical care, including non-pharmacologic treatment (such as support stockings), fluid expansion and lifestyle alterations. The indication is based on midodrine hydrochloride tablet's effect on increases in 1-minute standing systolic blood pressure, a surrogate marker considered likely to correspond to a clinical benefit. At present, however, clinical benefits of midodrine hydrochloride tablets, principally improved ability to perform life activities, have not been established. Further clinical trials are underway to verify and describe the clinical benefits of midodrine hydrochloride tablets. - After initiation of treatment, midodrine hydrochloride tablets should be continued only for patients who report significant symptomatic improvement. - Dosing Information - The recommended dose of midodrine hydrochloride tablets is 10 mg, 3 times daily. - Dosing should take place during the daytime hours when the patient needs to be upright, pursuing the activities of daily living. A suggested dosing schedule of approximately 4-hour intervals is as follows: shortly before or upon arising in the morning, midday and late afternoon (not later than 6 P.M.). Doses may be given in 3-hour intervals, if required, to control symptoms, but not more frequently. - Single doses as high as 20 mg have been given to patients, but severe and persistent systolic supine hypertension occurs at a high rate (about 45%) at this dose. In order to reduce the potential for supine hypertension during sleep, midodrine hydrochloride tablets should not be given after the evening meal or less than 4 hours before bedtime. Total daily doses greater than 30 mg have been tolerated by some patients, but their safety and usefulness have not been studied systematically or established. Because of the risk of supine hypertension, midodrine hydrochloride tablets should be continued only in patients who appear to attain symptomatic improvement during initial treatment. - The supine and standing blood pressure should be monitored regularly and the administration of midodrine hydrochloride tablets should be stopped if supine blood pressure increases excessively. - Because desglymidodrine is excreted renally, dosing in patients with abnormal renal function should be cautious; although this has not been systematically studied, it is recommended that treatment of these patients be initiated using 2.5 mg doses. - Blood levels of midodrine and desglymidodrine were similar when comparing levels in patients 65 or older vs. younger than 65 and when comparing males vs. females, suggesting dose modifications for these groups are not necessary. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Midodrine in adult patients. ### Non–Guideline-Supported Use - Dosing Information - Midodrine up to 15 mg 3 times daily was used to treat severely symptomatic neurocardiogenic syncope.[1][2] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Safety and effectiveness in pediatric patients have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Midodrine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Midodrine in pediatric patients. # Contraindications - Severe organic heart disease - Acute renal disease - Urinary retention - Pheochromocytoma - Thyrotoxicosis - Persistent and excessive supine hypertension # Warnings - Supine Hypertension - The most potentially serious adverse reaction associated with midodrine hydrochloride therapy is marked elevation of supine arterial blood pressure (supine hypertension). Systolic pressure of about 200 mmHg was seen overall in about 13.4% of patients given 10 mg of midodrine hydrochloride. Systolic elevations of this degree were most likely to be observed in patients with relatively elevated pre-treatment systolic blood pressures (mean 170 mmHg). There is no experience in patients with initial supine systolic pressure above 180 mmHg, as those patients were excluded from the clinical trials. Use of midodrine hydrochloride in such patients is not recommended. Sitting blood pressures were also elevated by midodrine hydrochloride therapy. It is essential to monitor supine and sitting blood pressures in patients maintained on midodrine hydrochloride. ### Precautions - The potential for supine and sitting hypertension should be evaluated at the beginning of midodrine hydrochloride therapy. Supine hypertension can often be controlled by preventing the patient from becoming fully supine, i.e., sleeping with the head of the bed elevated. The patient should be cautioned to report symptoms of supine hypertension immediately. Symptoms may include cardiac awareness, pounding in the ears, headache, blurred vision, etc. - The patient should be advised to discontinue the medication immediately if supine hypertension persists. Blood pressure should be monitored carefully when midodrine hydrochloride is used concomitantly with other agents that cause vasoconstriction, such as phenylephrine, ephedrine, dihydroergotamine, phenylpropanolamine or pseudoephedrine. - A slight slowing of the heart rate may occur after administration of midodrine hydrochloride, primarily due to vagal reflex. Caution should be exercised when midodrine hydrochloride is used concomitantly with cardiac glycosides (such as digitalis), psychopharmacologic agents, beta blockers or other agents that directly or indirectly reduce heart rate. Patients who experience any signs or symptoms suggesting bradycardia (pulse slowing, increased dizziness, syncope, cardiac awareness) should be advised to discontinue midodrine hydrochloride and should be re-evaluated. - Midodrine hydrochloride should be used cautiously in patients with urinary retention problems, as desglymidodrine acts on the alpha-adrenergic receptors of the bladder neck. - Midodrine hydrochloride should be used with caution in orthostatic hypotensive patients who are also diabetic, as well as those with a history of visual problems who are also taking fludrocortisone acetate, which is known to cause an increase in intraocular pressure and glaucoma. - Midodrine hydrochloride use has not been studied in patients with renal impairment. Because desglymidodrine is eliminated via the kidneys and higher blood levels would be expected in such patients, midodrine hydrochloride should be used with caution in patients with renal impairment, with a starting dose of 2.5 mg. Renal function should be assessed prior to initial use of midodrine hydrochloride. - Midodrine hydrochloride use has not been studied in patients with hepatic impairment. Midodrine hydrochloride should be used with caution in patients with hepatic impairment, as the liver has a role in the metabolism of midodrine. - Laboratory Tests - Since desglymidodrine is eliminated by the kidneys and the liver has a role in its metabolism, evaluation of the patient should include assessment of renal and hepatic function prior to initiating therapy and subsequently, as appropriate. # Adverse Reactions ## Clinical Trials Experience - The most frequent adverse reactions seen in controlled trials were supine and sitting hypertension; paresthesia and pruritus, mainly of the scalp; goosebumps; chills; urinary urge; urinary retention and urinary frequency. - The frequency of these events in a 3-week placebo-controlled trial is shown in the following table: - Less frequent adverse reactions were headache; feeling of pressure/fullness in the head; vasodilation/flushing face; confusion/thinking abnormality; dry mouth; nervousness/anxiety and rash. Other adverse reactions that occurred rarely were visual field defect; dizziness; skin hyperesthesia; insomnia; somnolence; erythema multiforme; canker sore; dry skin; dysuria; impaired urination; asthenia; backache; pyrosis; nausea; gastrointestinal distress; flatulence; and leg cramps. - The most potentially serious adverse reaction associated with midodrine hydrochloride therapy is supine hypertension. The feelings of paresthesia, pruritus, piloerection and chills are pilomotor reactions associated with the action of midodrine on the alpha-adrenergic receptors of the hair follicles. Feelings of urinary urgency, urinary retention and urinary frequency are associated with the action of midodrine on the alpha-receptors of the bladder neck. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Midodrine in the drug label. # Drug Interactions - When administered concomitantly with midodrine hydrochloride, cardiac glycosides may enhance or precipitate bradycardia, AV block or arrhythmia. - The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of midodrine hydrochloride. Therefore, caution should be used when midodrine hydrochloride is administered concomitantly with agents that cause vasoconstriction. - Midodrine hydrochloride has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with midodrine hydrochloride. Alpha-adrenergic blocking agents, such as prazosin, terazosin and doxazosin, can antagonize the effects of midodrine hydrochloride. - It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interaction with these drugs. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Midodrine hydrochloride increased the rate of embryo resorption, reduced fetal body weight in rats and rabbits and decreased fetal survival in rabbits when given in doses 13 (rat) and 7 (rabbit) times the maximum human dose based on body surface area (mg/m2). There are no adequate and well-controlled studies in pregnant women. Midodrine hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. No teratogenic effects have been observed in studies in rats and rabbits. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Midodrine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Midodrine during labor and delivery. ### Nursing Mothers - It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when midodrine hydrochloride is administered to a nursing woman. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use There is no FDA guidance on the use of Midodrine with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Midodrine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Midodrine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Midodrine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Midodrine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Midodrine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Midodrine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring - The supine and standing blood pressure should be monitored regularly and the administration of midodrine hydrochloride tablets should be stopped if supine blood pressure increases excessively. # IV Compatibility There is limited information regarding IV Compatibility of Midodrine in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - Symptoms of overdose could include hypertension, piloerection (goosebumps), a sensation of coldness and urinary retention. There are 2 reported cases of overdosage with midodrine hydrochloride, both in young males. One patient ingested midodrine hydrochloride drops, 250 mg, experienced systolic blood pressure greater than 200 mmHg, was treated with an IV injection of 20 mg of phentolamine and was discharged the same night without any complaints. - The other patient ingested 205 mg of midodrine hydrochloride (41 5-mg tablets) and was found lethargic and unable to talk, unresponsive to voice but responsive to painful stimuli, hypertensive and bradycardic. Gastric lavage was performed and the patient recovered fully by the next day without sequelae. The single doses that would be associated with symptoms of overdosage or would be potentially life-threatening are unknown. The oral LD50 is approximately 30 mg/kg to 50 mg/kg in rats, 675 mg/kg in mice and 125 mg/kg to 160 mg/kg in dogs. ### Management - Desglymidodrine is dialyzable. - Recommended general treatment, based on the pharmacology of the drug, includes induced emesis and administration of alpha-sympatholytic drugs (e.g., phentolamine). ## Chronic Overdose There is limited information regarding Chronic Overdose of Midodrine in the drug label. # Pharmacology ## Mechanism of Action - Midodrine hydrochloride forms an active metabolite, desglymidodrine, that is an alpha1-agonist and exerts its actions via activation of the alpha-adrenergic receptors of the arteriolar and venous vasculature, producing an increase in vascular tone and elevation of blood pressure. Desglymidodrine does not stimulate cardiac beta-adrenergic receptors. Desglymidodrine diffuses poorly across the blood-brain barrier and is therefore not associated with effects on the central nervous system. - Administration of midodrine hydrochloride results in a rise in standing, sitting and supine systolic and diastolic blood pressure in patients with orthostatic hypotension of various etiologies. Standing systolic blood pressure is elevated by approximately 15 mmHg to 30 mmHg at 1 hour after a 10 mg dose of midodrine, with some effect persisting for 2 to 3 hours. Midodrine hydrochloride has no clinically significant effect on standing or supine pulse rates in patients with autonomic failure. ## Structure - Midodrine hydrochloride is a vasopressor/antihypotensive agent. Midodrine hydrochloride is an odorless, white, crystalline powder, soluble in water and sparingly soluble in methanol having a pKa of 7.8 (0.3% aqueous solution), a pH of 3.5 to 5.5 (5% aqueous solution) and a melting range of 200°C to 203°C. It is chemically described as: (1) Acetamide, 2-amino-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]-monohydrochloride, (±)-; or (2) (±)-2-amino-N-(ß-hydroxy-2,5-dimethoxyphenethyl)acetamide monohydrochloride. Midodrine Hydrochloride’s molecular formula is C12H18N2O4HCl, its molecular weight is 290.7 and its structural formula is: - Each tablet for oral administration contains 2.5 mg, 5 mg or 10 mg of midodrine hydrochloride and the following inactive ingredients: pregelatinized starch (corn starch), microcrystalline cellulose, colloidal silicon dioxide, magnesium stearate. In addition, the 5 mg tablets contain FD&C yellow No. 6 aluminum lake and FD&C red No. 40 aluminum lake and the 10 mg tablets contain FD&C blue No. 2 aluminum lake. ## Pharmacodynamics - Thorough metabolic studies have not been conducted, but it appears that deglycination of midodrine to desglymidodrine takes place in many tissues and both compounds are metabolized in part by the liver. Neither midodrine nor desglymidodrine is a substrate for monoamine oxidase. Renal elimination of midodrine is insignificant. The renal clearance of desglymidodrine is of the order of 385 mL/minute, most, about 80%, by active renal secretion. The actual mechanism of active secretion has not been studied, but it is possible that it occurs by the base-secreting pathway responsible for the secretion of several other drugs that are bases ## Pharmacokinetics - Midodrine hydrochloride is a prodrug, i.e., the therapeutic effect of orally administered midodrine is due to the major metabolite desglymidodrine, formed by deglycination of midodrine. After oral administration, midodrine hydrochloride is rapidly absorbed. The plasma levels of the prodrug peak after about half an hour and decline with a half-life of approximately 25 minutes, while the metabolite reaches peak blood concentrations about 1 to 2 hours after a dose of midodrine and has a half-life of about 3 to 4 hours. The absolute bioavailability of midodrine (measured as desglymidodrine) is 93%. The bioavailability of desglymidodrine is not affected by food. Approximately the same amount of desglymidodrine is formed after intravenous and oral administration of midodrine. Neither midodrine nor desglymidodrine is bound to plasma proteins to any significant extent. ## Nonclinical Toxicology - Carcinogenesis, Mutagenesis, Impairment of Fertility - Long-term studies have been conducted in rats and mice at dosages of 3 to 4 times the maximum recommended daily human dose on a mg/m2 basis, with no indication of carcinogenic effects related to midodrine hydrochloride. Studies investigating the mutagenic potential of midodrine hydrochloride revealed no evidence of mutagenicity. Other than the dominant lethal assay in male mice, where no impairment of fertility was observed, there have been no studies on the effects of midodrine hydrochloride on fertility. # Clinical Studies - Midodrine has been studied in 3 principal controlled trials, one of 3-weeks duration and 2 of 1 to 2 days duration. All studies were randomized, double-blind and parallel-design trials in patients with orthostatic hypotension of any etiology and supine-to-standing fall of systolic blood pressure of at least 15 mmHg accompanied by at least moderate dizziness/lightheadedness. - Patients with pre-existing sustained supine hypertension above 180/110 mmHg were routinely excluded. In a 3-week study in 170 patients, most previously untreated with midodrine, the midodrine-treated patients (10 mg t.i.d., with the last dose not later than 6 P.M.) had significantly higher (by about 20 mmHg) 1-minute standing systolic pressure 1 hour after dosing (blood pressures were not measured at other times) for all 3 weeks. After week 1, midodrine-treated patients had small improvements in dizziness/ lightheadedness/unsteadiness scores and global evaluations, but these effects were made difficult to interpret by a high early drop-out rate (about 25% vs 5% on placebo). Supine and sitting blood pressure rose 16/8 mmHg and 20/10 mmHg, respectively, on average. - In a 2-day study, after open-label midodrine, known midodrine responders received midodrine 10 mg or placebo at 0, 3 and 6 hours. One-minute standing systolic blood pressures were increased 1 hour after each dose by about 15 mmHg and 3 hours after each dose by about 12 mmHg; 3-minute standing pressures were increased also at 1, but not 3, hours after dosing. There were increases in standing time seen intermittently 1 hour after dosing, but not at 3 hours. - In a 1-day, dose-response trial, single doses of 0 mg, 2.5 mg, 10 mg and 20 mg of midodrine were given to 25 patients. The 10 mg and 20 mg doses produced increases in standing 1-minute systolic pressure of about 30 mmHg at 1 hour; the increase was sustained in part for 2 hours after 10 mg and 4 hours after 20 mg. Supine systolic pressure was ≥200 mmHg in 22% of patients on 10 mg and 45% of patients on 20 mg; elevated pressures often lasted 6 hours or more. # How Supplied - Midodrine Hydrochloride Tablets, for oral administration, are available as: - 2.5 mg: White, round, flat-faced, bevelled edge, debossed “E“ over “40” on one side and bisected on the other side and supplied as: - 5 mg: Reddish-orange, round, flat-faced, bevelled edge, debossed “E“ over “43” on one side and bisected on the other side and supplied as: - 10 mg: Blue-grey, round, flat-faced, bevelled edge, debossed, “E“ over “149” on one side and bisected on the other side and supplied as: - Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. - Dispense contents in a tight, light-resistant container as defined in the USP with a child-resistant closure, as required. ## Storage There is limited information regarding Midodrine Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be told that certain agents in over-the-counter products, such as cold remedies and diet aids, can elevate blood pressure and therefore, should be used cautiously with midodrine hydrochloride, as they may enhance or potentiate the pressor effects of midodrine hydrochloride. Patients should also be made aware of the possibility of supine hypertension. They should be told to avoid taking their dose if they are to be supine for any length of time, i.e., they should take their last daily dose of midodrine hydrochloride 3 to 4 hours before bedtime to minimize nighttime supine hypertension. # Precautions with Alcohol - Alcohol-Midodrine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Proamatine® - Orvaten®[3] # Look-Alike Drug Names - Midodrine — Midrin®[4] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Midodrine
ed51c16e79f0806f0af0c01712ba9c5035ec8fe6	wikidoc	Miglustat	Miglustat # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Miglustat is a glucosylceramide synthase inhibitor that is FDA approved for the treatment of adult patients with mild/moderate type 1 Gaucher disease for whom enzyme replacement therapy is not a therapeutic option. Common adverse reactions include diarrhea, weight loss, stomach pain, gas, nausea, vomiting, headache, migraine, tremor, leg cramps, dizziness, weakness, vision problems, thrombocytopenia, muscle cramps, back pain, constipation, dry mouth, heaviness in arms and legs, memory loss, unsteady walking, anorexia, indigestion, paresthesia, stomach bloating, stomach pain not related to food, and menstrual changes. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Zavesca® is a glucosylceramide synthase inhibitor indicated as monotherapy for the treatment of adult patients with mild to moderate type 1 Gaucher disease for whom enzyme replacement therapy is not a therapeutic option (e.g. due to allergy, hypersensitivity, or poor venous access). - The recommended dose for the treatment of adult patients with type 1 Gaucher disease is one 100 mg capsule administered orally three times a day at regular intervals. If a dose is missed, the next Zavesca capsule should be taken at the next scheduled time. - It may be necessary to reduce the dose to one 100 mg capsule once or twice a day in some patients due to adverse reactions, such as tremor or diarrhea. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Miglustat in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Miglustat in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Miglustat in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Miglustat in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Miglustat in pediatric patients. # Contraindications - None. # Warnings ### Precautions - Therapy should be directed by physicians knowledgeable in the management of patients with Gaucher disease. - Peripheral Neuropathy - In clinical trials, cases of peripheral neuropathy have been reported in 3% of Gaucher's patients treated with Zavesca. All patients receiving Zavesca treatment should undergo baseline and repeat neurological evaluations at approximately 6-month intervals. Patients who develop symptoms of peripheral neuropathy such as pain, weakness, numbness and tingling should have a careful re-assessment of the risk/benefit of Zavesca therapy, and cessation of treatment may be considered. - Tremor - Approximately 30% of patients have reported tremor or exacerbation of existing tremor on treatment. These tremors were described as an exaggerated physiological tremor of the hands. Tremor usually began within the first month of therapy and in many cases resolved between 1 to 3 months during treatment. Reduce dose to ameliorate tremor or discontinue treatment if tremor does not resolve within days of dose reduction. - Diarrhea and Weight Loss - Diarrhea and weight loss were common in clinical studies of patients treated with Zavesca, occurring in approximately 85% and up to 65% of treated patients, respectively. Diarrhea appears to be the result of the inhibitory activity of Zavesca on intestinal disaccharidases such as sucrase-isomaltase in the gastrointestinal tract leading to reduced absorption of dietary disaccharides in the small intestine, with a resultant osmotic diarrhea. It is unclear if weight loss results from the diarrhea and associated gastrointestinal complaints, a decrease in food intake, or a combination of these or other factors. The incidence of weight loss was most evident in the first 12 months of treatment. Diarrhea decreased over time with continued Zavesca treatment, and may respond to individualized diet modification (e.g., reduction of sucrose, lactose and other carbohydrate intake), to taking Zavesca between meals, and/or to anti-diarrheal medications, most commonly loperamide. Patients may be instructed to avoid high carbohydrate content foods during treatment with Zavesca if they present with diarrhea. - Patients with persistent gastrointestinal events that continue during treatment with Zavesca, and who do not respond to usual interventions (e.g. diet modification), should be evaluated to determine whether significant underlying gastrointestinal disease is present. The safety of treatment with Zavesca has not been evaluated in patients with significant gastrointestinal disease, such as inflammatory bowel disease, and continued treatment of these patients with Zavesca should occur only after consideration of the risks and benefits of continued treatment. - Reductions in Platelet Count - In clinical trials evaluating the use of Zavesca for treatment of indications other than type 1 Gaucher disease, mild reductions in platelet counts without association with bleeding were observed in some patients; approximately 40% of patients in this trial had low platelet counts (defined as below 150 × 109/L) before starting treatment with Zavesca. Monitoring of platelet counts is recommended in patients with type 1 Gaucher disease. Mild reductions in platelet counts without association with bleeding were observed in patients with type 1 Gaucher disease who were switched from enzyme replacement therapy (ERT) to Zavesca. # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. - The data described below reflect exposure of 80 patients with type 1 Gaucher disease in two open-label, uncontrolled, monotherapy trials, one open-label, active-controlled trial, and two extensions, who received Zavesca at doses ranging from 50mg to 200 mg three times daily. Patients were aged 18 to 69 years at first treatment. The population was evenly distributed by gender. - The most common serious adverse reaction reported with Zavesca treatment in clinical trials was peripheral neuropathy. - The most commonly reported adverse reactions in patients treated with Zavesca (occuring in ≥5%) that were considered related to Zavesca are shown in Tables 1 and 2. - The most common adverse reactions requiring intervention were diarrhea and tremor. - In two open-label, uncontrolled monotherapy trials, adult type 1 Gaucher disease patients were treated with Zavesca at a starting dose of 100 mg three times daily (dose range 100 to 200 mg three times daily) for up to 12 months in 28 patients , or at a dose of 50 mg three times daily for up to 6 months in 18 patients . Table 1 below lists adverse reactions that occurred during the trials in ≥5% of patients. - In an open-label, active-controlled study, 36 adult type 1 Gaucher disease patients were treated with Zavesca, imiglucerase, or Zavesca plus imiglucerase for up to 12 months. Table 2 lists adverse reactions that occurred during the trial in ≥5% of patients. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Miglustat in the drug label. # Drug Interactions - While co-administration of Zavesca appeared to increase the clearance of imiglucerase by 70%, these results are not conclusive because of the small number of patients studied and because patients took variable doses of imiglucerase. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Risk Summary - There are no adequate and well controlled studies with Zavesca in pregnant women. However, animal reproduction studies have been conducted for Zavesca. In these animal studies, decreased live births and decreased fetal weight were observed in rats orally dosed with miglustat prior to mating and during organogenesis at doses with exposures at and greater than 2 times the human therapeutic systemic exposure. Maternal death and decreased body weight gain were observed in rabbits orally dosed with miglustat during organogenesis at doses with exposures less than the human therapeutic systemic exposure. Zavesca should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - Clinical Considerations - Disease-associated maternal and embryo-fetal risk - Women with Type 1 Gaucher disease have an increased risk of spontaneous abortion, especially if disease symptoms are not treated and controlled pre-conception and during a pregnancy. Pregnancy may exacerbate existing Type 1 Gaucher disease symptoms or result in new disease manifestations. Type 1 Gaucher disease manifestations may lead to adverse pregnancy outcomes including, hepatosplenomegaly which can interfere with the normal growth of a pregnancy and thrombocytopenia which can lead to increased bleeding and possible hemorrhage. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Miglustat in women who are pregnant. ### Labor and Delivery - Dystocia and delayed parturition were observed in rats dosed with miglustat gestation day 6 through lactation at systemic exposure ≥2 times the human therapeutic systemic exposure. ### Nursing Mothers - It is not known whether miglustat is present in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from miglustat, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the lactating woman. ### Pediatric Use - The safety and effectiveness of Zavesca in pediatric patients have not been established. - In a combined clinical trial safety data set of 45 patients less than 18 years of age exposed to Zavesca in indications other than type 1 Gaucher disease, the median weight and height percentiles adjusted for age and gender decreased during the first year of treatment but then stabilized. The mean length of exposure in these studies ranged from 2 to 2.6 years; some pediatric patients were exposed for up to 4 years. However, the effect of Zavesca on long-term gain in weight and height in pediatric patients is unclear. ### Geriatic Use - Clinical studies of Zavesca did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, and cardiac function and of concomitant disease or other drug therapy. ### Gender There is no FDA guidance on the use of Miglustat with respect to specific gender populations. ### Race There is no FDA guidance on the use of Miglustat with respect to specific racial populations. ### Renal Impairment - Miglustat is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. - In patients with mild renal impairment (adjusted creatinine clearance 50-70 mL/min/1.73 m2), Zavesca administration should commence at a dose of 100 mg twice per day. - In patients with moderate renal impairment (adjusted creatinine clearance of 30-50 mL/min/1.73 m2), Zavesca administration should commence at a dose of 100 mg once a day. - Use of Zavesca in patients with severe renal impairment (creatinine clearance < 30 mL/min/1.73 m2) is not recommended. - Since elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. The impact of hemodialysis on the disposition of Zavesca has not been investigated. ### Hepatic Impairment There is no FDA guidance on the use of Miglustat in patients with hepatic impairment. ### Females of Reproductive Potential and Males - Infertility - No effect on sperm concentration, motility, or morphology was seen in 7 healthy adult men who received miglustat 100 mg, orally, twice daily for 6 weeks. Decreased spermatogenesis with altered sperm morphology and motility and decreased fertility were observed in rats orally dosed with miglustat 14 days prior to mating with doses at exposures less than the human therapeutic systemic exposure based on body surface area comparisons (mg/m2). Decreased spermatogenesis was reversible in rats following 6 weeks of drug withdrawal. ### Immunocompromised Patients There is no FDA guidance one the use of Miglustat in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Miglustat in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Miglustat in the drug label. # Overdosage ## Chronic Overdose There is limited information regarding Chronic Overdose of Miglustat in the drug label. # Pharmacology ## Mechanism of Action - Type 1 Gaucher disease is caused by a functional deficiency of glucocerebrosidase, the enzyme that mediates the degradation of the glycosphingolipid glucosylceramide. - Miglustat functions as a competitive and reversible inhibitor of the enzyme glucosylceramide synthase, the initial enzyme in a series of reactions which results in the synthesis of most glycosphingolipids. - Zavesca helps reduce the rate of glycosphingolipid biosynthesis so that the amount of glycosphingolipid substrate is reduced to a level which allows the residual activity of the deficient glucocerebrosidase enzyme to be more effective (substrate reduction therapy). In vitro and in vivo studies have shown that miglustat can reduce the synthesis of glucosylceramide-based glycosphingolipids. ## Structure - Zavesca (miglustat capsules, 100 mg) is an inhibitor of the enzyme glucosylceramide synthase, which is a glucosyl transferase enzyme responsible for the first step in the synthesis of most glycosphingolipids. Zavesca is an N-alkylated imino sugar, a synthetic analog of D-glucose. - The chemical name for miglustat is 1,5-(butylimino)-1,5-dideoxy-D-glucitol with the chemical formula C10H21NO4 and a molecular weight of 219.28. - Miglustat is a white to off-white crystalline solid and has a bitter taste. It is highly soluble in water (>1000 mg/mL as a free base). - Zavesca is supplied in hard gelatin capsules each containing 100 mg miglustat for oral administration. Each Zavesca 100 mg capsule also contains sodium starch glycollate, povidone (K30), and magnesium stearate. Ingredients in the capsule shell include gelatin and titanium dioxide, and the shells are printed with edible ink consisting of black iron oxide and shellac. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Miglustat in the drug label. ## Pharmacokinetics - Absorption: After a 100 mg oral dose, the time to maximum observed plasma concentration of miglustat (tmax) ranged from 2 to 2.5 hours in Gaucher patients. Plasma concentrations show a biexponential decline, characterized by a short distribution phase and a longer elimination phase. The effective half-life of miglustat is approximately 6 to 7 hours, which predicts that steady-state will be achieved by 1.5 to 2 days following the start of three times daily dosing. - Miglustat, dosed at 50 and 100 mg three times daily in Gaucher patients, exhibits dose-proportional pharmacokinetics. The pharmacokinetics of miglustat were not altered after repeated dosing three times daily for up to 12 months. - In healthy subjects, co-administration of Zavesca with food results in a decrease in the rate of absorption of miglustat (maximum plasma concentration was decreased by 36% and tmax delayed 2 h) but had no statistically significant effect on the extent of absorption of miglustat (area-under-the-plasma-concentration time curve was decreased by 14%). The mean oral bioavailability of a 100-mg miglustat capsule is about 97% relative to an oral solution administered under fasting conditions. The pharmacokinetics of miglustat were similar between adult type 1 Gaucher disease patients and healthy subjects after a single dose administration of miglustat 100 mg. - Distribution: Miglustat does not bind to plasma proteins. Mean apparent volume of distribution of miglustat is 83-105 liters in Gaucher patients. At steady state, the concentration of miglustat in cerebrospinal fluid of six non-Gaucher patients was 31.4-67.2% of that in plasma, indicating that miglustat crosses the blood brain barrier. - Metabolism and Excretion: The major route of excretion of miglustat is via kidney. Following administration of a single dose of 100 mg 14C-miglustat to healthy volunteers, 83% of the radioactivity was recovered in urine and 12% in feces. In healthy subjects, 67% of the administered dose was excreted unchanged in urine over 72 hours. The most abundant metabolite in urine was miglustat glucuronide accounting for 5% of the dose. The terminal half-life of radioactivity in plasma was 150 hours, suggesting the presence of one or more metabolites with a prolonged half-life. The metabolite accounting for this observation has not been identified, but may accumulate and reach concentrations exceeding those of miglustat at steady state. - Specific Populations - Gender: There was no statistically significant gender difference in miglustat pharmacokinetics, based on pooled data analysis. - Race: Ethnic differences in miglustat pharmacokinetics have not been evaluated in Gaucher patients. However, apparent oral clearance of miglustat in patients of Ashkenazi Jewish descent was not statistically different to that in others (1 Asian and 15 Caucasians), based on a cross-study analysis. - Hepatic Impairment: No studies have been performed to assess the pharmacokinetics of miglustat in patients with hepatic impairment. - Renal Impairment: Limited data in non-Gaucher patients with impaired renal function indicate that the apparent oral clearance (CL/F) of miglustat decreases with decreasing renal function. While the number of subjects with mild and moderate renal impairment was very small, the data suggest an approximate decrease in the apparent oral clearance of 40% and 60% respectively, in mild and moderate renal impairment, justifying the need to decrease the dosing of miglustat in such patients dependent upon creatinine clearance levels. - Data in severe renal impairment are limited to two patients with creatinine clearances in the range 18-29 mL/min and cannot be extrapolated below this range. These data suggest a decrease in CL/F by at least 70% in patients with severe renal impairment. - Drug Interaction Studies - Miglustat does not inhibit the metabolism of various substrates of cytochrome P450 enzymes including, CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP4A11 in vitro; consequently significant interactions via inhibition of these enzymes are unlikely with drugs that are substrates of cytochrome P450 enzymes. - Drug interaction between Zavesca (miglustat 100 mg orally three times daily) and imiglucerase 7.5 or 15 U/kg/day was assessed in imiglucerase-stabilized patients after one month of co-administration. There was no significant effect of imiglucerase on the pharmacokinetics of miglustat, with the co-administration of imiglucerase and miglustat resulting in a 22% reduction in Cmax and a 14% reduction in the AUC for miglustat. While Zavesca appeared to increase the clearance of imiglucerase by 70%, these results are not conclusive because of the small number of subjects studied and because patients took variable doses of imiglucerase. - Concomitant therapy with loperamide during clinical trials did not appear to significantly alter the pharmacokinetics of miglustat. ## Nonclinical Toxicology - Carcinogenesis: Two-year carcinogenicity studies have been conducted with miglustat in CD-1 mice at oral doses up to 500 mg/kg/day and in Sprague Dawley rats at oral doses up to 180 mg/kg/day. Oral administration of miglustat for 104 weeks produced mucinous adenocarcinomas of the large intestine at 210, 420 and 500 mg/kg/day (about 3, 6 and 7 times the recommended human dose, respectively, based on the body surface area) in male mice and at 420 and 500 mg/kg/day (about 6 and 7 times the recommended human dose, based on the body surface area) in female mice. The adenocarcinomas were considered rare in CD-1 mice and occurred in the presence of inflammatory and hyperplastic lesions in the large intestine of both males and females. In rats, oral administration of miglustat for 100 weeks produced increased incidences of interstitial cell adenomas of the testis at 30, 60 and 180 mg/kg/day (about 1, 2 and 5 times the recommended human dose, respectively, based on the body surface area). - Mutagenesis: Miglustat was not mutagenic or clastogenic in a battery of in vitro and in vivo assays including the bacterial reverse mutation (Ames), chromosomal aberration (in human lymphocytes), gene mutation in mammalian cells (Chinese hamster ovary), and mouse micronucleus assays. - Impairment of Fertility: Male rats, given 20 mg/kg/day miglustat by (systemic exposure less than the human therapeutic systemic exposure based on body surface area comparisons, mg/m2) oral gavage 14 days prior to mating, had decreased spermatogenesis with altered sperm morphology and motility and decreased fertility. Decreased spermatogenesis was reversible following 6 weeks of drug withdrawal. A higher dose of 60 mg/kg/day (2 times the human therapeutic systemic exposure, based on body surface area comparison, mg/m2) resulted in seminiferous tubule and testicular atrophy/degeneration. - Female rats were given oral gavage doses of 20, 60, 180 mg/kg/day beginning 14 days before mating and continuing through gestation. Effects observed at 20 mg/kg/day (systemic exposure less than the human therapeutic systemic exposure, based on body surface area comparisons) included decreased corpora lutea, increased postimplantation loss, and decreased live births. - Animal Toxicology and/or Pharmacology - Histopathology findings in the absence of clinical signs in the central nervous system of the monkey (brain, spine) that included vascular mineralization, in addition to mineralization and necrosis of white matter were observed at >750 mg/kg/day (4 times the human therapeutic systemic exposure based on area-under-the-plasma-concentration curve comparisons) in a 52-week oral toxicity study using doses of 750 and 2000 mg/kg/d. Vacuolization of white matter was observed in rats dosed orally by gavage at ≥ 180 mg/kg/d (6 times the human therapeutic exposure based on surface area comparisons, mg/m2) in a 4-week study using doses of 180, 840, and 4200 mg/kg/d. Vacuolization can sometimes occur as an artifact of tissue processing. Findings in dogs included tremor and absent corneal reflexes at 105 mg/kg/day (10 times the human therapeutic systemic exposure, based on body surface area comparisons, mg/m2) after a 4-week oral gavage toxicity study using doses of 35, 70, 105, and 140 mg/kg/d. Ataxia, diminished/absent pupillary, palpebral, or patellar reflexes were observed in a dog at ≥495 mg/kg/day (50 times the human therapeutic systemic exposure based on body surface area comparisons, mg/m2), in a 2-week oral gavage toxicity study using doses of 85, 165, 495, and 825 mg/kg/d. - Cataracts were observed in rats at ≥180 mg/kg/day (4 times the human therapeutic systemic exposure, based on AUC) in a 52-week oral gavage toxicity study using doses of 180, 420, 840, and 1680 mg/kg/d. - Gastrointestinal necrosis, inflammation, and hemorrhage were observed in dogs at ≥ 85 mg/kg/day (9 times the human therapeutic systemic exposure based on body surface area comparisons, mg/m2) after a 2-week oral (capsule) toxicity study using doses of 85, 165, 495, and 825 mg/kg/d. Similar GI toxicity occurred in rats at 1200 mg/kg/day (7 times the human therapeutic systemic exposure, based on AUC) in a 26-week oral gavage toxicity study using doses of 300, 600, and 1200 mg/kg/d. In monkeys, similar GI toxicity occurred at ≥750 mg/kg/day (6 times the human therapeutic systemic exposure based on AUC) following a 52-week oral gavage toxicity study using doses of 750 and 2000 mg/kg/d. # Clinical Studies - The efficacy of Zavesca in type 1 Gaucher disease has been investigated in two open-label, uncontrolled trials and one randomized, open-label, active-controlled trial with enzyme replacement given as imiglucerase. Patients who received Zavesca were treated with doses ranging from 100 to 600 mg a day, although the majority of patients were maintained on doses between 200 to 300 mg a day. Efficacy parameters included the evaluation of liver and spleen organ volume, hemoglobin concentration, and platelet count. A total of 80 patients were exposed to Zavesca during the three trials and their extension period. - Open-Label Uncontrolled Monotherapy Trials - In Study 1, Zavesca was administered at a starting dose of 100 mg three times daily for 12 months (dose range of 100 once-daily to 200 mg three times daily) to 28 adult patients with type 1 Gaucher disease, who were unable to receive enzyme replacement therapy and who had not taken enzyme replacement therapy in the preceding 6 months. Twenty-two patients completed the trial. After 12 months of treatment, the results showed significant mean percent reductions from baseline in liver volume of 12% and spleen volume of 19%, a non-significant increase from baseline in mean absolute hemoglobin concentration of 0.26 g/dL and a mean absolute increase from baseline in platelet counts of 8 × 109/L (See Tables 3-6). - In Study 2, Zavesca was administered at a dose of 50 mg three times daily for 6 months to 18 adult patients with type 1 Gaucher disease who were unable to receive enzyme replacement therapy and who had not taken enzyme replacement therapy in the preceding 6 months. Seventeen patients completed the trial. After 6 months of treatment, the results showed significant mean percent reductions from baseline in liver volume of 6% and spleen volume of 5%. There was a non-significant mean absolute decrease from baseline in hemoglobin concentration of 0.13 g/dL and a non-significant mean absolute increase from baseline in platelet counts of 5 × 109/L (See Tables 3-6). - Extension Period - Eighteen patients were enrolled in a 12-month extension to Study 1. A subset of patients continuing in the extension had larger mean baseline liver volumes, and lower mean baseline platelet counts and hemoglobin concentrations than the original study population (See Tables 3-6). After a total of 24 months of treatment, there were significant mean decreases from baseline in liver and spleen organ volumes of 15% and 27%, respectively, and significant mean absolute increases from baseline in hemoglobin concentration and platelet count of 0.9 g/dL and 14 × 109/L, respectively (See Tables 3-6). - Sixteen patients were enrolled in a 6-month extension to Study 2. After a total of 12 months of treatment, there was a mean decrease from baseline in spleen organ volume of 10%, whereas the mean percent decrease in liver organ volume remained at 6%. There were no significant changes in hemoglobin concentrations or platelet counts (See Tables 3-6). - Liver volume results from Studies 1 and 2 and their extensions are summarized in Table 3: - Open-Label Active-Controlled Trial - Study 3 was an open-label, randomized, active-controlled study of 36 adult patients with type 1 Gaucher disease, who had been receiving enzyme replacement therapy with imiglucerase for a minimum of 2 years prior to study entry. Patients were randomized 1:1:1 to one of three treatment groups, as follows: - Zavesca 100 mg three times daily alone imiglucerase (patient's usual dose) alone Zavesca 100 mg three times daily and imiglucerase (usual dose) - Zavesca 100 mg three times daily alone - imiglucerase (patient's usual dose) alone - Zavesca 100 mg three times daily and imiglucerase (usual dose) - Patients were treated for 6 months, and 33 patients completed the study. Because Zavesca is only indicated as monotherapy, the results for the monotherapy arms are described below. At Month 6, the results showed a decrease in mean percent change in liver volume in the Zavesca treatment group compared to the imiglucerase alone group. There were no significant differences between the groups for mean absolute changes in liver and spleen volume and hemoglobin concentration. However, there was a significant difference between the Zavesca alone and imiglucerase alone groups in platelet counts at Month 6, with the Zavesca alone group having a mean absolute decrease in platelet count of 21.6 × 109/L and the imiglucerase alone group having a mean absolute increase in platelet count of 10.1 × 109/L (See Tables 7-10). - Extension period - Twenty-nine patients were enrolled in a 6-month extension to Study 3. In the extension phase, all 29 patients had withdrawn from imiglucerase and received open-label Zavesca 100 mg three times daily monotherapy. At Month 12, the results showed non-significant decreases in platelet counts from baseline in all the treatment groups (by original randomization). There was a significant decrease in platelet counts from Month 6 to Month 12 in the group originally randomized to treatment with imiglucerase, and a continued decrease in platelet counts in the group originally randomized to Zavesca alone. There were no significant changes in any treatment group for liver volume, spleen volume, or hemoglobin concentration (See Tables 7-10). - Liver volume results from Study 3 and extension are summarized in Table 7: - Patients with platelet counts above 150 × 109/L at baseline who were randomized to Zavesca treatment had significant decreases in platelet counts at Month 12. # How Supplied - Zavesca® is supplied in hard gelatin capsules containing 100 mg miglustat. Zavesca® 100 mg capsules are white opaque with "OGT 918" printed in black on the cap and "100" printed in black on the body. - Zavesca® 100 mg capsules are packed in blister cards. Five blister cards of 18 capsules are supplied in each carton. - NDC 66215-201-90: carton containing 90 capsules. - NDC 66215-201-18: blister card containing 18 capsules - Storage: Store at 20°C to 25°C (68° to 77°F). Brief exposure to 15°C to 30°C (59°F to 86°F) permitted. ## Storage There is limited information regarding Miglustat Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise patients that the most common serious adverse reactions reported with Zavesca are peripheral neuropathy. Advise patients to promptly report any numbness, tingling, pain, or burning in the hands and feet. - Advise patients that other adverse reactions include tremor and reductions in platelet counts. Advise patients to promptly report the development of tremor or worsening in an existing tremor. - Advise patients that other serious adverse reactions include diarrhea and weight loss. Advise patients to adhere to dietary instructions. - Advise patients to take the next Zavesca capsule at the next scheduled time if a dose is missed. - Inform patients of the potential risks and benefits of Zavesca and of alternative modes of therapy. # Precautions with Alcohol - Alcohol-Miglustat interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - ZAVESCA® # Look-Alike Drug Names - Zavesca (miglustat)® — Zavesca (escitalopram® # Drug Shortage Status # Price	Miglustat Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Miglustat is a glucosylceramide synthase inhibitor that is FDA approved for the treatment of adult patients with mild/moderate type 1 Gaucher disease for whom enzyme replacement therapy is not a therapeutic option. Common adverse reactions include diarrhea, weight loss, stomach pain, gas, nausea, vomiting, headache, migraine, tremor, leg cramps, dizziness, weakness, vision problems, thrombocytopenia, muscle cramps, back pain, constipation, dry mouth, heaviness in arms and legs, memory loss, unsteady walking, anorexia, indigestion, paresthesia, stomach bloating, stomach pain not related to food, and menstrual changes. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Zavesca® is a glucosylceramide synthase inhibitor indicated as monotherapy for the treatment of adult patients with mild to moderate type 1 Gaucher disease for whom enzyme replacement therapy is not a therapeutic option (e.g. due to allergy, hypersensitivity, or poor venous access). - The recommended dose for the treatment of adult patients with type 1 Gaucher disease is one 100 mg capsule administered orally three times a day at regular intervals. If a dose is missed, the next Zavesca capsule should be taken at the next scheduled time. - It may be necessary to reduce the dose to one 100 mg capsule once or twice a day in some patients due to adverse reactions, such as tremor or diarrhea. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Miglustat in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Miglustat in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Miglustat in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Miglustat in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Miglustat in pediatric patients. # Contraindications - None. # Warnings ### Precautions - Therapy should be directed by physicians knowledgeable in the management of patients with Gaucher disease. - Peripheral Neuropathy - In clinical trials, cases of peripheral neuropathy have been reported in 3% of Gaucher's patients treated with Zavesca. All patients receiving Zavesca treatment should undergo baseline and repeat neurological evaluations at approximately 6-month intervals. Patients who develop symptoms of peripheral neuropathy such as pain, weakness, numbness and tingling should have a careful re-assessment of the risk/benefit of Zavesca therapy, and cessation of treatment may be considered. - Tremor - Approximately 30% of patients have reported tremor or exacerbation of existing tremor on treatment. These tremors were described as an exaggerated physiological tremor of the hands. Tremor usually began within the first month of therapy and in many cases resolved between 1 to 3 months during treatment. Reduce dose to ameliorate tremor or discontinue treatment if tremor does not resolve within days of dose reduction. - Diarrhea and Weight Loss - Diarrhea and weight loss were common in clinical studies of patients treated with Zavesca, occurring in approximately 85% and up to 65% of treated patients, respectively. Diarrhea appears to be the result of the inhibitory activity of Zavesca on intestinal disaccharidases such as sucrase-isomaltase in the gastrointestinal tract leading to reduced absorption of dietary disaccharides in the small intestine, with a resultant osmotic diarrhea. It is unclear if weight loss results from the diarrhea and associated gastrointestinal complaints, a decrease in food intake, or a combination of these or other factors. The incidence of weight loss was most evident in the first 12 months of treatment. Diarrhea decreased over time with continued Zavesca treatment, and may respond to individualized diet modification (e.g., reduction of sucrose, lactose and other carbohydrate intake), to taking Zavesca between meals, and/or to anti-diarrheal medications, most commonly loperamide. Patients may be instructed to avoid high carbohydrate content foods during treatment with Zavesca if they present with diarrhea. - Patients with persistent gastrointestinal events that continue during treatment with Zavesca, and who do not respond to usual interventions (e.g. diet modification), should be evaluated to determine whether significant underlying gastrointestinal disease is present. The safety of treatment with Zavesca has not been evaluated in patients with significant gastrointestinal disease, such as inflammatory bowel disease, and continued treatment of these patients with Zavesca should occur only after consideration of the risks and benefits of continued treatment. - Reductions in Platelet Count - In clinical trials evaluating the use of Zavesca for treatment of indications other than type 1 Gaucher disease, mild reductions in platelet counts without association with bleeding were observed in some patients; approximately 40% of patients in this trial had low platelet counts (defined as below 150 × 109/L) before starting treatment with Zavesca. Monitoring of platelet counts is recommended in patients with type 1 Gaucher disease. Mild reductions in platelet counts without association with bleeding were observed in patients with type 1 Gaucher disease who were switched from enzyme replacement therapy (ERT) to Zavesca. # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. - The data described below reflect exposure of 80 patients with type 1 Gaucher disease in two open-label, uncontrolled, monotherapy trials, one open-label, active-controlled trial, and two extensions, who received Zavesca at doses ranging from 50mg to 200 mg three times daily. Patients were aged 18 to 69 years at first treatment. The population was evenly distributed by gender. - The most common serious adverse reaction reported with Zavesca treatment in clinical trials was peripheral neuropathy. - The most commonly reported adverse reactions in patients treated with Zavesca (occuring in ≥5%) that were considered related to Zavesca are shown in Tables 1 and 2. - The most common adverse reactions requiring intervention were diarrhea and tremor. - In two open-label, uncontrolled monotherapy trials, adult type 1 Gaucher disease patients were treated with Zavesca at a starting dose of 100 mg three times daily (dose range 100 to 200 mg three times daily) for up to 12 months in 28 patients [Study 1], or at a dose of 50 mg three times daily for up to 6 months in 18 patients [Study 2]. Table 1 below lists adverse reactions that occurred during the trials in ≥5% of patients. - In an open-label, active-controlled study, 36 adult type 1 Gaucher disease patients were treated with Zavesca, imiglucerase, or Zavesca plus imiglucerase [Study 3] for up to 12 months. Table 2 lists adverse reactions that occurred during the trial in ≥5% of patients. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Miglustat in the drug label. # Drug Interactions - While co-administration of Zavesca appeared to increase the clearance of imiglucerase by 70%, these results are not conclusive because of the small number of patients studied and because patients took variable doses of imiglucerase. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Risk Summary - There are no adequate and well controlled studies with Zavesca in pregnant women. However, animal reproduction studies have been conducted for Zavesca. In these animal studies, decreased live births and decreased fetal weight were observed in rats orally dosed with miglustat prior to mating and during organogenesis at doses with exposures at and greater than 2 times the human therapeutic systemic exposure. Maternal death and decreased body weight gain were observed in rabbits orally dosed with miglustat during organogenesis at doses with exposures less than the human therapeutic systemic exposure. Zavesca should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - Clinical Considerations - Disease-associated maternal and embryo-fetal risk - Women with Type 1 Gaucher disease have an increased risk of spontaneous abortion, especially if disease symptoms are not treated and controlled pre-conception and during a pregnancy. Pregnancy may exacerbate existing Type 1 Gaucher disease symptoms or result in new disease manifestations. Type 1 Gaucher disease manifestations may lead to adverse pregnancy outcomes including, hepatosplenomegaly which can interfere with the normal growth of a pregnancy and thrombocytopenia which can lead to increased bleeding and possible hemorrhage. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Miglustat in women who are pregnant. ### Labor and Delivery - Dystocia and delayed parturition were observed in rats dosed with miglustat gestation day 6 through lactation at systemic exposure ≥2 times the human therapeutic systemic exposure. ### Nursing Mothers - It is not known whether miglustat is present in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from miglustat, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the lactating woman. ### Pediatric Use - The safety and effectiveness of Zavesca in pediatric patients have not been established. - In a combined clinical trial safety data set of 45 patients less than 18 years of age exposed to Zavesca in indications other than type 1 Gaucher disease, the median weight and height percentiles adjusted for age and gender decreased during the first year of treatment but then stabilized. The mean length of exposure in these studies ranged from 2 to 2.6 years; some pediatric patients were exposed for up to 4 years. However, the effect of Zavesca on long-term gain in weight and height in pediatric patients is unclear. ### Geriatic Use - Clinical studies of Zavesca did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, and cardiac function and of concomitant disease or other drug therapy. ### Gender There is no FDA guidance on the use of Miglustat with respect to specific gender populations. ### Race There is no FDA guidance on the use of Miglustat with respect to specific racial populations. ### Renal Impairment - Miglustat is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. - In patients with mild renal impairment (adjusted creatinine clearance 50-70 mL/min/1.73 m2), Zavesca administration should commence at a dose of 100 mg twice per day. - In patients with moderate renal impairment (adjusted creatinine clearance of 30-50 mL/min/1.73 m2), Zavesca administration should commence at a dose of 100 mg once a day. - Use of Zavesca in patients with severe renal impairment (creatinine clearance < 30 mL/min/1.73 m2) is not recommended. - Since elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. The impact of hemodialysis on the disposition of Zavesca has not been investigated. ### Hepatic Impairment There is no FDA guidance on the use of Miglustat in patients with hepatic impairment. ### Females of Reproductive Potential and Males - Infertility - No effect on sperm concentration, motility, or morphology was seen in 7 healthy adult men who received miglustat 100 mg, orally, twice daily for 6 weeks. Decreased spermatogenesis with altered sperm morphology and motility and decreased fertility were observed in rats orally dosed with miglustat 14 days prior to mating with doses at exposures less than the human therapeutic systemic exposure based on body surface area comparisons (mg/m2). Decreased spermatogenesis was reversible in rats following 6 weeks of drug withdrawal. ### Immunocompromised Patients There is no FDA guidance one the use of Miglustat in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Miglustat in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Miglustat in the drug label. # Overdosage ## Chronic Overdose There is limited information regarding Chronic Overdose of Miglustat in the drug label. # Pharmacology ## Mechanism of Action - Type 1 Gaucher disease is caused by a functional deficiency of glucocerebrosidase, the enzyme that mediates the degradation of the glycosphingolipid glucosylceramide. - Miglustat functions as a competitive and reversible inhibitor of the enzyme glucosylceramide synthase, the initial enzyme in a series of reactions which results in the synthesis of most glycosphingolipids. - Zavesca helps reduce the rate of glycosphingolipid biosynthesis so that the amount of glycosphingolipid substrate is reduced to a level which allows the residual activity of the deficient glucocerebrosidase enzyme to be more effective (substrate reduction therapy). In vitro and in vivo studies have shown that miglustat can reduce the synthesis of glucosylceramide-based glycosphingolipids. ## Structure - Zavesca (miglustat capsules, 100 mg) is an inhibitor of the enzyme glucosylceramide synthase, which is a glucosyl transferase enzyme responsible for the first step in the synthesis of most glycosphingolipids. Zavesca is an N-alkylated imino sugar, a synthetic analog of D-glucose. - The chemical name for miglustat is 1,5-(butylimino)-1,5-dideoxy-D-glucitol with the chemical formula C10H21NO4 and a molecular weight of 219.28. - Miglustat is a white to off-white crystalline solid and has a bitter taste. It is highly soluble in water (>1000 mg/mL as a free base). - Zavesca is supplied in hard gelatin capsules each containing 100 mg miglustat for oral administration. Each Zavesca 100 mg capsule also contains sodium starch glycollate, povidone (K30), and magnesium stearate. Ingredients in the capsule shell include gelatin and titanium dioxide, and the shells are printed with edible ink consisting of black iron oxide and shellac. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Miglustat in the drug label. ## Pharmacokinetics - Absorption: After a 100 mg oral dose, the time to maximum observed plasma concentration of miglustat (tmax) ranged from 2 to 2.5 hours in Gaucher patients. Plasma concentrations show a biexponential decline, characterized by a short distribution phase and a longer elimination phase. The effective half-life of miglustat is approximately 6 to 7 hours, which predicts that steady-state will be achieved by 1.5 to 2 days following the start of three times daily dosing. - Miglustat, dosed at 50 and 100 mg three times daily in Gaucher patients, exhibits dose-proportional pharmacokinetics. The pharmacokinetics of miglustat were not altered after repeated dosing three times daily for up to 12 months. - In healthy subjects, co-administration of Zavesca with food results in a decrease in the rate of absorption of miglustat (maximum plasma concentration [Cmax] was decreased by 36% and tmax delayed 2 h) but had no statistically significant effect on the extent of absorption of miglustat (area-under-the-plasma-concentration time curve [AUC] was decreased by 14%). The mean oral bioavailability of a 100-mg miglustat capsule is about 97% relative to an oral solution administered under fasting conditions. The pharmacokinetics of miglustat were similar between adult type 1 Gaucher disease patients and healthy subjects after a single dose administration of miglustat 100 mg. - Distribution: Miglustat does not bind to plasma proteins. Mean apparent volume of distribution of miglustat is 83-105 liters in Gaucher patients. At steady state, the concentration of miglustat in cerebrospinal fluid of six non-Gaucher patients was 31.4-67.2% of that in plasma, indicating that miglustat crosses the blood brain barrier. - Metabolism and Excretion: The major route of excretion of miglustat is via kidney. Following administration of a single dose of 100 mg 14C-miglustat to healthy volunteers, 83% of the radioactivity was recovered in urine and 12% in feces. In healthy subjects, 67% of the administered dose was excreted unchanged in urine over 72 hours. The most abundant metabolite in urine was miglustat glucuronide accounting for 5% of the dose. The terminal half-life of radioactivity in plasma was 150 hours, suggesting the presence of one or more metabolites with a prolonged half-life. The metabolite accounting for this observation has not been identified, but may accumulate and reach concentrations exceeding those of miglustat at steady state. - Specific Populations - Gender: There was no statistically significant gender difference in miglustat pharmacokinetics, based on pooled data analysis. - Race: Ethnic differences in miglustat pharmacokinetics have not been evaluated in Gaucher patients. However, apparent oral clearance of miglustat in patients of Ashkenazi Jewish descent was not statistically different to that in others (1 Asian and 15 Caucasians), based on a cross-study analysis. - Hepatic Impairment: No studies have been performed to assess the pharmacokinetics of miglustat in patients with hepatic impairment. - Renal Impairment: Limited data in non-Gaucher patients with impaired renal function indicate that the apparent oral clearance (CL/F) of miglustat decreases with decreasing renal function. While the number of subjects with mild and moderate renal impairment was very small, the data suggest an approximate decrease in the apparent oral clearance of 40% and 60% respectively, in mild and moderate renal impairment, justifying the need to decrease the dosing of miglustat in such patients dependent upon creatinine clearance levels. - Data in severe renal impairment are limited to two patients with creatinine clearances in the range 18-29 mL/min and cannot be extrapolated below this range. These data suggest a decrease in CL/F by at least 70% in patients with severe renal impairment. - Drug Interaction Studies - Miglustat does not inhibit the metabolism of various substrates of cytochrome P450 enzymes including, CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP4A11 in vitro; consequently significant interactions via inhibition of these enzymes are unlikely with drugs that are substrates of cytochrome P450 enzymes. - Drug interaction between Zavesca (miglustat 100 mg orally three times daily) and imiglucerase 7.5 or 15 U/kg/day was assessed in imiglucerase-stabilized patients after one month of co-administration. There was no significant effect of imiglucerase on the pharmacokinetics of miglustat, with the co-administration of imiglucerase and miglustat resulting in a 22% reduction in Cmax and a 14% reduction in the AUC for miglustat. While Zavesca appeared to increase the clearance of imiglucerase by 70%, these results are not conclusive because of the small number of subjects studied and because patients took variable doses of imiglucerase. - Concomitant therapy with loperamide during clinical trials did not appear to significantly alter the pharmacokinetics of miglustat. ## Nonclinical Toxicology - Carcinogenesis: Two-year carcinogenicity studies have been conducted with miglustat in CD-1 mice at oral doses up to 500 mg/kg/day and in Sprague Dawley rats at oral doses up to 180 mg/kg/day. Oral administration of miglustat for 104 weeks produced mucinous adenocarcinomas of the large intestine at 210, 420 and 500 mg/kg/day (about 3, 6 and 7 times the recommended human dose, respectively, based on the body surface area) in male mice and at 420 and 500 mg/kg/day (about 6 and 7 times the recommended human dose, based on the body surface area) in female mice. The adenocarcinomas were considered rare in CD-1 mice and occurred in the presence of inflammatory and hyperplastic lesions in the large intestine of both males and females. In rats, oral administration of miglustat for 100 weeks produced increased incidences of interstitial cell adenomas of the testis at 30, 60 and 180 mg/kg/day (about 1, 2 and 5 times the recommended human dose, respectively, based on the body surface area). - Mutagenesis: Miglustat was not mutagenic or clastogenic in a battery of in vitro and in vivo assays including the bacterial reverse mutation (Ames), chromosomal aberration (in human lymphocytes), gene mutation in mammalian cells (Chinese hamster ovary), and mouse micronucleus assays. - Impairment of Fertility: Male rats, given 20 mg/kg/day miglustat by (systemic exposure less than the human therapeutic systemic exposure based on body surface area comparisons, mg/m2) oral gavage 14 days prior to mating, had decreased spermatogenesis with altered sperm morphology and motility and decreased fertility. Decreased spermatogenesis was reversible following 6 weeks of drug withdrawal. A higher dose of 60 mg/kg/day (2 times the human therapeutic systemic exposure, based on body surface area comparison, mg/m2) resulted in seminiferous tubule and testicular atrophy/degeneration. - Female rats were given oral gavage doses of 20, 60, 180 mg/kg/day beginning 14 days before mating and continuing through gestation. Effects observed at 20 mg/kg/day (systemic exposure less than the human therapeutic systemic exposure, based on body surface area comparisons) included decreased corpora lutea, increased postimplantation loss, and decreased live births. - Animal Toxicology and/or Pharmacology - Histopathology findings in the absence of clinical signs in the central nervous system of the monkey (brain, spine) that included vascular mineralization, in addition to mineralization and necrosis of white matter were observed at >750 mg/kg/day (4 times the human therapeutic systemic exposure based on area-under-the-plasma-concentration curve [AUC] comparisons) in a 52-week oral toxicity study using doses of 750 and 2000 mg/kg/d. Vacuolization of white matter was observed in rats dosed orally by gavage at ≥ 180 mg/kg/d (6 times the human therapeutic exposure based on surface area comparisons, mg/m2) in a 4-week study using doses of 180, 840, and 4200 mg/kg/d. Vacuolization can sometimes occur as an artifact of tissue processing. Findings in dogs included tremor and absent corneal reflexes at 105 mg/kg/day (10 times the human therapeutic systemic exposure, based on body surface area comparisons, mg/m2) after a 4-week oral gavage toxicity study using doses of 35, 70, 105, and 140 mg/kg/d. Ataxia, diminished/absent pupillary, palpebral, or patellar reflexes were observed in a dog at ≥495 mg/kg/day (50 times the human therapeutic systemic exposure based on body surface area comparisons, mg/m2), in a 2-week oral gavage toxicity study using doses of 85, 165, 495, and 825 mg/kg/d. - Cataracts were observed in rats at ≥180 mg/kg/day (4 times the human therapeutic systemic exposure, based on AUC) in a 52-week oral gavage toxicity study using doses of 180, 420, 840, and 1680 mg/kg/d. - Gastrointestinal necrosis, inflammation, and hemorrhage were observed in dogs at ≥ 85 mg/kg/day (9 times the human therapeutic systemic exposure based on body surface area comparisons, mg/m2) after a 2-week oral (capsule) toxicity study using doses of 85, 165, 495, and 825 mg/kg/d. Similar GI toxicity occurred in rats at 1200 mg/kg/day (7 times the human therapeutic systemic exposure, based on AUC) in a 26-week oral gavage toxicity study using doses of 300, 600, and 1200 mg/kg/d. In monkeys, similar GI toxicity occurred at ≥750 mg/kg/day (6 times the human therapeutic systemic exposure based on AUC) following a 52-week oral gavage toxicity study using doses of 750 and 2000 mg/kg/d. # Clinical Studies - The efficacy of Zavesca in type 1 Gaucher disease has been investigated in two open-label, uncontrolled trials and one randomized, open-label, active-controlled trial with enzyme replacement given as imiglucerase. Patients who received Zavesca were treated with doses ranging from 100 to 600 mg a day, although the majority of patients were maintained on doses between 200 to 300 mg a day. Efficacy parameters included the evaluation of liver and spleen organ volume, hemoglobin concentration, and platelet count. A total of 80 patients were exposed to Zavesca during the three trials and their extension period. - Open-Label Uncontrolled Monotherapy Trials - In Study 1, Zavesca was administered at a starting dose of 100 mg three times daily for 12 months (dose range of 100 once-daily to 200 mg three times daily) to 28 adult patients with type 1 Gaucher disease, who were unable to receive enzyme replacement therapy and who had not taken enzyme replacement therapy in the preceding 6 months. Twenty-two patients completed the trial. After 12 months of treatment, the results showed significant mean percent reductions from baseline in liver volume of 12% and spleen volume of 19%, a non-significant increase from baseline in mean absolute hemoglobin concentration of 0.26 g/dL and a mean absolute increase from baseline in platelet counts of 8 × 109/L (See Tables 3-6). - In Study 2, Zavesca was administered at a dose of 50 mg three times daily for 6 months to 18 adult patients with type 1 Gaucher disease who were unable to receive enzyme replacement therapy and who had not taken enzyme replacement therapy in the preceding 6 months. Seventeen patients completed the trial. After 6 months of treatment, the results showed significant mean percent reductions from baseline in liver volume of 6% and spleen volume of 5%. There was a non-significant mean absolute decrease from baseline in hemoglobin concentration of 0.13 g/dL and a non-significant mean absolute increase from baseline in platelet counts of 5 × 109/L (See Tables 3-6). - Extension Period - Eighteen patients were enrolled in a 12-month extension to Study 1. A subset of patients continuing in the extension had larger mean baseline liver volumes, and lower mean baseline platelet counts and hemoglobin concentrations than the original study population (See Tables 3-6). After a total of 24 months of treatment, there were significant mean decreases from baseline in liver and spleen organ volumes of 15% and 27%, respectively, and significant mean absolute increases from baseline in hemoglobin concentration and platelet count of 0.9 g/dL and 14 × 109/L, respectively (See Tables 3-6). - Sixteen patients were enrolled in a 6-month extension to Study 2. After a total of 12 months of treatment, there was a mean decrease from baseline in spleen organ volume of 10%, whereas the mean percent decrease in liver organ volume remained at 6%. There were no significant changes in hemoglobin concentrations or platelet counts (See Tables 3-6). - Liver volume results from Studies 1 and 2 and their extensions are summarized in Table 3: - Open-Label Active-Controlled Trial - Study 3 was an open-label, randomized, active-controlled study of 36 adult patients with type 1 Gaucher disease, who had been receiving enzyme replacement therapy with imiglucerase for a minimum of 2 years prior to study entry. Patients were randomized 1:1:1 to one of three treatment groups, as follows: - Zavesca 100 mg three times daily alone imiglucerase (patient's usual dose) alone Zavesca 100 mg three times daily and imiglucerase (usual dose) - Zavesca 100 mg three times daily alone - imiglucerase (patient's usual dose) alone - Zavesca 100 mg three times daily and imiglucerase (usual dose) - Patients were treated for 6 months, and 33 patients completed the study. Because Zavesca is only indicated as monotherapy, the results for the monotherapy arms are described below. At Month 6, the results showed a decrease in mean percent change in liver volume in the Zavesca treatment group compared to the imiglucerase alone group. There were no significant differences between the groups for mean absolute changes in liver and spleen volume and hemoglobin concentration. However, there was a significant difference between the Zavesca alone and imiglucerase alone groups in platelet counts at Month 6, with the Zavesca alone group having a mean absolute decrease in platelet count of 21.6 × 109/L and the imiglucerase alone group having a mean absolute increase in platelet count of 10.1 × 109/L (See Tables 7-10). - Extension period - Twenty-nine patients were enrolled in a 6-month extension to Study 3. In the extension phase, all 29 patients had withdrawn from imiglucerase and received open-label Zavesca 100 mg three times daily monotherapy. At Month 12, the results showed non-significant decreases in platelet counts from baseline in all the treatment groups (by original randomization). There was a significant decrease in platelet counts from Month 6 to Month 12 in the group originally randomized to treatment with imiglucerase, and a continued decrease in platelet counts in the group originally randomized to Zavesca alone. There were no significant changes in any treatment group for liver volume, spleen volume, or hemoglobin concentration (See Tables 7-10). - Liver volume results from Study 3 and extension are summarized in Table 7: - Patients with platelet counts above 150 × 109/L at baseline who were randomized to Zavesca treatment had significant decreases in platelet counts at Month 12. # How Supplied - Zavesca® is supplied in hard gelatin capsules containing 100 mg miglustat. Zavesca® 100 mg capsules are white opaque with "OGT 918" printed in black on the cap and "100" printed in black on the body. - Zavesca® 100 mg capsules are packed in blister cards. Five blister cards of 18 capsules are supplied in each carton. - NDC 66215-201-90: carton containing 90 capsules. - NDC 66215-201-18: blister card containing 18 capsules - Storage: Store at 20°C to 25°C (68° to 77°F). Brief exposure to 15°C to 30°C (59°F to 86°F) permitted. ## Storage There is limited information regarding Miglustat Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise patients that the most common serious adverse reactions reported with Zavesca are peripheral neuropathy. Advise patients to promptly report any numbness, tingling, pain, or burning in the hands and feet. - Advise patients that other adverse reactions include tremor and reductions in platelet counts. Advise patients to promptly report the development of tremor or worsening in an existing tremor. - Advise patients that other serious adverse reactions include diarrhea and weight loss. Advise patients to adhere to dietary instructions. - Advise patients to take the next Zavesca capsule at the next scheduled time if a dose is missed. - Inform patients of the potential risks and benefits of Zavesca and of alternative modes of therapy. # Precautions with Alcohol - Alcohol-Miglustat interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - ZAVESCA®[1] # Look-Alike Drug Names - Zavesca (miglustat)® — Zavesca (escitalopram®[2] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Miglustat
884c228d8db32a161656b1df9bfd1a5f1ae4bec8	wikidoc	Migraleve	Migraleve Migraleve is the brand name of a range of migraine-relief medications made by Pfizer. There are two variants of Migraleve: Yellow and pink, which all contain the analgesic paracetomol and codeine. The yellow variant is designed to address the symptoms of headache and discomfort, whilst the pink variant also addresses symptoms of nausea and vomiting. # Migraleve Yellow The active ingredients of Migraleve Yellow are: - paracetamol DC 96% 520 mg equivalent to paracetamol 500 mg and codeine phosphate 8 mg. Other ingredients: magnesium stearate, colloidal anhydrous silica, stearic acid, pregelatinised maize starch, gelatin, hypromellose, macrogol, E104 (quinoline yellow), aluminium oxide, E171 (titanium dioxide) and E172 (iron oxide yellow). # Migraleve Pink The active ingredients of Migraleve Pink are: - paracetamol DC 96% 520 mg equivalent to paracetamol 500 mg, codeine phosphate 8 mg and buclizine hydrochloride 6.25 mg. Other ingredients: magnesium stearate, colloidal anhydrous silica, stearic acid, pregelatinised maize starch, gelatin, hypromellose, macrogol, E127 (erythrosine), aluminium oxide and E171 (titanium dioxide). # License and manufacture The Product Licence Holder is: Pfizer Consumer Healthcare, Walton-on-the-Hill, Surrey, KT20 7NS The manufacturer is: Gödecke GmbH, Mooswaldallee 1, 79090, Freiburg, Germany.	Migraleve Migraleve is the brand name of a range of migraine-relief medications made by Pfizer. There are two variants of Migraleve: Yellow and pink, which all contain the analgesic paracetomol and codeine. The yellow variant is designed to address the symptoms of headache and discomfort, whilst the pink variant also addresses symptoms of nausea and vomiting. # Migraleve Yellow The active ingredients of Migraleve Yellow are: - paracetamol DC 96% 520 mg equivalent to paracetamol 500 mg and codeine phosphate 8 mg. Other ingredients: magnesium stearate, colloidal anhydrous silica, stearic acid, pregelatinised maize starch, gelatin, hypromellose, macrogol, E104 (quinoline yellow), aluminium oxide, E171 (titanium dioxide) and E172 (iron oxide yellow). # Migraleve Pink The active ingredients of Migraleve Pink are: - paracetamol DC 96% 520 mg equivalent to paracetamol 500 mg, codeine phosphate 8 mg and buclizine hydrochloride 6.25 mg. Other ingredients: magnesium stearate, colloidal anhydrous silica, stearic acid, pregelatinised maize starch, gelatin, hypromellose, macrogol, E127 (erythrosine), aluminium oxide and E171 (titanium dioxide). # License and manufacture The Product Licence Holder is: Pfizer Consumer Healthcare, Walton-on-the-Hill, Surrey, KT20 7NS [1] The manufacturer is: Gödecke GmbH, Mooswaldallee 1, 79090, Freiburg, Germany.	https://www.wikidoc.org/index.php/Migraleve
4caa7c94d41474d0f38c6b8b313512efc80ab92e	wikidoc	Mike Reed	Mike Reed Dr. Mike Reed, DC, DACBSP, CCSP, CSCS - is a Doctor of Chiropractic who has been serving the US Olympic Committee for several years, and was a doctor with "additional responsibilities" in the Chiropractic care, for the US Team in Beijing, China at the Summer Olympic Games in 2008. He is the Medical Director for team USA at the Winter games at Vancouver 2010. # Career 2007-Present - Medical Director - Sports Performance Division, US Olympic Committee 2004-2007 - Faculty and Director, Sports Medicine Residency Division, Southern California University of Health Sciences	Mike Reed Dr. Mike Reed, DC, DACBSP, CCSP, CSCS - is a Doctor of Chiropractic who has been serving the US Olympic Committee for several years, and was a doctor with "additional responsibilities" in the Chiropractic care, for the US Team in Beijing, China at the Summer Olympic Games in 2008. [1][2] He is the Medical Director for team USA at the Winter games at Vancouver 2010.[citation needed] # Career 2007-Present - Medical Director - Sports Performance Division, US Olympic Committee 2004-2007 - Faculty and Director, Sports Medicine Residency Division, Southern California University of Health Sciences	https://www.wikidoc.org/index.php/Mike_Reed
1dc04027ddbe94fae858039589b99b35f7ae7131	wikidoc	Milrinone	Milrinone # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Milrinone is a inotropic agent and vasodilator that is FDA approved for the treatment of acute decompensated heart failure. Common adverse reactions include hypotension, ventricular arrhythmia, and headache. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Milrinone should be administered with a loading dose followed by a continuous infusion (maintenance dose) according to the following guidelines: - Dosing Information - Loading Dose - The loading dose may be given undiluted, but diluting to a rounded total volume of 10 or 20 mL may simplify the visualization of the injection rate. - Milrinone drawn from vials should be diluted prior to maintenance dose administration. The diluents that may be used are 0.45% Sodium Chloride Injection, 0.9% Sodium Chloride Injection, or 5% Dextrose Injection. The table below shows the volume of diluent in milliliters (mL) that must be used to achieve 200 mcg/mL concentration for infusion, and the resultant total volumes. - The infusion rate should be adjusted according to hemodynamic and clinical response. Patients should be closely monitored. In controlled clinical studies, most patients showed an improvement in hemodynamic status as evidenced by increases in cardiac output and reductions in pulmonary capillary wedge pressure. - Maintenance Dose - The maintenance dose in mL/hr by patient body weight (kg) may be determined by reference to the following table. - When administering milrinone lactate by continuous infusion, it is advisable to use a calibrated electronic infusion device. - Data obtained from patients with severe renal impairment (creatinine clearance = 0 to 30 mL/min) but without congestive heart failure have demonstrated that the presence of renal impairment significantly increases the terminal elimination half-life of milrinone. Reductions in infusion rate may be necessary in patients with renal impairment. For patients with clinical evidence of renal impairment, the recommended infusion rate can be obtained from the following table: - Intravenous drug products should be inspected visually and should not be used if particulate matter or discoloration is present. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Milrinone in adult patients. ### Non–Guideline-Supported Use - Bridging therapy in patients with severe heart failure - Dosing Information - Loading dose of 50mcg/kg; mean maintenance dose was 0.43 mcg/kg/minute for a mean of 12 days. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Safety and effectiveness in pediatric patients have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Milrinone in pediatric patients. ### Non–Guideline-Supported Use - In pediatric patients with nonhyperdynamic septic shock, intravenous milrinone (loading dose of 50 mg/kg followed by a continuous infusion of 0.5 mg/kg/min) improves cardiovascular function when administered with catecholamines. # Contraindications - Milrinone is contraindicated in patients who are hypersensitive to it. # Warnings - Whether given orally or by continuous or intermittent intravenous infusion, milrinone has not been shown to be safe or effective in the longer (greater than 48 hours) treatment of patients with heart failure. In a multicenter trial of 1088 patients with Class III and IV heart failure, long-term oral treatment with milrinone was associated with no improvement in symptoms and an increased risk of hospitalization and death. In this study, patients with Class IV symptoms appeared to be at particular risk of life-threatening cardiovascular reactions. There is no evidence that milrinone given by long-term continuous or intermittent infusion does not carry a similar risk. - The use of milrinone both intravenously and orally has been associated with increased frequency of ventricular arrhythmias, including nonsustained ventricular tachycardia. Long-term oral use has been associated with an increased risk of sudden death. Hence, patients receiving milrinone should be observed closely with the use of continuous electrocardiographic monitoring to allow the prompt detection and management of ventricular arrhythmias. ### Precautions - General - Milrinone should not be used in patients with severe obstructive aortic or pulmonic valvular disease in lieu of surgical relief of the obstruction. Like other inotropic agents, it may aggravate outflow tract obstruction in hypertrophic subaortic stenosis. - Supraventricular and ventricular arrhythmias have been observed in the high-risk population treated. In some patients, injections of milrinone and oral milrinone have been shown to increase ventricular ectopy, including nonsustained ventricular tachycardia. The potential for arrhythmia, present in congestive heart failure itself, may be increased by many drugs or combinations of drugs. Patients receiving milrinone should be closely monitored during infusion. - Milrinone produces a slight shortening of AV node conduction time, indicating a potential for an increased ventricular response rate in patients with atrial flutter/fibrillation which is not controlled with digitalis therapy. - During therapy with milrinone, blood pressure and heart rate should be monitored and the rate of infusion slowed or stopped in patients showing excessive decreases in blood pressure. - If prior vigorous diuretic therapy is suspected to have caused significant decreases in cardiac filling pressure, milrinone should be cautiously administered with monitoring of blood pressure, heart rate, and clinical symptomatology. - There is no experience in controlled trials with infusions of milrinone for periods exceeding 48 hours. Cases of infusion site reactions have been reported with intravenous milrinone therapy. Consequently, careful monitoring of the infusion site should be maintained to avoid possible extravasation. - Use in Acute Myocardial Infarction - No clinical studies have been conducted in patients in the acute phase of post myocardial infarction. Until further clinical experience with this class of drugs is gained, milrinone is not recommended in these patients. - Laboratory Tests - Fluid and electrolyte changes and renal function should be carefully monitored during therapy with milrinone. Improvement in cardiac output with resultant diuresis may necessitate a reduction in the dose of diuretic. Potassium loss due to excessive diuresis may predispose digitalized patients to arrhythmias. Therefore, hypokalemia should be corrected by potassium supplementation in advance of or during use of milrinone. # Adverse Reactions ## Clinical Trials Experience - In patients receiving milrinone in Phase II and III clinical trials, ventricular arrhythmias were reported in 12.1%: Ventricular ectopic activity, 8.5%; nonsustained ventricular tachycardia, 2.8%; sustained ventricular tachycardia, 1% and ventricular fibrillation, 0.2% (2 patients experienced more than one type of arrhythmia). Holter recordings demonstrated that in some patients injection of milrinone increased ventricular ectopy, including nonsustained ventricular tachycardia. Life-threatening arrhythmias were infrequent and when present have been associated with certain underlying factors such as preexisting arrhythmias, metabolic abnormalities (e.g., hypokalemia), abnormal digoxin levels and catheter insertion. Milrinone was not shown to be arrhythmogenic in an electrophysiology study. Supraventricular arrhythmias were reported in 3.8% of the patients receiving milrinone. The incidence of both supraventricular and ventricular arrhythmias has not been related to the dose or plasma milrinone concentration. - Other cardiovascular adverse reactions include hypotension, 2.9% and angina/chest pain, 1.2%. - Headaches, usually mild to moderate in severity, have been reported in 2.9% of patients receiving milrinone. - Other adverse reactions reported, but not definitely related to the administration of milrinone include hypokalemia, 0.6%; tremor, 0.4%; and thrombocytopenia, 0.4%. ## Postmarketing Experience - In addition to adverse events reported from clinical trials, the following events have been reported from worldwide post-marketing experience with milrinone: - Isolated spontaneous reports of bronchospasm and anaphylactic shock. - Liver function test abnormalities and skin reactions such as rash. - Administration site conditions: Infusion site reaction. - In the post-marketing experience, there have been rare cases of “torsades de pointes” reported. # Drug Interactions - Drug Interactions - No untoward clinical manifestations have been observed in limited experience with patients in whom milrinone was used concurrently with the following drugs: digitalis glycosides; lidocaine, quinidine; hydralazine, prazosin; isosorbide dinitrate, nitroglycerin; chlorthalidone, furosemide, hydrochlorothiazide, spironolactone; captopril; heparin, warfarin, diazepam, insulin; and potassium supplements. - Chemical Interactions - There is an immediate chemical interaction which is evidenced by the formation of a precipitate when furosemide is injected into an intravenous line of an infusion of milrinone. Therefore, furosemide should not be administered in intravenous lines containing milrinone. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Oral administration of milrinone to pregnant rats and rabbits during organogenesis produced no evidence of teratogenicity at dose levels up to 40 mg/kg/day and 12 mg/kg/day, respectively. Milrinone did not appear to be teratogenic when administered intravenously to pregnant rats at doses up to 3 mg/kg/day (about 2.5 times the maximum recommended clinical intravenous dose) or pregnant rabbits at doses up to 12 mg/kg/day, although an increased resorption rate was apparent at both 8 mg/kg/day and 12 mg/kg/day (intravenous) in the latter species. There are no adequate and well-controlled studies in pregnant women. Milrinone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Milrinone in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Milrinone during labor and delivery. ### Nursing Mothers - Caution should be exercised when milrinone is administered to nursing women, since it is not known whether it is excreted in human milk. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use - There are no special dosage recommendations for the elderly patient. Ninety percent of all patients administered milrinone in clinical studies were within the age range of 45 to 70 years, with a mean age of 61 years. Patients in all age groups demonstrated clinically and statistically significant responses. No age-related effects on the incidence of adverse reactions have been observed. Controlled pharmacokinetic studies have not disclosed any age-related effects on the distribution and elimination of milrinone. ### Gender There is no FDA guidance on the use of Milrinone with respect to specific gender populations. ### Race There is no FDA guidance on the use of Milrinone with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Milrinone in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Milrinone in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Milrinone in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Milrinone in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring There is limited information regarding Monitoring of Milrinone in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Milrinone in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - Doses of milrinone may produce hypotension because of its vasodilator effect. If this occurs, administration of milrinone should be reduced or temporarily discontinued until the patient's condition stabilizes. ### Management - No specific antidote is known, but general measures for circulatory support should be taken. ## Chronic Overdose There is limited information regarding Chronic Overdose of Milrinone in the drug label. # Pharmacology ## Mechanism of Action - Milrinone is a positive inotrope and vasodilator, with little chronotropic activity different in structure and mode of action from either the digitalis glycosides or catecholamines. - Milrinone, at relevant inotropic and vasorelaxant concentrations, is a selective inhibitor of peak III cAMP phosphodiesterase isozyme in cardiac and vascular muscle. This inhibitory action is consistent with cAMP mediated increases in intracellular ionized calcium and contractile force in cardiac muscle, as well as with cAMP dependent contractile protein phosphorylation and relaxation in vascular muscle. Additional experimental evidence also indicates that milrinone is not a beta-adrenergic agonist nor does it inhibit sodium-potassium adenosine triphosphatase activity as do the digitalis glycosides. ## Structure - Milrinone Lactate Injection, is a member of a new class of bipyridine inotropic/vasodilator agents with phosphodiesterase inhibitor activity, distinct from digitalis glycosides or catecholamines. Milrinone lactate is designated chemically as 1,6-Dihydro-2-methyl-6-oxo-5-carbonitrile lactate and has the following structural formula: - Milrinone is an off-white to tan crystalline compound with a molecular weight of 211.2 and a molecular formula of C12H9N3O. It is slightly soluble in methanol, and very slightly soluble in chloroform and in water. As the lactate salt, it is stable and colorless to pale yellow in solution. Milrinone lactate injection is available as sterile aqueous solutions of the lactate salt of milrinone for injection or infusion intravenously. - Sterile, single-dose vials: Single-dose vials of 10, 20 and 50 mL contain in each mL milrinone lactate equivalent to 1 mg milrinone and 47 mg Dextrose, Anhydrous, in Water for Injection. The pH is adjusted to between 3.2 and 4.0 with lactic acid and/or sodium hydroxide. The total concentration of lactic acid can vary between 0.95 mg/mL and 1.29 mg/mL. These vials require preparation of dilutions prior to administration to patients intravenously. - Clinical studies in patients with congestive heart failure have shown that milrinone produces dose-related and plasma drug concentration-related increases in the maximum rate of increase of left ventricular pressure. Studies in normal subjects have shown that milrinone produces increases in the slope of the left ventricular pressure-dimension relationship, indicating a direct inotropic effect of the drug. Milrinone also produces dose-related and plasma concentration-related increases in forearm blood flow in patients with congestive heart failure, indicating a direct arterial vasodilator activity of the drug. - Both the inotropic and vasodilatory effects have been observed over the therapeutic range of plasma milrinone concentrations of 100 ng/mL to 300 ng/mL. - In addition to increasing myocardial contractility, milrinone improves diastolic function as evidenced by improvements in left ventricular diastolic relaxation. - The acute administration of intravenous milrinone has also been evaluated in clinical trials in excess of 1600 patients, with chronic heart failure, heart failure associated with cardiac surgery, and heart failure associated with myocardial infarction. - The total number of deaths, either on therapy or shortly thereafter (24 hours) was 15, less than 0.9%, few of which were thought to be drug-related. ## Pharmacodynamics - In patients with heart failure due to depressed myocardial function, milrinone produced a prompt dose and plasma concentration related increase in cardiac output and decreases in pulmonary capillary wedge pressure and vascular resistance, which were accompanied by mild-to-moderate increases in heart rate. Additionally, there is no increased effect on myocardial oxygen consumption. In uncontrolled studies, hemodynamic improvement during intravenous therapy with milrinone was accompanied by clinical symptomatic improvement, but the ability of milrinone to relieve symptoms has not been evaluated in controlled clinical trials. The great majority of patients experience improvements in hemodynamic function within 5 to 15 minutes of initiation of therapy. - In studies in congestive heart failure patients, milrinone when administered as a loading injection followed by a maintenance infusion produced significant mean initial increases in cardiac index of 25 percent, 38 percent, and 42 percent at dose regimens of 37.5 mcg/kg/0.375 mcg/kg/min, 50 mcg/kg/0.50 mcg/kg/min, and 75 mcg/kg/0.75 mcg/kg/min, respectively. Over the same range of loading injections and maintenance infusions, pulmonary capillary wedge pressure significantly decreased by 20 percent, 23 percent, and 36 percent, respectively, while systemic vascular resistance significantly decreased by 17 percent, 21 percent, and 37 percent. Mean arterial pressure fell by up to 5 percent at the two lower dose regimens, but by 17 percent at the highest dose. Patients evaluated for 48 hours maintained improvements in hemodynamic function, with no evidence of diminished response (tachyphylaxis). A smaller number of patients have received infusions of milrinone for periods up to 72 hours without evidence of tachyphylaxis. - The duration of therapy should depend upon patient responsiveness. - Milrinone has a favorable inotropic effect in fully digitalized patients without causing signs of glycoside toxicity. Theoretically, in cases of atrial flutter/fibrillation, it is possible that milrinone may increase ventricular response rate because of its slight enhancement of AV node conduction. In these cases, digitalis should be considered prior to the institution of therapy with milrinone. - Improvement in left ventricular function in patients with ischemic heart disease has been observed. The improvement has occurred without inducing symptoms or electrocardiographic signs of myocardial ischemia. - The steady-state plasma milrinone concentrations after approximately 6 to 12 hours of unchanging maintenance infusion of 0.50 mcg/kg/min are approximately 200 ng/mL. Near maximum favorable effects of milrinone on cardiac output and pulmonary capillary wedge pressure are seen at plasma milrinone concentrations in the 150 ng/mL to 250 ng/mL range. ## Pharmacokinetics - Following intravenous injections of 12.5 mcg/kg to 125 mcg/kg to congestive heart failure patients, milrinone had a volume of distribution of 0.38 liters/kg, a mean terminal elimination half-life of 2.3 hours, and a clearance of 0.13 liters/kg/hr. Following intravenous infusions of 0.20 mcg/kg/min to 0.70 mcg/kg/min to congestive heart failure patients, the drug had a volume of distribution of about 0.45 liters/kg, a mean terminal elimination half-life of 2.4 hours, and a clearance of 0.14 liters/kg/hr. These pharmacokinetic parameters were not dose-dependent, and the area under the plasma concentration versus time curve following injections was significantly dose-dependent. - Milrinone has been shown (by equilibrium dialysis) to be approximately 70% bound to human plasma protein. - The primary route of excretion of milrinone in man is via the urine. The major urinary excretions of orally administered milrinone in man are milrinone (83%) and its 0-glucuronide metabolite (12%). Elimination in normal subjects via the urine is rapid, with approximately 60% recovered within the first two hours following dosing and approximately 90% recovered within the first eight hours following dosing. The mean renal clearance of milrinone is approximately 0.3 liters/min, indicative of active secretion. ## Nonclinical Toxicology - Carcinogenesis, Mutagenesis, Impairment of Fertility - Twenty-four months of oral administration of milrinone to mice at doses up to 40 mg/kg/day (about 50 times the human oral therapeutic dose in a 50 kg patient) was unassociated with evidence of carcinogenic potential. Neither was there evidence of carcinogenic potential when milrinone was orally administered to rats at doses up to 5 mg/kg/day (about 6 times the human oral therapeutic dose) for twenty-four months or at 25 mg/kg/day (about 30 times the human oral therapeutic dose) for up to 18 months in males and 20 months in females. Whereas the Chinese Hamster Ovary Chromosome Aberration Assay was positive in the presence of a metabolic activation system, results from the Ames Test, the Mouse Lymphoma Assay, the Micronucleus Test, and the in vivo Rat Bone Marrow Metaphase Analysis indicated an absence of mutagenic potential. In reproductive performance studies in rats, milrinone had no effect on male or female fertility at oral doses up to 32 mg/kg/day. - Animal Toxicity - Oral and intravenous administration of toxic dosages of milrinone to rats and dogs resulted in myocardial degeneration/fibrosis and endocardial hemorrhage, principally affecting the left ventricular papillary muscles. Coronary vascular lesions characterized by periarterial edema and inflammation have been observed in dogs only. The myocardial/endocardial changes are similar to those produced by beta-adrenergic receptor agonists such as isoproterenol, while the vascular changes are similar to those produced by minoxidil and hydralazine. Doses within the recommended clinical dose range (up to 1.13 mg/kg/day) for congestive heart failure patients have not produced significant adverse effects in animals. # Clinical Studies There is limited information regarding Clinical Studies of Milrinone in the drug label. # How Supplied - Milrinone Lactate Injection is supplied as 10 mL (1 mg/mL) NDC 55390-019-10, box of 10; 20 mL (1 mg/mL) NDC 55390-020-10, box of 10; and 50 mL (1 mg/mL) NDC 55390-021-01, individually-boxed, single-dose vials containing a sterile, clear, colorless to pale yellow solution. Each mL contains milrinone lactate equivalent to 1 mg milrinone. - Discard unused portion after initial use. Store at controlled room temperature 15° to 30°C (59° to 86°F). Avoid freezing. - Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. Protect from freezing. ## Storage There is limited information regarding Milrinone Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Milrinone in the drug label. # Precautions with Alcohol - Alcohol-Milrinone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Primacor® # Look-Alike Drug Names - N/A # Drug Shortage Status # Price	Milrinone Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gerald Chi # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Milrinone is a inotropic agent and vasodilator that is FDA approved for the treatment of acute decompensated heart failure. Common adverse reactions include hypotension, ventricular arrhythmia, and headache. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Milrinone should be administered with a loading dose followed by a continuous infusion (maintenance dose) according to the following guidelines: - Dosing Information - Loading Dose - The loading dose may be given undiluted, but diluting to a rounded total volume of 10 or 20 mL may simplify the visualization of the injection rate. - Milrinone drawn from vials should be diluted prior to maintenance dose administration. The diluents that may be used are 0.45% Sodium Chloride Injection, 0.9% Sodium Chloride Injection, or 5% Dextrose Injection. The table below shows the volume of diluent in milliliters (mL) that must be used to achieve 200 mcg/mL concentration for infusion, and the resultant total volumes. - The infusion rate should be adjusted according to hemodynamic and clinical response. Patients should be closely monitored. In controlled clinical studies, most patients showed an improvement in hemodynamic status as evidenced by increases in cardiac output and reductions in pulmonary capillary wedge pressure. - Maintenance Dose - The maintenance dose in mL/hr by patient body weight (kg) may be determined by reference to the following table. - When administering milrinone lactate by continuous infusion, it is advisable to use a calibrated electronic infusion device. - Data obtained from patients with severe renal impairment (creatinine clearance = 0 to 30 mL/min) but without congestive heart failure have demonstrated that the presence of renal impairment significantly increases the terminal elimination half-life of milrinone. Reductions in infusion rate may be necessary in patients with renal impairment. For patients with clinical evidence of renal impairment, the recommended infusion rate can be obtained from the following table: - Intravenous drug products should be inspected visually and should not be used if particulate matter or discoloration is present. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Milrinone in adult patients. ### Non–Guideline-Supported Use - Bridging therapy in patients with severe heart failure - Dosing Information - Loading dose of 50mcg/kg; mean maintenance dose was 0.43 mcg/kg/minute for a mean of 12 days.[1] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Safety and effectiveness in pediatric patients have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Milrinone in pediatric patients. ### Non–Guideline-Supported Use - In pediatric patients with nonhyperdynamic septic shock, intravenous milrinone (loading dose of 50 mg/kg followed by a continuous infusion of 0.5 mg/kg/min) improves cardiovascular function when administered with catecholamines.[2] # Contraindications - Milrinone is contraindicated in patients who are hypersensitive to it. # Warnings - Whether given orally or by continuous or intermittent intravenous infusion, milrinone has not been shown to be safe or effective in the longer (greater than 48 hours) treatment of patients with heart failure. In a multicenter trial of 1088 patients with Class III and IV heart failure, long-term oral treatment with milrinone was associated with no improvement in symptoms and an increased risk of hospitalization and death. In this study, patients with Class IV symptoms appeared to be at particular risk of life-threatening cardiovascular reactions. There is no evidence that milrinone given by long-term continuous or intermittent infusion does not carry a similar risk. - The use of milrinone both intravenously and orally has been associated with increased frequency of ventricular arrhythmias, including nonsustained ventricular tachycardia. Long-term oral use has been associated with an increased risk of sudden death. Hence, patients receiving milrinone should be observed closely with the use of continuous electrocardiographic monitoring to allow the prompt detection and management of ventricular arrhythmias. ### Precautions - General - Milrinone should not be used in patients with severe obstructive aortic or pulmonic valvular disease in lieu of surgical relief of the obstruction. Like other inotropic agents, it may aggravate outflow tract obstruction in hypertrophic subaortic stenosis. - Supraventricular and ventricular arrhythmias have been observed in the high-risk population treated. In some patients, injections of milrinone and oral milrinone have been shown to increase ventricular ectopy, including nonsustained ventricular tachycardia. The potential for arrhythmia, present in congestive heart failure itself, may be increased by many drugs or combinations of drugs. Patients receiving milrinone should be closely monitored during infusion. - Milrinone produces a slight shortening of AV node conduction time, indicating a potential for an increased ventricular response rate in patients with atrial flutter/fibrillation which is not controlled with digitalis therapy. - During therapy with milrinone, blood pressure and heart rate should be monitored and the rate of infusion slowed or stopped in patients showing excessive decreases in blood pressure. - If prior vigorous diuretic therapy is suspected to have caused significant decreases in cardiac filling pressure, milrinone should be cautiously administered with monitoring of blood pressure, heart rate, and clinical symptomatology. - There is no experience in controlled trials with infusions of milrinone for periods exceeding 48 hours. Cases of infusion site reactions have been reported with intravenous milrinone therapy. Consequently, careful monitoring of the infusion site should be maintained to avoid possible extravasation. - Use in Acute Myocardial Infarction - No clinical studies have been conducted in patients in the acute phase of post myocardial infarction. Until further clinical experience with this class of drugs is gained, milrinone is not recommended in these patients. - Laboratory Tests - Fluid and electrolyte changes and renal function should be carefully monitored during therapy with milrinone. Improvement in cardiac output with resultant diuresis may necessitate a reduction in the dose of diuretic. Potassium loss due to excessive diuresis may predispose digitalized patients to arrhythmias. Therefore, hypokalemia should be corrected by potassium supplementation in advance of or during use of milrinone. # Adverse Reactions ## Clinical Trials Experience - In patients receiving milrinone in Phase II and III clinical trials, ventricular arrhythmias were reported in 12.1%: Ventricular ectopic activity, 8.5%; nonsustained ventricular tachycardia, 2.8%; sustained ventricular tachycardia, 1% and ventricular fibrillation, 0.2% (2 patients experienced more than one type of arrhythmia). Holter recordings demonstrated that in some patients injection of milrinone increased ventricular ectopy, including nonsustained ventricular tachycardia. Life-threatening arrhythmias were infrequent and when present have been associated with certain underlying factors such as preexisting arrhythmias, metabolic abnormalities (e.g., hypokalemia), abnormal digoxin levels and catheter insertion. Milrinone was not shown to be arrhythmogenic in an electrophysiology study. Supraventricular arrhythmias were reported in 3.8% of the patients receiving milrinone. The incidence of both supraventricular and ventricular arrhythmias has not been related to the dose or plasma milrinone concentration. - Other cardiovascular adverse reactions include hypotension, 2.9% and angina/chest pain, 1.2%. - Headaches, usually mild to moderate in severity, have been reported in 2.9% of patients receiving milrinone. - Other adverse reactions reported, but not definitely related to the administration of milrinone include hypokalemia, 0.6%; tremor, 0.4%; and thrombocytopenia, 0.4%. ## Postmarketing Experience - In addition to adverse events reported from clinical trials, the following events have been reported from worldwide post-marketing experience with milrinone: - Isolated spontaneous reports of bronchospasm and anaphylactic shock. - Liver function test abnormalities and skin reactions such as rash. - Administration site conditions: Infusion site reaction. - In the post-marketing experience, there have been rare cases of “torsades de pointes” reported. # Drug Interactions - Drug Interactions - No untoward clinical manifestations have been observed in limited experience with patients in whom milrinone was used concurrently with the following drugs: digitalis glycosides; lidocaine, quinidine; hydralazine, prazosin; isosorbide dinitrate, nitroglycerin; chlorthalidone, furosemide, hydrochlorothiazide, spironolactone; captopril; heparin, warfarin, diazepam, insulin; and potassium supplements. - Chemical Interactions - There is an immediate chemical interaction which is evidenced by the formation of a precipitate when furosemide is injected into an intravenous line of an infusion of milrinone. Therefore, furosemide should not be administered in intravenous lines containing milrinone. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Oral administration of milrinone to pregnant rats and rabbits during organogenesis produced no evidence of teratogenicity at dose levels up to 40 mg/kg/day and 12 mg/kg/day, respectively. Milrinone did not appear to be teratogenic when administered intravenously to pregnant rats at doses up to 3 mg/kg/day (about 2.5 times the maximum recommended clinical intravenous dose) or pregnant rabbits at doses up to 12 mg/kg/day, although an increased resorption rate was apparent at both 8 mg/kg/day and 12 mg/kg/day (intravenous) in the latter species. There are no adequate and well-controlled studies in pregnant women. Milrinone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Milrinone in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Milrinone during labor and delivery. ### Nursing Mothers - Caution should be exercised when milrinone is administered to nursing women, since it is not known whether it is excreted in human milk. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use - There are no special dosage recommendations for the elderly patient. Ninety percent of all patients administered milrinone in clinical studies were within the age range of 45 to 70 years, with a mean age of 61 years. Patients in all age groups demonstrated clinically and statistically significant responses. No age-related effects on the incidence of adverse reactions have been observed. Controlled pharmacokinetic studies have not disclosed any age-related effects on the distribution and elimination of milrinone. ### Gender There is no FDA guidance on the use of Milrinone with respect to specific gender populations. ### Race There is no FDA guidance on the use of Milrinone with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Milrinone in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Milrinone in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Milrinone in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Milrinone in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring There is limited information regarding Monitoring of Milrinone in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Milrinone in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - Doses of milrinone may produce hypotension because of its vasodilator effect. If this occurs, administration of milrinone should be reduced or temporarily discontinued until the patient's condition stabilizes. ### Management - No specific antidote is known, but general measures for circulatory support should be taken. ## Chronic Overdose There is limited information regarding Chronic Overdose of Milrinone in the drug label. # Pharmacology ## Mechanism of Action - Milrinone is a positive inotrope and vasodilator, with little chronotropic activity different in structure and mode of action from either the digitalis glycosides or catecholamines. - Milrinone, at relevant inotropic and vasorelaxant concentrations, is a selective inhibitor of peak III cAMP phosphodiesterase isozyme in cardiac and vascular muscle. This inhibitory action is consistent with cAMP mediated increases in intracellular ionized calcium and contractile force in cardiac muscle, as well as with cAMP dependent contractile protein phosphorylation and relaxation in vascular muscle. Additional experimental evidence also indicates that milrinone is not a beta-adrenergic agonist nor does it inhibit sodium-potassium adenosine triphosphatase activity as do the digitalis glycosides. ## Structure - Milrinone Lactate Injection, is a member of a new class of bipyridine inotropic/vasodilator agents with phosphodiesterase inhibitor activity, distinct from digitalis glycosides or catecholamines. Milrinone lactate is designated chemically as 1,6-Dihydro-2-methyl-6-oxo[3,4'-bipyridine]-5-carbonitrile lactate and has the following structural formula: - Milrinone is an off-white to tan crystalline compound with a molecular weight of 211.2 and a molecular formula of C12H9N3O. It is slightly soluble in methanol, and very slightly soluble in chloroform and in water. As the lactate salt, it is stable and colorless to pale yellow in solution. Milrinone lactate injection is available as sterile aqueous solutions of the lactate salt of milrinone for injection or infusion intravenously. - Sterile, single-dose vials: Single-dose vials of 10, 20 and 50 mL contain in each mL milrinone lactate equivalent to 1 mg milrinone and 47 mg Dextrose, Anhydrous, in Water for Injection. The pH is adjusted to between 3.2 and 4.0 with lactic acid and/or sodium hydroxide. The total concentration of lactic acid can vary between 0.95 mg/mL and 1.29 mg/mL. These vials require preparation of dilutions prior to administration to patients intravenously. - Clinical studies in patients with congestive heart failure have shown that milrinone produces dose-related and plasma drug concentration-related increases in the maximum rate of increase of left ventricular pressure. Studies in normal subjects have shown that milrinone produces increases in the slope of the left ventricular pressure-dimension relationship, indicating a direct inotropic effect of the drug. Milrinone also produces dose-related and plasma concentration-related increases in forearm blood flow in patients with congestive heart failure, indicating a direct arterial vasodilator activity of the drug. - Both the inotropic and vasodilatory effects have been observed over the therapeutic range of plasma milrinone concentrations of 100 ng/mL to 300 ng/mL. - In addition to increasing myocardial contractility, milrinone improves diastolic function as evidenced by improvements in left ventricular diastolic relaxation. - The acute administration of intravenous milrinone has also been evaluated in clinical trials in excess of 1600 patients, with chronic heart failure, heart failure associated with cardiac surgery, and heart failure associated with myocardial infarction. * The total number of deaths, either on therapy or shortly thereafter (24 hours) was 15, less than 0.9%, few of which were thought to be drug-related. ## Pharmacodynamics - In patients with heart failure due to depressed myocardial function, milrinone produced a prompt dose and plasma concentration related increase in cardiac output and decreases in pulmonary capillary wedge pressure and vascular resistance, which were accompanied by mild-to-moderate increases in heart rate. Additionally, there is no increased effect on myocardial oxygen consumption. In uncontrolled studies, hemodynamic improvement during intravenous therapy with milrinone was accompanied by clinical symptomatic improvement, but the ability of milrinone to relieve symptoms has not been evaluated in controlled clinical trials. The great majority of patients experience improvements in hemodynamic function within 5 to 15 minutes of initiation of therapy. - In studies in congestive heart failure patients, milrinone when administered as a loading injection followed by a maintenance infusion produced significant mean initial increases in cardiac index of 25 percent, 38 percent, and 42 percent at dose regimens of 37.5 mcg/kg/0.375 mcg/kg/min, 50 mcg/kg/0.50 mcg/kg/min, and 75 mcg/kg/0.75 mcg/kg/min, respectively. Over the same range of loading injections and maintenance infusions, pulmonary capillary wedge pressure significantly decreased by 20 percent, 23 percent, and 36 percent, respectively, while systemic vascular resistance significantly decreased by 17 percent, 21 percent, and 37 percent. Mean arterial pressure fell by up to 5 percent at the two lower dose regimens, but by 17 percent at the highest dose. Patients evaluated for 48 hours maintained improvements in hemodynamic function, with no evidence of diminished response (tachyphylaxis). A smaller number of patients have received infusions of milrinone for periods up to 72 hours without evidence of tachyphylaxis. - The duration of therapy should depend upon patient responsiveness. - Milrinone has a favorable inotropic effect in fully digitalized patients without causing signs of glycoside toxicity. Theoretically, in cases of atrial flutter/fibrillation, it is possible that milrinone may increase ventricular response rate because of its slight enhancement of AV node conduction. In these cases, digitalis should be considered prior to the institution of therapy with milrinone. - Improvement in left ventricular function in patients with ischemic heart disease has been observed. The improvement has occurred without inducing symptoms or electrocardiographic signs of myocardial ischemia. - The steady-state plasma milrinone concentrations after approximately 6 to 12 hours of unchanging maintenance infusion of 0.50 mcg/kg/min are approximately 200 ng/mL. Near maximum favorable effects of milrinone on cardiac output and pulmonary capillary wedge pressure are seen at plasma milrinone concentrations in the 150 ng/mL to 250 ng/mL range. ## Pharmacokinetics - Following intravenous injections of 12.5 mcg/kg to 125 mcg/kg to congestive heart failure patients, milrinone had a volume of distribution of 0.38 liters/kg, a mean terminal elimination half-life of 2.3 hours, and a clearance of 0.13 liters/kg/hr. Following intravenous infusions of 0.20 mcg/kg/min to 0.70 mcg/kg/min to congestive heart failure patients, the drug had a volume of distribution of about 0.45 liters/kg, a mean terminal elimination half-life of 2.4 hours, and a clearance of 0.14 liters/kg/hr. These pharmacokinetic parameters were not dose-dependent, and the area under the plasma concentration versus time curve following injections was significantly dose-dependent. - Milrinone has been shown (by equilibrium dialysis) to be approximately 70% bound to human plasma protein. - The primary route of excretion of milrinone in man is via the urine. The major urinary excretions of orally administered milrinone in man are milrinone (83%) and its 0-glucuronide metabolite (12%). Elimination in normal subjects via the urine is rapid, with approximately 60% recovered within the first two hours following dosing and approximately 90% recovered within the first eight hours following dosing. The mean renal clearance of milrinone is approximately 0.3 liters/min, indicative of active secretion. ## Nonclinical Toxicology - Carcinogenesis, Mutagenesis, Impairment of Fertility - Twenty-four months of oral administration of milrinone to mice at doses up to 40 mg/kg/day (about 50 times the human oral therapeutic dose in a 50 kg patient) was unassociated with evidence of carcinogenic potential. Neither was there evidence of carcinogenic potential when milrinone was orally administered to rats at doses up to 5 mg/kg/day (about 6 times the human oral therapeutic dose) for twenty-four months or at 25 mg/kg/day (about 30 times the human oral therapeutic dose) for up to 18 months in males and 20 months in females. Whereas the Chinese Hamster Ovary Chromosome Aberration Assay was positive in the presence of a metabolic activation system, results from the Ames Test, the Mouse Lymphoma Assay, the Micronucleus Test, and the in vivo Rat Bone Marrow Metaphase Analysis indicated an absence of mutagenic potential. In reproductive performance studies in rats, milrinone had no effect on male or female fertility at oral doses up to 32 mg/kg/day. - Animal Toxicity - Oral and intravenous administration of toxic dosages of milrinone to rats and dogs resulted in myocardial degeneration/fibrosis and endocardial hemorrhage, principally affecting the left ventricular papillary muscles. Coronary vascular lesions characterized by periarterial edema and inflammation have been observed in dogs only. The myocardial/endocardial changes are similar to those produced by beta-adrenergic receptor agonists such as isoproterenol, while the vascular changes are similar to those produced by minoxidil and hydralazine. Doses within the recommended clinical dose range (up to 1.13 mg/kg/day) for congestive heart failure patients have not produced significant adverse effects in animals. # Clinical Studies There is limited information regarding Clinical Studies of Milrinone in the drug label. # How Supplied - Milrinone Lactate Injection is supplied as 10 mL (1 mg/mL) NDC 55390-019-10, box of 10; 20 mL (1 mg/mL) NDC 55390-020-10, box of 10; and 50 mL (1 mg/mL) NDC 55390-021-01, individually-boxed, single-dose vials containing a sterile, clear, colorless to pale yellow solution. Each mL contains milrinone lactate equivalent to 1 mg milrinone. - Discard unused portion after initial use. Store at controlled room temperature 15° to 30°C (59° to 86°F). Avoid freezing. - Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. Protect from freezing. ## Storage There is limited information regarding Milrinone Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Milrinone in the drug label. # Precautions with Alcohol - Alcohol-Milrinone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Primacor®[3] # Look-Alike Drug Names - N/A[4] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Milrinone
4d5da48a739dc8568cc7cc2f42a660add043c78e	wikidoc	Mimivirus	Mimivirus Mimivirus is a viral genus containing a single identified species named Acanthamoeba polyphaga mimivirus (APMV). In colloquial speech, APMV is more commonly referred to as just “mimivirus”. It has the largest capsid diameter of all known viruses, as well as a large and complex genome compared to other viruses. Though knowledge of the virus is relatively limited, the discovery of the virus excited many people due to the implications of its complex nature, with people hailing it as everything from a new domain of life to a missing link between viruses and bacteria. # Discovery APMV was discovered serendipitously in 1992 within the amoeba Acanthamoeba polyphaga, for which it is named, during research into Legionellosis. The virus was observed in a gram stain and mistakenly thought to be a gram-positive bacterium. As a consequence it was named "Bradfordcoccus", after the district the amoeba was sourced from in Bradford, England. In 2003, researchers at the Université de la Méditerranée in Marseille, France published a paper in Science identifying the micro-organism as a virus. Mimivirus may be a causative agent of some forms of pneumonia, however, this is a tentative proposal based solely on indirect evidence in the form of antibodies to the virus discovered in pneumonia patients. Although the classification of mimivirus as a pathogen is tentative, evidence is accumulating that it can cause viral pneumonia. # Classification It has not been placed into a viral family by the International Committee on Taxonomy of Viruses but more members of the proposed family Mimiviridae are thought to exist based on metagenomic data. It has however, been placed into Group I of the Baltimore classification system. Whilst not strictly a method of classification, Mimivirus joins a group of large viruses known as nucleocytoplasmic large DNA viruses (NCLDV), which includes four other families: Poxviridae, Iridoviridae, Phycodnaviridae, Asfarviridae and Coccolithoviridae. They are all large viruses which share both molecular characteristics and large genomes. The mimivirus genome also possesses 21 genes encoding homologs to proteins which are seen to be highly conserved in the majority of NCLDVs, and further work suggests that mimivirus is an early divergent of the general NCLDV group. # Structure Mimivirus is the largest known virus, with a capsid diameter of 400 nm. Protein filaments measuring 100 nm project from the surface of the capsid, bringing the total length of the virus up to 600 nm. Variation in scientific literature renders these figures as highly approximate, with the “size” of the virion being casually listed as anywhere between 400 nm and 800 nm, depending on whether total length or capsid diameter is actually quoted. The capsid appears hexagonal under an electron microscope, therefore the capsid symmetry is icosahedral. It does not appear to possess an outer viral envelope, suggesting that the virus does not exit the host cell by exocytosis. Mimivirus shares several morphological characteristics in common with all members of the NCLDV group of viruses. As an internal lipid layer surrounding the central core is present in all other NCLDV viruses, it has been suggested by M. Suzan-Monti et al. that this may also be present in mimivirus. The condensed central core of the virion appears as a dark region under the electron microscope. The large genome of the virus resides within this area. Several mRNA transcripts can be recovered from purified virions. Like other NCLDVs, transcripts for DNA polymerase, a capsid protein and a TFII-like transcription factor were found. However, three distinct aminoacyl tRNA synthetase enzyme transcripts and four unknown mRNA molecules specific to mimivirus were also found. These pre-packaged transcripts can be translated without viral gene expression and are likely to be necessary to Mimivirus for replication. Other DNA viruses, such as the Human cytomegalovirus and Herpes simplex virus type-1, also feature pre-packaged mRNA transcripts (M. Suzan-Monti, 2006). # Genome The mimivirus genome is a linear, double-stranded molecule of DNA roughly 1.2 million base pairs in length. This makes it the largest viral genome in scientific knowledge, outstripping the next-largest virus genome of the myovirus Bacillus phage G by a little over double. In addition, it is larger than at least 30 cellular organisms. In addition to the large size of the genome, mimivirus possesses an estimated 911 protein-coding genes, far exceeding the minimum 4 genes required for viruses to exist (c.f. MS2 and Qβ viruses). Analysis of its genome revealed the presence of genes not seen in any other viruses, including aminoacyl tRNA synthetases, and other genes thought only to be encoded by cellular organisms. Like other large DNA viruses, mimivirus contains several genes for sugar, lipid and amino acid metabolism, as well as some metabolic genes not found in any other virus (M. Suzan-Monti, 2006). Roughly 90% of the genome was of coding capacity, with the other 10% being “junk DNA”. # Replication The stages of mimivirus replication are not well known, but as a minimum it is known that mimivirus attaches to a chemical receptor on the surface of an amoeba cell and is taken into the cell. Once inside, an eclipse phase begins, in which the virus disappears and all appears normal within the cell. After about four hours small accumulations can be seen in areas of the cell. Eight hours after infection many mimivirus virions are clearly visible within the cell. The cell cytoplasm continues to fill with newly synthesised virions and about 24 hours after initial infection the cell likely bursts open to release the new mimivirus virions. Little is known about the details of this replication cycle, most obviously attachment to the cell surface and entry, viral core release, DNA replication, transcription, translation, assembly and release of progeny virions. However, scientists have established the general overview given above using electron micrographs of infected cells. These micrographs show mimivirus capsid assembly in the nucleus, acquisition of an inner lipid membrane via budding from the nucleus, and particles similar to those found in many other viruses, including all NCLDV members. These particles are known in other viruses as viral factories and allow efficient viral assembly by modifying large areas of the host cell. # Implications for defining "life" Mimivirus possesses many characteristics which place it at the boundary of living and non-living. It is as large as several bacterial species, such as Rickettsia conorii and Tropheryma whipplei, possesses a genome of comparable size to several bacteria, including those above, and codes for products previously not thought to be encoded by viruses. In addition, mimivirus possesses genes coding for nucleotide and amino acid synthesis, which even some small obligate intracellular bacteria lack. This means that unlike these bacteria, mimivirus is not dependent on the host cell genome for coding the metabolic pathways for these products. They do however, lack genes for ribosomal proteins, making mimivirus dependent for protein translation and energy metabolism. These factors combined have thrown scientists into debate over whether mimivirus is a distinct form of life, comparable on a domain scale to Eukarya, Archaea and Bacteria. Nevertheless, mimivirus does not exhibit the following characteristics, all of which are part of many conventional definitions of life: homeostasis, response to stimuli, growth in the normal sense of the term (instead replicating via self-assembly of individual components) or undergoing cellular division. Because its lineage is very old and could have emerged prior to cellular organisms, mimivirus has added to the debate over the origins of life. Some genes unique to mimivirus, including those coding for the capsid, have been conserved in a variety of viruses which infect organisms from all domains - Eukarya, Archaea and Bacteria. This has been used to suggest that mimivirus is related to a type of DNA virus that emerged before cellular organisms and played a key role in the development of all life on Earth. An alternative hypothesis is that there were three distinct types of DNA viruses that were involved in generating the three known domains of life . # References in Popular Culture A "pseudo-mimi" drove much of the plot of Vernor Vinge's novel Rainbows End. In the book, it was a tailored virus used for highly effective and subtle mind control. The virus's relatively large genetic capacity was central to this idea.	Mimivirus Mimivirus is a viral genus containing a single identified species named Acanthamoeba polyphaga mimivirus (APMV). In colloquial speech, APMV is more commonly referred to as just “mimivirus”. It has the largest capsid diameter of all known viruses, as well as a large and complex genome compared to other viruses. Though knowledge of the virus is relatively limited, the discovery of the virus excited many people due to the implications of its complex nature, with people hailing it as everything from a new domain of life to a missing link between viruses and bacteria. # Discovery APMV was discovered serendipitously in 1992 within the amoeba Acanthamoeba polyphaga, for which it is named, during research into Legionellosis. The virus was observed in a gram stain and mistakenly thought to be a gram-positive bacterium. As a consequence it was named "Bradfordcoccus", after the district the amoeba was sourced from in Bradford, England. In 2003, researchers at the Université de la Méditerranée in Marseille, France published a paper in Science identifying the micro-organism as a virus[1]. Mimivirus may be a causative agent of some forms of pneumonia, however, this is a tentative proposal based solely on indirect evidence in the form of antibodies to the virus discovered in pneumonia patients.[2] Although the classification of mimivirus as a pathogen is tentative, evidence is accumulating that it can cause viral pneumonia.[3] # Classification It has not been placed into a viral family by the International Committee on Taxonomy of Viruses but more members of the proposed family Mimiviridae are thought to exist based on metagenomic data.[4] It has however, been placed into Group I of the Baltimore classification system. Whilst not strictly a method of classification, Mimivirus joins a group of large viruses known as nucleocytoplasmic large DNA viruses (NCLDV), which includes four other families: Poxviridae, Iridoviridae, Phycodnaviridae, Asfarviridae and Coccolithoviridae. They are all large viruses which share both molecular characteristics and large genomes. The mimivirus genome also possesses 21 genes encoding homologs to proteins which are seen to be highly conserved in the majority of NCLDVs, and further work suggests that mimivirus is an early divergent of the general NCLDV group[1]. # Structure Mimivirus is the largest known virus, with a capsid diameter of 400 nm. Protein filaments measuring 100 nm project from the surface of the capsid, bringing the total length of the virus up to 600 nm. Variation in scientific literature renders these figures as highly approximate, with the “size” of the virion being casually listed as anywhere between 400 nm and 800 nm, depending on whether total length or capsid diameter is actually quoted. The capsid appears hexagonal under an electron microscope, therefore the capsid symmetry is icosahedral. It does not appear to possess an outer viral envelope, suggesting that the virus does not exit the host cell by exocytosis[5]. Mimivirus shares several morphological characteristics in common with all members of the NCLDV group of viruses. As an internal lipid layer surrounding the central core is present in all other NCLDV viruses, it has been suggested by M. Suzan-Monti et al. that this may also be present in mimivirus. The condensed central core of the virion appears as a dark region under the electron microscope. The large genome of the virus resides within this area. Several mRNA transcripts can be recovered from purified virions. Like other NCLDVs, transcripts for DNA polymerase, a capsid protein and a TFII-like transcription factor were found. However, three distinct aminoacyl tRNA synthetase enzyme transcripts and four unknown mRNA molecules specific to mimivirus were also found. These pre-packaged transcripts can be translated without viral gene expression and are likely to be necessary to Mimivirus for replication. Other DNA viruses, such as the Human cytomegalovirus and Herpes simplex virus type-1, also feature pre-packaged mRNA transcripts (M. Suzan-Monti, 2006). # Genome The mimivirus genome is a linear, double-stranded molecule of DNA roughly 1.2 million base pairs in length. This makes it the largest viral genome in scientific knowledge, outstripping the next-largest virus genome of the myovirus Bacillus phage G by a little over double. In addition, it is larger than at least 30 cellular organisms[6]. In addition to the large size of the genome, mimivirus possesses an estimated 911 protein-coding genes, far exceeding the minimum 4 genes required for viruses to exist (c.f. MS2 and Qβ viruses[7]). Analysis of its genome revealed the presence of genes not seen in any other viruses, including aminoacyl tRNA synthetases, and other genes thought only to be encoded by cellular organisms. Like other large DNA viruses, mimivirus contains several genes for sugar, lipid and amino acid metabolism, as well as some metabolic genes not found in any other virus (M. Suzan-Monti, 2006). Roughly 90% of the genome was of coding capacity, with the other 10% being “junk DNA”. # Replication The stages of mimivirus replication are not well known, but as a minimum it is known that mimivirus attaches to a chemical receptor on the surface of an amoeba cell and is taken into the cell. Once inside, an eclipse phase begins, in which the virus disappears and all appears normal within the cell. After about four hours small accumulations can be seen in areas of the cell. Eight hours after infection many mimivirus virions are clearly visible within the cell. The cell cytoplasm continues to fill with newly synthesised virions and about 24 hours after initial infection the cell likely bursts open to release the new mimivirus virions.[8] Little is known about the details of this replication cycle, most obviously attachment to the cell surface and entry, viral core release, DNA replication, transcription, translation, assembly and release of progeny virions. However, scientists have established the general overview given above using electron micrographs of infected cells. These micrographs show mimivirus capsid assembly in the nucleus, acquisition of an inner lipid membrane via budding from the nucleus, and particles similar to those found in many other viruses, including all NCLDV members. These particles are known in other viruses as viral factories and allow efficient viral assembly by modifying large areas of the host cell. # Implications for defining "life" Mimivirus possesses many characteristics which place it at the boundary of living and non-living. It is as large as several bacterial species, such as Rickettsia conorii and Tropheryma whipplei, possesses a genome of comparable size to several bacteria, including those above, and codes for products previously not thought to be encoded by viruses. In addition, mimivirus possesses genes coding for nucleotide and amino acid synthesis, which even some small obligate intracellular bacteria lack. This means that unlike these bacteria, mimivirus is not dependent on the host cell genome for coding the metabolic pathways for these products. They do however, lack genes for ribosomal proteins, making mimivirus dependent for protein translation and energy metabolism. These factors combined have thrown scientists into debate over whether mimivirus is a distinct form of life, comparable on a domain scale to Eukarya, Archaea and Bacteria. Nevertheless, mimivirus does not exhibit the following characteristics, all of which are part of many conventional definitions of life: homeostasis, response to stimuli, growth in the normal sense of the term (instead replicating via self-assembly of individual components) or undergoing cellular division. Because its lineage is very old and could have emerged prior to cellular organisms, mimivirus has added to the debate over the origins of life. Some genes unique to mimivirus, including those coding for the capsid, have been conserved in a variety of viruses which infect organisms from all domains - Eukarya, Archaea and Bacteria. This has been used to suggest that mimivirus is related to a type of DNA virus that emerged before cellular organisms and played a key role in the development of all life on Earth[9]. An alternative hypothesis is that there were three distinct types of DNA viruses that were involved in generating the three known domains of life [10]. # References in Popular Culture A "pseudo-mimi" drove much of the plot of Vernor Vinge's novel Rainbows End. In the book, it was a tailored virus used for highly effective and subtle mind control. The virus's relatively large genetic capacity was central to this idea.	https://www.wikidoc.org/index.php/Mimivirus
7f0b84d1eaf31013c56ea1081bd8a9e3f0554531	wikidoc	Mistletoe	Mistletoe Mistletoe is a plant parasitic on the branches of a tree or shrub. All mistletoes are parasitic plants in the order Santalales. This mistletoe habit has evolved independently five times: 1) Misodendraceae, 2) Loranthaceae, 3) Santalaceae (formerly considered the separate family Eremolepidaceae), and Santalaceae ( formerly treated as the separate family Viscaceae). Although Viscaceae and Eremolepidaceae were placed in a broadly-defined Santalaceae by APG2, these two mistletoe lineages have independent origins. . The name was originally applied to Viscum album (European Mistletoe, Santalaceae; the only species native in Great Britain and much of Europe), and subsequently to other related species, including Phoradendron serotinum (the Eastern Mistletoe of eastern North America, also Santalaceae). The European Mistletoe is readily recognized by its smooth-edged oval leaves in pairs along the woody stem, and waxy white berries in dense clusters of 2-6 together. In America, the Eastern Mistletoe is similar, but has shorter, broader leaves and longer clusters of ten or more berries together. . The largest family of Mistletoes is Loranthaceae with 73 genera and over 900 species. . Some of these species have small, insect-pollinated flowers (as with Santalaceae), but others have spectacularly showy, large, bird-pollinated flowers. Mistletoe biodiversity is markedly higher in subtropical and tropical climates; Australia has 85 species, of which 71 are in Loranthaceae, and 14 in Santalaceae. . The species grow on a wide range of trees, and can eventually prove fatal to them where infestation is heavy, though damage more commonly only results in growth reduction. All mistletoes are hemiparasites, bearing evergreen leaves that carry out some photosynthesis on their own, relying on the host mainly for water and the mineral nutrients it carries. The genus Arceuthobium (dwarf mistletoe; Santalaceae) has reduced photosynthesis. As an adult, it manufactures only a small percentage of the sugars it needs from its own photosythesis but as a seedling it actively photosynthesizes until a connection to the host is established. Most mistletoes seeds are spread by birds (e.g. the Mistle Thrush in Europe, the Phainopepla in southwestern North America, and Dicaeum of Asia and Australia), which derive sustenance through eating the fruits (drupes). The seeds are egested in their droppings and stick to twigs, or more commonly the bird grips the fruit in its bill, squeezes the sticky coated seed out to the side, and then wipes its bill clean on a suitable branch. The seeds are coated with a sticky material called viscin (containing both cellulosic stands and mucopolysaccharides), which hardens and attaches the seed firmly to its future host. The word 'mistletoe' is of uncertain etymology; it may be related to German Mist, for dung and Tang for branch, but Old English mistel was also used for basil. While historically often considered a pest that kills trees and devalues natural habitats, mistletoe has recently become recognized as an ecological keystone, an organism that has a disproportionately pervasive influence over its community. A broad array of animals depend on mistletoe for food, consuming the leaves and young shoots as well as transferring pollen between plants and dispersing the sticky seeds. The dense evergreen witches' brooms formed by the dwarf mistletoes (Arceuthobium) of western North America also make excellent locations for roosting and nesting of the Northern Spotted Owls and the Marbled Murrelets. In Australia the Diamond Firetails and Painted Honeyeaters are recorded as nesting in different mistletoes. This behavior is probably far more widespread than currently recognized; more than 240 species of birds that nest in foliage in Australia have been recorded nesting in mistletoe, representing more than 75% of the resident avifauna. . These interactions lead to dramatic influences on diversity, as areas with greater mistletoe densities support higher diversities of animals. Thus, rather than being a pest, mistletoe can have a positive effect on biodiversity, providing high quality food and habitat for a broad range of animals in forests and woodlands worldwide. # Uses and mythology The leaves and young twigs are the parts used by herbalists, and it is popular in Europe, especially in Germany, for treating circulatory and respiratory system problems, and cancer. . Mistletoe is being studied as a potential treatment for tumors. Although such use is not yet permitted in the U.S., mistletoe is prescribed in Europe . Mistletoe figured prominently in Norse mythology (which some believe is the origin of the modern Western custom of kissing under bunches of it hung as holiday decorations). The god Baldur was killed with a weapon made of mistletoe. In previous times the tradition was that the couple took away a fruit each time until they were all used up and at this point the mistletoe lost its vitality. The appearance and nature of the fruit's content (viscin) is very similar or suggestive of human semen and this has strengthened its pagan connections. Mistletoe also bears fruit at the time of the Winter Solstice (the birth of the new year) and may have been used in a fertility rite in Ancient Britain. The fertility rite may be a more likely source of the 'kissing under the mistletoe' tradition which originated from Britain rather than Scandinavia, but the pagan ritual was maybe brought into Britain by the Saxons, who worshipped the same gods as Norsemen. The tradition has spread throughout the English speaking world but is largely unknown in the rest of Europe. Christian beliefs combined with existing pagan feasts and winter rituals to create many long-standing traditions of Christmas celebrations. For example, ancient Europeans believed that the mistletoe plant held magic powers to bestow life and fertility, to bring about peace, and to protect against disease. Northern Europeans associated the plant with the Norse goddess of love, Freyja, and developed the custom of kissing underneath mistletoe branches. Christians incorporated this custom into their Christmas celebrations, and kissing under a mistletoe branch eventually became a part of secular Christmas tradition. In Celtic mythology and in Druid rituals, it was considered an antidote to poison, but it is now known that the fruits of many mistletoes are poisonous if ingested as they contain viscotoxins. In Romanian traditions, mistletoe (vâsc in Romanian) is considered as a source of good fortune. The medical and the supposed magical properties of the plant are still used, especially in rural areas. This custom is inherited from Dacians. Mistletoe has sometimes been nick-named the vampire plant because it can probe beneath the tree bark to drain water and minerals, enabling it to survive during a drought. William Shakespeare gives it an unflattering reference in Titus Andronicus, Act II, Scene I: "Overcome with moss and baleful mistletoe" Nowadays, mistletoe is commonly used as a Christmas decoration. Viscum album is used in Europe whereas Phoradendron serotinum is used in North America. According to a custom of Christmas cheer, any two people who meet under a hanging of mistletoe are obliged to kiss. Mistletoe is the state floral emblem for the State of Oklahoma. The state did not have an official flower, leaving the Mistletoe as the assumed state flower until the Oklahoma Rose was designated as such in 2004. In a popular myth, confusing Mistletoe and the Holly 'holy' Tree, the most sacred tree of the Druids, it is said that Mistletoe was cut with a gold sickle and it lost its power if it fell and touched the ground. The confusion arises from both plants being green all year and both having colorful fruits as well as sharing similar history concerning the winter months. - Mistletoe in an apple tree in Essex, England Mistletoe in an apple tree in Essex, England - Mistletoe in an apple tree in Essex, England Mistletoe in an apple tree in Essex, England - Mistletoe bush on a eucalyptus tree Mistletoe bush on a eucalyptus tree - Mistletoe attached to eucalyptus host Mistletoe attached to eucalyptus host - Mistletoe fruits Mistletoe fruits - The sticky seed of the mistletoe on a branch The sticky seed of the mistletoe on a branch - Red mistletoe, New Zealand Red mistletoe, New Zealand - Mistletoe in San Bernardino Mountains Mistletoe in San Bernardino Mountains	Mistletoe Mistletoe is a plant parasitic on the branches of a tree or shrub. All mistletoes are parasitic plants in the order Santalales. This mistletoe habit has evolved independently five times: 1) Misodendraceae, 2) Loranthaceae, 3) Santalaceae (formerly considered the separate family Eremolepidaceae), and Santalaceae ( formerly treated as the separate family Viscaceae). Although Viscaceae and Eremolepidaceae were placed in a broadly-defined Santalaceae by APG2, these two mistletoe lineages have independent origins.[citation needed] . The name was originally applied to Viscum album (European Mistletoe, Santalaceae; the only species native in Great Britain and much of Europe), and subsequently to other related species, including Phoradendron serotinum (the Eastern Mistletoe of eastern North America, also Santalaceae). The European Mistletoe is readily recognized by its smooth-edged oval leaves in pairs along the woody stem, and waxy white berries in dense clusters of 2-6 together. In America, the Eastern Mistletoe is similar, but has shorter, broader leaves and longer clusters of ten or more berries together.[citation needed] . The largest family of Mistletoes is Loranthaceae with 73 genera and over 900 species.[citation needed] . Some of these species have small, insect-pollinated flowers (as with Santalaceae), but others have spectacularly showy, large, bird-pollinated flowers. Mistletoe biodiversity is markedly higher in subtropical and tropical climates; Australia has 85 species, of which 71 are in Loranthaceae, and 14 in Santalaceae.[citation needed] . The species grow on a wide range of trees, and can eventually prove fatal to them where infestation is heavy, though damage more commonly only results in growth reduction. All mistletoes are hemiparasites, bearing evergreen leaves that carry out some photosynthesis on their own, relying on the host mainly for water and the mineral nutrients it carries. The genus Arceuthobium (dwarf mistletoe; Santalaceae) has reduced photosynthesis. As an adult, it manufactures only a small percentage of the sugars it needs from its own photosythesis but as a seedling it actively photosynthesizes until a connection to the host is established. Most mistletoes seeds are spread by birds (e.g. the Mistle Thrush in Europe, the Phainopepla in southwestern North America, and Dicaeum of Asia and Australia), which derive sustenance through eating the fruits (drupes). The seeds are egested in their droppings and stick to twigs, or more commonly the bird grips the fruit in its bill, squeezes the sticky coated seed out to the side, and then wipes its bill clean on a suitable branch.[citation needed] The seeds are coated with a sticky material called viscin (containing both cellulosic stands and mucopolysaccharides), which hardens and attaches the seed firmly to its future host. The word 'mistletoe' is of uncertain etymology; it may be related to German Mist, for dung and Tang for branch, but Old English mistel was also used for basil. While historically often considered a pest that kills trees and devalues natural habitats, mistletoe has recently become recognized as an ecological keystone, an organism that has a disproportionately pervasive influence over its community. A broad array of animals depend on mistletoe for food, consuming the leaves and young shoots as well as transferring pollen between plants and dispersing the sticky seeds. The dense evergreen witches' brooms formed by the dwarf mistletoes (Arceuthobium) of western North America also make excellent locations for roosting and nesting of the Northern Spotted Owls and the Marbled Murrelets. In Australia the Diamond Firetails and Painted Honeyeaters are recorded as nesting in different mistletoes. This behavior is probably far more widespread than currently recognized; more than 240 species of birds that nest in foliage in Australia have been recorded nesting in mistletoe, representing more than 75% of the resident avifauna.[citation needed] . These interactions lead to dramatic influences on diversity, as areas with greater mistletoe densities support higher diversities of animals. Thus, rather than being a pest, mistletoe can have a positive effect on biodiversity, providing high quality food and habitat for a broad range of animals in forests and woodlands worldwide. # Uses and mythology The leaves and young twigs are the parts used by herbalists, and it is popular in Europe, especially in Germany, for treating circulatory and respiratory system problems, and cancer.[1] [2]. Mistletoe is being studied as a potential treatment for tumors. Although such use is not yet permitted in the U.S., mistletoe is prescribed in Europe [3] [4]. Mistletoe figured prominently in Norse mythology (which some believe is the origin of the modern Western custom of kissing under bunches of it hung as holiday decorations). The god Baldur was killed with a weapon made of mistletoe.[1] In previous times the tradition was that the couple took away a fruit each time until they were all used up and at this point the mistletoe lost its vitality. The appearance and nature of the fruit's content (viscin) is very similar or suggestive of human semen and this has strengthened its pagan connections. Mistletoe also bears fruit at the time of the Winter Solstice (the birth of the new year) and may have been used in a fertility rite in Ancient Britain. The fertility rite may be a more likely source of the 'kissing under the mistletoe' tradition which originated from Britain rather than Scandinavia, but the pagan ritual was maybe brought into Britain by the Saxons, who worshipped the same gods as Norsemen. The tradition has spread throughout the English speaking world but is largely unknown in the rest of Europe. Christian beliefs combined with existing pagan feasts and winter rituals to create many long-standing traditions of Christmas celebrations. For example, ancient Europeans believed that the mistletoe plant held magic powers to bestow life and fertility, to bring about peace, and to protect against disease. Northern Europeans associated the plant with the Norse goddess of love, Freyja, and developed the custom of kissing underneath mistletoe branches. Christians incorporated this custom into their Christmas celebrations, and kissing under a mistletoe branch eventually became a part of secular Christmas tradition.[2] In Celtic mythology and in Druid rituals, it was considered an antidote to poison, but it is now known that the fruits of many mistletoes are poisonous if ingested as they contain viscotoxins. In Romanian traditions, mistletoe (vâsc in Romanian) is considered as a source of good fortune. The medical and the supposed magical properties of the plant are still used, especially in rural areas. This custom is inherited from Dacians. Mistletoe has sometimes been nick-named the vampire plant because it can probe beneath the tree bark to drain water and minerals, enabling it to survive during a drought. William Shakespeare gives it an unflattering reference in Titus Andronicus, Act II, Scene I: "Overcome with moss and baleful mistletoe" Nowadays, mistletoe is commonly used as a Christmas decoration. Viscum album is used in Europe whereas Phoradendron serotinum is used in North America. According to a custom of Christmas cheer, any two people who meet under a hanging of mistletoe are obliged to kiss. Mistletoe is the state floral emblem for the State of Oklahoma. The state did not have an official flower, leaving the Mistletoe as the assumed state flower until the Oklahoma Rose was designated as such in 2004. In a popular myth, confusing Mistletoe and the Holly 'holy' Tree, the most sacred tree of the Druids, it is said that Mistletoe was cut with a gold sickle and it lost its power if it fell and touched the ground. The confusion arises from both plants being green all year and both having colorful fruits as well as sharing similar history concerning the winter months. - Mistletoe in an apple tree in Essex, England Mistletoe in an apple tree in Essex, England - Mistletoe in an apple tree in Essex, England Mistletoe in an apple tree in Essex, England - Mistletoe bush on a eucalyptus tree Mistletoe bush on a eucalyptus tree - Mistletoe attached to eucalyptus host Mistletoe attached to eucalyptus host - Mistletoe fruits Mistletoe fruits - The sticky seed of the mistletoe on a branch The sticky seed of the mistletoe on a branch - Red mistletoe, New Zealand Red mistletoe, New Zealand - Mistletoe in San Bernardino Mountains Mistletoe in San Bernardino Mountains	https://www.wikidoc.org/index.php/Mistletoe
7687a280928e029e60a4f0cdb0074c7e3135d92f	wikidoc	Mitocheck	Mitocheck MitoCheck is an integrated research project which brings together leading European research groups to study systematically the regulation of mitosis in human cells. It is funded within the Sixth Framework programme of the European Commission for 4 years from the April 1 2004 and co-ordinated by Dr Jan-Michael Peters from the Institute of Molecular Pathology (IMP) in Vienna. The full list of participants includes groups from Austria, Germany, Italy, France and the United Kingdom. The project aims to test all human genes for involvement in mitosis by RNAi, then identify a subset which will be studied intensively for changes in phosphorylation, subcellular localization and involvement in protein complexes. Other aspects will look at engineering mitotic kinases and translational opportunities for human health.	Mitocheck MitoCheck is an integrated research project which brings together leading European research groups to study systematically the regulation of mitosis in human cells. It is funded within the Sixth Framework programme of the European Commission for 4 years from the April 1 2004 and co-ordinated by Dr Jan-Michael Peters from the Institute of Molecular Pathology (IMP) in Vienna. The full list of participants includes groups from Austria, Germany, Italy, France and the United Kingdom. The project aims to test all human genes for involvement in mitosis by RNAi, then identify a subset which will be studied intensively for changes in phosphorylation, subcellular localization and involvement in protein complexes. Other aspects will look at engineering mitotic kinases and translational opportunities for human health. # External links - MitoCheck homepage - Sixth Framework Programme - European Commission Template:Harvesternavi Template:WH Template:WS	https://www.wikidoc.org/index.php/Mitocheck
4a159f4c506d805acf0fe545285a0603b8e7e648	wikidoc	Mitotoxin	Mitotoxin Maitotoxin is the toxin that causes ciguatera poisoning. Maitotoxin was named from the ciguateric fish Ctenochaetus striatus—called “maito” in Tahiti—from which maitotoxin was isolated for the first time. Later on, it was revealed that maitotoxin is made by the dinoflagellate Gambierdiscus toxicus. The toxicity of maitotoxin to mice is the highest in nonprotein toxins: the LD50 is 50 ng/kg. Maitotoxin induces Ca2+ influx into cell lines when its concentration is nanomolar to picomolar, and at lower concentrations than picomolar, maitotoxin stimulates degradation of inositol phosphate. The mechanisms of the activities have not been determined yet. Maitotoxin's molecular formula is C164H256O68S2Na2, and its molecular weight is 3422: it is the largest natural product among compounds that do not have well-known units like proteins or polysaccharides. Maitotoxin includes 32 ether rings, 22 methyls, 28 hydroxyls, and 2 sulfuric acid esters. Maitotoxin has an amphipathic structure: polar radicals localize at the A to O rings, and methyls localize at the R to F' rings. The chemical structure of mitotoxin was determined in 1996 by using high-resolution nuclear magnetic resonance spectrum, mass spectroscopy, and synthetic chemical methods.	Mitotoxin Maitotoxin is the toxin that causes ciguatera poisoning. Maitotoxin was named from the ciguateric fish Ctenochaetus striatus—called “maito” in Tahiti—from which maitotoxin was isolated for the first time. Later on, it was revealed that maitotoxin is made by the dinoflagellate Gambierdiscus toxicus. The toxicity of maitotoxin to mice is the highest in nonprotein toxins: the LD50 is 50 ng/kg. Maitotoxin induces Ca2+ influx into cell lines when its concentration is nanomolar to picomolar, and at lower concentrations than picomolar, maitotoxin stimulates degradation of inositol phosphate. The mechanisms of the activities have not been determined yet. Maitotoxin's molecular formula is C164H256O68S2Na2, and its molecular weight is 3422: it is the largest natural product among compounds that do not have well-known units like proteins or polysaccharides. Maitotoxin includes 32 ether rings, 22 methyls, 28 hydroxyls, and 2 sulfuric acid esters. Maitotoxin has an amphipathic structure: polar radicals localize at the A to O rings, and methyls localize at the R to F' rings. The chemical structure of mitotoxin was determined in 1996 by using high-resolution nuclear magnetic resonance spectrum, mass spectroscopy, and synthetic chemical methods. # External links Template:WH Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Mitotoxin
e046f4aeeab286b38275a6aa90161dae4094211f	wikidoc	Molindone	Molindone # Overview Molindone (Moban) is a therapeutic antipsychotic, used in the treatment of schizophrenia. It works by blocking the effects of dopamine in the brain, leading to diminished psychoses. It is rapidly absorbed when taken orally. It is sometimes described as a typical antipsychotic, and sometimes described as an atypical antipsychotic. Molindone was discontinued by its sole supplier, Endo Pharmaceuticals, on January 13, 2010. # Adverse effects The side effect profile of molindone is similar to that of other typical antipsychotics. Unlike most antipsychotics, however, molindone use is associated with weight loss.	Molindone Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Molindone (Moban) is a therapeutic antipsychotic, used in the treatment of schizophrenia.[1] It works by blocking the effects of dopamine in the brain, leading to diminished psychoses. It is rapidly absorbed when taken orally. It is sometimes described as a typical antipsychotic,[2] and sometimes described as an atypical antipsychotic.[3] Molindone was discontinued by its sole supplier, Endo Pharmaceuticals, on January 13, 2010. [4] # Adverse effects The side effect profile of molindone is similar to that of other typical antipsychotics. Unlike most antipsychotics, however, molindone use is associated with weight loss.[3][5]	https://www.wikidoc.org/index.php/Moban
25911043177e6afd7370e01989f81343df7b2a16	wikidoc	Modafinil	Modafinil # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Modafinil is a CNS Stimulant that is FDA approved for the {{{indicationType}}} of narcolepsy, obstructive sleep apnea, and shift work disorder.. Common adverse reactions include rash, nausea, dizziness, headache, insomnia, anxiety, feeling nervous. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - The recommended dose of modafinil is 200 mg given once a day. - Modafinil should be taken as a single dose in the morning. - Dosing Information - In OSA, modafinil is indicated as an adjunct to standard treatment(s) for the underlying obstruction. If continuous positive airway pressure (CPAP) is the treatment of choice for a patient, a maximal effort to treat with CPAP for an adequate period of time should be made prior to initiating modafinil. If modafinil is used adjunctively with CPAP, the encouragement of and periodic assessment of CPAP compliance is necessary. - The recommended dose of modafinil is 200 mg given once a day. - Modafinil should be taken as a single dose in the morning. - Dosing Information - The recommended dose of modafinil is 200 mg given once a day. - For patients with SWD, modafinil should be taken approximately 1 hour prior to the start of their work shift. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Modafinil in adult patients. ### Non–Guideline-Supported Use - Dosing Information - 200 mg/day Modafinil. - Dosing Information - A single oral 200-mg dose of Modafinil. - Dosing Information - Modafinil 200 mg twice in 1 week. - Dosing Information - 16-week course of oral Modafinil was initiated at 200 mg/day, and could be increased to maximum 400 mg/day. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Modafinil in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Modafinil in pediatric patients. ### Non–Guideline-Supported Use - Dosing Information - Modafinil 340 mg or 425 mg, depending on weight (less than 30 kg and 30 kg or more, respectively). # Contraindications - Modafinil is contraindicated in patients with known hypersensitivity to modafinil, armodafinil or its inactive ingredients. # Warnings - Serious Rash, including Stevens-Johnson Syndrome - Serious rash requiring hospitalization and discontinuation of treatment has been reported in adults and children in association with the use of modafinil. - Modafinil is not approved for use in pediatric patients for any indication. - In clinical trials of modafinil, the incidence of rash resulting in discontinuation was approximately 0.8% (13 per 1,585) in pediatric patients (age <17 years); these rashes included 1 case of possible Stevens-Johnson syndrome (SJS) and 1 case of apparent multiorgan hypersensitivity reaction. Several of the cases were associated with fever and other abnormalities (e.g., vomiting, leukopenia). The median time to rash that resulted in discontinuation was 13 days. No such cases were observed among 380 pediatric patients who received placebo. No serious skin rashes have been reported in adult clinical trials (0 per 4,264) of modafinil. - Rare cases of serious or life-threatening rash, including SJS, Toxic Epidermal Necrolysis (TEN), and Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) have been reported in adults and children in worldwide postmarketing experience. The reporting rate of TEN and SJS associated with modafinil use, which is generally accepted to be an underestimate due to underreporting, exceeds the background incidence rate. Estimates of the background incidence rate for these serious skin reactions in the general population range between 1 to 2 cases per million-person years. - There are no factors that are known to predict the risk of occurrence or the severity of rash associated with modafinil. Nearly all cases of serious rash associated with modafinil occurred within 1 to 5 weeks after treatment initiation. However, isolated cases have been reported after prolonged treatment (e.g., 3 months). Accordingly, duration of therapy cannot be relied upon as a means to predict the potential risk heralded by the first appearance of a rash. - Although benign rashes also occur with modafinil, it is not possible to reliably predict which rashes will prove to be serious. Accordingly, modafinil should ordinarily be discontinued at the first sign of rash, unless the rash is clearly not drug-related. Discontinuation of treatment may not prevent a rash from becoming life-threatening or permanently disabling or disfiguring. - Angioedema and Anaphylactoid Reactions - One serious case of angioedema and one case of hypersensitivity (with rash, dysphagia, and bronchospasm), were observed among 1,595 patients treated with armodafinil, the R enantiomer of modafinil (which is the racemic mixture). No such cases were observed in modafinil clinical trials. However, angioedema has been reported in postmarketing experience with modafinil. Patients should be advised to discontinue therapy and immediately report to their physician any signs or symptoms suggesting angioedema or anaphylaxis (e.g., swelling of face, eyes, lips, tongue or larynx; difficulty in swallowing or breathing; hoarseness). - Multiorgan Hypersensitivity Reactions - Multiorgan hypersensitivity reactions, including at least one fatality in postmarketing experience, have occurred in close temporal association (median time to detection 13 days: range 4-33) to the initiation of modafinil. - Although there have been a limited number of reports, multiorgan hypersensitivity reactions may result in hospitalization or be life-threatening. There are no factors that are known to predict the risk of occurrence or the severity of multiorgan hypersensitivity reactions associated with modafinil. Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement. Other associated manifestations included myocarditis, hepatitis, liver function test abnormalities, hematological abnormalities (e.g., eosinophilia, leukopenia, thrombocytopenia), pruritus, and asthenia. Because multiorgan hypersensitivity is variable in its expression, other organ system symptoms and signs, not noted here, may occur. - If a multiorgan hypersensitivity reaction is suspected, modafinil should be discontinued. Although there are no case reports to indicate cross-sensitivity with other drugs that produce this syndrome, the experience with drugs associated with multiorgan hypersensitivity would indicate this to be a possibility. - Persistent Sleepiness - Patients with abnormal levels of sleepiness who take modafinil should be advised that their level of wakefulness may not return to normal. Patients with excessive sleepiness, including those taking modafinil, should be frequently reassessed for their degree of sleepiness and, if appropriate, advised to avoid driving or any other potentially dangerous activity. Prescribers should also be aware that patients may not acknowledge sleepiness or drowsiness until directly questioned about drowsiness or sleepiness during specific activities. - Psychiatric Symptoms - Psychiatric adverse experiences have been reported in patients treated with modafinil. Postmarketing adverse events associated with the use of modafinil have included mania, delusions, hallucinations, suicidal ideation and aggression, some resulting in hospitalization. Many, but not all, patients had a prior psychiatric history. One healthy male volunteer developed ideas of reference, paranoid delusions, and auditory hallucinations in association with multiple daily 600 mg doses of modafinil and sleep deprivation. There was no evidence of psychosis 36 hours after drug discontinuation. - In the adult modafinil controlled trials database, psychiatric symptoms resulting in treatment discontinuation (at a frequency ≥0.3%) and reported more often in patients treated with modafinil compared to those treated with placebo were anxiety (1%), nervousness (1%), insomnia (<1%), confusion (<1%), agitation (<1%), and depression (<1%). Caution should be exercised when modafinil is given to patients with a history of psychosis, depression, or mania. Consideration should be given to the possible emergence or exacerbation of psychiatric symptoms in patients treated with modafinil. If psychiatric symptoms develop in association with modafinil administration, consider discontinuing modafinil. ### Precautions - Diagnosis of Sleep Disorders - Modafinil should be used only in patients who have had a complete evaluation of their excessive sleepiness, and in whom a diagnosis of either narcolepsy, OSA, and/or SWD has been made in accordance with ICSD or DSM diagnostic criteria. Such an evaluation usually consists of a complete history and physical examination, and it may be supplemented with testing in a laboratory setting. Some patients may have more than one sleep disorder contributing to their excessive sleepiness (e.g., OSA and SWD coincident in the same patient). - General - Although modafinil has not been shown to produce functional impairment, any drug affecting the CNS may alter judgment, thinking or motor skills. Patients should be cautioned about operating an automobile or other hazardous machinery until they are reasonably certain that modafinil therapy will not adversely affect their ability to engage in such activities. - CPAP Use in Patients with OSA - In OSA, modafinil is indicated as an adjunct to standard treatment(s) for the underlying obstruction. If continuous positive airway pressure (CPAP) is the treatment of choice for a patient, a maximal effort to treat with CPAP for an adequate period of time should be made prior to initiating modafinil. If modafinil is used adjunctively with CPAP, the encouragement of and periodic assessment of CPAP compliance is necessary. - Cardiovascular System - Modafinil has not been evaluated in patients with a recent history of myocardial infarction or unstable angina, and such patients should be treated with caution. - In clinical studies of modafinil, signs and symptoms including chest pain, palpitations, dyspnea and transient ischemic T-wave changes on ECG were observed in three subjects in association with mitral valve prolapse or left ventricular hypertrophy. It is recommended that modafinil tablets not be used in patients with a history of left ventricular hypertrophy or in patients with mitral valve prolapse who have experienced the mitral valve prolapse syndrome when previously receiving CNS stimulants. Such signs may include but are not limited to ischemic ECG changes, chest pain, or arrhythmia. If new onset of any of these symptoms occurs, consider cardiac evaluation. Blood pressure monitoring in short-term (<3 months) controlled trials showed no clinically significant changes in mean systolic and diastolic blood pressure in patients receiving modafinil as compared to placebo. However, a retrospective analysis of the use of antihypertensive medication in these studies showed that a greater proportion of patients on modafinil required new or increased use of antihypertensive medications (2.4%) compared to patients on placebo (0.7%). The differential use was slightly larger when only studies in OSA were included, with 3.4% of patients on modafinil and 1.1% of patients on placebo requiring such alterations in the use of antihypertensive medication. Increased monitoring of blood pressure may be appropriate in patients on modafinil. - Patients Using Steroidal Contraceptives - The effectiveness of steroidal contraceptives may be reduced when used with modafinil tablets and for one month after discontinuation of therapy. Alternative or concomitant methods of contraception are recommended for patients treated with modafinil tablets, and for one month after discontinuation of modafinil. - Patients Using Cyclosporine - The blood levels of cyclosporine may be reduced when used with modafinil. Monitoring of circulating cyclosporine concentrations and appropriate dosage adjustment for cyclosporine should be considered when these drugs are used concomitantly. - Patients with Severe Hepatic Impairment - In patients with severe hepatic impairment, with or without cirrhosis, modafinil should be administered at a reduced dose. - Patients with Severe Renal Impairment - There is inadequate information to determine safety and efficacy of dosing in patients with severe renal impairment. - Elderly Patients - In elderly patients, elimination of modafinil and its metabolites may be reduced as a consequence of aging. Therefore, consideration should be given to the use of lower doses in this population. # Adverse Reactions ## Clinical Trials Experience - Modafinil has been evaluated for safety in over 3500 patients, of whom more than 2000 patients with excessive sleepiness associated with primary disorders of sleep and wakefulness were given at least one dose of modafinil. In clinical trials, modafinil has been found to be generally well tolerated and most adverse experiences were mild to moderate. - The most commonly observed adverse events (≥5%) associated with the use of modafinil more frequently than placebo-treated patients in the placebo-controlled clinical studies in primary disorders of sleep and wakefulness were headache, nausea, nervousness, rhinitis, diarrhea, back pain, anxiety, insomnia, dizziness, and dyspepsia. The adverse event profile was similar across these studies. - In the placebo-controlled clinical trials, 74 of the 934 patients (8%) who received modafinil discontinued due to an adverse experience compared to 3% of patients that received placebo. The most frequent reasons for discontinuation that occurred at a higher rate for modafinil than placebo patients were headache (2%), nausea, anxiety, dizziness, insomnia, chest pain and nervousness (each <1%). In a Canadian clinical trial, a 35 year old obese narcoleptic male with a prior history of syncopal episodes experienced a 9-second episode of asystole after 27 days of modafinil treatment (300 mg/day in divided doses). - Incidence in Controlled Trials - The following table (Table 3) presents the adverse experiences that occurred at a rate of 1% or more and were more frequent in adult patients treated with modafinil than in placebo-treated patients in the principal, placebo-controlled clinical trials. - The prescriber should be aware that the figures provided below cannot be used to predict the frequency of adverse experiences in the course of usual medical practice, where patient characteristics and other factors may differ from those occurring during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. Review of these frequencies, however, provides prescribers with a basis to estimate the relative contribution of drug and non-drug factors to the incidence of adverse events in the population studied. - Dose Dependency of Adverse Events - In the adult placebo-controlled clinical trials which compared doses of 200, 300, and 400 mg/day of modafinil and placebo, the only adverse events that were clearly dose related were headache and anxiety. - Vital Sign Changes - While there was no consistent change in mean values of heart rate or systolic and diastolic blood pressure, the requirement for antihypertensive medication was slightly greater in patients on modafinil compared to placebo. - Weight Changes - There were no clinically significant differences in body weight change in patients treated with modafinil compared to placebo-treated patients in the placebo-controlled clinical trials. - Laboratory Changes - Clinical chemistry, hematology, and urinalysis parameters were monitored in Phase 1, 2, and 3 studies. In these studies, mean plasma levels of gamma glutamyltransferase (GGT) and alkaline phosphatase (AP) were found to be higher following administration of modafinil, but not placebo. Few subjects, however, had GGT or AP elevations outside of the normal range. Shifts to higher, but not clinically significantly abnormal, GGT and AP values appeared to increase with time in the population treated with modafinil in the Phase 3 clinical trials. No differences were apparent in alanine aminotransferase, aspartate aminotransferase, total protein, albumin, or total bilirubin. - ECG Changes - No treatment-emergent pattern of ECG abnormalities was found in placebo-controlled clinical trials following administration of modafinil. ## Postmarketing Experience - The following adverse reactions have been identified during post-approval use of modafinil. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of the reporting, or (3) strength of causal connection to modafinil. # Drug Interactions - CNS Active Drugs - Methylphenidate - In a single-dose study in healthy volunteers, simultaneous administration of modafinil (200 mg) with methylphenidate (40 mg) did not cause any significant alterations in the pharmacokinetics of either drug. However, the absorption of modafinil may be delayed by approximately one hour when coadministered with methylphenidate. - In a multiple-dose, steady-state study in healthy volunteers, modafinil was administered once daily at 200 mg/day for 7 days followed by 400 mg/day for 21 days. Administration of methylphenidate (20 mg/day) during days 22-28 of modafinil treatment 8 hours after the daily dose of modafinil did not cause any significant alterations in the pharmacokinetics of modafinil. - Dextroamphetamine - In a single dose study in healthy volunteers, simultaneous administration of modafinil (200 mg) with dextroamphetamine (10 mg) did not cause any significant alterations in the pharmacokinetics of either drug. However, the absorption of modafinil may be delayed by approximately one hour when coadministered with dextroamphetamine. - In a multiple-dose, steady-state study in healthy volunteers, modafinil was administered once daily at 200 mg/day for 7 days followed by 400 mg/day for 21 days. Administration of dextroamphetamine (20 mg/day) during days 22-28 of modafinil treatment 7 hours after the daily dose of modafinil did not cause any significant alterations in the pharmacokinetics of modafinil. - Clomipramine - The coadministration of a single dose of clomipramine (50 mg) on the first of three days of treatment with modafinil (200 mg/day) in healthy volunteers did not show an effect on the pharmacokinetics of either drug. However, one incident of increased levels of clomipramine and its active metabolite desmethylclomipramine has been reported in a patient with narcolepsy during treatment with modafinil. - Triazolam - In the drug interaction study between modafinil and ethinyl estradiol (EE2), on the same days as those for the plasma sampling for EE2 pharmacokinetics, a single dose of triazolam (0.125 mg) was also administered. Mean Cmax and AUC0-∞ of triazolam were decreased by 42% and 59%, respectively, and its elimination half-life was decreased by approximately an hour after the modafinil treatment. - Monoamine Oxidase (MAO) Inhibitors - Interaction studies with monoamine oxidase inhibitors have not been performed. Therefore, caution should be used when concomitantly administering MAO inhibitors and modafinil. - Other Drugs - Warfarin - There were no significant changes in the pharmacokinetic profiles of R- and S- warfarin in healthy subjects given a single dose of racemic warfarin (5 mg) following chronic administration of modafinil (200 mg/day for 7 days followed by 400 mg/day for 27 days) relative to the profiles in subjects given placebo. However, more frequent monitoring of prothrombin times/INR is advisable whenever modafinil is coadministered with warfarin. - Ethinyl Estradiol - Administration of modafinil to female volunteers once daily at 200 mg/day for 7 days followed by 400 mg/day for 21 days resulted in a mean 11% decrease in Cmax and 18% decrease in AUC0-24 of ethinyl estradiol (EE2; 0.035 mg; administered orally with norgestimate). There was no apparent change in the elimination rate of ethinyl estradiol. - Cyclosporie - One case of an interaction between modafinil and cyclosporine, a substrate of CYP3A4, has been reported in a 41 year old woman who had undergone an organ transplant. After one month of administration of 200 mg/day of modafinil, cyclosporine blood levels were decreased by 50%. The interaction was postulated to be due to the increased metabolism of cyclosporine, since no other factor expected to affect the disposition of the drug had changed. Dosage adjustment for cyclosporine may be needed. - Potential Interactions with Drugs That Inhibit, Induce, or are Metabolized by Cytochrome P-450 Isoenzymes and Other Hepatic Enzymes - In in vitro studies using primary human hepatocyte cultures, modafinil was shown to slightly induce CYP1A2, CYP2B6 and CYP3A4 in a concentration-dependent manner. Although induction results based on in vitro experiments are not necessarily predictive of response in vivo, caution needs to be exercised when modafinil is coadministered with drugs that depend on these three enzymes for their clearance. Specifically, lower blood levels of such drugs could result. - The exposure of human hepatocytes to modafinil in vitro produced an apparent concentration-related suppression of expression of CYP2C9 activity suggesting that there is a potential for a metabolic interaction between modafinil and the substrates of this enzyme (e.g., S-warfarin and phenytoin). In a subsequent clinical study in healthy volunteers, chronic modafinil treatment did not show a significant effect on the single-dose pharmacokinetics of warfarin when compared to placebo. - In vitro studies using human liver microsomes showed that modafinil reversibly inhibited CYP2C19 at pharmacologically relevant concentrations of modafinil. CYP2C19 is also reversibly inhibited, with similar potency, by a circulating metabolite, modafinil sulfone. Although the maximum plasma concentrations of modafinil sulfone are much lower than those of parent modafinil, the combined effect of both compounds could produce sustained partial inhibition of the enzyme. Drugs that are largely eliminated via CYP2C19 metabolism, such as diazepam, propranolol, phenytoin (also via CYP2C9) or S-mephenytoin may have prolonged elimination upon coadministration with modafinil and may require dosage reduction and monitoring for toxicity. - Tricyclic antidepressants - CYP2C19 also provides an ancillary pathway for the metabolism of certain tricyclic antidepressants (e.g., clomipramine and desipramine) that are primarily metabolized by CYP2D6. In tricyclic-treated patients deficient in CYP2D6 (i.e., those who are poor metabolizers of debrisoquine; 7-10% of the Caucasian population; similar or lower in other populations), the amount of metabolism by CYP2C19 may be substantially increased. Modafinil may cause elevation of the levels of the tricyclics in this subset of patients. Physicians should be aware that a reduction in the dose of tricyclic agents might be needed in these patients. - In addition, due to the partial involvement of CYP3A4 in the metabolic elimination of modafinil, coadministration of potent inducers of CYP3A4 (e.g., carbamazepine, phenobarbital, rifampin) or inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole) could alter the plasma levels of modafinil. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - In studies conducted in rats and rabbits, developmental toxicity was observed at clinically relevant exposures. - Modafinil (50, 100, or 200 mg/kg/day) administered orally to pregnant rats throughout the period of organogenesis caused, in the absence of maternal toxicity, an increase in resorptions and an increased incidence of visceral and skeletal variations in the offspring at the highest dose. The higher no-effect dose for rat embryofetal developmental toxicity was associated with a plasma modafinil exposure approximately 0.5 times the AUC in humans at the recommended daily dose (RHD) of 200 mg. However, in a subsequent study of up to 480 mg/kg/day (plasma modafinil exposure approximately 2 times the AUC in humans at the RHD) no adverse effects on embryofetal development were observed. - Modafinil administered orally to pregnant rabbits throughout the period of organogenesis at doses of 45, 90, and 180 mg/kg/day increased the incidences of fetal structural alterations and embryofetal death at the highest dose. The highest no-effect dose for developmental toxicity was associated with a plasma modafinil AUC approximately equal to the AUC in humans at the RHD. - Oral administration of armodafinil (the R-enantiomer of modafinil; 60, 200, or 600 mg/kg/day) to pregnant rats throughout the period of organogenesis resulted in increased incidences of fetal visceral and skeletal variations at the intermediate dose or greater and decreased fetal body weights at the highest dose. The no-effect dose for rat embryofetal developmental toxicity was associated with a plasma armodafinil exposure (AUC) approximately one-tenth times the AUC for armodafinil in humans treated with modafinil at the RHD. - Modafinil administration to rats throughout gestation and lactation at oral doses of up to 200 mg/kg/day resulted in decreased viability in the offspring at doses greater than 20 mg/kg/day (plasma modafinil AUC approximately 0.1 times the AUC in humans at the RHD). No effects on postnatal developmental and neurobehavioral parameters were observed in surviving offspring. - There are no adequate and well-controlled studies in pregnant women. Two cases of intrauterine growth retardation and one case of spontaneous abortion have been reported in association with armodafinil and modafinil. Although the pharmacology of modafinil and armodafinil is not identical to that of the sympathomimetic amines, they do share some pharmacologic properties with this class. Certain of these drugs have been associated with intrauterine growth retardation and spontaneous abortions. Whether the cases reported are drug-related is unknown. - Modafinil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Modafinil in women who are pregnant. ### Labor and Delivery - The effect of modafinil on labor and delivery in humans has not been systematically investigated. ### Nursing Mothers - It is not known whether modafinil or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when modafinil tablets are administered to a nursing woman. ### Pediatric Use - Safety and effectiveness in pediatric patients, below age 17, have not been established. Serious skin rashes, including erythema multiforme major (EMM) and Stevens-Johnson syndrome (SJS) have been associated with modafinil use in pediatric patients. - In a controlled 6-week study, 165 pediatric patients (aged 5-17 years) with narcolepsy were treated with modafinil (n=123), or placebo (n=42). There were no statistically significant differences favoring modafinil over placebo in prolonging sleep latency as measured by MSLT, or in perceptions of sleepiness as determined by the clinical global impression-clinician scale (CGI-C). - In the controlled and open-label clinical studies, treatment emergent adverse events of the psychiatric and nervous system included Tourette's syndrome, insomnia, hostility, increased cataplexy, increased hypnagogic hallucinations and suicidal ideation. Transient leukopenia, which resolved without medical intervention, was also observed. In the controlled clinical study, 3 of 38 girls, ages 12 or older, treated with modafinil experienced dysmenorrhea compared to 0 of 10 girls who received placebo. - There were three 7 to 9 week, double-blind, placebo-controlled, parallel group studies in children and adolescents (aged 6-17 years) with Attention-Deficit Hyperactivity Disorder (ADHD, DSMIV). Two of the studies were flexible-dose studies (up to 425 mg/day), and the third was a fixed-dose study (340 mg/day for patients <30 kg and 425 mg/day for patients ≥30 kg). Although these studies showed statistically significant differences favoring modafinil over placebo in reducing ADHD symptoms as measured by the ADHD-RS (school version), there were 3 cases of serious rash including one case of possible SJS among 933 patients exposed to modafinil in this program. - Modafinil is not approved for use in pediatric patients for any indication, including ADHD , Serious Rash, including Stevens-Johnson Syndrome. ### Geriatic Use - Experience in a limited number of patients who were greater than 65 years of age in clinical trials showed an incidence of adverse experiences similar to other age groups. In elderly patients, elimination of modafinil and its metabolites may be reduced as a consequence of aging. Therefore, consideration should be given to the use of lower doses in this population. ### Gender There is no FDA guidance on the use of Modafinil with respect to specific gender populations. ### Race There is no FDA guidance on the use of Modafinil with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Modafinil in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Modafinil in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Modafinil in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Modafinil in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Modafinil in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Modafinil in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - In clinical trials, a total of 151 protocol-specified doses ranging from 1000 to 1600 mg/day (5 to 8 times the recommended daily dose of 200 mg) have been administered to 32 subjects, including 13 subjects who received doses of 1000 or 1200 mg/day for 7 to 21 consecutive days. In addition, several intentional acute overdoses occurred; the two largest being 4500 mg and 4000 mg taken by two subjects participating in foreign depression studies. None of these study subjects experienced any unexpected or life-threatening effects. Adverse experiences that were reported at these doses included excitation or agitation, insomnia, and slight or moderate elevations in hemodynamic parameters. Other observed high-dose effects in clinical studies have included anxiety, irritability, aggressiveness, confusion, nervousness, tremor, palpitations, sleep disturbances, nausea, diarrhea and decreased prothrombin time. - From postmarketing experience, there have been no reports of fatal overdoses involving modafinil alone (doses up to 12 grams). Overdoses involving multiple drugs, including modafinil, have resulted in fatal outcomes. Symptoms most often accompanying modafinil overdose, alone or in combination with other drugs have included: insomnia; central nervous system symptoms such as restlessness, disorientation, confusion, excitation and hallucination; digestive changes such as nausea and diarrhea; and cardiovascular changes such as tachycardia, bradycardia, hypertension and chest pain. - Cases of accidental ingestion/overdose have been reported in children as young as 11 months of age. The highest reported accidental ingestion on a mg/kg basis occurred in a three-year-old boy who ingested 800 to 1000 mg (50 to 63 mg/kg) of modafinil. The child remained stable. The symptoms associated with overdose in children were similar to those observed in adults. ### Management - No specific antidote to the toxic effects of modafinil overdose has been identified to date. Such overdoses should be managed with primarily supportive care, including cardiovascular monitoring. If there are no contraindications, induced emesis or gastric lavage should be considered. There are no data to suggest the utility of dialysis or urinary acidification or alkalinization in enhancing drug elimination. The physician should consider contacting a poison-control center on the treatment of any overdose. ## Chronic Overdose There is limited information regarding Chronic Overdose of Modafinil in the drug label. # Pharmacology ## Mechanism of Action - The precise mechanism(s) through which modafinil promotes wakefulness is unknown. Modafinil has wake-promoting actions similar to sympathomimetic agents like amphetamine and methylphenidate, although the pharmacologic profile is not identical to that of sympathomimetic amines. - Modafinil has weak to negligible interactions with receptors for norepinephrine, serotonin, dopamine, GABA, adenosine, histamine-3, melatonin, and benzodiazepines. Modafinil also does not inhibit the activities of MAO-B or phosphodiesterases II-V. - Modafinil-induced wakefulness can be attenuated by the α1-adrenergic receptor antagonist prazosin; however, modafinil is inactive in other in vitro assay systems known to be responsive to α-adrenergic agonists, such as the rat vas deferens preparation. - Modafinil is not a direct- or indirect-acting dopamine receptor agonist. However, in vitro, modafinil binds to the dopamine transporter and inhibits dopamine reuptake. This activity has been associated in vivo with increased extracellular dopamine levels in some brain regions of animals. In genetically engineered mice lacking the dopamine transporter (DAT), modafinil lacked wake-promoting activity, suggesting that this activity was DAT-dependent. However, the wake-promoting effects of modafinil, unlike those of amphetamine, were not antagonized by the dopamine receptor antagonist haloperidol in rats. In addition, alpha-methyl-p-tyrosine, a dopamine synthesis inhibitor, blocks the action of amphetamine, but does not block locomotor activity induced by modafinil. - In the cat, equal wakefulness-promoting doses of methylphenidate and amphetamine increased neuronal activation throughout the brain. Modafinil at an equivalent wakefulness-promoting dose selectively and prominently increased neuronal activation in more discrete regions of the brain. The relationship of this finding in cats to the effects of modafinil in humans is unknown. - In addition to its wake-promoting effects and ability to increase locomotor activity in animals, modafinil produces psychoactive and euphoric effects, alterations in mood, perception, thinking, and feelings typical of other CNS stimulants in humans. Modafinil has reinforcing properties, as evidenced by its self-administration in monkeys previously trained to self-administer cocaine. Modafinil was also partially discriminated as stimulant-like. - The optical enantiomers of modafinil have similar pharmacological actions in animals. Two major metabolites of modafinil, modafinil acid and modafinil sulfone, do not appear to contribute to the CNS-activating properties of modafinil. ## Structure - Modafinil is a wakefulness-promoting agent for oral administration. Modafinil is a racemic compound. The chemical name for modafinil is 2-acetamide. The molecular formula is C15H15NO2S and the molecular weight is 273.35. - The chemical structure is: - Modafinil is a white to off-white, crystalline powder that is practically insoluble in water and cyclohexane. It is sparingly to slightly soluble in methanol and acetone. Modafinil tablets contain 100 mg or 200 mg of modafinil and the following inactive ingredients: Lactose Monohydrate, Corn Starch dried, Crospovidone , Croscarmellose Sodium, Colloidal Silicon Dioxide, Magnesium Stearate, and Talc. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Modafinil in the drug label. ## Pharmacokinetics - Modafinil is a racemic compound, whose enantiomers have different pharmacokinetics (e.g., the half-life of the l-isomer is approximately three times that of the d-isomer in adult humans). The enantiomers do not interconvert. At steady state, total exposure to the l-isomer is approximately three times that for the d-isomer. The trough concentration (Cminss) of circulating modafinil after once daily dosing consists of 90% of the l-isomer and 10% of the d-isomer. The effective elimination half-life of modafinil after multiple doses is about 15 hours. The enantiomers of modafinil exhibit linear kinetics upon multiple dosing of 200 to 600 mg/day once daily in healthy volunteers. Apparent steady states of total modafinil and l-(-)-modafinil are reached after 2-4 days of dosing. - Absorption - Absorption of modafinil tablets is rapid, with peak plasma concentrations occurring at 2-4 hours. The bioavailability of modafinil tablets is approximately equal to that of an aqueous suspension. The absolute oral bioavailability was not determined due to the aqueous insolubility (<1 mg/mL) of modafinil, which precluded intravenous administration. Food has no effect on overall modafinil bioavailability; however, its absorption (tmax) may be delayed by approximately one hour if taken with food. - Distribution - Modafinil is well distributed in body tissue with an apparent volume of distribution (~0.9 L/kg) larger than the volume of total body water (0.6 L/kg). In human plasma, in vitro, modafinil is moderately bound to plasma protein (~60%, mainly to albumin). At serum concentrations obtained at steady state after doses of 200 mg/day, modafinil exhibits no displacement of protein binding of warfarin, diazepam or propranolol. Even at much larger concentrations (1000 μM; > 25 times the Cmax of 40 μM at steady state at 400 mg/day), modafinil has no effect on warfarin binding. Modafinil acid at concentrations >500 μM decreases the extent of warfarin binding, but these concentrations are >35 times those achieved therapeutically. - Metabolism and Elimination - The major route of elimination is metabolism (~90%), primarily by the liver, with subsequent renal elimination of the metabolites. Urine alkalinization has no effect on the elimination of modafinil. - Metabolism occurs through hydrolytic deamidation, S-oxidation, aromatic ring hydroxylation, and glucuronide conjugation. Less than 10% of an administered dose is excreted as the parent compound. In a clinical study using radiolabeled modafinil, a total of 81% of the administered radioactivity was recovered in 11 days post-dose, predominantly in the urine (80% vs. 1% in the feces). The largest fraction of the drug in urine was modafinil acid, but at least six other metabolites were present in lower concentrations. Only two metabolites reach appreciable concentrations in plasma, i.e., modafinil acid and modafinil sulfone. In preclinical models, modafinil acid, modafinil sulfone, 2-acetic acid and 4-hydroxy modafinil, were inactive or did not appear to mediate the arousal effects of modafinil. - In adults, decreases in trough levels of modafinil have sometimes been observed after multiple weeks of dosing, suggesting auto-induction, but the magnitude of the decreases and the inconsistency of their occurrence suggest that their clinical significance is minimal. Significant accumulation of modafinil sulfone has been observed after multiple doses due to its long elimination half-life of 40 hours. Induction of metabolizing enzymes, most importantly cytochrome P-450 (CYP) 3A4, has also been observed in vitro after incubation of primary cultures of human hepatocytes with modafinil and in vivo after extended administration of modafinil at 400 mg/day. (For further discussion of the effects of modafinil on CYP enzyme activities. - Drug-Drug Interactions: Based on in vitro data, modafinil is metabolized partially by the 3A isoform subfamily of hepatic cytochrome P450 (CYP3A4). In addition, modafinil has the potential to inhibit CYP2C19, suppress CYP2C9, and induce CYP3A4, CYP2B6, and CYP1A2. Because modafinil and modafinil sulfone are reversible inhibitors of the drug-metabolizing enzyme CYP2C19, coadministration of modafinil with drugs such as diazepam, phenytoin and propranolol, which are largely eliminated via that pathway, may increase the circulating levels of those compounds. In addition, in individuals deficient in the enzyme CYP2D6 (i.e., 7-10% of the Caucasian population; similar or lower in other populations), the levels of CYP2D6 substrates such as tricyclic antidepressants and selective serotonin reuptake inhibitors, which have ancillary routes of elimination through CYP2C19, may be increased by coadministration of modafinil. Dose adjustments may be necessary for patients being treated with these and similar medications. An in vitro study demonstrated that armodafinil (one of the enantiomers of modafinil) is a substrate of P-glycoprotein. - Coadministration of modafinil with other CNS active drugs such as methylphenidate and dextroamphetamine did not significantly alter the pharmacokinetics of either drug. - Chronic administration of modafinil 400 mg was found to decrease the systemic exposure to two CYP3A4 substrates, ethinyl estradiol and triazolam, after oral administration suggesting that CYP3A4 had been induced. Chronic administration of modafinil can increase the elimination of substrates of CYP3A4. Dose adjustments may be necessary for patients being treated with these and similar medications. - An apparent concentration-related suppression of CYP2C9 activity was observed in human hepatocytes after exposure to modafinil in vitro suggesting that there is a potential for a metabolic interaction between modafinil and the substrates of this enzyme (e.g., S-warfarin, phenytoin). However, in an interaction study in healthy volunteers, chronic modafinil treatment did not show a significant effect on the pharmacokinetics of warfarin when compared to placebo. - Special Populations - Gender Effect: The pharmacokinetics of modafinil are not affected by gender. - Age Effect: A slight decrease (~20%) in the oral clearance (CL/F) of modafinil was observed in a single dose study at 200 mg in 12 subjects with a mean age of 63 years (range 53 – 72 years), but the change was considered not likely to be clinically significant. In a multiple dose study (300 mg/day) in 12 patients with a mean age of 82 years (range 67 – 87 years), the mean levels of modafinil in plasma were approximately two times those historically obtained in matched younger subjects. Due to potential effects from the multiple concomitant medications with which most of the patients were being treated, the apparent difference in modafinil pharmacokinetics may not be attributable solely to the effects of aging. However, the results suggest that the clearance of modafinil may be reduced in the elderly. - Race Effect: The influence of race on the pharmacokinetics of modafinil has not been studied. - Renal Impairment: In a single dose 200 mg modafinil study, severe chronic renal failure (creatinine clearance ≤ 20 mL/min) did not significantly influence the pharmacokinetics of modafinil, but exposure to modafinil acid (an inactive metabolite) was increased 9-fold. - Hepatic Impairment: Pharmacokinetics and metabolism were examined in patients with cirrhosis of the liver (6 males and 3 females). Three patients had stage B or B+ cirrhosis (per the Child criteria) and 6 patients had stage C or C+ cirrhosis. Clinically 8 of 9 patients were icteric and all had ascites. In these patients, the oral clearance of modafinil was decreased by about 60% and the steady state concentration was doubled compared to normal patients. The dose of modafinil should be reduced in patients with severe hepatic impairment. ## Nonclinical Toxicology - Carcinogenesis - Carcinogenicity studies were conducted in which modafinil was administered in the diet to mice for 78 weeks and to rats for 104 weeks at doses of 6, 30, and 60 mg/kg/day. The highest dose studied is 1.5 (mouse) or 3 (rat) times greater than the recommended adult human daily dose of modafinil (200 mg) on a mg/m2 basis. There was no evidence of tumorigenesis associated with modafinil administration in these studies. However, since the mouse study used an inadequate high dose that was not representative of a maximum tolerated dose, a subsequent carcinogenicity study was conducted in the Tg.AC transgenic mouse. Doses evaluated in the Tg.AC assay were 125, 250, and 500 mg/kg/day, administered dermally. There was no evidence of tumorigenicity associated with modafinil administration; however, this dermal model may not adequately assess the carcinogenic potential of an orally administered drug. - Mutagenesis - Modafinil demonstrated no evidence of mutagenic or clastogenic potential in a series of in vitro (i.e., bacterial reverse mutation assay, mouse lymphoma tk assay, chromosomal aberration assay in human lymphocytes, cell transformation assay in BALB/3T3 mouse embryo cells) assays in the absence or presence of metabolic activation, or in vivo (mouse bone marrow micronucleus) assays. Modafinil was also negative in the unscheduled DNA synthesis assay in rat hepatocytes. - Impairment of Fertility - Oral administration of modafinil (doses of up to 480 mg/kg/day) to male and female rats prior to and throughout mating, and continuing in females through day 7 of gestation produced an increase in the time to mate at the highest dose; no effects were observed on other fertility or reproductive parameters. The no-effect dose of 240 mg/kg/day was associated with a plasma modafinil exposure (AUC) approximately equal to that in humans at the recommended dose of 200 mg. # Clinical Studies - The effectiveness of modafinil in reducing excessive sleepiness has been established in the following sleep disorders: narcolepsy, obstructive sleep apnea (OSA), and shift work disorder (SWD). - The effectiveness of modafinil in reducing the excessive sleepiness (ES) associated with narcolepsy was established in two U.S. 9-week, multicenter, placebo-controlled, two-dose (200 mg per day and 400 mg per day) parallel-group, double-blind studies of outpatients who met the ICD-9 and American Sleep Disorders Association criteria for narcolepsy (which are also consistent with the American Psychiatric Association DSM-IV criteria). These criteria include either 1) recurrent daytime naps or lapses into sleep that occur almost daily for at least three months, plus sudden bilateral loss of postural muscle tone in association with intense emotion (cataplexy) or 2) a complaint of excessive sleepiness or sudden muscle weakness with associated features: sleep paralysis, hypnagogic hallucinations, automatic behaviors, disrupted major sleep episode; and polysomnography demonstrating one of the following: sleep latency less than 10 minutes or rapid eye movement (REM) sleep latency less than 20 minutes. In addition, for entry into these studies, all patients were required to have objectively documented excessive daytime sleepiness, a Multiple Sleep Latency Test (MSLT) with two or more sleep onset REM periods, and the absence of any other clinically significant active medical or psychiatric disorder. The MSLT, an objective daytime polysomnographic assessment of the patient's ability to fall asleep in an unstimulating environment, measures latency (in minutes) to sleep onset averaged over 4 test sessions at 2-hour intervals following nocturnal polysomnography. For each test session, the subject was told to lie quietly and attempt to sleep. Each test session was terminated after 20 minutes if no sleep occurred or 15 minutes after sleep onset. - In both studies, the primary measures of effectiveness were 1) sleep latency, as assessed by the Maintenance of Wakefulness Test (MWT) and 2) the change in the patient's overall disease status, as measured by the Clinical Global Impression of Change (CGI-C). For a successful trial, both measures had to show significant improvement. - The MWT measures latency (in minutes) to sleep onset averaged over 4 test sessions at 2 hour intervals following nocturnal polysomnography. For each test session, the subject was asked to attempt to remain awake without using extraordinary measures. Each test session was terminated after 20 minutes if no sleep occurred or 10 minutes after sleep onset. The CGI-C is a 7-point scale, centered at No Change, and ranging from Very Much Worse to Very Much Improved. Patients were rated by evaluators who had no access to any data about the patients other than a measure of their baseline severity. Evaluators were not given any specific guidance about the criteria they were to apply when rating patients. - Other assessments of effect included the Multiple Sleep Latency Test (MSLT), Epworth Sleepiness Scale (ESS; a series of questions designed to assess the degree of sleepiness in everyday situations), the Steer Clear Performance Test (SCPT; a computer-based evaluation of a patient's ability to avoid hitting obstacles in a simulated driving situation), standard nocturnal polysomnography, and patient's daily sleep log. Patients were also assessed with the Quality of Life in Narcolepsy (QOLIN) scale, which contains the validated SF-36 health questionnaire. - Both studies demonstrated improvement in objective and subjective measures of excessive daytime sleepiness for both the 200 mg and 400 mg doses compared to placebo. Patients treated with either dose of modafinil showed a statistically significantly enhanced ability to remain awake on the MWT (all p values <0.001) at weeks 3, 6, 9, and final visit compared to placebo and a statistically significantly greater global improvement, as rated on the CGI-C scale (all p values <0.05). - The average sleep latencies (in minutes) on the MWT at baseline for the 2 controlled trials are shown in Table 1 below, along with the average change from baseline on the MWT at final visit. - The percentages of patients who showed any degree of improvement on the CGI-C in the two clinical trials are shown in Table 2 below. - Similar statistically significant treatment-related improvements were seen on other measures of impairment in narcolepsy, including a patient assessed level of daytime sleepiness on the ESS (p<0.001 for each dose in comparison to placebo). - Nighttime sleep measured with polysomnography was not affected by the use of modafinil. - The effectiveness of modafinil in reducing the excessive sleepiness associated with OSA was established in two clinical trials. In both studies, patients were enrolled who met the International Classification of Sleep Disorders (ICSD) criteria for OSA (which are also consistent with the American Psychiatric Association DSM-IV criteria). These criteria include either, 1) excessive sleepiness or insomnia, plus frequent episodes of impaired breathing during sleep, and associated features such as loud snoring, morning headaches and dry mouth upon awakening; or 2) excessive sleepiness or insomnia and polysomnography demonstrating one of the following: more than five obstructive apneas, each greater than 10 seconds in duration, per hour of sleep and one or more of the following: frequent arousals from sleep associated with the apneas, bradytachycardia, and arterial oxygen desaturation in association with the apneas. In addition, for entry into these studies, all patients were required to have excessive sleepiness as demonstrated by a score ≥10 on the Epworth Sleepiness Scale, despite treatment with continuous positive airway pressure (CPAP). Evidence that CPAP was effective in reducing episodes of apnea/hypopnea was required along with documentation of CPAP use. - In the first study, a 12-week multicenter placebo-controlled trial, a total of 327 patients were randomized to receive modafinil 200 mg/day, modafinil 400 mg/day, or matching placebo. The majority of patients (80%) were fully compliant with CPAP, defined as CPAP use > 4 hours/night on > 70% nights. The remainder were partially CPAP compliant, defined as CPAP use 30% nights. CPAP use continued throughout the study. The primary measures of effectiveness were 1) sleep latency, as assessed by the Maintenance of Wakefulness Test (MWT) and 2) the change in the patient's overall disease status, as measured by the Clinical Global Impression of Change (CGI-C) at week 12 or the final visit. - Patients treated with modafinil showed a statistically significant improvement in the ability to remain awake compared to placebo-treated patients as measured by the MWT (p<0.001) at endpoint . Modafinil -treated patients also showed a statistically significant improvement in clinical condition as rated by the CGI-C scale (p<0.001) . The two doses of modafinil performed similarly. - In the second study, a 4-week multicenter placebo-controlled trial, 157 patients were randomized to either modafinil 400 mg/day or placebo. Documentation of regular CPAP use (at least 4 hours/night on 70% of nights) was required for all patients. The primary outcome measure was the change from baseline on the ESS at week 4 or final visit. The baseline ESS scores for the modafinil and placebo groups were 14.2 and 14.4, respectively. At week 4, the ESS was reduced by 4.6 in the modafinil group and by 2.0 in the placebo group, a difference that was statistically significant (p<0.0001). - Nighttime sleep measured with polysomnography was not affected by the use of modafinil. - The effectiveness of modafinil for the excessive sleepiness associated with SWD was demonstrated in a 12-week placebo-controlled clinical trial. A total of 209 patients with chronic SWD were randomized to receive modafinil 200 mg/day or placebo. All patients met the International Classification of Sleep Disorders (ICSD-10) criteria for chronic SWD (which are consistent with the American Psychiatric Association DSM-IV criteria for Circadian Rhythm Sleep Disorder: Shift Work Type). These criteria include 1) either: a) a primary complaint of excessive sleepiness or insomnia which is temporally associated with a work period (usually night work) that occurs during the habitual sleep phase, or b) polysomnography and the MSLT demonstrate loss of a normal sleep-wake pattern (i.e., disturbed chronobiological rhythmicity); and 2) no other medical or mental disorder accounts for the symptoms, and 3) the symptoms do not meet criteria for any other sleep disorder producing insomnia or excessive sleepiness (e.g., time zone change jet lag syndrome). - It should be noted that not all patients with a complaint of sleepiness who are also engaged in shift work meet the criteria for the diagnosis of SWD. In the clinical trial, only patients who were symptomatic for at least 3 months were enrolled. - Enrolled patients were also required to work a minimum of 5 night shifts per month, have excessive sleepiness at the time of their night shifts (MSLT score < 6 minutes), and have daytime insomnia documented by a daytime polysomnogram (PSG). - The primary measures of effectiveness were 1) sleep latency, as assessed by the Multiple Sleep Latency Test (MSLT) performed during a simulated night shift at week 12 or the final visit and 2) the change in the patient's overall disease status, as measured by the Clinical Global Impression of Change (CGI-C) at week 12 or the final visit. Patients treated with modafinil showed a statistically significant prolongation in the time to sleep onset compared to placebo-treated patients, as measured by the nighttime MSLT (p<0.05). Improvement on the CGI-C was also observed to be statistically significant (p<0.001). - Daytime sleep measured with polysomnography was not affected by the use of modafinil. # How Supplied - Store at 20° - 25° C (68° - 77° F). ## Storage There is limited information regarding Modafinil Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Physicians are advised to discuss the following issues with patients for whom they prescribe modafinil. - Modafinil is indicated for patients who have abnormal levels of sleepiness. Modafinil has been shown to improve, but not eliminate this abnormal tendency to fall asleep. Therefore, patients should not alter their previous behavior with regard to potentially dangerous activities (e.g., driving, operating machinery) or other activities requiring appropriate levels of wakefulness, until and unless treatment with modafinil has been shown to produce levels of wakefulness that permit such activities. Patients should be advised that modafinil is not a replacement for sleep. - Patients should be informed that it may be critical that they continue to take their previously prescribed treatments (e.g., patients with OSA receiving CPAP should continue to do so). - Patients should be informed of the availability of a Medication Guide, and they should be instructed to read it prior to taking modafinil. The complete text of the Medication Guide is provided at the end of this labeling. - Patients should be advised to contact their physician if they experience chest pain, rash, depression, anxiety, or signs of psychosis or mania. # Precautions with Alcohol - Patients should be advised that the use of modafinil in combination with alcohol has not been studied. Patients should be advised that it is prudent to avoid alcohol while taking modafinil. # Brand Names - MODAFINIL® # Look-Alike Drug Names - Provigil® — Plaquenil® # Drug Shortage Status # Price	Modafinil Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Modafinil is a CNS Stimulant that is FDA approved for the {{{indicationType}}} of narcolepsy, obstructive sleep apnea, and shift work disorder.. Common adverse reactions include rash, nausea, dizziness, headache, insomnia, anxiety, feeling nervous. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - The recommended dose of modafinil is 200 mg given once a day. - Modafinil should be taken as a single dose in the morning. - Dosing Information - In OSA, modafinil is indicated as an adjunct to standard treatment(s) for the underlying obstruction. If continuous positive airway pressure (CPAP) is the treatment of choice for a patient, a maximal effort to treat with CPAP for an adequate period of time should be made prior to initiating modafinil. If modafinil is used adjunctively with CPAP, the encouragement of and periodic assessment of CPAP compliance is necessary. - The recommended dose of modafinil is 200 mg given once a day. - Modafinil should be taken as a single dose in the morning. - Dosing Information - The recommended dose of modafinil is 200 mg given once a day. - For patients with SWD, modafinil should be taken approximately 1 hour prior to the start of their work shift. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Modafinil in adult patients. ### Non–Guideline-Supported Use - Dosing Information - 200 mg/day Modafinil. - Dosing Information - A single oral 200-mg dose of Modafinil. - Dosing Information - Modafinil 200 mg twice in 1 week. - Dosing Information - 16-week course of oral Modafinil was initiated at 200 mg/day, and could be increased to maximum 400 mg/day. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Modafinil in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Modafinil in pediatric patients. ### Non–Guideline-Supported Use - Dosing Information - Modafinil 340 mg or 425 mg, depending on weight (less than 30 kg and 30 kg or more, respectively). # Contraindications - Modafinil is contraindicated in patients with known hypersensitivity to modafinil, armodafinil or its inactive ingredients. # Warnings - Serious Rash, including Stevens-Johnson Syndrome - Serious rash requiring hospitalization and discontinuation of treatment has been reported in adults and children in association with the use of modafinil. - Modafinil is not approved for use in pediatric patients for any indication. - In clinical trials of modafinil, the incidence of rash resulting in discontinuation was approximately 0.8% (13 per 1,585) in pediatric patients (age <17 years); these rashes included 1 case of possible Stevens-Johnson syndrome (SJS) and 1 case of apparent multiorgan hypersensitivity reaction. Several of the cases were associated with fever and other abnormalities (e.g., vomiting, leukopenia). The median time to rash that resulted in discontinuation was 13 days. No such cases were observed among 380 pediatric patients who received placebo. No serious skin rashes have been reported in adult clinical trials (0 per 4,264) of modafinil. - Rare cases of serious or life-threatening rash, including SJS, Toxic Epidermal Necrolysis (TEN), and Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) have been reported in adults and children in worldwide postmarketing experience. The reporting rate of TEN and SJS associated with modafinil use, which is generally accepted to be an underestimate due to underreporting, exceeds the background incidence rate. Estimates of the background incidence rate for these serious skin reactions in the general population range between 1 to 2 cases per million-person years. - There are no factors that are known to predict the risk of occurrence or the severity of rash associated with modafinil. Nearly all cases of serious rash associated with modafinil occurred within 1 to 5 weeks after treatment initiation. However, isolated cases have been reported after prolonged treatment (e.g., 3 months). Accordingly, duration of therapy cannot be relied upon as a means to predict the potential risk heralded by the first appearance of a rash. - Although benign rashes also occur with modafinil, it is not possible to reliably predict which rashes will prove to be serious. Accordingly, modafinil should ordinarily be discontinued at the first sign of rash, unless the rash is clearly not drug-related. Discontinuation of treatment may not prevent a rash from becoming life-threatening or permanently disabling or disfiguring. - Angioedema and Anaphylactoid Reactions - One serious case of angioedema and one case of hypersensitivity (with rash, dysphagia, and bronchospasm), were observed among 1,595 patients treated with armodafinil, the R enantiomer of modafinil (which is the racemic mixture). No such cases were observed in modafinil clinical trials. However, angioedema has been reported in postmarketing experience with modafinil. Patients should be advised to discontinue therapy and immediately report to their physician any signs or symptoms suggesting angioedema or anaphylaxis (e.g., swelling of face, eyes, lips, tongue or larynx; difficulty in swallowing or breathing; hoarseness). - Multiorgan Hypersensitivity Reactions - Multiorgan hypersensitivity reactions, including at least one fatality in postmarketing experience, have occurred in close temporal association (median time to detection 13 days: range 4-33) to the initiation of modafinil. - Although there have been a limited number of reports, multiorgan hypersensitivity reactions may result in hospitalization or be life-threatening. There are no factors that are known to predict the risk of occurrence or the severity of multiorgan hypersensitivity reactions associated with modafinil. Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement. Other associated manifestations included myocarditis, hepatitis, liver function test abnormalities, hematological abnormalities (e.g., eosinophilia, leukopenia, thrombocytopenia), pruritus, and asthenia. Because multiorgan hypersensitivity is variable in its expression, other organ system symptoms and signs, not noted here, may occur. - If a multiorgan hypersensitivity reaction is suspected, modafinil should be discontinued. Although there are no case reports to indicate cross-sensitivity with other drugs that produce this syndrome, the experience with drugs associated with multiorgan hypersensitivity would indicate this to be a possibility. - Persistent Sleepiness - Patients with abnormal levels of sleepiness who take modafinil should be advised that their level of wakefulness may not return to normal. Patients with excessive sleepiness, including those taking modafinil, should be frequently reassessed for their degree of sleepiness and, if appropriate, advised to avoid driving or any other potentially dangerous activity. Prescribers should also be aware that patients may not acknowledge sleepiness or drowsiness until directly questioned about drowsiness or sleepiness during specific activities. - Psychiatric Symptoms - Psychiatric adverse experiences have been reported in patients treated with modafinil. Postmarketing adverse events associated with the use of modafinil have included mania, delusions, hallucinations, suicidal ideation and aggression, some resulting in hospitalization. Many, but not all, patients had a prior psychiatric history. One healthy male volunteer developed ideas of reference, paranoid delusions, and auditory hallucinations in association with multiple daily 600 mg doses of modafinil and sleep deprivation. There was no evidence of psychosis 36 hours after drug discontinuation. - In the adult modafinil controlled trials database, psychiatric symptoms resulting in treatment discontinuation (at a frequency ≥0.3%) and reported more often in patients treated with modafinil compared to those treated with placebo were anxiety (1%), nervousness (1%), insomnia (<1%), confusion (<1%), agitation (<1%), and depression (<1%). Caution should be exercised when modafinil is given to patients with a history of psychosis, depression, or mania. Consideration should be given to the possible emergence or exacerbation of psychiatric symptoms in patients treated with modafinil. If psychiatric symptoms develop in association with modafinil administration, consider discontinuing modafinil. ### Precautions - Diagnosis of Sleep Disorders - Modafinil should be used only in patients who have had a complete evaluation of their excessive sleepiness, and in whom a diagnosis of either narcolepsy, OSA, and/or SWD has been made in accordance with ICSD or DSM diagnostic criteria. Such an evaluation usually consists of a complete history and physical examination, and it may be supplemented with testing in a laboratory setting. Some patients may have more than one sleep disorder contributing to their excessive sleepiness (e.g., OSA and SWD coincident in the same patient). - General - Although modafinil has not been shown to produce functional impairment, any drug affecting the CNS may alter judgment, thinking or motor skills. Patients should be cautioned about operating an automobile or other hazardous machinery until they are reasonably certain that modafinil therapy will not adversely affect their ability to engage in such activities. - CPAP Use in Patients with OSA - In OSA, modafinil is indicated as an adjunct to standard treatment(s) for the underlying obstruction. If continuous positive airway pressure (CPAP) is the treatment of choice for a patient, a maximal effort to treat with CPAP for an adequate period of time should be made prior to initiating modafinil. If modafinil is used adjunctively with CPAP, the encouragement of and periodic assessment of CPAP compliance is necessary. - Cardiovascular System - Modafinil has not been evaluated in patients with a recent history of myocardial infarction or unstable angina, and such patients should be treated with caution. - In clinical studies of modafinil, signs and symptoms including chest pain, palpitations, dyspnea and transient ischemic T-wave changes on ECG were observed in three subjects in association with mitral valve prolapse or left ventricular hypertrophy. It is recommended that modafinil tablets not be used in patients with a history of left ventricular hypertrophy or in patients with mitral valve prolapse who have experienced the mitral valve prolapse syndrome when previously receiving CNS stimulants. Such signs may include but are not limited to ischemic ECG changes, chest pain, or arrhythmia. If new onset of any of these symptoms occurs, consider cardiac evaluation. Blood pressure monitoring in short-term (<3 months) controlled trials showed no clinically significant changes in mean systolic and diastolic blood pressure in patients receiving modafinil as compared to placebo. However, a retrospective analysis of the use of antihypertensive medication in these studies showed that a greater proportion of patients on modafinil required new or increased use of antihypertensive medications (2.4%) compared to patients on placebo (0.7%). The differential use was slightly larger when only studies in OSA were included, with 3.4% of patients on modafinil and 1.1% of patients on placebo requiring such alterations in the use of antihypertensive medication. Increased monitoring of blood pressure may be appropriate in patients on modafinil. - Patients Using Steroidal Contraceptives - The effectiveness of steroidal contraceptives may be reduced when used with modafinil tablets and for one month after discontinuation of therapy. Alternative or concomitant methods of contraception are recommended for patients treated with modafinil tablets, and for one month after discontinuation of modafinil. - Patients Using Cyclosporine - The blood levels of cyclosporine may be reduced when used with modafinil. Monitoring of circulating cyclosporine concentrations and appropriate dosage adjustment for cyclosporine should be considered when these drugs are used concomitantly. - Patients with Severe Hepatic Impairment - In patients with severe hepatic impairment, with or without cirrhosis, modafinil should be administered at a reduced dose. - Patients with Severe Renal Impairment - There is inadequate information to determine safety and efficacy of dosing in patients with severe renal impairment. - Elderly Patients - In elderly patients, elimination of modafinil and its metabolites may be reduced as a consequence of aging. Therefore, consideration should be given to the use of lower doses in this population. # Adverse Reactions ## Clinical Trials Experience - Modafinil has been evaluated for safety in over 3500 patients, of whom more than 2000 patients with excessive sleepiness associated with primary disorders of sleep and wakefulness were given at least one dose of modafinil. In clinical trials, modafinil has been found to be generally well tolerated and most adverse experiences were mild to moderate. - The most commonly observed adverse events (≥5%) associated with the use of modafinil more frequently than placebo-treated patients in the placebo-controlled clinical studies in primary disorders of sleep and wakefulness were headache, nausea, nervousness, rhinitis, diarrhea, back pain, anxiety, insomnia, dizziness, and dyspepsia. The adverse event profile was similar across these studies. - In the placebo-controlled clinical trials, 74 of the 934 patients (8%) who received modafinil discontinued due to an adverse experience compared to 3% of patients that received placebo. The most frequent reasons for discontinuation that occurred at a higher rate for modafinil than placebo patients were headache (2%), nausea, anxiety, dizziness, insomnia, chest pain and nervousness (each <1%). In a Canadian clinical trial, a 35 year old obese narcoleptic male with a prior history of syncopal episodes experienced a 9-second episode of asystole after 27 days of modafinil treatment (300 mg/day in divided doses). - Incidence in Controlled Trials - The following table (Table 3) presents the adverse experiences that occurred at a rate of 1% or more and were more frequent in adult patients treated with modafinil than in placebo-treated patients in the principal, placebo-controlled clinical trials. - The prescriber should be aware that the figures provided below cannot be used to predict the frequency of adverse experiences in the course of usual medical practice, where patient characteristics and other factors may differ from those occurring during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. Review of these frequencies, however, provides prescribers with a basis to estimate the relative contribution of drug and non-drug factors to the incidence of adverse events in the population studied. - Dose Dependency of Adverse Events - In the adult placebo-controlled clinical trials which compared doses of 200, 300, and 400 mg/day of modafinil and placebo, the only adverse events that were clearly dose related were headache and anxiety. - Vital Sign Changes - While there was no consistent change in mean values of heart rate or systolic and diastolic blood pressure, the requirement for antihypertensive medication was slightly greater in patients on modafinil compared to placebo. - Weight Changes - There were no clinically significant differences in body weight change in patients treated with modafinil compared to placebo-treated patients in the placebo-controlled clinical trials. - Laboratory Changes - Clinical chemistry, hematology, and urinalysis parameters were monitored in Phase 1, 2, and 3 studies. In these studies, mean plasma levels of gamma glutamyltransferase (GGT) and alkaline phosphatase (AP) were found to be higher following administration of modafinil, but not placebo. Few subjects, however, had GGT or AP elevations outside of the normal range. Shifts to higher, but not clinically significantly abnormal, GGT and AP values appeared to increase with time in the population treated with modafinil in the Phase 3 clinical trials. No differences were apparent in alanine aminotransferase, aspartate aminotransferase, total protein, albumin, or total bilirubin. - ECG Changes - No treatment-emergent pattern of ECG abnormalities was found in placebo-controlled clinical trials following administration of modafinil. ## Postmarketing Experience - The following adverse reactions have been identified during post-approval use of modafinil. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of the reporting, or (3) strength of causal connection to modafinil. # Drug Interactions - CNS Active Drugs - Methylphenidate - In a single-dose study in healthy volunteers, simultaneous administration of modafinil (200 mg) with methylphenidate (40 mg) did not cause any significant alterations in the pharmacokinetics of either drug. However, the absorption of modafinil may be delayed by approximately one hour when coadministered with methylphenidate. - In a multiple-dose, steady-state study in healthy volunteers, modafinil was administered once daily at 200 mg/day for 7 days followed by 400 mg/day for 21 days. Administration of methylphenidate (20 mg/day) during days 22-28 of modafinil treatment 8 hours after the daily dose of modafinil did not cause any significant alterations in the pharmacokinetics of modafinil. - Dextroamphetamine - In a single dose study in healthy volunteers, simultaneous administration of modafinil (200 mg) with dextroamphetamine (10 mg) did not cause any significant alterations in the pharmacokinetics of either drug. However, the absorption of modafinil may be delayed by approximately one hour when coadministered with dextroamphetamine. - In a multiple-dose, steady-state study in healthy volunteers, modafinil was administered once daily at 200 mg/day for 7 days followed by 400 mg/day for 21 days. Administration of dextroamphetamine (20 mg/day) during days 22-28 of modafinil treatment 7 hours after the daily dose of modafinil did not cause any significant alterations in the pharmacokinetics of modafinil. - Clomipramine - The coadministration of a single dose of clomipramine (50 mg) on the first of three days of treatment with modafinil (200 mg/day) in healthy volunteers did not show an effect on the pharmacokinetics of either drug. However, one incident of increased levels of clomipramine and its active metabolite desmethylclomipramine has been reported in a patient with narcolepsy during treatment with modafinil. - Triazolam - In the drug interaction study between modafinil and ethinyl estradiol (EE2), on the same days as those for the plasma sampling for EE2 pharmacokinetics, a single dose of triazolam (0.125 mg) was also administered. Mean Cmax and AUC0-∞ of triazolam were decreased by 42% and 59%, respectively, and its elimination half-life was decreased by approximately an hour after the modafinil treatment. - Monoamine Oxidase (MAO) Inhibitors - Interaction studies with monoamine oxidase inhibitors have not been performed. Therefore, caution should be used when concomitantly administering MAO inhibitors and modafinil. - Other Drugs - Warfarin - There were no significant changes in the pharmacokinetic profiles of R- and S- warfarin in healthy subjects given a single dose of racemic warfarin (5 mg) following chronic administration of modafinil (200 mg/day for 7 days followed by 400 mg/day for 27 days) relative to the profiles in subjects given placebo. However, more frequent monitoring of prothrombin times/INR is advisable whenever modafinil is coadministered with warfarin. - Ethinyl Estradiol - Administration of modafinil to female volunteers once daily at 200 mg/day for 7 days followed by 400 mg/day for 21 days resulted in a mean 11% decrease in Cmax and 18% decrease in AUC0-24 of ethinyl estradiol (EE2; 0.035 mg; administered orally with norgestimate). There was no apparent change in the elimination rate of ethinyl estradiol. - Cyclosporie - One case of an interaction between modafinil and cyclosporine, a substrate of CYP3A4, has been reported in a 41 year old woman who had undergone an organ transplant. After one month of administration of 200 mg/day of modafinil, cyclosporine blood levels were decreased by 50%. The interaction was postulated to be due to the increased metabolism of cyclosporine, since no other factor expected to affect the disposition of the drug had changed. Dosage adjustment for cyclosporine may be needed. - Potential Interactions with Drugs That Inhibit, Induce, or are Metabolized by Cytochrome P-450 Isoenzymes and Other Hepatic Enzymes - In in vitro studies using primary human hepatocyte cultures, modafinil was shown to slightly induce CYP1A2, CYP2B6 and CYP3A4 in a concentration-dependent manner. Although induction results based on in vitro experiments are not necessarily predictive of response in vivo, caution needs to be exercised when modafinil is coadministered with drugs that depend on these three enzymes for their clearance. Specifically, lower blood levels of such drugs could result. - The exposure of human hepatocytes to modafinil in vitro produced an apparent concentration-related suppression of expression of CYP2C9 activity suggesting that there is a potential for a metabolic interaction between modafinil and the substrates of this enzyme (e.g., S-warfarin and phenytoin). In a subsequent clinical study in healthy volunteers, chronic modafinil treatment did not show a significant effect on the single-dose pharmacokinetics of warfarin when compared to placebo. - In vitro studies using human liver microsomes showed that modafinil reversibly inhibited CYP2C19 at pharmacologically relevant concentrations of modafinil. CYP2C19 is also reversibly inhibited, with similar potency, by a circulating metabolite, modafinil sulfone. Although the maximum plasma concentrations of modafinil sulfone are much lower than those of parent modafinil, the combined effect of both compounds could produce sustained partial inhibition of the enzyme. Drugs that are largely eliminated via CYP2C19 metabolism, such as diazepam, propranolol, phenytoin (also via CYP2C9) or S-mephenytoin may have prolonged elimination upon coadministration with modafinil and may require dosage reduction and monitoring for toxicity. - Tricyclic antidepressants - CYP2C19 also provides an ancillary pathway for the metabolism of certain tricyclic antidepressants (e.g., clomipramine and desipramine) that are primarily metabolized by CYP2D6. In tricyclic-treated patients deficient in CYP2D6 (i.e., those who are poor metabolizers of debrisoquine; 7-10% of the Caucasian population; similar or lower in other populations), the amount of metabolism by CYP2C19 may be substantially increased. Modafinil may cause elevation of the levels of the tricyclics in this subset of patients. Physicians should be aware that a reduction in the dose of tricyclic agents might be needed in these patients. - In addition, due to the partial involvement of CYP3A4 in the metabolic elimination of modafinil, coadministration of potent inducers of CYP3A4 (e.g., carbamazepine, phenobarbital, rifampin) or inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole) could alter the plasma levels of modafinil. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - In studies conducted in rats and rabbits, developmental toxicity was observed at clinically relevant exposures. - Modafinil (50, 100, or 200 mg/kg/day) administered orally to pregnant rats throughout the period of organogenesis caused, in the absence of maternal toxicity, an increase in resorptions and an increased incidence of visceral and skeletal variations in the offspring at the highest dose. The higher no-effect dose for rat embryofetal developmental toxicity was associated with a plasma modafinil exposure approximately 0.5 times the AUC in humans at the recommended daily dose (RHD) of 200 mg. However, in a subsequent study of up to 480 mg/kg/day (plasma modafinil exposure approximately 2 times the AUC in humans at the RHD) no adverse effects on embryofetal development were observed. - Modafinil administered orally to pregnant rabbits throughout the period of organogenesis at doses of 45, 90, and 180 mg/kg/day increased the incidences of fetal structural alterations and embryofetal death at the highest dose. The highest no-effect dose for developmental toxicity was associated with a plasma modafinil AUC approximately equal to the AUC in humans at the RHD. - Oral administration of armodafinil (the R-enantiomer of modafinil; 60, 200, or 600 mg/kg/day) to pregnant rats throughout the period of organogenesis resulted in increased incidences of fetal visceral and skeletal variations at the intermediate dose or greater and decreased fetal body weights at the highest dose. The no-effect dose for rat embryofetal developmental toxicity was associated with a plasma armodafinil exposure (AUC) approximately one-tenth times the AUC for armodafinil in humans treated with modafinil at the RHD. - Modafinil administration to rats throughout gestation and lactation at oral doses of up to 200 mg/kg/day resulted in decreased viability in the offspring at doses greater than 20 mg/kg/day (plasma modafinil AUC approximately 0.1 times the AUC in humans at the RHD). No effects on postnatal developmental and neurobehavioral parameters were observed in surviving offspring. - There are no adequate and well-controlled studies in pregnant women. Two cases of intrauterine growth retardation and one case of spontaneous abortion have been reported in association with armodafinil and modafinil. Although the pharmacology of modafinil and armodafinil is not identical to that of the sympathomimetic amines, they do share some pharmacologic properties with this class. Certain of these drugs have been associated with intrauterine growth retardation and spontaneous abortions. Whether the cases reported are drug-related is unknown. - Modafinil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Modafinil in women who are pregnant. ### Labor and Delivery - The effect of modafinil on labor and delivery in humans has not been systematically investigated. ### Nursing Mothers - It is not known whether modafinil or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when modafinil tablets are administered to a nursing woman. ### Pediatric Use - Safety and effectiveness in pediatric patients, below age 17, have not been established. Serious skin rashes, including erythema multiforme major (EMM) and Stevens-Johnson syndrome (SJS) have been associated with modafinil use in pediatric patients. - In a controlled 6-week study, 165 pediatric patients (aged 5-17 years) with narcolepsy were treated with modafinil (n=123), or placebo (n=42). There were no statistically significant differences favoring modafinil over placebo in prolonging sleep latency as measured by MSLT, or in perceptions of sleepiness as determined by the clinical global impression-clinician scale (CGI-C). - In the controlled and open-label clinical studies, treatment emergent adverse events of the psychiatric and nervous system included Tourette's syndrome, insomnia, hostility, increased cataplexy, increased hypnagogic hallucinations and suicidal ideation. Transient leukopenia, which resolved without medical intervention, was also observed. In the controlled clinical study, 3 of 38 girls, ages 12 or older, treated with modafinil experienced dysmenorrhea compared to 0 of 10 girls who received placebo. - There were three 7 to 9 week, double-blind, placebo-controlled, parallel group studies in children and adolescents (aged 6-17 years) with Attention-Deficit Hyperactivity Disorder (ADHD, DSMIV). Two of the studies were flexible-dose studies (up to 425 mg/day), and the third was a fixed-dose study (340 mg/day for patients <30 kg and 425 mg/day for patients ≥30 kg). Although these studies showed statistically significant differences favoring modafinil over placebo in reducing ADHD symptoms as measured by the ADHD-RS (school version), there were 3 cases of serious rash including one case of possible SJS among 933 patients exposed to modafinil in this program. - Modafinil is not approved for use in pediatric patients for any indication, including ADHD , Serious Rash, including Stevens-Johnson Syndrome. ### Geriatic Use - Experience in a limited number of patients who were greater than 65 years of age in clinical trials showed an incidence of adverse experiences similar to other age groups. In elderly patients, elimination of modafinil and its metabolites may be reduced as a consequence of aging. Therefore, consideration should be given to the use of lower doses in this population. ### Gender There is no FDA guidance on the use of Modafinil with respect to specific gender populations. ### Race There is no FDA guidance on the use of Modafinil with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Modafinil in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Modafinil in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Modafinil in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Modafinil in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Modafinil in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Modafinil in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - In clinical trials, a total of 151 protocol-specified doses ranging from 1000 to 1600 mg/day (5 to 8 times the recommended daily dose of 200 mg) have been administered to 32 subjects, including 13 subjects who received doses of 1000 or 1200 mg/day for 7 to 21 consecutive days. In addition, several intentional acute overdoses occurred; the two largest being 4500 mg and 4000 mg taken by two subjects participating in foreign depression studies. None of these study subjects experienced any unexpected or life-threatening effects. Adverse experiences that were reported at these doses included excitation or agitation, insomnia, and slight or moderate elevations in hemodynamic parameters. Other observed high-dose effects in clinical studies have included anxiety, irritability, aggressiveness, confusion, nervousness, tremor, palpitations, sleep disturbances, nausea, diarrhea and decreased prothrombin time. - From postmarketing experience, there have been no reports of fatal overdoses involving modafinil alone (doses up to 12 grams). Overdoses involving multiple drugs, including modafinil, have resulted in fatal outcomes. Symptoms most often accompanying modafinil overdose, alone or in combination with other drugs have included: insomnia; central nervous system symptoms such as restlessness, disorientation, confusion, excitation and hallucination; digestive changes such as nausea and diarrhea; and cardiovascular changes such as tachycardia, bradycardia, hypertension and chest pain. - Cases of accidental ingestion/overdose have been reported in children as young as 11 months of age. The highest reported accidental ingestion on a mg/kg basis occurred in a three-year-old boy who ingested 800 to 1000 mg (50 to 63 mg/kg) of modafinil. The child remained stable. The symptoms associated with overdose in children were similar to those observed in adults. ### Management - No specific antidote to the toxic effects of modafinil overdose has been identified to date. Such overdoses should be managed with primarily supportive care, including cardiovascular monitoring. If there are no contraindications, induced emesis or gastric lavage should be considered. There are no data to suggest the utility of dialysis or urinary acidification or alkalinization in enhancing drug elimination. The physician should consider contacting a poison-control center on the treatment of any overdose. ## Chronic Overdose There is limited information regarding Chronic Overdose of Modafinil in the drug label. # Pharmacology ## Mechanism of Action - The precise mechanism(s) through which modafinil promotes wakefulness is unknown. Modafinil has wake-promoting actions similar to sympathomimetic agents like amphetamine and methylphenidate, although the pharmacologic profile is not identical to that of sympathomimetic amines. - Modafinil has weak to negligible interactions with receptors for norepinephrine, serotonin, dopamine, GABA, adenosine, histamine-3, melatonin, and benzodiazepines. Modafinil also does not inhibit the activities of MAO-B or phosphodiesterases II-V. - Modafinil-induced wakefulness can be attenuated by the α1-adrenergic receptor antagonist prazosin; however, modafinil is inactive in other in vitro assay systems known to be responsive to α-adrenergic agonists, such as the rat vas deferens preparation. - Modafinil is not a direct- or indirect-acting dopamine receptor agonist. However, in vitro, modafinil binds to the dopamine transporter and inhibits dopamine reuptake. This activity has been associated in vivo with increased extracellular dopamine levels in some brain regions of animals. In genetically engineered mice lacking the dopamine transporter (DAT), modafinil lacked wake-promoting activity, suggesting that this activity was DAT-dependent. However, the wake-promoting effects of modafinil, unlike those of amphetamine, were not antagonized by the dopamine receptor antagonist haloperidol in rats. In addition, alpha-methyl-p-tyrosine, a dopamine synthesis inhibitor, blocks the action of amphetamine, but does not block locomotor activity induced by modafinil. - In the cat, equal wakefulness-promoting doses of methylphenidate and amphetamine increased neuronal activation throughout the brain. Modafinil at an equivalent wakefulness-promoting dose selectively and prominently increased neuronal activation in more discrete regions of the brain. The relationship of this finding in cats to the effects of modafinil in humans is unknown. - In addition to its wake-promoting effects and ability to increase locomotor activity in animals, modafinil produces psychoactive and euphoric effects, alterations in mood, perception, thinking, and feelings typical of other CNS stimulants in humans. Modafinil has reinforcing properties, as evidenced by its self-administration in monkeys previously trained to self-administer cocaine. Modafinil was also partially discriminated as stimulant-like. - The optical enantiomers of modafinil have similar pharmacological actions in animals. Two major metabolites of modafinil, modafinil acid and modafinil sulfone, do not appear to contribute to the CNS-activating properties of modafinil. ## Structure - Modafinil is a wakefulness-promoting agent for oral administration. Modafinil is a racemic compound. The chemical name for modafinil is 2-[(diphenylmethyl)sulfinyl]acetamide. The molecular formula is C15H15NO2S and the molecular weight is 273.35. - The chemical structure is: - Modafinil is a white to off-white, crystalline powder that is practically insoluble in water and cyclohexane. It is sparingly to slightly soluble in methanol and acetone. Modafinil tablets contain 100 mg or 200 mg of modafinil and the following inactive ingredients: Lactose Monohydrate, Corn Starch dried, Crospovidone , Croscarmellose Sodium, Colloidal Silicon Dioxide, Magnesium Stearate, and Talc. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Modafinil in the drug label. ## Pharmacokinetics - Modafinil is a racemic compound, whose enantiomers have different pharmacokinetics (e.g., the half-life of the l-isomer is approximately three times that of the d-isomer in adult humans). The enantiomers do not interconvert. At steady state, total exposure to the l-isomer is approximately three times that for the d-isomer. The trough concentration (Cminss) of circulating modafinil after once daily dosing consists of 90% of the l-isomer and 10% of the d-isomer. The effective elimination half-life of modafinil after multiple doses is about 15 hours. The enantiomers of modafinil exhibit linear kinetics upon multiple dosing of 200 to 600 mg/day once daily in healthy volunteers. Apparent steady states of total modafinil and l-(-)-modafinil are reached after 2-4 days of dosing. - Absorption - Absorption of modafinil tablets is rapid, with peak plasma concentrations occurring at 2-4 hours. The bioavailability of modafinil tablets is approximately equal to that of an aqueous suspension. The absolute oral bioavailability was not determined due to the aqueous insolubility (<1 mg/mL) of modafinil, which precluded intravenous administration. Food has no effect on overall modafinil bioavailability; however, its absorption (tmax) may be delayed by approximately one hour if taken with food. - Distribution - Modafinil is well distributed in body tissue with an apparent volume of distribution (~0.9 L/kg) larger than the volume of total body water (0.6 L/kg). In human plasma, in vitro, modafinil is moderately bound to plasma protein (~60%, mainly to albumin). At serum concentrations obtained at steady state after doses of 200 mg/day, modafinil exhibits no displacement of protein binding of warfarin, diazepam or propranolol. Even at much larger concentrations (1000 μM; > 25 times the Cmax of 40 μM at steady state at 400 mg/day), modafinil has no effect on warfarin binding. Modafinil acid at concentrations >500 μM decreases the extent of warfarin binding, but these concentrations are >35 times those achieved therapeutically. - Metabolism and Elimination - The major route of elimination is metabolism (~90%), primarily by the liver, with subsequent renal elimination of the metabolites. Urine alkalinization has no effect on the elimination of modafinil. - Metabolism occurs through hydrolytic deamidation, S-oxidation, aromatic ring hydroxylation, and glucuronide conjugation. Less than 10% of an administered dose is excreted as the parent compound. In a clinical study using radiolabeled modafinil, a total of 81% of the administered radioactivity was recovered in 11 days post-dose, predominantly in the urine (80% vs. 1% in the feces). The largest fraction of the drug in urine was modafinil acid, but at least six other metabolites were present in lower concentrations. Only two metabolites reach appreciable concentrations in plasma, i.e., modafinil acid and modafinil sulfone. In preclinical models, modafinil acid, modafinil sulfone, 2-[(diphenylmethyl)sulfonyl]acetic acid and 4-hydroxy modafinil, were inactive or did not appear to mediate the arousal effects of modafinil. - In adults, decreases in trough levels of modafinil have sometimes been observed after multiple weeks of dosing, suggesting auto-induction, but the magnitude of the decreases and the inconsistency of their occurrence suggest that their clinical significance is minimal. Significant accumulation of modafinil sulfone has been observed after multiple doses due to its long elimination half-life of 40 hours. Induction of metabolizing enzymes, most importantly cytochrome P-450 (CYP) 3A4, has also been observed in vitro after incubation of primary cultures of human hepatocytes with modafinil and in vivo after extended administration of modafinil at 400 mg/day. (For further discussion of the effects of modafinil on CYP enzyme activities. - Drug-Drug Interactions: Based on in vitro data, modafinil is metabolized partially by the 3A isoform subfamily of hepatic cytochrome P450 (CYP3A4). In addition, modafinil has the potential to inhibit CYP2C19, suppress CYP2C9, and induce CYP3A4, CYP2B6, and CYP1A2. Because modafinil and modafinil sulfone are reversible inhibitors of the drug-metabolizing enzyme CYP2C19, coadministration of modafinil with drugs such as diazepam, phenytoin and propranolol, which are largely eliminated via that pathway, may increase the circulating levels of those compounds. In addition, in individuals deficient in the enzyme CYP2D6 (i.e., 7-10% of the Caucasian population; similar or lower in other populations), the levels of CYP2D6 substrates such as tricyclic antidepressants and selective serotonin reuptake inhibitors, which have ancillary routes of elimination through CYP2C19, may be increased by coadministration of modafinil. Dose adjustments may be necessary for patients being treated with these and similar medications. An in vitro study demonstrated that armodafinil (one of the enantiomers of modafinil) is a substrate of P-glycoprotein. - Coadministration of modafinil with other CNS active drugs such as methylphenidate and dextroamphetamine did not significantly alter the pharmacokinetics of either drug. - Chronic administration of modafinil 400 mg was found to decrease the systemic exposure to two CYP3A4 substrates, ethinyl estradiol and triazolam, after oral administration suggesting that CYP3A4 had been induced. Chronic administration of modafinil can increase the elimination of substrates of CYP3A4. Dose adjustments may be necessary for patients being treated with these and similar medications. - An apparent concentration-related suppression of CYP2C9 activity was observed in human hepatocytes after exposure to modafinil in vitro suggesting that there is a potential for a metabolic interaction between modafinil and the substrates of this enzyme (e.g., S-warfarin, phenytoin). However, in an interaction study in healthy volunteers, chronic modafinil treatment did not show a significant effect on the pharmacokinetics of warfarin when compared to placebo. - Special Populations - Gender Effect: The pharmacokinetics of modafinil are not affected by gender. - Age Effect: A slight decrease (~20%) in the oral clearance (CL/F) of modafinil was observed in a single dose study at 200 mg in 12 subjects with a mean age of 63 years (range 53 – 72 years), but the change was considered not likely to be clinically significant. In a multiple dose study (300 mg/day) in 12 patients with a mean age of 82 years (range 67 – 87 years), the mean levels of modafinil in plasma were approximately two times those historically obtained in matched younger subjects. Due to potential effects from the multiple concomitant medications with which most of the patients were being treated, the apparent difference in modafinil pharmacokinetics may not be attributable solely to the effects of aging. However, the results suggest that the clearance of modafinil may be reduced in the elderly. - Race Effect: The influence of race on the pharmacokinetics of modafinil has not been studied. - Renal Impairment: In a single dose 200 mg modafinil study, severe chronic renal failure (creatinine clearance ≤ 20 mL/min) did not significantly influence the pharmacokinetics of modafinil, but exposure to modafinil acid (an inactive metabolite) was increased 9-fold. - Hepatic Impairment: Pharmacokinetics and metabolism were examined in patients with cirrhosis of the liver (6 males and 3 females). Three patients had stage B or B+ cirrhosis (per the Child criteria) and 6 patients had stage C or C+ cirrhosis. Clinically 8 of 9 patients were icteric and all had ascites. In these patients, the oral clearance of modafinil was decreased by about 60% and the steady state concentration was doubled compared to normal patients. The dose of modafinil should be reduced in patients with severe hepatic impairment. ## Nonclinical Toxicology - Carcinogenesis - Carcinogenicity studies were conducted in which modafinil was administered in the diet to mice for 78 weeks and to rats for 104 weeks at doses of 6, 30, and 60 mg/kg/day. The highest dose studied is 1.5 (mouse) or 3 (rat) times greater than the recommended adult human daily dose of modafinil (200 mg) on a mg/m2 basis. There was no evidence of tumorigenesis associated with modafinil administration in these studies. However, since the mouse study used an inadequate high dose that was not representative of a maximum tolerated dose, a subsequent carcinogenicity study was conducted in the Tg.AC transgenic mouse. Doses evaluated in the Tg.AC assay were 125, 250, and 500 mg/kg/day, administered dermally. There was no evidence of tumorigenicity associated with modafinil administration; however, this dermal model may not adequately assess the carcinogenic potential of an orally administered drug. - Mutagenesis - Modafinil demonstrated no evidence of mutagenic or clastogenic potential in a series of in vitro (i.e., bacterial reverse mutation assay, mouse lymphoma tk assay, chromosomal aberration assay in human lymphocytes, cell transformation assay in BALB/3T3 mouse embryo cells) assays in the absence or presence of metabolic activation, or in vivo (mouse bone marrow micronucleus) assays. Modafinil was also negative in the unscheduled DNA synthesis assay in rat hepatocytes. - Impairment of Fertility - Oral administration of modafinil (doses of up to 480 mg/kg/day) to male and female rats prior to and throughout mating, and continuing in females through day 7 of gestation produced an increase in the time to mate at the highest dose; no effects were observed on other fertility or reproductive parameters. The no-effect dose of 240 mg/kg/day was associated with a plasma modafinil exposure (AUC) approximately equal to that in humans at the recommended dose of 200 mg. # Clinical Studies - The effectiveness of modafinil in reducing excessive sleepiness has been established in the following sleep disorders: narcolepsy, obstructive sleep apnea (OSA), and shift work disorder (SWD). - The effectiveness of modafinil in reducing the excessive sleepiness (ES) associated with narcolepsy was established in two U.S. 9-week, multicenter, placebo-controlled, two-dose (200 mg per day and 400 mg per day) parallel-group, double-blind studies of outpatients who met the ICD-9 and American Sleep Disorders Association criteria for narcolepsy (which are also consistent with the American Psychiatric Association DSM-IV criteria). These criteria include either 1) recurrent daytime naps or lapses into sleep that occur almost daily for at least three months, plus sudden bilateral loss of postural muscle tone in association with intense emotion (cataplexy) or 2) a complaint of excessive sleepiness or sudden muscle weakness with associated features: sleep paralysis, hypnagogic hallucinations, automatic behaviors, disrupted major sleep episode; and polysomnography demonstrating one of the following: sleep latency less than 10 minutes or rapid eye movement (REM) sleep latency less than 20 minutes. In addition, for entry into these studies, all patients were required to have objectively documented excessive daytime sleepiness, a Multiple Sleep Latency Test (MSLT) with two or more sleep onset REM periods, and the absence of any other clinically significant active medical or psychiatric disorder. The MSLT, an objective daytime polysomnographic assessment of the patient's ability to fall asleep in an unstimulating environment, measures latency (in minutes) to sleep onset averaged over 4 test sessions at 2-hour intervals following nocturnal polysomnography. For each test session, the subject was told to lie quietly and attempt to sleep. Each test session was terminated after 20 minutes if no sleep occurred or 15 minutes after sleep onset. - In both studies, the primary measures of effectiveness were 1) sleep latency, as assessed by the Maintenance of Wakefulness Test (MWT) and 2) the change in the patient's overall disease status, as measured by the Clinical Global Impression of Change (CGI-C). For a successful trial, both measures had to show significant improvement. - The MWT measures latency (in minutes) to sleep onset averaged over 4 test sessions at 2 hour intervals following nocturnal polysomnography. For each test session, the subject was asked to attempt to remain awake without using extraordinary measures. Each test session was terminated after 20 minutes if no sleep occurred or 10 minutes after sleep onset. The CGI-C is a 7-point scale, centered at No Change, and ranging from Very Much Worse to Very Much Improved. Patients were rated by evaluators who had no access to any data about the patients other than a measure of their baseline severity. Evaluators were not given any specific guidance about the criteria they were to apply when rating patients. - Other assessments of effect included the Multiple Sleep Latency Test (MSLT), Epworth Sleepiness Scale (ESS; a series of questions designed to assess the degree of sleepiness in everyday situations), the Steer Clear Performance Test (SCPT; a computer-based evaluation of a patient's ability to avoid hitting obstacles in a simulated driving situation), standard nocturnal polysomnography, and patient's daily sleep log. Patients were also assessed with the Quality of Life in Narcolepsy (QOLIN) scale, which contains the validated SF-36 health questionnaire. - Both studies demonstrated improvement in objective and subjective measures of excessive daytime sleepiness for both the 200 mg and 400 mg doses compared to placebo. Patients treated with either dose of modafinil showed a statistically significantly enhanced ability to remain awake on the MWT (all p values <0.001) at weeks 3, 6, 9, and final visit compared to placebo and a statistically significantly greater global improvement, as rated on the CGI-C scale (all p values <0.05). - The average sleep latencies (in minutes) on the MWT at baseline for the 2 controlled trials are shown in Table 1 below, along with the average change from baseline on the MWT at final visit. - The percentages of patients who showed any degree of improvement on the CGI-C in the two clinical trials are shown in Table 2 below. - Similar statistically significant treatment-related improvements were seen on other measures of impairment in narcolepsy, including a patient assessed level of daytime sleepiness on the ESS (p<0.001 for each dose in comparison to placebo). - Nighttime sleep measured with polysomnography was not affected by the use of modafinil. - The effectiveness of modafinil in reducing the excessive sleepiness associated with OSA was established in two clinical trials. In both studies, patients were enrolled who met the International Classification of Sleep Disorders (ICSD) criteria for OSA (which are also consistent with the American Psychiatric Association DSM-IV criteria). These criteria include either, 1) excessive sleepiness or insomnia, plus frequent episodes of impaired breathing during sleep, and associated features such as loud snoring, morning headaches and dry mouth upon awakening; or 2) excessive sleepiness or insomnia and polysomnography demonstrating one of the following: more than five obstructive apneas, each greater than 10 seconds in duration, per hour of sleep and one or more of the following: frequent arousals from sleep associated with the apneas, bradytachycardia, and arterial oxygen desaturation in association with the apneas. In addition, for entry into these studies, all patients were required to have excessive sleepiness as demonstrated by a score ≥10 on the Epworth Sleepiness Scale, despite treatment with continuous positive airway pressure (CPAP). Evidence that CPAP was effective in reducing episodes of apnea/hypopnea was required along with documentation of CPAP use. - In the first study, a 12-week multicenter placebo-controlled trial, a total of 327 patients were randomized to receive modafinil 200 mg/day, modafinil 400 mg/day, or matching placebo. The majority of patients (80%) were fully compliant with CPAP, defined as CPAP use > 4 hours/night on > 70% nights. The remainder were partially CPAP compliant, defined as CPAP use < 4 hours/night on >30% nights. CPAP use continued throughout the study. The primary measures of effectiveness were 1) sleep latency, as assessed by the Maintenance of Wakefulness Test (MWT) and 2) the change in the patient's overall disease status, as measured by the Clinical Global Impression of Change (CGI-C) at week 12 or the final visit. - Patients treated with modafinil showed a statistically significant improvement in the ability to remain awake compared to placebo-treated patients as measured by the MWT (p<0.001) at endpoint [Table 1]. Modafinil -treated patients also showed a statistically significant improvement in clinical condition as rated by the CGI-C scale (p<0.001) [Table 2]. The two doses of modafinil performed similarly. - In the second study, a 4-week multicenter placebo-controlled trial, 157 patients were randomized to either modafinil 400 mg/day or placebo. Documentation of regular CPAP use (at least 4 hours/night on 70% of nights) was required for all patients. The primary outcome measure was the change from baseline on the ESS at week 4 or final visit. The baseline ESS scores for the modafinil and placebo groups were 14.2 and 14.4, respectively. At week 4, the ESS was reduced by 4.6 in the modafinil group and by 2.0 in the placebo group, a difference that was statistically significant (p<0.0001). - Nighttime sleep measured with polysomnography was not affected by the use of modafinil. - The effectiveness of modafinil for the excessive sleepiness associated with SWD was demonstrated in a 12-week placebo-controlled clinical trial. A total of 209 patients with chronic SWD were randomized to receive modafinil 200 mg/day or placebo. All patients met the International Classification of Sleep Disorders (ICSD-10) criteria for chronic SWD (which are consistent with the American Psychiatric Association DSM-IV criteria for Circadian Rhythm Sleep Disorder: Shift Work Type). These criteria include 1) either: a) a primary complaint of excessive sleepiness or insomnia which is temporally associated with a work period (usually night work) that occurs during the habitual sleep phase, or b) polysomnography and the MSLT demonstrate loss of a normal sleep-wake pattern (i.e., disturbed chronobiological rhythmicity); and 2) no other medical or mental disorder accounts for the symptoms, and 3) the symptoms do not meet criteria for any other sleep disorder producing insomnia or excessive sleepiness (e.g., time zone change jet lag syndrome). - It should be noted that not all patients with a complaint of sleepiness who are also engaged in shift work meet the criteria for the diagnosis of SWD. In the clinical trial, only patients who were symptomatic for at least 3 months were enrolled. - Enrolled patients were also required to work a minimum of 5 night shifts per month, have excessive sleepiness at the time of their night shifts (MSLT score < 6 minutes), and have daytime insomnia documented by a daytime polysomnogram (PSG). - The primary measures of effectiveness were 1) sleep latency, as assessed by the Multiple Sleep Latency Test (MSLT) performed during a simulated night shift at week 12 or the final visit and 2) the change in the patient's overall disease status, as measured by the Clinical Global Impression of Change (CGI-C) at week 12 or the final visit. Patients treated with modafinil showed a statistically significant prolongation in the time to sleep onset compared to placebo-treated patients, as measured by the nighttime MSLT [Table 1] (p<0.05). Improvement on the CGI-C was also observed to be statistically significant (p<0.001). - Daytime sleep measured with polysomnography was not affected by the use of modafinil. # How Supplied - Store at 20° - 25° C (68° - 77° F). ## Storage There is limited information regarding Modafinil Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Physicians are advised to discuss the following issues with patients for whom they prescribe modafinil. - Modafinil is indicated for patients who have abnormal levels of sleepiness. Modafinil has been shown to improve, but not eliminate this abnormal tendency to fall asleep. Therefore, patients should not alter their previous behavior with regard to potentially dangerous activities (e.g., driving, operating machinery) or other activities requiring appropriate levels of wakefulness, until and unless treatment with modafinil has been shown to produce levels of wakefulness that permit such activities. Patients should be advised that modafinil is not a replacement for sleep. - Patients should be informed that it may be critical that they continue to take their previously prescribed treatments (e.g., patients with OSA receiving CPAP should continue to do so). - Patients should be informed of the availability of a Medication Guide, and they should be instructed to read it prior to taking modafinil. The complete text of the Medication Guide is provided at the end of this labeling. - Patients should be advised to contact their physician if they experience chest pain, rash, depression, anxiety, or signs of psychosis or mania. # Precautions with Alcohol - Patients should be advised that the use of modafinil in combination with alcohol has not been studied. Patients should be advised that it is prudent to avoid alcohol while taking modafinil. # Brand Names - MODAFINIL®[2] # Look-Alike Drug Names - Provigil® — Plaquenil®[3] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Modafinil
8fb30c0f5bca7fba4cf633cad2b0bc8b8c03ee9f	wikidoc	Moexipril	Moexipril - Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. - Moexipril hydrochloride tablets are indicated for treatment of patients with hypertension. It may be used alone or in combination with thiazide diuretics. - In using moexipril hydrochloride tablets, consideration should be given to the fact that another ACE inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen-vascular disease. Available data are insufficient to show that moexipril hydrochloride tablets do not have a similar risk. # Dosage Hypertension - The recommended initial dose of moexipril hydrochloride tablets in patients not receiving diuretics is 7.5 mg, one hour prior to meals, once daily. Dosage should be adjusted according to blood pressure response. The antihypertensive effect of moexipril hydrochloride tablets may diminish towards the end of the dosing interval. Blood pressure should, therefore, be measured just prior to dosing to determine whether satisfactory blood pressure control is obtained. If control is not adequate, increased dose or divided dosing can be tried. The recommended dose range is 7.5 to 30 mg daily, administered in one or two divided doses one hour before meals. Total daily doses above 60 mg a day have not been studied in hypertensive patients. - In patients who are currently being treated with a diuretic, symptomatic hypotension may occasionally occur following the initial dose of moexipril hydrochloride tablets. The diuretic should, if possible, be discontinued for 2 to 3 days before therapy with moexipril hydrochloride tablets is begun, to reduce the likelihood of hypotension. If the patient’s blood pressure is not controlled with moexipril hydrochloride tablets alone, diuretic therapy may then be reinstituted. If diuretic therapy cannot be discontinued, an initial dose of 3.75 mg of moexipril hydrochloride tablets should be used with medical supervision until blood pressure has stabilized. Dosage Adjustment in Renal Impairment - For patients with a creatinine clearance ≤ 40 mL/min/1.73 m2, an initial dose of 3.75 mg once daily should be given cautiously. Doses may be titrated upward to a maximum daily dose of 15 mg. - In considering use of moexipril hydrochloride tablets, it should be noted that in controlled trials ACE inhibitors have an effect on blood pressure that is less in black patients than in non-blacks. In addition, ACE inhibitors (for which adequate data are available) cause a higher rate of angioedema in black than in non-black patients. - Do not coadminister aliskiren with moexipril hydrochloride in patients with diabetes. - Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors, including moexipril hydrochloride, may be subject to a variety of adverse reactions, some of them serious. Head and Neck Angioedema - Angioedema involving the face, extremities, lips, tongue, glottis, and/or larynx has been reported in patients treated with ACE inhibitors, including moexipril hydrochloride. Symptoms suggestive of angioedema or facial edema occurred in < 0.5% of moexipril-treated patients in placebo-controlled trials. None of the cases were considered life-threatening and all resolved either without treatment or with medication (antihistamines or glucocorticoids). One patient treated with hydrochlorothiazide alone experienced laryngeal edema. No instances of angioedema were reported in placebo-treated patients. - In cases of angioedema, treatment should be promptly discontinued and the patient carefully observed until the swelling disappears. In instances where swelling has been confined to the face and lips, the condition has generally resolved without treatment, although antihistamines have been useful in relieving symptoms. - Angioedema associated with involvement of the tongue, glottis, or larynx, may be fatal due to airway obstruction. Appropriate therapy, e.g., subcutaneous epinephrine solution 1:1000 (0.3 to 0.5 mL) and/or measures to ensure a patent airway, should be promptly provided. Intestinal Angioedema - Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain. Anaphylactoid Reactions During Desensitization - Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions did not occur when ACE inhibitors were temporarily withheld, but they reappeared when the ACE inhibitors were inadvertently readministered. Anaphylactoid Reactions During Membrane Exposure - Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption. Hypotension - Moexipril hydrochloride can cause symptomatic hypotension, although, as with other ACE inhibitors, this is unusual in uncomplicated hypertensive patients treated with moexipril hydrochloride alone. Symptomatic hypotension was seen in 0.5% of patients given moexipril and led to discontinuation of therapy in about 0.25%. Symptomatic hypotension is most likely to occur in patients who have been salt- and volume-depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. Volume- and salt-depletion should be corrected and, in general, diuretics stopped, before initiating therapy with moexipril hydrochloride. - In patients with congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria or progressive azotemia, and rarely, with acute renal failure and death. In these patients, moexipril hydrochloride therapy should be started under close medical supervision, and patients should be followed closely for the first two weeks of treatment and whenever the dose of moexipril or an accompanying diuretic is increased. Care in avoiding hypotension should also be taken in patients with ischemic heart disease, aortic stenosis, or cerebrovascular disease, in whom an excessive decrease in blood pressure could result in a myocardial infarction or a cerebrovascular accident. - If hypotension occurs, the patient should be placed in a supine position and, if necessary, treated with an intravenous infusion of normal saline. Moexipril hydrochloride treatment usually can be continued following restoration of blood pressure and volume. Neutropenia/Agranulocytosis - Another ACE inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression, rarely in patients with uncomplicated hypertension, but more frequently in hypertensive patients with renal impairment, especially if they also have a collagen-vascular disease such as systemic lupus erythematosus or scleroderma. Although there were no instances of severe neutropenia (absolute neutrophil count < 500/mm3) among patients given moexipril hydrochloride, as with other ACE inhibitors, monitoring of white blood cell counts should be considered for patients who have collagen-vascular disease, especially if the disease is associated with impaired renal function. Available data from clinical trials of moexipril hydrochloride are insufficient to show that moexipril hydrochloride does not cause agranulocytosis at rates similar to captopril. Fetal Toxicity - Pregnancy category D - Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue moexipril hydrochloride as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. - In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue moexipril hydrochloride, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to moexipril hydrochloride for hypotension, oliguria, and hyperkalemia. - No embryotoxic, fetotoxic, or teratogenic effects were seen in rats or in rabbits treated with up to 90.9 and 0.7 times, respectively, the Maximum Recommended Human Dose (MRHD) on a mg/m2 basis. Hepatic Failure - Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and sometimes death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up. - Reported adverse experiences were usually mild and transient, and there were no differences in adverse reaction rates related to gender, race, age, duration of therapy, or total daily dosage within the range of 3.75 mg to 60 mg. Discontinuation of therapy because of adverse experiences was required in 3.4% of patients treated with moexipril hydrochloride and in 1.8% of patients treated with placebo. The most common reasons for discontinuation in patients treated with moexipril hydrochloride were cough (0.7%) and dizziness (0.4%). - All adverse experiences considered at least possibly related to treatment that occurred at any dose in placebo-controlled trials of once-daily dosing in more than 1% of patients treated with moexipril hydrochloride alone and that were at least as frequent in the moexipril hydrochloride group as in the placebo group are shown in the following table: - Other adverse events occurring in more than 1% of patients on moexipril that were at least as frequent on placebo include: headache, upper respiratory infection, pain, rhinitis, dyspepsia, nausea, peripheral edema, sinusitis, chest pain, and urinary frequency ,anaphylactoid reactions, angioedema, hypotension, neutropenia/agranulocytosis, second and third trimester fetal/neonatal morbidity and mortality, hyperkalemia, and cough. - Other potentially important adverse experiences reported in controlled or uncontrolled clinical trials in less than 1% of moexipril patients or that have been attributed to other ACE inhibitors include the following: - Cardiovascular - Symptomatic hypotension, postural hypotension, or syncope were seen in 9/1750 (0.51%) patients; these reactions led to discontinuation of therapy in controlled trials in 3/1254 (0.24%) patients who had received moexipril hydrochloride monotherapy and in 1/344 (0.3%) patients who had received moexipril hydrochloride with hydrochlorothiazide. Other adverse events included angina/myocardial infarction, palpitations, rhythm disturbances, and cerebrovascular accident. - Renal - Of hypertensive patients with no apparent preexisting renal disease, 1% of patients receiving moexipril hydrochloride alone and 2% of patients receiving moexipril hydrochloride with hydrochlorothiazide experienced increases in serum creatinine to at least 140% of their baseline values. - Gastrointestinal - Abdominal pain, constipation, vomiting, appetite/weight change, dry mouth, pancreatitis, hepatitis. - Respiratory - Bronchospasm, dyspnea, eosinophilic pneumonitis. - Urogenital - Renal insufficiency, oliguria. - Dermatologic - Apparent hypersensitivity reactions - Manifested by urticaria, rash, pemphigus, pruritus, photosensitivity, alopecia. - Neurological and Psychiatric - Drowsiness, sleep disturbances, nervousness, mood changes, anxiety. - Other - Angioedema , taste disturbances, tinnitus, sweating, malaise, arthralgia, hemolytic anemia. - Clinical Laboratory Test Findings - Serum Electrolytes Hyperkalemia, hyponatremia. - Creatinine and Blood Urea Nitrogen - As with other ACE inhibitors, minor increases in blood urea nitrogen or serum creatinine, reversible upon discontinuation of therapy, were observed in approximately 1% of patients with essential hypertension who were treated with moexipril hydrochloride. Increases are more likely to occur in patients receiving concomitant diuretics and in patients with compromised renal function. - Other (Causal Relationship Unknown) - Clinically important changes in standard laboratory tests were rarely associated with moexipril hydrochloride administration. Elevations of liver enzymes and uric acid have been reported. In trials, less than 1% of moexipril-treated patients discontinued moexipril hydrochloride treatment because of laboratory abnormalities. The incidence of abnormal laboratory values with moexipril was similar to that in the placebo-treated group. - Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with moexipril hydrochloride can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with moexipril hydrochloride. If this is not possible, the starting dose of moexipril should be reduced . Potassium Supplements and Potassium-Sparing Diuretics - Moexipril hydrochloride can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient’s serum potassium should be monitored. Oral Anticoagulants - Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium - Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Gold - Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including moexipril hydrochloride. Non-Steroidal Anti-Inflammatory Agents Including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors - In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDS, including selective COX-2 inhibitors, with ACE inhibitors, including moexipril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving moexipril and NSAID therapy. - The antihypertensive effect of ACE inhibitors, including moexipril, may be attenuated by NSAIDS. Dual Blockade of the Renin-Angiotensin System (RAS) - Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function and electrolytes in patients on moexipril hydrochloride and other agents that affect the RAS. - Do not coadminister aliskiren with moexipril hydrochloride in patients with diabetes. Avoid use of aliskiren with moexipril hydrochloride in patients with renal impairment (GFR < 60 mL/min). Other Agents - No clinically important pharmacokinetic interactions occurred when moexipril hydrochloride was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. - Moexipril hydrochloride has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. - Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue moexipril hydrochloride as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. - In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue moexipril hydrochloride, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to moexipril hydrochloride for hypotension, oliguria, and hyperkalemia. - No embryotoxic, fetotoxic, or teratogenic effects were seen in rats or in rabbits treated with up to 90.9 and 0.7 times, respectively, the Maximum Recommended Human Dose (MRHD) on a mg/m2 basis. There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Moexipril in women who are pregnant. - If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. - Safety and effectiveness of moexipril hydrochloride in pediatric patients have not been established. - Some hypertensive patients with no apparent preexisting renal vascular disease have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially when moexipril hydrochloride has been given concomitantly with a thiazide diuretic. This is more likely to occur in patients with preexisting renal impairment. There may be a need for dose adjustment of moexipril hydrochloride and/or the discontinuation of the thiazide diuretic. - Evaluation of hypertensive patients should always include assessment of renal function - No data are available to suggest that physiological maneuvers (e.g., maneuvers to change the pH of the urine) would accelerate elimination of moexipril and its metabolites. The dialyzability of moexipril is not known. - Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of moexipril overdose, but angiotensin II is essentially unavailable outside of research facilities. Because the hypotensive effect of moexipril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat moexipril overdose by infusion of normal saline solution. In addition, renal function and serum potassium should be monitored. - Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of moexipril remains to be elucidated. Although the principal mechanism of moexipril in blood pressure reduction is believed to be through the renin-angiotensin-aldosterone system, ACE inhibitors have some effect on blood pressure even in apparent low-renin hypertension. As is the case with other ACE inhibitors, however, the antihypertensive effect of moexipril is considerably smaller in black patients, a predominantly low-renin population, than in non-black hypertensive patients. - Moexipril hydrochloride is a fine white to off-white powder. It is soluble (about 10% weight-to-volume) in distilled water at room temperature. - Moexipril hydrochloride tablets are supplied as bisected, coated tablets containing 7.5 mg and 15 mg of moexipril hydrochloride for oral administration. In addition to the active ingredient, moexipril hydrochloride, the tablet core contains the following inactive ingredients: crospovidone, lactose monohydrate, magnesium stearate, pregelatinized starch and sodium bicarbonate. The film coating of the 7.5 mg tablet contains: hypromellose, iron oxide red, lactose monohydrate, titanium dioxide and triacetin. The film coating of the 15 mg tablet contains: hypromellose, iron oxide red, lactose monohydrate, titanium dioxide and triacetin. Absorption - Moexipril is incompletely absorbed, with bioavailability as moexiprilat of about 13%. Bioavailability varies with formulation and food intake which reduces Cmax and AUC by about 70% and 40% respectively after the ingestion of a low-fat breakfast or by 80% and 50% respectively after the ingestion of a high-fat breakfast. Distribution - The clearance (CL) for moexipril is 441 mL/min and for moexiprilat 232 mL/min with a t1/2 of 1.3 and 9.8 hours, respectively. Moexiprilat is about 50% protein bound. The volume of distribution of moexiprilat is about 183 liters. Metabolism and Excretion - Moexipril is relatively rapidly converted to its active metabolite moexiprilat, but persists longer than some other ACE inhibitor prodrugs, such that its t1/2 is over one hour and it has a significant AUC. Both moexipril and moexiprilat are converted to diketopiperazine derivatives and unidentified metabolites. After I.V. administration of moexipril, about 40% of the dose appears in urine as moexiprilat, about 26% as moexipril, with small amounts of the metabolites; about 20% of the I.V. dose appears in feces, principally as moexiprilat. After oral administration, only about 7% of the dose appears in urine as moexiprilat, about 1% as moexipril, with about 5% as other metabolites. Fifty-two percent of the dose is recovered in feces as moexiprilat and 1% as moexipril. Special Populations Decreased renal function - The effective elimination of t1/2 and AUC of both moexipril and moexiprilat are increased with decreasing renal function. There is insufficient information available to characterize this relationship fully, but at creatinine clearances in the range of 10 to 40 mL/min, the t1/2 of moexiprilat is increased by a factor of 3 to 4. Decreased hepatic function - In patients with mild to moderate cirrhosis given single 15 mg doses of moexipril, the Cmax of moexipril was increased by about 50% and the AUC increased by about 120%, while the Cmax for moexiprilat was decreased by about 50% and the AUC increased by almost 300%. Elderly patients - In elderly male subjects (65 to 80 years old) with clinically normal renal and hepatic function, the AUC and Cmax of moexiprilat is about 30% greater than those of younger subjects (19 to 42 years old). Pharmacokinetic Interactions With Other Drugs - No clinically important pharmacokinetic interactions occurred when moexipril hydrochloride was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. Pharmacodynamics and Clinical Effect - Single and multiple doses of 15 mg or more of moexipril hydrochloride tablets gives sustained inhibition of plasma ACE activity of 80 to 90%, beginning within 2 hours and lasting 24 hours (80%). - In controlled trials, the peak effects of orally administered moexipril increased with the dose administered over a dose range of 7.5 to 60 mg, given once a day. Antihypertensive effects were first detectable about 1 hour after dosing, with a peak effect between 3 and 6 hours after dosing. Just before dosing (i.e., at trough), the antihypertensive effects were less prominently related to dose and the antihypertensive effect tended to diminish during the 24 hour dosing interval when the drug was administered once a day. - In multiple dose studies in the dose range of 7.5 to 30 mg once daily, moexipril hydrochloride tablets lowered sitting diastolic and systolic blood pressure effects at trough by 3 to 6 mmHg and 4 to 11 mmHg more than placebo, respectively. There was a tendency toward increased response with higher doses over this range. These effects are typical of ACE inhibitors but, to date, there are no trials of adequate size comparing moexipril with other antihypertensive agents. - The trough diastolic blood pressure effects of moexipril were approximately 3 to 6 mmHg in various studies. Generally, higher doses of moexipril leave a greater fraction of the peak blood pressure effect still present at trough. During dose titration, any decision as to the adequacy of a dosing regimen should be based on trough blood pressure measurements. If diastolic blood pressure control is not adequate at the end of the dosing interval, the dose can be increased or given as a divided (BID) regimen. - During chronic therapy, the antihypertensive effect of any dose of moexipril hydrochloride is generally evident within 2 weeks of treatment, with maximal reduction after 4 weeks. The antihypertensive effects of moexipril hydrochloride have been proven to continue during therapy for up to 24 months. - Moexipril hydrochloride, like other ACE inhibitors, is less effective in decreasing trough blood pressures in blacks than in non-blacks. Placebo-corrected trough group mean diastolic blood pressure effects in blacks in the proposed dose range varied between +1 to -3 mmHg compared with responses in non-blacks of -4 to -6 mmHg. - The effectiveness of moexipril hydrochloride was not significantly influenced by patient age, gender, or weight. Moexipril hydrochloride has been shown to have antihypertensive activity in both pre- and postmenopausal women who have participated in placebo-controlled clinical trials. - Formal interaction studies with moexipril have not been carried out with antihypertensive agents other than thiazide diuretics. In these studies, the added effect of moexipril was similar to its effect as monotherapy. In general, ACE inhibitors have less than additive effects with beta-adrenergic blockers, presumably because both work by inhibiting the renin-angiotensin system. - No evidence of carcinogenicity was detected in long-term studies in mice and rats at doses up to 14 or 27.3 times the Maximum Recommended Human Dose (MRHD) on a mg/m2 basis. - No mutagenicity was detected in the Ames test and microbial reverse mutation assay, with and without metabolic activation, or in an in vivo nucleus anomaly test. However, increased chromosomal aberration frequency in Chinese hamster ovary cells was detected under metabolic activation conditions at a 20 hour harvest time. - Reproduction studies have been performed in rabbits at oral doses up to 0.7 times the MRHD on a mg/m2 basis, and in rats up to 90.9 times the MRHD on a mg/m2 basis. No indication of impaired fertility, reproductive toxicity, or teratogenicity was observed. - Moexipril hydrochloride tablets, 15 mg, are pink, film-coated, oval, convex tablets debossed “5150” on one side and “93” to the left of a bisect on the other side. They are available in bottles of 100. Patients should be advised to take moexipril one hour before meals. Angioedema - Angioedema, including laryngeal edema, may occur with treatment with ACE inhibitors, usually occurring early in therapy (within the first month). Patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema (swelling of the face, extremities, eyes, lips, tongue, difficulty in breathing) and to take no more moexipril hydrochloride until they have consulted with the prescribing physician. Symptomatic Hypotension - Patients should be cautioned that lightheadedness can occur with moexipril hydrochloride, especially during the first few days of therapy. If fainting occurs, the patient should stop taking moexipril hydrochloride and consult the prescribing physician. - All patients should be cautioned that excessive perspiration and dehydration may lead to an excessive fall in blood pressure because of reduction in fluid volume. Other causes of volume depletion such as vomiting or diarrhea may also lead to a fall in blood pressure; patients should be advised to consult their physician if they develop these conditions. Hyperkalemia - Patients should be told not to use potassium supplements or salt substitutes containing potassium without consulting their physician. Neutropenia - Patients should be told to report promptly any indication of infection (e.g., sore throat, fever) that could be a sign of neutropenia. Pregnancy - Female patients of childbearing age should be told about the consequences of exposure to moexipril hydrochloride during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible. - ↑ "". External link in \|title= (help).mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}	Moexipril - Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. - Moexipril hydrochloride tablets are indicated for treatment of patients with hypertension. It may be used alone or in combination with thiazide diuretics. - In using moexipril hydrochloride tablets, consideration should be given to the fact that another ACE inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen-vascular disease. Available data are insufficient to show that moexipril hydrochloride tablets do not have a similar risk. # Dosage Hypertension - The recommended initial dose of moexipril hydrochloride tablets in patients not receiving diuretics is 7.5 mg, one hour prior to meals, once daily. Dosage should be adjusted according to blood pressure response. The antihypertensive effect of moexipril hydrochloride tablets may diminish towards the end of the dosing interval. Blood pressure should, therefore, be measured just prior to dosing to determine whether satisfactory blood pressure control is obtained. If control is not adequate, increased dose or divided dosing can be tried. The recommended dose range is 7.5 to 30 mg daily, administered in one or two divided doses one hour before meals. Total daily doses above 60 mg a day have not been studied in hypertensive patients. - In patients who are currently being treated with a diuretic, symptomatic hypotension may occasionally occur following the initial dose of moexipril hydrochloride tablets. The diuretic should, if possible, be discontinued for 2 to 3 days before therapy with moexipril hydrochloride tablets is begun, to reduce the likelihood of hypotension. If the patient’s blood pressure is not controlled with moexipril hydrochloride tablets alone, diuretic therapy may then be reinstituted. If diuretic therapy cannot be discontinued, an initial dose of 3.75 mg of moexipril hydrochloride tablets should be used with medical supervision until blood pressure has stabilized. Dosage Adjustment in Renal Impairment - For patients with a creatinine clearance ≤ 40 mL/min/1.73 m2, an initial dose of 3.75 mg once daily should be given cautiously. Doses may be titrated upward to a maximum daily dose of 15 mg. - In considering use of moexipril hydrochloride tablets, it should be noted that in controlled trials ACE inhibitors have an effect on blood pressure that is less in black patients than in non-blacks. In addition, ACE inhibitors (for which adequate data are available) cause a higher rate of angioedema in black than in non-black patients. - Do not coadminister aliskiren with moexipril hydrochloride in patients with diabetes. - Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors, including moexipril hydrochloride, may be subject to a variety of adverse reactions, some of them serious. Head and Neck Angioedema - Angioedema involving the face, extremities, lips, tongue, glottis, and/or larynx has been reported in patients treated with ACE inhibitors, including moexipril hydrochloride. Symptoms suggestive of angioedema or facial edema occurred in < 0.5% of moexipril-treated patients in placebo-controlled trials. None of the cases were considered life-threatening and all resolved either without treatment or with medication (antihistamines or glucocorticoids). One patient treated with hydrochlorothiazide alone experienced laryngeal edema. No instances of angioedema were reported in placebo-treated patients. - In cases of angioedema, treatment should be promptly discontinued and the patient carefully observed until the swelling disappears. In instances where swelling has been confined to the face and lips, the condition has generally resolved without treatment, although antihistamines have been useful in relieving symptoms. - Angioedema associated with involvement of the tongue, glottis, or larynx, may be fatal due to airway obstruction. Appropriate therapy, e.g., subcutaneous epinephrine solution 1:1000 (0.3 to 0.5 mL) and/or measures to ensure a patent airway, should be promptly provided. Intestinal Angioedema - Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain. Anaphylactoid Reactions During Desensitization - Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions did not occur when ACE inhibitors were temporarily withheld, but they reappeared when the ACE inhibitors were inadvertently readministered. Anaphylactoid Reactions During Membrane Exposure - Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption. Hypotension - Moexipril hydrochloride can cause symptomatic hypotension, although, as with other ACE inhibitors, this is unusual in uncomplicated hypertensive patients treated with moexipril hydrochloride alone. Symptomatic hypotension was seen in 0.5% of patients given moexipril and led to discontinuation of therapy in about 0.25%. Symptomatic hypotension is most likely to occur in patients who have been salt- and volume-depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. Volume- and salt-depletion should be corrected and, in general, diuretics stopped, before initiating therapy with moexipril hydrochloride. - In patients with congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria or progressive azotemia, and rarely, with acute renal failure and death. In these patients, moexipril hydrochloride therapy should be started under close medical supervision, and patients should be followed closely for the first two weeks of treatment and whenever the dose of moexipril or an accompanying diuretic is increased. Care in avoiding hypotension should also be taken in patients with ischemic heart disease, aortic stenosis, or cerebrovascular disease, in whom an excessive decrease in blood pressure could result in a myocardial infarction or a cerebrovascular accident. - If hypotension occurs, the patient should be placed in a supine position and, if necessary, treated with an intravenous infusion of normal saline. Moexipril hydrochloride treatment usually can be continued following restoration of blood pressure and volume. Neutropenia/Agranulocytosis - Another ACE inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression, rarely in patients with uncomplicated hypertension, but more frequently in hypertensive patients with renal impairment, especially if they also have a collagen-vascular disease such as systemic lupus erythematosus or scleroderma. Although there were no instances of severe neutropenia (absolute neutrophil count < 500/mm3) among patients given moexipril hydrochloride, as with other ACE inhibitors, monitoring of white blood cell counts should be considered for patients who have collagen-vascular disease, especially if the disease is associated with impaired renal function. Available data from clinical trials of moexipril hydrochloride are insufficient to show that moexipril hydrochloride does not cause agranulocytosis at rates similar to captopril. Fetal Toxicity - Pregnancy category D - Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue moexipril hydrochloride as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. - In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue moexipril hydrochloride, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to moexipril hydrochloride for hypotension, oliguria, and hyperkalemia. - No embryotoxic, fetotoxic, or teratogenic effects were seen in rats or in rabbits treated with up to 90.9 and 0.7 times, respectively, the Maximum Recommended Human Dose (MRHD) on a mg/m2 basis. Hepatic Failure - Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and sometimes death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up. - Reported adverse experiences were usually mild and transient, and there were no differences in adverse reaction rates related to gender, race, age, duration of therapy, or total daily dosage within the range of 3.75 mg to 60 mg. Discontinuation of therapy because of adverse experiences was required in 3.4% of patients treated with moexipril hydrochloride and in 1.8% of patients treated with placebo. The most common reasons for discontinuation in patients treated with moexipril hydrochloride were cough (0.7%) and dizziness (0.4%). - All adverse experiences considered at least possibly related to treatment that occurred at any dose in placebo-controlled trials of once-daily dosing in more than 1% of patients treated with moexipril hydrochloride alone and that were at least as frequent in the moexipril hydrochloride group as in the placebo group are shown in the following table: - Other adverse events occurring in more than 1% of patients on moexipril that were at least as frequent on placebo include: headache, upper respiratory infection, pain, rhinitis, dyspepsia, nausea, peripheral edema, sinusitis, chest pain, and urinary frequency ,anaphylactoid reactions, angioedema, hypotension, neutropenia/agranulocytosis, second and third trimester fetal/neonatal morbidity and mortality, hyperkalemia, and cough. - Other potentially important adverse experiences reported in controlled or uncontrolled clinical trials in less than 1% of moexipril patients or that have been attributed to other ACE inhibitors include the following: - Cardiovascular - Symptomatic hypotension, postural hypotension, or syncope were seen in 9/1750 (0.51%) patients; these reactions led to discontinuation of therapy in controlled trials in 3/1254 (0.24%) patients who had received moexipril hydrochloride monotherapy and in 1/344 (0.3%) patients who had received moexipril hydrochloride with hydrochlorothiazide. Other adverse events included angina/myocardial infarction, palpitations, rhythm disturbances, and cerebrovascular accident. - Renal - Of hypertensive patients with no apparent preexisting renal disease, 1% of patients receiving moexipril hydrochloride alone and 2% of patients receiving moexipril hydrochloride with hydrochlorothiazide experienced increases in serum creatinine to at least 140% of their baseline values. - Gastrointestinal - Abdominal pain, constipation, vomiting, appetite/weight change, dry mouth, pancreatitis, hepatitis. - Respiratory - Bronchospasm, dyspnea, eosinophilic pneumonitis. - Urogenital - Renal insufficiency, oliguria. - Dermatologic - Apparent hypersensitivity reactions - Manifested by urticaria, rash, pemphigus, pruritus, photosensitivity, alopecia. - Neurological and Psychiatric - Drowsiness, sleep disturbances, nervousness, mood changes, anxiety. - Other - Angioedema , taste disturbances, tinnitus, sweating, malaise, arthralgia, hemolytic anemia. - Clinical Laboratory Test Findings - Serum Electrolytes Hyperkalemia, hyponatremia. - Creatinine and Blood Urea Nitrogen - As with other ACE inhibitors, minor increases in blood urea nitrogen or serum creatinine, reversible upon discontinuation of therapy, were observed in approximately 1% of patients with essential hypertension who were treated with moexipril hydrochloride. Increases are more likely to occur in patients receiving concomitant diuretics and in patients with compromised renal function. - Other (Causal Relationship Unknown) - Clinically important changes in standard laboratory tests were rarely associated with moexipril hydrochloride administration. Elevations of liver enzymes and uric acid have been reported. In trials, less than 1% of moexipril-treated patients discontinued moexipril hydrochloride treatment because of laboratory abnormalities. The incidence of abnormal laboratory values with moexipril was similar to that in the placebo-treated group. - Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with moexipril hydrochloride can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with moexipril hydrochloride. If this is not possible, the starting dose of moexipril should be reduced . Potassium Supplements and Potassium-Sparing Diuretics - Moexipril hydrochloride can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient’s serum potassium should be monitored. Oral Anticoagulants - Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium - Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Gold - Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including moexipril hydrochloride. Non-Steroidal Anti-Inflammatory Agents Including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors - In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDS, including selective COX-2 inhibitors, with ACE inhibitors, including moexipril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving moexipril and NSAID therapy. - The antihypertensive effect of ACE inhibitors, including moexipril, may be attenuated by NSAIDS. Dual Blockade of the Renin-Angiotensin System (RAS) - Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function and electrolytes in patients on moexipril hydrochloride and other agents that affect the RAS. - Do not coadminister aliskiren with moexipril hydrochloride in patients with diabetes. Avoid use of aliskiren with moexipril hydrochloride in patients with renal impairment (GFR < 60 mL/min). Other Agents - No clinically important pharmacokinetic interactions occurred when moexipril hydrochloride was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. - Moexipril hydrochloride has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. - Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue moexipril hydrochloride as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. - In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue moexipril hydrochloride, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to moexipril hydrochloride for hypotension, oliguria, and hyperkalemia. - No embryotoxic, fetotoxic, or teratogenic effects were seen in rats or in rabbits treated with up to 90.9 and 0.7 times, respectively, the Maximum Recommended Human Dose (MRHD) on a mg/m2 basis. There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Moexipril in women who are pregnant. - If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. - Safety and effectiveness of moexipril hydrochloride in pediatric patients have not been established. - Some hypertensive patients with no apparent preexisting renal vascular disease have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially when moexipril hydrochloride has been given concomitantly with a thiazide diuretic. This is more likely to occur in patients with preexisting renal impairment. There may be a need for dose adjustment of moexipril hydrochloride and/or the discontinuation of the thiazide diuretic. - Evaluation of hypertensive patients should always include assessment of renal function - No data are available to suggest that physiological maneuvers (e.g., maneuvers to change the pH of the urine) would accelerate elimination of moexipril and its metabolites. The dialyzability of moexipril is not known. - Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of moexipril overdose, but angiotensin II is essentially unavailable outside of research facilities. Because the hypotensive effect of moexipril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat moexipril overdose by infusion of normal saline solution. In addition, renal function and serum potassium should be monitored. - Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of moexipril remains to be elucidated. Although the principal mechanism of moexipril in blood pressure reduction is believed to be through the renin-angiotensin-aldosterone system, ACE inhibitors have some effect on blood pressure even in apparent low-renin hypertension. As is the case with other ACE inhibitors, however, the antihypertensive effect of moexipril is considerably smaller in black patients, a predominantly low-renin population, than in non-black hypertensive patients. - Moexipril hydrochloride is a fine white to off-white powder. It is soluble (about 10% weight-to-volume) in distilled water at room temperature. - Moexipril hydrochloride tablets are supplied as bisected, coated tablets containing 7.5 mg and 15 mg of moexipril hydrochloride for oral administration. In addition to the active ingredient, moexipril hydrochloride, the tablet core contains the following inactive ingredients: crospovidone, lactose monohydrate, magnesium stearate, pregelatinized starch and sodium bicarbonate. The film coating of the 7.5 mg tablet contains: hypromellose, iron oxide red, lactose monohydrate, titanium dioxide and triacetin. The film coating of the 15 mg tablet contains: hypromellose, iron oxide red, lactose monohydrate, titanium dioxide and triacetin. Absorption - Moexipril is incompletely absorbed, with bioavailability as moexiprilat of about 13%. Bioavailability varies with formulation and food intake which reduces Cmax and AUC by about 70% and 40% respectively after the ingestion of a low-fat breakfast or by 80% and 50% respectively after the ingestion of a high-fat breakfast. Distribution - The clearance (CL) for moexipril is 441 mL/min and for moexiprilat 232 mL/min with a t1/2 of 1.3 and 9.8 hours, respectively. Moexiprilat is about 50% protein bound. The volume of distribution of moexiprilat is about 183 liters. Metabolism and Excretion - Moexipril is relatively rapidly converted to its active metabolite moexiprilat, but persists longer than some other ACE inhibitor prodrugs, such that its t1/2 is over one hour and it has a significant AUC. Both moexipril and moexiprilat are converted to diketopiperazine derivatives and unidentified metabolites. After I.V. administration of moexipril, about 40% of the dose appears in urine as moexiprilat, about 26% as moexipril, with small amounts of the metabolites; about 20% of the I.V. dose appears in feces, principally as moexiprilat. After oral administration, only about 7% of the dose appears in urine as moexiprilat, about 1% as moexipril, with about 5% as other metabolites. Fifty-two percent of the dose is recovered in feces as moexiprilat and 1% as moexipril. Special Populations Decreased renal function - The effective elimination of t1/2 and AUC of both moexipril and moexiprilat are increased with decreasing renal function. There is insufficient information available to characterize this relationship fully, but at creatinine clearances in the range of 10 to 40 mL/min, the t1/2 of moexiprilat is increased by a factor of 3 to 4. Decreased hepatic function - In patients with mild to moderate cirrhosis given single 15 mg doses of moexipril, the Cmax of moexipril was increased by about 50% and the AUC increased by about 120%, while the Cmax for moexiprilat was decreased by about 50% and the AUC increased by almost 300%. Elderly patients - In elderly male subjects (65 to 80 years old) with clinically normal renal and hepatic function, the AUC and Cmax of moexiprilat is about 30% greater than those of younger subjects (19 to 42 years old). Pharmacokinetic Interactions With Other Drugs - No clinically important pharmacokinetic interactions occurred when moexipril hydrochloride was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. Pharmacodynamics and Clinical Effect - Single and multiple doses of 15 mg or more of moexipril hydrochloride tablets gives sustained inhibition of plasma ACE activity of 80 to 90%, beginning within 2 hours and lasting 24 hours (80%). - In controlled trials, the peak effects of orally administered moexipril increased with the dose administered over a dose range of 7.5 to 60 mg, given once a day. Antihypertensive effects were first detectable about 1 hour after dosing, with a peak effect between 3 and 6 hours after dosing. Just before dosing (i.e., at trough), the antihypertensive effects were less prominently related to dose and the antihypertensive effect tended to diminish during the 24 hour dosing interval when the drug was administered once a day. - In multiple dose studies in the dose range of 7.5 to 30 mg once daily, moexipril hydrochloride tablets lowered sitting diastolic and systolic blood pressure effects at trough by 3 to 6 mmHg and 4 to 11 mmHg more than placebo, respectively. There was a tendency toward increased response with higher doses over this range. These effects are typical of ACE inhibitors but, to date, there are no trials of adequate size comparing moexipril with other antihypertensive agents. - The trough diastolic blood pressure effects of moexipril were approximately 3 to 6 mmHg in various studies. Generally, higher doses of moexipril leave a greater fraction of the peak blood pressure effect still present at trough. During dose titration, any decision as to the adequacy of a dosing regimen should be based on trough blood pressure measurements. If diastolic blood pressure control is not adequate at the end of the dosing interval, the dose can be increased or given as a divided (BID) regimen. - During chronic therapy, the antihypertensive effect of any dose of moexipril hydrochloride is generally evident within 2 weeks of treatment, with maximal reduction after 4 weeks. The antihypertensive effects of moexipril hydrochloride have been proven to continue during therapy for up to 24 months. - Moexipril hydrochloride, like other ACE inhibitors, is less effective in decreasing trough blood pressures in blacks than in non-blacks. Placebo-corrected trough group mean diastolic blood pressure effects in blacks in the proposed dose range varied between +1 to -3 mmHg compared with responses in non-blacks of -4 to -6 mmHg. - The effectiveness of moexipril hydrochloride was not significantly influenced by patient age, gender, or weight. Moexipril hydrochloride has been shown to have antihypertensive activity in both pre- and postmenopausal women who have participated in placebo-controlled clinical trials. - Formal interaction studies with moexipril have not been carried out with antihypertensive agents other than thiazide diuretics. In these studies, the added effect of moexipril was similar to its effect as monotherapy. In general, ACE inhibitors have less than additive effects with beta-adrenergic blockers, presumably because both work by inhibiting the renin-angiotensin system. - No evidence of carcinogenicity was detected in long-term studies in mice and rats at doses up to 14 or 27.3 times the Maximum Recommended Human Dose (MRHD) on a mg/m2 basis. - No mutagenicity was detected in the Ames test and microbial reverse mutation assay, with and without metabolic activation, or in an in vivo nucleus anomaly test. However, increased chromosomal aberration frequency in Chinese hamster ovary cells was detected under metabolic activation conditions at a 20 hour harvest time. - Reproduction studies have been performed in rabbits at oral doses up to 0.7 times the MRHD on a mg/m2 basis, and in rats up to 90.9 times the MRHD on a mg/m2 basis. No indication of impaired fertility, reproductive toxicity, or teratogenicity was observed. - Moexipril hydrochloride tablets, 15 mg, are pink, film-coated, oval, convex tablets debossed “5150” on one side and “93” to the left of a bisect on the other side. They are available in bottles of 100. Patients should be advised to take moexipril one hour before meals. Angioedema - Angioedema, including laryngeal edema, may occur with treatment with ACE inhibitors, usually occurring early in therapy (within the first month). Patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema (swelling of the face, extremities, eyes, lips, tongue, difficulty in breathing) and to take no more moexipril hydrochloride until they have consulted with the prescribing physician. Symptomatic Hypotension - Patients should be cautioned that lightheadedness can occur with moexipril hydrochloride, especially during the first few days of therapy. If fainting occurs, the patient should stop taking moexipril hydrochloride and consult the prescribing physician. - All patients should be cautioned that excessive perspiration and dehydration may lead to an excessive fall in blood pressure because of reduction in fluid volume. Other causes of volume depletion such as vomiting or diarrhea may also lead to a fall in blood pressure; patients should be advised to consult their physician if they develop these conditions. Hyperkalemia - Patients should be told not to use potassium supplements or salt substitutes containing potassium without consulting their physician. Neutropenia - Patients should be told to report promptly any indication of infection (e.g., sore throat, fever) that could be a sign of neutropenia. Pregnancy - Female patients of childbearing age should be told about the consequences of exposure to moexipril hydrochloride during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible. - ↑ "http://www.ismp.org". 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ed2d9a97e8c21bcfa9c98efa5d7b29e846b12722	wikidoc	Monoblast	Monoblast Monoblasts are normally found in bone marrow and do not appear in the normal peripheral blood. They mature into monocytes which in turn develop into macrophages. # Structure A typical monoblast is about 12 to 20 µm in diameter, has a nuclear to cytoplasm ration of 4:1 to 3:1, and, like most myeloid blasts, has a round to oval nucleus with fine chromatin structure. One to four nucleoli are usually visible. The nucleus can be central or eccentric and it can show evidence of indentation or folding. The cytoplasm is agranular, stains moderately to lightly basophilic, and often has an intensely stained periphery and a prominent perinuclear zone. # Maturation The monoblast is the first stage of monocyte-macrophage maturation. The developmental stages of the monoblast are: CFU-GM (pluripotential hemopoietic stem cell or hemocytoblast) -> monoblast -> promonocyte -> monocyte-> macrophage. # Additional images - Blood cell lineage - Hematopoiesis	Monoblast Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Monoblasts are normally found in bone marrow and do not appear in the normal peripheral blood. They mature into monocytes which in turn develop into macrophages. # Structure A typical monoblast is about 12 to 20 µm in diameter, has a nuclear to cytoplasm ration of 4:1 to 3:1, and, like most myeloid blasts, has a round to oval nucleus with fine chromatin structure. One to four nucleoli are usually visible. The nucleus can be central or eccentric and it can show evidence of indentation or folding. The cytoplasm is agranular, stains moderately to lightly basophilic, and often has an intensely stained periphery and a prominent perinuclear zone. # Maturation The monoblast is the first stage of monocyte-macrophage maturation. The developmental stages of the monoblast are: CFU-GM (pluripotential hemopoietic stem cell or hemocytoblast) -> monoblast -> promonocyte -> monocyte-> macrophage. # Additional images - Blood cell lineage - Hematopoiesis	https://www.wikidoc.org/index.php/Monoblast
2f1e1d2288a668b0052a8863fe65a3b1a878f838	wikidoc	Monomania	Monomania # Background In psychiatry, monomania (from Greek monos, one, and mania, mania) is a type of paranoia in which the patient has only one idea or type of ideas. Emotional monomania is that in which the patient is obsessed with only one emotion or several related to it; intellectual monomania is that which is related to only one kind of delirious idea or ideas. In colloquial terms, the term monomania is often attached to subcultures that to the general public appear esoteric. However, the differences between monomania and passion can be very subtle and difficult to recognize. # Monomania in literature The 19th century writer Edgar Allan Poe would often write tales in which the narrator and protagonist would suffer some form of monomania, becoming excessively fixated on an idea, an urge, an object, or a person, often to the point of mental and/or physical destruction. Poe uses the theme of monomania in: - "The Black Cat" (a man fears his cat and kills it, adopts another cat, kills his wife, and is then punished by the cat) - "The Oval Portrait" (about a painter who is obsessed with painting his wife) - "Berenice" (about a madman who wants to marry his sick cousin only for her beautiful teeth) - "The Masque of the Red Death" (a prince fears a terrible disease but finally gets ill from the red death and dies) - "The Tell-Tale Heart" (a madman is obsessed with an elderly man's eye) It is said that Flaubert's hatred of the bourgeois and their bêtise (willful idiocy), that began in his childhood, developed into a kind of monomania. It is monomania from which Flaubert's tragic heroine Madame Bovary suffers; in her case it takes the form of an incessant guilt and fear of discovery. The same monomanic fear is explored in great depth in M E Braddon's novel, Lady Audley's Secret, through the protagonist Robert Audley, whom the guilty woman accuses of monomania in his relentless attempt to prove her guilt. She describes monomania thus: What is one of the strangest diagnostics of madness--what is the first appalling sign of mental aberration? The mind becomes stationary; the brain stagnates; the even current of reflection is interrupted; the thinking power of the brain resolves itself into a monotone. As the waters of a tideless pool putrefy by reason of their stagnation, the mind becomes turbid and corrupt through lack of action; and the perpetual reflection upon one subject resolves itself into monomania. In Crime and Punishment, by the renowned Russian novelist Fyodor Dostoevsky, the main character, Raskolnikov, is said to be a monomaniac on numerous occasions. In Moby-Dick by Herman Melville (1851), Captain Ahab is a monomaniac, as shown by his quest to kill Moby Dick. One particular situation where he is shown as a monomaniac is in the crew's first encounter with the whale, stating "in his narrow-flowing monomania, not one jot of Ahab's broad madness had been left behind; so in that broad madness, not one jot of his great natural intellect had perished.” In Emily Brontë's Wuthering Heights, Heathcliff is described as a monomaniac, obsessing over his reunion with Cathy in the final chapters of the novel. The Marvel Comics supervillain Bullseye is a professional assassin who obsesses over his targets. In one of his more recent appearances, he was revealed to be a monomaniac. de:Monomanie nl:Monomanie	Monomania Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Background In psychiatry, monomania (from Greek monos, one, and mania, mania) is a type of paranoia in which the patient has only one idea or type of ideas. Emotional monomania is that in which the patient is obsessed with only one emotion or several related to it; intellectual monomania is that which is related to only one kind of delirious idea or ideas. In colloquial terms, the term monomania is often attached to subcultures that to the general public appear esoteric. However, the differences between monomania and passion can be very subtle and difficult to recognize. # Monomania in literature The 19th century writer Edgar Allan Poe would often write tales in which the narrator and protagonist would suffer some form of monomania, becoming excessively fixated on an idea, an urge, an object, or a person, often to the point of mental and/or physical destruction. Poe uses the theme of monomania in: - "The Black Cat" (a man fears his cat and kills it, adopts another cat, kills his wife, and is then punished by the cat) - "The Oval Portrait" (about a painter who is obsessed with painting his wife) - "Berenice" (about a madman who wants to marry his sick cousin only for her beautiful teeth) - "The Masque of the Red Death" (a prince fears a terrible disease but finally gets ill from the red death and dies) - "The Tell-Tale Heart" (a madman is obsessed with an elderly man's eye) It is said that Flaubert's hatred of the bourgeois and their bêtise (willful idiocy), that began in his childhood, developed into a kind of monomania. It is monomania from which Flaubert's tragic heroine Madame Bovary suffers; in her case it takes the form of an incessant guilt and fear of discovery. The same monomanic fear is explored in great depth in M E Braddon's novel, Lady Audley's Secret, through the protagonist Robert Audley, whom the guilty woman accuses of monomania in his relentless attempt to prove her guilt. She describes monomania thus: What is one of the strangest diagnostics of madness--what is the first appalling sign of mental aberration? The mind becomes stationary; the brain stagnates; the even current of reflection is interrupted; the thinking power of the brain resolves itself into a monotone. As the waters of a tideless pool putrefy by reason of their stagnation, the mind becomes turbid and corrupt through lack of action; and the perpetual reflection upon one subject resolves itself into monomania. In Crime and Punishment, by the renowned Russian novelist Fyodor Dostoevsky, the main character, Raskolnikov, is said to be a monomaniac on numerous occasions. In Moby-Dick by Herman Melville (1851), Captain Ahab is a monomaniac, as shown by his quest to kill Moby Dick. One particular situation where he is shown as a monomaniac is in the crew's first encounter with the whale, stating "in his narrow-flowing monomania, not one jot of Ahab's broad madness had been left behind; so in that broad madness, not one jot of his great natural intellect had perished.” [Citation needed] In Emily Brontë's Wuthering Heights, Heathcliff is described as a monomaniac, obsessing over his reunion with Cathy in the final chapters of the novel. The Marvel Comics supervillain Bullseye is a professional assassin who obsesses over his targets. In one of his more recent appearances, he was revealed to be a monomaniac. de:Monomanie nl:Monomanie Template:WS	https://www.wikidoc.org/index.php/Monomania
dd4d0317c9356e650bf99094a03e4eefd7da89a0	wikidoc	Moraxella	Moraxella Moraxella is a genus of Gram negative bacteria in the Moraxellaceae family. Moraxella catarrhalis is associated with human disease, being linked with respiratory tract infections. In the past, M. catarrhalis, which appears as pairs of cocci and is a gram negative bacterium that morphologically resembles Neisseria by Gram stain, was called Neisseria catarrhalis. However, unlike Neisseria, which grows on chocolate agar, M. catarrhalis grows on blood agar. (Note that up until ten years ago, M. catarrhalis was called Branhamella catarrhalis.) # Epidemiology and Disease M. catarrhalis resides in the human nasopharynx. This bacterium causes similar symptoms to nontypable–Haemophilus influenzae (NTHI), although it is much less virulent. M. catarrhalis is the third most common bacterial cause of otitis media and sinusitis after Streptococcus pneumoniae and Haemophilus, respectively. In patients with pre-existing chronic lung disease, tracheobronchitis and pneumonia can ensue. Of further note, M. catarrhalis hardly ever causes bacteremia or meningitis, unlike Neisseria meningitidis, which is a morphologic cousin of M. catarrhalis (see above). The species Moraxella bovis causes infectious bovine keratoconjunctivitis in cattle. # Host Response The immune response to M. catarrhalis is likely mediated by an antibody to the outer membrane proteins of this organism. Any other immune mechanisms are unknown at this time. # Treatment The antibiotic susceptibility of M. catarrhalis is similar to NTHI. The majority of these organisms make beta-lactamase, an enzyme that renders beta-lactam antibiotics useless; thus, they are resistant to beta lactams such as penicillin. There currently exists no vaccine to M. catarrhalis, but number of outer membrane proteins are currently being studied for the development of such a vaccine.	Moraxella Moraxella is a genus of Gram negative bacteria in the Moraxellaceae family. Moraxella catarrhalis is associated with human disease, being linked with respiratory tract infections. In the past, M. catarrhalis, which appears as pairs of cocci and is a gram negative bacterium that morphologically resembles Neisseria by Gram stain, was called Neisseria catarrhalis. However, unlike Neisseria, which grows on chocolate agar, M. catarrhalis grows on blood agar. (Note that up until ten years ago, M. catarrhalis was called Branhamella catarrhalis.) # Epidemiology and Disease M. catarrhalis resides in the human nasopharynx. This bacterium causes similar symptoms to nontypable–Haemophilus influenzae (NTHI), although it is much less virulent. M. catarrhalis is the third most common bacterial cause of otitis media and sinusitis after Streptococcus pneumoniae and Haemophilus, respectively. In patients with pre-existing chronic lung disease, tracheobronchitis and pneumonia can ensue. Of further note, M. catarrhalis hardly ever causes bacteremia or meningitis, unlike Neisseria meningitidis, which is a morphologic cousin of M. catarrhalis (see above). The species Moraxella bovis causes infectious bovine keratoconjunctivitis in cattle. # Host Response The immune response to M. catarrhalis is likely mediated by an antibody to the outer membrane proteins of this organism. Any other immune mechanisms are unknown at this time. # Treatment The antibiotic susceptibility of M. catarrhalis is similar to NTHI. The majority of these organisms make beta-lactamase, an enzyme that renders beta-lactam antibiotics useless; thus, they are resistant to beta lactams such as penicillin. There currently exists no vaccine to M. catarrhalis, but number of outer membrane proteins are currently being studied for the development of such a vaccine.	https://www.wikidoc.org/index.php/Moraxella
190cb390467b9088cf266c1809fbc467ea54cf70	wikidoc	Morbidity	Morbidity # Overview # Morbidity In medicine, epidemiology and actuarial science, the term morbidity can refer to - the state of being diseased (from Latin morbidus: sick, unhealthy), - the degree or severity of a disease, - the prevalence of a disease: the total number of cases in a particular population at a particular point in time, - the incidence of a disease: the number of new cases in a particular population during a particular time interval. - disability irrespective of cause (e.g., disability caused by accidents). # Morbidity Rate The term morbidity rate can refer either to the incidence rate or to the prevalence rate of a disease. Compare this with the mortality rate of a condition, which is the number of people dying during a given time interval, divided by the total number of people in the population. Morbidity is often measured by ICU scoring systems. # Related Chapters - Morbidity & Mortality about the medical conference - Morbidity and Mortality Weekly Report a publication de:Morbidität id:Morbiditas it:Morbosità (medicina) sr:Морбидитет sv:Morbiditet	Morbidity Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview # Morbidity In medicine, epidemiology and actuarial science, the term morbidity can refer to - the state of being diseased (from Latin morbidus: sick, unhealthy), - the degree or severity of a disease, - the prevalence of a disease: the total number of cases in a particular population at a particular point in time, - the incidence of a disease: the number of new cases in a particular population during a particular time interval. - disability irrespective of cause (e.g., disability caused by accidents). # Morbidity Rate The term morbidity rate can refer either to the incidence rate or to the prevalence rate of a disease. Compare this with the mortality rate of a condition, which is the number of people dying during a given time interval, divided by the total number of people in the population. Morbidity is often measured by ICU scoring systems. # Related Chapters - Morbidity & Mortality about the medical conference - Morbidity and Mortality Weekly Report a publication de:Morbidität id:Morbiditas it:Morbosità (medicina) sr:Морбидитет sv:Morbiditet Template:WH Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Morbidity
798cf81344f10aa45477aad1151e2ac136b7c46c	wikidoc	Morchella	Morchella Lua error in Module:Redirect at line 65: could not parse redirect on page "Morel". Morchella, the true morels, is a genus of edible mushrooms closely related to anatomically simpler cup fungi. These distinctive mushrooms appear honeycomblike in that the upper portion is composed of a network of ridges with pits between them. These ascocarps are prized by gourmet cooks, particularly for French cuisine. Commercial value aside, morels are hunted by thousands of people every year simply for their taste and the joy of the hunt. Morels have been called by many local names; some of the more colorful include "merkels" or "miracles," based on a story of how a mountain family was saved from starvation by eating morels , and Dryland fish, due to their similarity in taste to fish. # Location of morels The morel grows abundantly in the two and sometimes three years immediately following a forest fire. However, where fire suppression is practiced, they may grow regularly in small amounts in the same spot year after year. Commercial pickers and buyers in North America will follow forest fires to gather morels. The Finnish name, huhtasieni, refers to huhta, area cleared for agriculture by slash and burn method. These spots may be jealously guarded by mushroom pickers, as the mushrooms are a delicacy and sometimes a cash crop. Although no symbiotic relationships have been proven between morels and certain tree species, experienced morel hunters swear by these relationships. Trees commonly associated with morels include ash, sycamore, tuliptree, dead and dying elms, and old apple trees (remnants of orchards). Morels have not yet been successfully farmed on a large scale, and the commercial morel industry is largely based on harvest of wild mushrooms. Morels are a feature of many cuisines, including Provençal. # Different types of morel mushrooms The best known morels are the Yellow Morel or Common Morel (Morchella esculenta); the White Morel (M. deliciosa); and the Black Morel (M. elata). Other common names for morels include Merkel, Sponge Mushroom, and Land Fish. When gathering morels, care must be taken to distinguish them from the poisonous false morel (Gyromitra esculenta and others). Other species of true morels include M. semilibera and M. vulgaris. Discriminating between the various species is complicated by uncertainty regarding which species are truly biologically distinct. Mushroom hunters refer to them by their color (e.g., gray, yellow, black) as the species are very similar in appearance and vary considerably within species and age of individual.	Morchella Lua error in Module:Redirect at line 65: could not parse redirect on page "Morel". Morchella, the true morels, is a genus of edible mushrooms closely related to anatomically simpler cup fungi. These distinctive mushrooms appear honeycomblike in that the upper portion is composed of a network of ridges with pits between them. These ascocarps are prized by gourmet cooks, particularly for French cuisine. Commercial value aside, morels are hunted by thousands of people every year simply for their taste and the joy of the hunt. Morels have been called by many local names; some of the more colorful include "merkels" or "miracles," based on a story of how a mountain family was saved from starvation by eating morels ["The Day the Sun Came Out" by Dorothy M. Johnson], and Dryland fish, due to their similarity in taste to fish. # Location of morels The morel grows abundantly in the two and sometimes three years immediately following a forest fire. However, where fire suppression is practiced, they may grow regularly in small amounts in the same spot year after year. Commercial pickers and buyers in North America will follow forest fires to gather morels. The Finnish name, huhtasieni, refers to huhta, area cleared for agriculture by slash and burn method. These spots may be jealously guarded by mushroom pickers, as the mushrooms are a delicacy and sometimes a cash crop. Although no symbiotic relationships have been proven between morels and certain tree species, experienced morel hunters swear by these relationships. Trees commonly associated with morels include ash, sycamore, tuliptree, dead and dying elms, and old apple trees (remnants of orchards). Morels have not yet been successfully farmed on a large scale, and the commercial morel industry is largely based on harvest of wild mushrooms. Morels are a feature of many cuisines, including Provençal.[1] # Different types of morel mushrooms The best known morels are the Yellow Morel or Common Morel (Morchella esculenta); the White Morel (M. deliciosa); and the Black Morel (M. elata). Other common names for morels include Merkel, Sponge Mushroom, and Land Fish. When gathering morels, care must be taken to distinguish them from the poisonous false morel (Gyromitra esculenta and others). Other species of true morels include M. semilibera and M. vulgaris. Discriminating between the various species is complicated by uncertainty regarding which species are truly biologically distinct. Mushroom hunters refer to them by their color (e.g., gray, yellow, black) as the species are very similar in appearance and vary considerably within species and age of individual.	https://www.wikidoc.org/index.php/Morchella
02e88e234ffbf264aa3615c6fe5ec5eafafdf611	wikidoc	Morphogen	Morphogen A morphogen is a substance governing the pattern of tissue development and, in particular, the positions of the various specialized cell types within a tissue. It spreads from a localized source and forms a concentration gradient across a developing tissue. In developmental biology a morphogen is rigorously used to mean a signaling molecule that acts directly on cells (not through serial induction) to produce specific cellular responses dependent on morphogen concentration. Well-known morphogens include: Decapentaplegic / Transforming growth factor beta, Hedgehog / Sonic Hedgehog, Wingless / Wnt, Epidermal growth factor, and Fibroblast growth factor. Morphogens are defined conceptually, not chemically, so simple chemicals such as retinoic acid may also act as morphogens. # Introduction During early development, morphogen gradients generate different cell types in distinct spatial order. The morphogen provides spatial information by forming a concentration gradient that subdivides a field of cells by inducing or maintaining the expression of different target genes at distinct concentration thresholds. Thus, cells far from the source of the morphogen will receive low levels of morphogen and express only low-threshold target genes. In contrast, cells close to the source of morphogen will receive high levels of morphogen and will express both low- and high-threshold target genes. Distinct cell types emerge as a consequence of the different combinations of target gene expression. In this way, the field of cells is subdivided into different types according to their position relative to the source of the morphogen. This is a general mechanism by which cell type diversity can be generated in animal development. Some of the earliest and best-studied morphogens are transcription factors that diffuse within early Drosophila melanogaster (fruit fly) embryos. However, most morphogens are secreted proteins that signal between cells. # Fruit fly Drosophila melanogaster has an unusual developmental system, in which the first thirteen cell divisions of the embryo occur within a syncytium prior to cellularization. Essentially the embryo remains a single cell with over 8000 nuclei evenly spaced near the membrane until the fourteenth cell division, when independent membranes furrow between the nuclei, separating them into independent cells. As a result, in fly embryos transcription factors such as Bicoid or Hunchback can act as morphogens because they can freely diffuse between nuclei to produce smooth gradients of concentration without relying on specialized intercellular signalling mechanisms. Although there is some evidence that homeobox transcription factors similar to these can pass directly through cell membranes, this mechanism is not believed to contribute greatly to morphogenesis in cellularized systems. In most developmental systems, such as human embryos or later Drosophila development, syncytia occur only rarely (such as in skeletal muscle), and morphogens are generally secreted signalling proteins. These proteins bind to the extracellular domains of transmembrane receptor proteins, which use an elaborate process of signal transduction to communicate the level of morphogen to the nucleus. The nuclear targets of signal transduction pathways are usually transcription factors, whose activity is regulated in a manner that reflects the level of morphogen received at the cell surface. Thus, secreted morphogens act to generate gradients of transcription factor activity just like those that are generated in the syncitial Drosophila embryo. Discrete target genes respond to different thresholds of morphogen activity. The expression of target genes is controlled by segments of DNA called 'enhancers' to which transcription factors bind directly. Once bound, the transcription factor then stimulates or inhibits the transcription of the gene and thus controls the level of expression of the gene product (usually a protein). 'Low-threshold' target genes require only low levels of morphogen activity to be regulated and feature enhancers that contain many high-affinity binding sites for the transcription factor. 'High-threshold' target genes have relatively fewer binding sites or low-affinity binding sites that require much greater levels of transcription factor activity to be regulated. Thus, the general mechanism by which morphogens subdivide tissues into patterns of distinct cell types is well understood. However, morphogens often have additional activities such as controlling the growth of the tissue or orienting the polarity of cells within it (for example, the hairs on your forearm point in one direction). These activities of morphogens are much less understood and are the subject of current research efforts in the field of developmental biology. # Discovery The morphogen idea has a long history in developmental biology, dating back to the work of the pioneering Drosophila geneticist, Thomas Hunt Morgan, in the early 20th century. However, it was Lewis Wolpert who refined the morphogen concept in the 1960s with his famous French flag model which described how morphogen could subdivide a tissue into domains of different target gene expression (corresponding to the colours of the French flag). This model was championed by the leading Drosophila biologist, Peter Lawrence. Christiane Nusslein-Volhard identified the first morphogen, Bicoid, one of the transcription factors present in a gradient in the Drosophila syncitial embryo. Two labs, that of Gary Struhl and that of Stephen Cohen, then demonstrated that a secreted signalling protein, Decapentaplegic (the Drosophila homolgue of Transforming Growth Factor Beta), acted as a morphogen during later stages of Drosophila development. Subsequent studies of the development of many different animals has confirmed the widespread importance of morphogens in governing animal development.	Morphogen A morphogen is a substance governing the pattern of tissue development and, in particular, the positions of the various specialized cell types within a tissue. It spreads from a localized source and forms a concentration gradient across a developing tissue. In developmental biology a morphogen is rigorously used to mean a signaling molecule that acts directly on cells (not through serial induction) to produce specific cellular responses dependent on morphogen concentration. Well-known morphogens include: Decapentaplegic / Transforming growth factor beta, Hedgehog / Sonic Hedgehog, Wingless / Wnt, Epidermal growth factor, and Fibroblast growth factor. Morphogens are defined conceptually, not chemically, so simple chemicals such as retinoic acid may also act as morphogens. # Introduction During early development, morphogen gradients generate different cell types in distinct spatial order. The morphogen provides spatial information by forming a concentration gradient that subdivides a field of cells by inducing or maintaining the expression of different target genes at distinct concentration thresholds. Thus, cells far from the source of the morphogen will receive low levels of morphogen and express only low-threshold target genes. In contrast, cells close to the source of morphogen will receive high levels of morphogen and will express both low- and high-threshold target genes. Distinct cell types emerge as a consequence of the different combinations of target gene expression. In this way, the field of cells is subdivided into different types according to their position relative to the source of the morphogen. This is a general mechanism by which cell type diversity can be generated in animal development. Some of the earliest and best-studied morphogens are transcription factors that diffuse within early Drosophila melanogaster (fruit fly) embryos. However, most morphogens are secreted proteins that signal between cells. # Fruit fly Drosophila melanogaster has an unusual developmental system, in which the first thirteen cell divisions of the embryo occur within a syncytium prior to cellularization. Essentially the embryo remains a single cell with over 8000 nuclei evenly spaced near the membrane until the fourteenth cell division, when independent membranes furrow between the nuclei, separating them into independent cells. As a result, in fly embryos transcription factors such as Bicoid or Hunchback can act as morphogens because they can freely diffuse between nuclei to produce smooth gradients of concentration without relying on specialized intercellular signalling mechanisms. Although there is some evidence that homeobox transcription factors similar to these can pass directly through cell membranes, this mechanism is not believed to contribute greatly to morphogenesis in cellularized systems. In most developmental systems, such as human embryos or later Drosophila development, syncytia occur only rarely (such as in skeletal muscle), and morphogens are generally secreted signalling proteins. These proteins bind to the extracellular domains of transmembrane receptor proteins, which use an elaborate process of signal transduction to communicate the level of morphogen to the nucleus. The nuclear targets of signal transduction pathways are usually transcription factors, whose activity is regulated in a manner that reflects the level of morphogen received at the cell surface. Thus, secreted morphogens act to generate gradients of transcription factor activity just like those that are generated in the syncitial Drosophila embryo. Discrete target genes respond to different thresholds of morphogen activity. The expression of target genes is controlled by segments of DNA called 'enhancers' to which transcription factors bind directly. Once bound, the transcription factor then stimulates or inhibits the transcription of the gene and thus controls the level of expression of the gene product (usually a protein). 'Low-threshold' target genes require only low levels of morphogen activity to be regulated and feature enhancers that contain many high-affinity binding sites for the transcription factor. 'High-threshold' target genes have relatively fewer binding sites or low-affinity binding sites that require much greater levels of transcription factor activity to be regulated. Thus, the general mechanism by which morphogens subdivide tissues into patterns of distinct cell types is well understood. However, morphogens often have additional activities such as controlling the growth of the tissue or orienting the polarity of cells within it (for example, the hairs on your forearm point in one direction). These activities of morphogens are much less understood and are the subject of current research efforts in the field of developmental biology. # Discovery The morphogen idea has a long history in developmental biology, dating back to the work of the pioneering Drosophila geneticist, Thomas Hunt Morgan, in the early 20th century. However, it was Lewis Wolpert who refined the morphogen concept in the 1960s with his famous French flag model which described how morphogen could subdivide a tissue into domains of different target gene expression (corresponding to the colours of the French flag). This model was championed by the leading Drosophila biologist, Peter Lawrence. Christiane Nusslein-Volhard identified the first morphogen, Bicoid, one of the transcription factors present in a gradient in the Drosophila syncitial embryo. Two labs, that of Gary Struhl and that of Stephen Cohen, then demonstrated that a secreted signalling protein, Decapentaplegic (the Drosophila homolgue of Transforming Growth Factor Beta), acted as a morphogen during later stages of Drosophila development. Subsequent studies of the development of many different animals has confirmed the widespread importance of morphogens in governing animal development. # External links Excellent resources for further study of this topic include: - Interactive Fly - Flybase ## NCBI resources From the National Center for Biotechnology Information: - OMIM - PubMed de:Morphogen fi:Morfogeeni sv:morfogen Template:WH Template:WS	https://www.wikidoc.org/index.php/Morphogen
6a79574dc4332b3942f5d045a2179a51d7fb3f9d	wikidoc	Morrhuate	Morrhuate # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Morrhuate is a sclerosing agent that is FDA approved for the treatment of primary varicosed veins that consist of simple dilation with competent valves. Common adverse reactions include burning or cramping sensations and urticaria. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Morrhuate Sodium Injection is used for the obliteration of primary varicosed veins that consist of simple dilation with competent valves. - Sclerotherapy should not be used in patients with significant valvular or deep vein incompetence. - Although Morrhuate Sodium has been used as a sclerosing agent for the treatment of internal hemorrhoids, there is no substantial evidence that the drug is useful for this purpose. - Most patients with symptomatic primary varicosed veins should be treated initially with compression stockings. If this treatment is inadequate, surgery may be required. Sclerosing agents may be useful as a supplement to venous ligation to obliterate residual varicosed veins or in patients who have conditions which increase the risk of surgery. However, many clinicians consider if sclerotherapy is not effective it may decrease the potential success of later surgery, should this be required. - Morrhuate Sodium is administered only by INTRAVENOUS injection. Care must be taken to avoid extravasation. Specialized references should be consulted for specific procedures and techniques of administration. When small veins are injected, or the injection solution is cold, or if solid matter has separated in the solution, the vial should be warmed by immersing in hot water. The solution should become clear on warming. Only a clear solution should be used. Because the solution froths easily, a large bore needle should be used to fill the syringe. However, a small bore needle should be used for the injection. - To determine possible sensitivity to the drug, some clinicians recommend injection of 0.25 to 1 mL of 5% Morrhuate Sodium Injection into a varicosity 24 hours before administration of a large dose. - Dosage of Morrhuate Sodium depends on the size and degree of varicosity. The usual adult dose for obliteration of small or medium veins is 50 to 100 mg (1 to 2 mL of the 5% injection). For large veins, 150 to 250 mg (3 to 5 mL of the injection) is used. The drug may be given as multiple injections at one time or in single doses. Therapy may be repeated 5 to 7 day intervals, according to the patient's response. Following injection of Morrhuate Sodium, the vein promptly becomes hard and swollen for 2 to 4 inches, depending on the size and response of the vein. After 24 hours, the vein is hard and slightly tender to the touch (with little or no periphlebitis). The skin around the injection becomes light-bronze. This color usually disappears shortly. An aching sensation and feeling of stiffness usually occurs and lasts approximately 48 hours. - Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Morrhuate in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Morrhuate in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Morrhuate in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Morrhuate in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Morrhuate in pediatric patients. # Contraindications - Morrhuate Sodium is contraindicated in patients who have shown a previous hypersensitivity reaction to the drug or to the fatty acids of cod liver oil. Continued administration of the drug is contraindicated when an unusual local reaction at the injection site or a systemic reaction occurs. - Thrombosis induced by Morrhuate Sodium may extend into the deep venous system in patients with significant valvular incompetence, therefore, valvular competency, deep vein patency, and deep vein competency should be determined by angiography and/or by tests such as the Trendelenberg and Perthes before injection of sclerosing agents. The drug is contraindicated for obliterations of superficial veins in patients with persistent occlusion of the deep veins. Morrhuate Sodium is also contraindicated in patients with acute superficial thrombophlebitis; underlying arterial disease; varicosities caused by abdominal and pelvic tumors, uncontrolled diabetes mellitus, thyrotoxicosis, tuberculosis, neoplasms, asthma, sepsis, blood dyscrasias, acute respiratory or skin disease; and in bedridden patients. Treatment with Morrhuate Sodium should be delayed in patients with acute local or systemic infections (including infected ulcers). Extensive therapy with the drug is inadvisable in patients who are severely debilitated or senile. # Warnings - Burning or cramping sensations indicate local reactions. Urticaria may result. Sloughing and necrosis of tissue may occur with extravasation of the drug. Technique development is essential for optimal success in sclerotherapy, therefore the drug should be administered only by a physician familiar with proper injection technique. Drowsiness and headache may occur rarely. Pulmonary embolism has been reported. Rarely, patients may have, or may develop hypersensitivity to Morrhuate Sodium, characterized by dizziness, weakness, vascular collapse, asthma, respiratory depression, gastrointestinal disturbances (i.e., nausea, vomiting), and urticaria. Anaphylactic reactions may occur within a few minutes after injection of the drug and are most likely to occur when therapy is reinstituted after an interval of several weeks. Morrhuate Sodium should only be administered when adequate facilities, drugs (i.e., epinephrine, antihistamines, corticosteroids), and personnel are available for the treatment of anaphylactic reactions. # Adverse Reactions ## Clinical Trials Experience - Burning or cramping sensations indicate local reactions. Urticaria may result. Sloughing and necrosis of tissue may occur with extravasation of the drug. Technique development is essential for optimal success in sclerotherapy, therefore the drug should be administered only by a physician familiar with proper injection technique. Drowsiness and headache may occur rarely. Pulmonary embolism has been reported. - Rarely, patients may have, or may develop hypersensitivity to Morrhuate Sodium, characterized by dizziness, weakness, vascular collapse, asthma, respiratory depression, gastrointestinal disturbances (i.e., nausea, vomiting), and urticaria. Anaphylactic reactions may occur within a few minutes after injection of the drug and are most likely to occur when therapy is reinstituted after an interval of several weeks. Morrhuate Sodium should only be administered when adequate facilities, drugs (i.e., epinephrine, antihistamines, corticosteroids), and personnel are available for the treatment of anaphylactic reactions. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Morrhuate in the drug label. # Drug Interactions There is limited information regarding Morrhuate Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Animal reproduction studies have not been performed. It is not known whether Morrhuate Sodium Injection can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Use of Morrhuate Sodium in women of childbearing potential requires that anticipated benefits be weighed against the possible hazards. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Morrhuate in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Morrhuate during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Morrhuate with respect to nursing mothers. ### Pediatric Use There is no FDA guidance on the use of Morrhuate with respect to pediatric patients. ### Geriatic Use There is no FDA guidance on the use of Morrhuate with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Morrhuate with respect to specific gender populations. ### Race There is no FDA guidance on the use of Morrhuate with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Morrhuate in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Morrhuate in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Morrhuate in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Morrhuate in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring There is limited information regarding Monitoring of Morrhuate in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Morrhuate in the drug label. # Overdosage There is limited information regarding Chronic Overdose of Morrhuate in the drug label. # Pharmacology There is limited information regarding Morrhuate Pharmacology in the drug label. ## Mechanism of Action - Morrhuate Sodium, when injected into the vein, causes inflammation of the intima and formation of a thrombus. This blood clot occludes the injected vein and fibrous tissue develops, resulting in the obliteration of the vein. ## Structure - Morrhuate Sodium Injection, USP, is a mixture of the sodium salts of the saturated and unsaturated fatty acids of Cod Liver Oil. Morrhuate Sodium Injection, USP is prepared by the saponification of selected Cod Liver Oils. Morrhuate Sodium occurs as a pale-yellowish, granular powder with a slight fishy odor and is soluble in water and in alcohol. Each mL contains: Morrhuate Sodium 50 mg, Benzyl Alcohol 2% (as a local anesthetic), Water for Injection q.s. pH adjusted with Hydrochloric Acid and/or Sodium Hydroxide. - The pH of the injection is adjusted to approximately 9.5. NOTE: PRODUCT MAY SHOW A SEPARATION OF A SOLID MATTER ON STANDING. DO NOT USE IF SUCH SOLID DOES NOT DISSOLVE COMPLETELY UPON WARMING. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Morrhuate in the drug label. ## Pharmacokinetics There is limited information regarding Pharmacokinetics of Morrhuate in the drug label. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Morrhuate in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of Morrhuate in the drug label. # How Supplied - Morrhuate Sodium Injection, USP 50 mg/mL - NDC 0517-3065-01 30 mL Multiple Dose Vial Individually Packaged - Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) (See USP Controlled Room Temperature). ## Storage There is limited information regarding Morrhuate Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Morrhuate in the drug label. # Precautions with Alcohol - Alcohol-Morrhuate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names There is limited information regarding Morrhuate Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Morrhuate Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Morrhuate Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, M.B.B.S. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Morrhuate is a sclerosing agent that is FDA approved for the treatment of primary varicosed veins that consist of simple dilation with competent valves. Common adverse reactions include burning or cramping sensations and urticaria. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Morrhuate Sodium Injection is used for the obliteration of primary varicosed veins that consist of simple dilation with competent valves. - Sclerotherapy should not be used in patients with significant valvular or deep vein incompetence. - Although Morrhuate Sodium has been used as a sclerosing agent for the treatment of internal hemorrhoids, there is no substantial evidence that the drug is useful for this purpose. - Most patients with symptomatic primary varicosed veins should be treated initially with compression stockings. If this treatment is inadequate, surgery may be required. Sclerosing agents may be useful as a supplement to venous ligation to obliterate residual varicosed veins or in patients who have conditions which increase the risk of surgery. However, many clinicians consider if sclerotherapy is not effective it may decrease the potential success of later surgery, should this be required. - Morrhuate Sodium is administered only by INTRAVENOUS injection. Care must be taken to avoid extravasation. Specialized references should be consulted for specific procedures and techniques of administration. When small veins are injected, or the injection solution is cold, or if solid matter has separated in the solution, the vial should be warmed by immersing in hot water. The solution should become clear on warming. Only a clear solution should be used. Because the solution froths easily, a large bore needle should be used to fill the syringe. However, a small bore needle should be used for the injection. - To determine possible sensitivity to the drug, some clinicians recommend injection of 0.25 to 1 mL of 5% Morrhuate Sodium Injection into a varicosity 24 hours before administration of a large dose. - Dosage of Morrhuate Sodium depends on the size and degree of varicosity. The usual adult dose for obliteration of small or medium veins is 50 to 100 mg (1 to 2 mL of the 5% injection). For large veins, 150 to 250 mg (3 to 5 mL of the injection) is used. The drug may be given as multiple injections at one time or in single doses. Therapy may be repeated 5 to 7 day intervals, according to the patient's response. Following injection of Morrhuate Sodium, the vein promptly becomes hard and swollen for 2 to 4 inches, depending on the size and response of the vein. After 24 hours, the vein is hard and slightly tender to the touch (with little or no periphlebitis). The skin around the injection becomes light-bronze. This color usually disappears shortly. An aching sensation and feeling of stiffness usually occurs and lasts approximately 48 hours. - Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Morrhuate in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Morrhuate in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Morrhuate in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Morrhuate in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Morrhuate in pediatric patients. # Contraindications - Morrhuate Sodium is contraindicated in patients who have shown a previous hypersensitivity reaction to the drug or to the fatty acids of cod liver oil. Continued administration of the drug is contraindicated when an unusual local reaction at the injection site or a systemic reaction occurs. - Thrombosis induced by Morrhuate Sodium may extend into the deep venous system in patients with significant valvular incompetence, therefore, valvular competency, deep vein patency, and deep vein competency should be determined by angiography and/or by tests such as the Trendelenberg and Perthes before injection of sclerosing agents. The drug is contraindicated for obliterations of superficial veins in patients with persistent occlusion of the deep veins. Morrhuate Sodium is also contraindicated in patients with acute superficial thrombophlebitis; underlying arterial disease; varicosities caused by abdominal and pelvic tumors, uncontrolled diabetes mellitus, thyrotoxicosis, tuberculosis, neoplasms, asthma, sepsis, blood dyscrasias, acute respiratory or skin disease; and in bedridden patients. Treatment with Morrhuate Sodium should be delayed in patients with acute local or systemic infections (including infected ulcers). Extensive therapy with the drug is inadvisable in patients who are severely debilitated or senile. # Warnings - Burning or cramping sensations indicate local reactions. Urticaria may result. Sloughing and necrosis of tissue may occur with extravasation of the drug. Technique development is essential for optimal success in sclerotherapy, therefore the drug should be administered only by a physician familiar with proper injection technique. Drowsiness and headache may occur rarely. Pulmonary embolism has been reported. Rarely, patients may have, or may develop hypersensitivity to Morrhuate Sodium, characterized by dizziness, weakness, vascular collapse, asthma, respiratory depression, gastrointestinal disturbances (i.e., nausea, vomiting), and urticaria. Anaphylactic reactions may occur within a few minutes after injection of the drug and are most likely to occur when therapy is reinstituted after an interval of several weeks. Morrhuate Sodium should only be administered when adequate facilities, drugs (i.e., epinephrine, antihistamines, corticosteroids), and personnel are available for the treatment of anaphylactic reactions. # Adverse Reactions ## Clinical Trials Experience - Burning or cramping sensations indicate local reactions. Urticaria may result. Sloughing and necrosis of tissue may occur with extravasation of the drug. Technique development is essential for optimal success in sclerotherapy, therefore the drug should be administered only by a physician familiar with proper injection technique. Drowsiness and headache may occur rarely. Pulmonary embolism has been reported. - Rarely, patients may have, or may develop hypersensitivity to Morrhuate Sodium, characterized by dizziness, weakness, vascular collapse, asthma, respiratory depression, gastrointestinal disturbances (i.e., nausea, vomiting), and urticaria. Anaphylactic reactions may occur within a few minutes after injection of the drug and are most likely to occur when therapy is reinstituted after an interval of several weeks. Morrhuate Sodium should only be administered when adequate facilities, drugs (i.e., epinephrine, antihistamines, corticosteroids), and personnel are available for the treatment of anaphylactic reactions. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Morrhuate in the drug label. # Drug Interactions There is limited information regarding Morrhuate Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Animal reproduction studies have not been performed. It is not known whether Morrhuate Sodium Injection can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Use of Morrhuate Sodium in women of childbearing potential requires that anticipated benefits be weighed against the possible hazards. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Morrhuate in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Morrhuate during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Morrhuate with respect to nursing mothers. ### Pediatric Use There is no FDA guidance on the use of Morrhuate with respect to pediatric patients. ### Geriatic Use There is no FDA guidance on the use of Morrhuate with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Morrhuate with respect to specific gender populations. ### Race There is no FDA guidance on the use of Morrhuate with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Morrhuate in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Morrhuate in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Morrhuate in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Morrhuate in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring There is limited information regarding Monitoring of Morrhuate in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Morrhuate in the drug label. # Overdosage There is limited information regarding Chronic Overdose of Morrhuate in the drug label. # Pharmacology There is limited information regarding Morrhuate Pharmacology in the drug label. ## Mechanism of Action - Morrhuate Sodium, when injected into the vein, causes inflammation of the intima and formation of a thrombus. This blood clot occludes the injected vein and fibrous tissue develops, resulting in the obliteration of the vein. ## Structure - Morrhuate Sodium Injection, USP, is a mixture of the sodium salts of the saturated and unsaturated fatty acids of Cod Liver Oil. Morrhuate Sodium Injection, USP is prepared by the saponification of selected Cod Liver Oils. Morrhuate Sodium occurs as a pale-yellowish, granular powder with a slight fishy odor and is soluble in water and in alcohol. Each mL contains: Morrhuate Sodium 50 mg, Benzyl Alcohol 2% (as a local anesthetic), Water for Injection q.s. pH adjusted with Hydrochloric Acid and/or Sodium Hydroxide. - The pH of the injection is adjusted to approximately 9.5. NOTE: PRODUCT MAY SHOW A SEPARATION OF A SOLID MATTER ON STANDING. DO NOT USE IF SUCH SOLID DOES NOT DISSOLVE COMPLETELY UPON WARMING. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Morrhuate in the drug label. ## Pharmacokinetics There is limited information regarding Pharmacokinetics of Morrhuate in the drug label. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Morrhuate in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of Morrhuate in the drug label. # How Supplied - Morrhuate Sodium Injection, USP 50 mg/mL - NDC 0517-3065-01 30 mL Multiple Dose Vial Individually Packaged - Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) (See USP Controlled Room Temperature). ## Storage There is limited information regarding Morrhuate Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Morrhuate in the drug label. # Precautions with Alcohol - Alcohol-Morrhuate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names There is limited information regarding Morrhuate Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Morrhuate Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Morrhuate
51ad3c4e804bf063bbec0e68b6b5815ca3728315	wikidoc	Mouthwash	Mouthwash Mouthwash or mouth rinse is a product used for oral hygiene. Antiseptic and anti-plaque mouth rinse claims to kill the bacterial plaque causes caries, gingivitis, and bad breath. Anti-cavity mouth rinse uses fluoride to protect against tooth decay. However, it is generally agreed that the use of mouthwash does not eliminate the need for both brushing and flossing. In the absence of a ready-made mouthwash, gargling with plain water is preferable, to remove food particles, sugars and other pollutants in the mouth. Mouth washes may also be used to help remove mucous and food particles deeper down in the throat. Alcoholic and strong flavored mouth washes may cause coughing for this purpose. # History The first known reference to mouth rinsing is in the Chinese medicine, about 2700 BCE, for treatment of gingivitis. Later, in the Greek and Roman periods, mouthrinsing following mechanical cleansing became common among the upper classes, and Hippocrates recommended a mixture of salt, alum and vinegar. The Jewish Talmud, dating back about 1800 years, suggests a cure for gum ailments containing "dough water" and olive oil. Anton van Leeuwenhoek, the famous 17th century microscopist, discovered living organisms (living, because they were motile) in deposits on the teeth (what we now call dental plaque). He also found organisms in water from the canal next to his home in Delft. He experimented with samples by adding vinegar or brandy and found that this resulted in the immediate immobilization or killing of the organisms suspended in water. Next he tried rinsing the mouth of himself and somebody else with a rather foul mouthwash containing vinegar or brandy and found that living organisms remained in the dental plaque. He concluded — correctly — that the mouthwash either did not reach, or was not present long enough, to kill the plaque organisms. That remained the state of affairs until the late 1960s when Harald Loe (at the time a professor at the Royal Dental College in Aarhus, Denmark) demonstrated that a chlorhexidine compound could prevent the build-up of dental plaque. The reason for chlorhexidine effectiveness is that it strongly adheres to surfaces in the mouth and thus remains present in effective concentrations for many hours. Since then commercial interest in mouthwashes has been intense and several newer products claim effectiveness in reducing the build-up in dental plaque and the associated severity of gingivitis (inflammation of the gums), in addition to fighting bad breath. Many of these solutions aim to control the Volatile Sulfur Compound (VSC)-creating anaerobic bacteria that live in the mouth and excrete substances that lead to bad breath and unpleasant mouth taste. # Usage Common use involves rinsing the mouth with about 20ml (2/3 fl oz) of mouthwash two times a day after brushing. The wash is typically swished or gargled for about half a minute and then spat out. In some brands, the expectorate is stained, so that one can see the bacteria and debris. However it is probably advisable to use mouthwash at least an hour after brushing with toothpaste, since the anionic compounds in the toothpaste can inactivate cationic agents present in the mouthrinse. Probably the most effective time to rinse and gargle with a mouthrinse is at bed time. # Composition Active ingredients in commercial brands of mouthwash can include thymol, eucalyptol, hexetidine, methyl salicylate, menthol, chlorhexidine gluconate, benzalkonium chloride, cetylpyridinium chloride, methylparaben, hydrogen peroxide, domiphen bromide and sometimes fluoride, enzymes and calcium. Ingredients also include water, sweeteners such as sorbitol, Sucralose, sodium saccharine, and xylitol (which doubles as a bacterial inhibitor). Sometimes a significant amount of alcohol (up to around 20%) is added, as a carrier for the flavor, to provide "bite" and to contribute an antibacterial effect. Because of the alcohol content, it is possible to fail a breathalyzer test after rinsing; in addition, alcohol is a drying agent and may worsen chronic bad breath. As such, it is possible for alcoholics to abuse mouthwash. Recently, some assumptions were made of a possible carcinogenic character of alcohol used in mouthrinses, but no clear evidence was found. Commercial mouthwashes usually contain a preservative such as sodium benzoate to preserve freshness once the container has been opened. Many newer brands are alcohol-free and contain odor-elimination agents such as oxidizers, as well as odor-preventing agents such as zinc ion technology to keep future bad breath from developing. A salt mouthwash is a home treatment for mouth infections and/or injuries, or post extraction, and is made by dissolving a teaspoon of salt in a cup of warm water. Plain (diluted) hydrogen peroxide is another common mouthwash. One thing to note is that many commercial mouthwashes are very acidic on the pH scale. If you have heartburn, acid reflux or acid indigestion, it is important to use a mouthwash with a neutral pH to avoid irritation..	Mouthwash Mouthwash or mouth rinse is a product used for oral hygiene. Antiseptic and anti-plaque mouth rinse claims to kill the bacterial plaque causes caries, gingivitis, and bad breath. Anti-cavity mouth rinse uses fluoride to protect against tooth decay. However, it is generally agreed that the use of mouthwash does not eliminate the need for both brushing and flossing[1][2]. In the absence of a ready-made mouthwash, gargling with plain water is preferable, to remove food particles, sugars and other pollutants in the mouth[citation needed]. Mouth washes may also be used to help remove mucous and food particles deeper down in the throat. Alcoholic and strong flavored mouth washes may cause coughing for this purpose. # History The first known reference to mouth rinsing is in the Chinese medicine, about 2700 BCE, for treatment of gingivitis. Later, in the Greek and Roman periods, mouthrinsing following mechanical cleansing became common among the upper classes, and Hippocrates recommended a mixture of salt, alum and vinegar[3]. The Jewish Talmud, dating back about 1800 years, suggests a cure for gum ailments containing "dough water" and olive oil[4]. Anton van Leeuwenhoek, the famous 17th century microscopist, discovered living organisms (living, because they were motile) in deposits on the teeth (what we now call dental plaque). He also found organisms in water from the canal next to his home in Delft. He experimented with samples by adding vinegar or brandy and found that this resulted in the immediate immobilization or killing of the organisms suspended in water. Next he tried rinsing the mouth of himself and somebody else with a rather foul mouthwash containing vinegar or brandy and found that living organisms remained in the dental plaque. He concluded — correctly — that the mouthwash either did not reach, or was not present long enough, to kill the plaque organisms.[citation needed] That remained the state of affairs until the late 1960s when Harald Loe (at the time a professor at the Royal Dental College in Aarhus, Denmark) demonstrated that a chlorhexidine compound could prevent the build-up of dental plaque. The reason for chlorhexidine effectiveness is that it strongly adheres to surfaces in the mouth and thus remains present in effective concentrations for many hours[5]. Since then commercial interest in mouthwashes has been intense and several newer products claim effectiveness in reducing the build-up in dental plaque and the associated severity of gingivitis (inflammation of the gums), in addition to fighting bad breath. Many of these solutions aim to control the Volatile Sulfur Compound (VSC)-creating anaerobic bacteria that live in the mouth and excrete substances that lead to bad breath and unpleasant mouth taste[6][7]. # Usage Common use involves rinsing the mouth with about 20ml (2/3 fl oz) of mouthwash two times a day after brushing. The wash is typically swished or gargled for about half a minute and then spat out. In some brands, the expectorate is stained, so that one can see the bacteria and debris[8][9]. However it is probably advisable to use mouthwash at least an hour after brushing with toothpaste, since the anionic compounds in the toothpaste can inactivate cationic agents present in the mouthrinse. Probably the most effective time to rinse and gargle with a mouthrinse is at bed time[10]. # Composition Active ingredients in commercial brands of mouthwash can include thymol, eucalyptol[11], hexetidine, methyl salicylate, menthol, chlorhexidine gluconate[12][9], benzalkonium chloride, cetylpyridinium chloride[13], methylparaben, hydrogen peroxide, domiphen bromide and sometimes fluoride[14], enzymes and calcium. Ingredients also include water, sweeteners such as sorbitol, Sucralose, sodium saccharine, and xylitol (which doubles as a bacterial inhibitor)[15]. Sometimes a significant amount of alcohol (up to around 20%) is added, as a carrier for the flavor, to provide "bite" and to contribute an antibacterial effect. Because of the alcohol content, it is possible to fail a breathalyzer test after rinsing; in addition, alcohol is a drying agent and may worsen chronic bad breath. As such, it is possible for alcoholics to abuse mouthwash[16]. Recently, some assumptions were made of a possible carcinogenic character of alcohol used in mouthrinses, but no clear evidence was found[17][18]. Commercial mouthwashes usually contain a preservative such as sodium benzoate to preserve freshness once the container has been opened. Many newer brands are alcohol-free and contain odor-elimination agents such as oxidizers, as well as odor-preventing agents such as zinc ion technology to keep future bad breath from developing[citation needed]. A salt mouthwash is a home treatment for mouth infections and/or injuries, or post extraction, and is made by dissolving a teaspoon of salt in a cup of warm water. Plain (diluted) hydrogen peroxide is another common mouthwash[19]. One thing to note is that many commercial mouthwashes are very acidic on the pH scale. If you have heartburn, acid reflux or acid indigestion, it is important to use a mouthwash with a neutral pH to avoid irritation.[20].	https://www.wikidoc.org/index.php/Mouthwash
7f03865b2c3ed8d50843e015ee254425dd0dde29	wikidoc	Mucositis	Mucositis # Overview Mucositis is the painful inflammation and ulceration of the mucous membranes lining the digestive tract, usually as an adverse effect of chemotherapy and radiotherapy treatment for cancer. Oral and gastrointestinal (GI) mucositis can affect up to 100% of patients undergoing high-dose chemotherapy and hematopoietic stem cell transplantation, 80% of patients with malignancies of the head and neck receiving radiotherapy, and a wide range of patients receiving chemotherapy. Alimentary track mucositis increases mortality and morbidity and contributes to rising health care costs. For most cancer treatment, about 5-15% of patients get mucositis. However, with 5-flurouracil (5-FU), up to 40% get mucocitis, and 10-15% get grade 3-4 oral mucositis. Iirinotecan is associated with severe GI mucositis in over 20% of patients. 75-85% of bone marrow transplantation recipients experience mucositis, of which oral mucositis is the most common and most debilitating, especially when melphalan is used. In grade 3 oral mucositis, the patient is unable to eat solid food, and in grade 4, the patient is unable to consume liquids as well. Radiotherapy to the head and neck or to the pelvis or abdomen is associated with Grade 3 and Grade 4 oral or GI mucositis, respectively, often exceeding 50% of patients. Among patients undergoing head and neck radiotherapy, pain and decreased oral function may persist long after the conclusion of therapy. Fractionated radiation dosage increases the risk of mucositis to > 70% of patients in most trials. Oral mucositis is particularly profound and prolonged among HSCT recipients who receive total-body irradiation. # Causes ## Common Causes - Doxorubicin Hydrochloride - Epirubicin hydrochloride - Irinotecan hydrochloride - Ixabepilone - Pralatrexate - Sunitinib - Teniposide ## Causes by Organ System ## Causes in Alphabetical Order - Adriamycin pfs - Adriamycin rdf - Cosmegen - Cyclophosphamide - Cytarabine hydrochloride - Cytosar-u - Cytoxan - Dactinomycin - Doxil injection - Doxolem - Doxorubicin hydrochloride - Epirubicin hydrochloride - Erlotinib - Gemtuzumab ozogamicin - Hematopoietic stem cell transplantation - Irinotecan hydrochloride - Ixabepilone - Neosar - Olaratumab - Pemetrexed - Pralatrexate - Raltitrexed - Rasburicase - Regorafenib - Rubex - Sorafenib - Stomatitis - Sunitinib - Teniposide # Pathophysiology The pathophysiology of mucositis can be divided into its 5 stages; including an initiation phase, a message generation phase, a signaling and amplification phase, an ulceration phase, and a healing phase. Different cytokines are responsible for the various stages. The initiation phase is caused by the production of free radicals caused by the chemo- or radio- therapy, which damages cell DNA. This causes the production of cell transcription factors such as NFkB, which upregulates inflammatory cytokines, marking the beginning of the ulceration phase. Main inflammatory cytokines involved are IL-1 and TNF-alpha. During the healing phase, epithelial cells are attracted to the site of the ulcer and begin the re-epithelialization of the ulcers. # Clinical manifestations Cancer patients undergoing chemotherapy usually become symptomatic four to five days after beginning treatment, reaching a peak at around day 10, and then slowly improving over the course of a few weeks. Mucositis associated with radiotherapy usually appears at the end of the second week of treatment and may last for six to eight weeks. As a result of cell death in reaction to chemo- or radio-therapy, the mucosal lining of the mouth becomes thin, may slough off and then become red, inflamed and ulcerated. The ulcers may become covered by a yellowish white fibrin clot called a pseudomembrane. Peripheral erythema is usually present. Ulcers may range from 0.5 cm to greater than 4 cm. Oral mucositis can be severely painful. The degree of pain is usually related to the extent of the tissue damage. Pain is often described as a burning sensation accompanied by reddening. Due to pain, the patient may experience trouble speaking, eating, or even opening the mouth. Dysgeusia, or an alteration in taste perception, is common, especially for those who are receiving concomitant radiation therapy to the neck and mouth area. "Taste blindness," or an altered sense of taste, is a temporary condition that occurs because of effects on taste buds that are mostly located in the tongue. Sometimes, only partial recovery of taste occurs. Common complaints are of food tasting too sweet or too bitter or of a continuous metallic taste. # Diagnosis Diagnosis is based on the symptoms the patient is experiencing and the appearance of the tissues of the mouth following chemotherapy, bone marrow transplant or radiotherapy. Red burn-like sores or ulcers throughout the mouth is enough to diagnose mucositis. # Treatment Treatment of mucositis is mainly supportive. Oral hygiene is the mainstay of treatment; patients are encouraged to clean their mouth every four hours and at bedtime, more often if the mucositis becomes worse. Water-soluble jellies can be used to lubricate the mouth. Salt mouthwash can soothe the pain and keep food particles clear so as to avoid infection. Patients are also encouraged to drink plenty of liquids, at least three liters a day, and avoid alcohol. Citrus fruits, alcohol, and foods that are hot are all known to aggravate mucositis lesions. Medicinal mouthwashes may be used such as Chlorhexidine gluconate and viscous Lidocain for relief of pain. Palifermin, brand name "Kepivance", is a human KGF (keratinocyte growth factor) that has shown to enhance epithelial cell proliferation, differentiation, and migration. Experimental therapies have been reported, including the use of cytokines and other modifiers of inflammation (eg, IL-1, IL-11, TGF-beta3), amino acid supplementation (eg, glutamine), vitamins, colony-stimulating factors, cryotherapy, and laser therapy. # Complications Sores or ulcerations can become infected by virus, bacteria or fungus. Pain and loss of taste perception makes it more difficult to eat, which leads to weight loss. Ulcers may act as a site for local infection and a portal of entry for oral flora that, in some instances, may cause septicemia (especially in immunosuppressed patients). Approximately half of all patients who receive chemotherapy develop such severe OM that it becomes dose-limiting such that the patient's cancer treatment must be modified, compromising the prognosis.	Mucositis Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Template:Search infobox Mucositis is the painful inflammation and ulceration of the mucous membranes lining the digestive tract, usually as an adverse effect of chemotherapy and radiotherapy treatment for cancer. Oral and gastrointestinal (GI) mucositis can affect up to 100% of patients undergoing high-dose chemotherapy and hematopoietic stem cell transplantation, 80% of patients with malignancies of the head and neck receiving radiotherapy, and a wide range of patients receiving chemotherapy. Alimentary track mucositis increases mortality and morbidity and contributes to rising health care costs.[1] For most cancer treatment, about 5-15% of patients get mucositis. However, with 5-flurouracil (5-FU), up to 40% get mucocitis, and 10-15% get grade 3-4 oral mucositis. Iirinotecan is associated with severe GI mucositis in over 20% of patients. 75-85% of bone marrow transplantation recipients experience mucositis, of which oral mucositis is the most common and most debilitating, especially when melphalan is used. In grade 3 oral mucositis, the patient is unable to eat solid food, and in grade 4, the patient is unable to consume liquids as well.[2] Radiotherapy to the head and neck or to the pelvis or abdomen is associated with Grade 3 and Grade 4 oral or GI mucositis, respectively, often exceeding 50% of patients. Among patients undergoing head and neck radiotherapy, pain and decreased oral function may persist long after the conclusion of therapy. Fractionated radiation dosage increases the risk of mucositis to > 70% of patients in most trials. Oral mucositis is particularly profound and prolonged among HSCT recipients who receive total-body irradiation.[3] # Causes ## Common Causes - Doxorubicin Hydrochloride - Epirubicin hydrochloride - Irinotecan hydrochloride - Ixabepilone - Pralatrexate - Sunitinib - Teniposide ## Causes by Organ System ## Causes in Alphabetical Order - Adriamycin pfs - Adriamycin rdf - Cosmegen - Cyclophosphamide - Cytarabine hydrochloride - Cytosar-u - Cytoxan - Dactinomycin - Doxil injection - Doxolem - Doxorubicin hydrochloride - Epirubicin hydrochloride - Erlotinib - Gemtuzumab ozogamicin - Hematopoietic stem cell transplantation - Irinotecan hydrochloride - Ixabepilone - Neosar - Olaratumab - Pemetrexed - Pralatrexate - Raltitrexed - Rasburicase - Regorafenib - Rubex - Sorafenib - Stomatitis - Sunitinib - Teniposide # Pathophysiology The pathophysiology of mucositis can be divided into its 5 stages; including an initiation phase, a message generation phase, a signaling and amplification phase, an ulceration phase, and a healing phase. Different cytokines are responsible for the various stages. The initiation phase is caused by the production of free radicals caused by the chemo- or radio- therapy, which damages cell DNA. This causes the production of cell transcription factors such as NFkB, which upregulates inflammatory cytokines, marking the beginning of the ulceration phase. Main inflammatory cytokines involved are IL-1 and TNF-alpha. During the healing phase, epithelial cells are attracted to the site of the ulcer and begin the re-epithelialization of the ulcers. # Clinical manifestations Cancer patients undergoing chemotherapy usually become symptomatic four to five days after beginning treatment, reaching a peak at around day 10, and then slowly improving over the course of a few weeks. Mucositis associated with radiotherapy usually appears at the end of the second week of treatment and may last for six to eight weeks. As a result of cell death in reaction to chemo- or radio-therapy, the mucosal lining of the mouth becomes thin, may slough off and then become red, inflamed and ulcerated. The ulcers may become covered by a yellowish white fibrin clot called a pseudomembrane. Peripheral erythema is usually present. Ulcers may range from 0.5 cm to greater than 4 cm. Oral mucositis can be severely painful. The degree of pain is usually related to the extent of the tissue damage. Pain is often described as a burning sensation accompanied by reddening. Due to pain, the patient may experience trouble speaking, eating, or even opening the mouth. Dysgeusia, or an alteration in taste perception, is common, especially for those who are receiving concomitant radiation therapy to the neck and mouth area. "Taste blindness," or an altered sense of taste, is a temporary condition that occurs because of effects on taste buds that are mostly located in the tongue. Sometimes, only partial recovery of taste occurs. Common complaints are of food tasting too sweet or too bitter or of a continuous metallic taste. # Diagnosis Diagnosis is based on the symptoms the patient is experiencing and the appearance of the tissues of the mouth following chemotherapy, bone marrow transplant or radiotherapy. Red burn-like sores or ulcers throughout the mouth is enough to diagnose mucositis. # Treatment Treatment of mucositis is mainly supportive. Oral hygiene is the mainstay of treatment; patients are encouraged to clean their mouth every four hours and at bedtime, more often if the mucositis becomes worse. Water-soluble jellies can be used to lubricate the mouth. Salt mouthwash can soothe the pain and keep food particles clear so as to avoid infection. Patients are also encouraged to drink plenty of liquids, at least three liters a day, and avoid alcohol. Citrus fruits, alcohol, and foods that are hot are all known to aggravate mucositis lesions. Medicinal mouthwashes may be used such as Chlorhexidine gluconate and viscous Lidocain for relief of pain. Palifermin, brand name "Kepivance", is a human KGF (keratinocyte growth factor) that has shown to enhance epithelial cell proliferation, differentiation, and migration. Experimental therapies have been reported, including the use of cytokines and other modifiers of inflammation (eg, IL-1, IL-11, TGF-beta3), amino acid supplementation (eg, glutamine), vitamins, colony-stimulating factors, cryotherapy, and laser therapy. # Complications Sores or ulcerations can become infected by virus, bacteria or fungus. Pain and loss of taste perception makes it more difficult to eat, which leads to weight loss. Ulcers may act as a site for local infection and a portal of entry for oral flora that, in some instances, may cause septicemia (especially in immunosuppressed patients). Approximately half of all patients who receive chemotherapy develop such severe OM that it becomes dose-limiting such that the patient's cancer treatment must be modified, compromising the prognosis.	https://www.wikidoc.org/index.php/Mucositis
0423a56cd74a7d6bf66cb5c7d3fbc483ee63fe64	wikidoc	Symbiosis	Symbiosis # Overview The term symbiosis (from the Greek: συμ, sym, "with"; and βίοσίς, biosis, "living") commonly describes close and often long-term interactions between different biological species. The term was first used in 1879 by the German mycologist, Heinrich Anton de Bary, who defined it as: "the living together of unlike organisms". The definition of symbiosis is in flux and the term has been applied to a wide range of biological interactions. The symbiotic relationship may be categorized as being mutualistic, parasitic, or commensal in nature . Others define it more narrowly, as only those relationships from which both organisms benefit, in which case it would be synonymous with mutualism. Symbiotic relationships included those associations in which one organisms lives on another (ectosymbiosis, such as mistletoe), or where one partner lives inside another (endosymbiosis, such as lactobacilli and other bacteria in humans or zooxanthelles in corals). Symbiotic relationships may be either obligate, i.e., necessary to the survival of at least one of the organisms involved, or facultative, where the relationship is beneficial but not essential to survival of the organisms. # Physical interaction Endosymbiosis is any symbiotic relationship in which the symbiote lives within the tissues of the host; either in the intracellular space or extracellularly. Examples are nitrogen-fixing bacteria (called rhizobia) which live in root nodules on legume roots, Actinomycete nitrogen-bacteria called Frankia which live in Alder tree root nodules, single-celled algae inside reef-building corals, and bacterial endosymbionts that provide essential nutrients to about 10%–15% of insects. Ectosymbiosis, also referred to as exosymbiosis, is any symbiotic relationship in which the symbiont lives on the body surface of the host, including the inner surface of the digestive tract or the ducts of exocrine glands. Examples of this include ectoparasites such as lice, commensal ectosymbionts, such as the barnacles that attach themselves to the jaw of baleen whales, and mutualist ectosymbionts such as cleaner fish. # Mutualism The term Mutualism describes any relationship between individuals of different species where both individuals derive a fitness benefit. Generally only lifelong interactions involving close physical and biochemical contact, can properly be considered symbiotic. Mutualistic relationships, may be either obligate for both species, obligate for one but facultative for the other, or facultative for both. Many biologists restrict the definition of symbiosis to close mutualist relationships. A large percentage of herbivores have mutualistic gut fauna that help them digest plant matter, which is more difficult to digest than animal prey. Coral reefs are the result of mutualisms between coral organisms and various types of algae that live inside them. Most land plants and land ecosystems rely on mutualisms between the plants which fix carbon from the air, and Mycorrhyzal fungi which help in extracting minerals from the ground. Another example is the goby fish, which sometimes lives together with a shrimp. The shrimp digs and cleans up a burrow in the sand in which both the shrimp and the goby fish live. The shrimp is almost blind leaving it vulnerable to predators when above ground. In case of danger the goby fish touches the shrimp with its tail to warn it. When that happens both the shrimp and goby fish quickly retract into the burrow. One of the most spectacular examples of obligate mutualism is between the siboglinid tube worms and symbiotic bacteria that live at hydrothermal vents and cold seeps. The worm has no digestive tract and is solely reliant on their internal symbionts for nutrition. The bacteria oxidize either hydrogen sulfide or methane which the host supplies to them. These worms were discovered in the late 1980s at the hydrothermal vents near the Galapagos Islands and have since been found at deep-sea hydrothermal vents and cold seeps in all of the world's oceans. # Commensalism Commensalism describes a relationship between two living organisms where one benefits and the other is not significantly harmed or helped. It is derived from the English word commensal, meaning the sharing of food, and used of human social interaction. The word derives from the Latin com mensa, meaning sharing a table. Commensal relationships may involve an organism using another for transportation (phoresy), for housing (inquilinism), or it may also involve an organism using something another created, after the death of the first (metabiosis). An example is the hermit crabs that use gastropod shells to protect their bodies. Further examples include spiders building their webs on trees. # Parasitism A parasitic relationship is one in which one member of the association benefits while the other is harmed. Parasitic symbioses take many forms, from endoparasites that live within the host's body, to ectoparasites that live on its surface. In addition, parasites may be necrotrophic, which is to say they kill their host, or biotrophic, meaning they rely on their host surviving. Biotrophic parasitism is an extremely successful mode of life. Depending on the definition used, as many as half of all animals have at least one parasitic phase in their life cycles, and it is also frequent in plants and fungi. Moreover, almost all free-living animals are host to one or more parasite taxa. # Symbiosis and evolution While historically, symbiosis has received less attention than other interactions such as predation or competition, it is increasingly recognised as an important selective force behind evolution, with many species having a long history of interdependent co-evolution. In fact the evolution of all eukaryotes (plants, animals, fungi, protists) is believed to have resulted from a symbiosis between various sorts of bacteria. ## Symbiogenesis The biologist Lynn Margulis, famous for the work on endosymbiosis, contends that symbiosis is a major driving force behind evolution. She considers Darwin's notion of evolution, driven by competition, as incomplete, and claims evolution is strongly based on co-operation, interaction, and mutual dependence among organisms. According to Margulis and Dorion Sagan, "Life did not take over the globe by combat, but by networking." ## Co-evolution Symbiosis played a major role in the co-evolution of flowering plants and the animals that pollinate them. Many plants that are pollinated by insects, bats or birds, have very specialized flowers modified to promote pollination by a specific pollinator that is also correspondingly adapted. The first flowering plants in the fossil record had relatively simple flowers. Adaptive speciation quickly gave rise to many diverse groups of plants, and at the same time, corresponding speciation occurred in certain insects groups. Some groups of plants developed nectar and large sticky pollen while insects evolved more specialized morphologies to access and collect these rich food sources. In some taxa of plants and insects the relationship has become dependent, where the plant species can only be pollinated by one species of insect. ## Objections Creationists have long claimed that obligate symbioses are evidence against evolution, arguing that since neither organism can survive without the other, they must have come into existence at exactly the same time. This point of view is countered in scientific claims by the extreme variety of symbiotic relationships as well the mutability of species over time: obligate mutualisms could have evolved from facultative relationships in which neither species is fully committed. Many examples of facultative symbioses and multiple theoretical and computational models describing how such a relationship would evolve do in fact exist. # Notes - ↑ Lee 2003 - ↑ Wilkinson 2001 - ↑ Douglas 1994, p. 1 - ↑ Dethlefsen L, McFall-Ngai M, Relman DA (2007). "An ecological and evolutionary perspective on human-microbe mutualism and disease". Nature. 449: 811–808. doi:10.1038/nature06245. PMID 17943117.CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} - ↑ Paszkowski U. (2006). "Mutualism and parasitism: the yin and yang of plant symbioses". Curr Opin Plant Biol. 9: 364–370. doi:10.1016/j.pbi.2006.05.008. PMID 16713732. - ↑ Wilkinson 2001 - ↑ Isaac 1992, p. 266 - ↑ Saffo 1993 - ↑ Moran 2006 - ↑ Ahmadjian & Paracer 2000, p. 12 - ↑ Ahmadjian & Paracer 2000, p. 12 - ↑ Sapp 1994, p. 142 - ↑ Ahmadjian & Paracer 2000, p. 12 - ↑ Nardon & Charles 2002 - ↑ Ahmadjian & Paracer 2000, p. 6 - ↑ Moran 2006 - ↑ Toller, Rowan & Knowlton 2001 - ↑ Harrison 2005 - ↑ Facey, Helfman & Collette 1997 - ↑ Cordes 2005 - ↑ Ahmadjian & Paracer 2000, p. 6 - ↑ Nair 2005 - ↑ Ahmadjian & Paracer 2000, p. 7 - ↑ Townsend, Begon & Harper 1996 - ↑ Wernegreen 2004 - ↑ Moran 2006 - ↑ Ahmadjian & Paracer 2000, p. 3-4 - ↑ Brinkman 2002 - ↑ Golding & Gupta 1995 - ↑ Moran 2006 - ↑ Sagan & Margulis 1986 - ↑ Harrison 2002 - ↑ Danforth & Ascher 1997 - ↑ Isaak 2004 - ↑ Roughgarden 1975 - ↑ Powell 1992 - ↑ Weiblen 2002 - ↑ Boucher 1988	Symbiosis Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview The term symbiosis (from the Greek: συμ, sym, "with"; and βίοσίς, biosis, "living") commonly describes close and often long-term interactions between different biological species. The term was first used in 1879 by the German mycologist, Heinrich Anton de Bary, who defined it as: "the living together of unlike organisms".[2][3] The definition of symbiosis is in flux and the term has been applied to a wide range of biological interactions. The symbiotic relationship may be categorized as being mutualistic, parasitic, or commensal in nature [4][5]. Others define it more narrowly, as only those relationships from which both organisms benefit, in which case it would be synonymous with mutualism.[6][7][8] Symbiotic relationships included those associations in which one organisms lives on another (ectosymbiosis, such as mistletoe), or where one partner lives inside another (endosymbiosis, such as lactobacilli and other bacteria in humans or zooxanthelles in corals). Symbiotic relationships may be either obligate, i.e., necessary to the survival of at least one of the organisms involved, or facultative, where the relationship is beneficial but not essential to survival of the organisms. [9][10] # Physical interaction Endosymbiosis is any symbiotic relationship in which the symbiote lives within the tissues of the host; either in the intracellular space or extracellularly.[11][12] Examples are nitrogen-fixing bacteria (called rhizobia) which live in root nodules on legume roots, Actinomycete nitrogen-bacteria called Frankia which live in Alder tree root nodules, single-celled algae inside reef-building corals, and bacterial endosymbionts that provide essential nutrients to about 10%–15% of insects. Ectosymbiosis, also referred to as exosymbiosis, is any symbiotic relationship in which the symbiont lives on the body surface of the host, including the inner surface of the digestive tract or the ducts of exocrine glands.[13][14] Examples of this include ectoparasites such as lice, commensal ectosymbionts, such as the barnacles that attach themselves to the jaw of baleen whales, and mutualist ectosymbionts such as cleaner fish. # Mutualism The term Mutualism describes any relationship between individuals of different species where both individuals derive a fitness benefit.[15] Generally only lifelong interactions involving close physical and biochemical contact, can properly be considered symbiotic. Mutualistic relationships, may be either obligate for both species, obligate for one but facultative for the other, or facultative for both. Many biologists restrict the definition of symbiosis to close mutualist relationships. A large percentage of herbivores have mutualistic gut fauna that help them digest plant matter, which is more difficult to digest than animal prey.[16] Coral reefs are the result of mutualisms between coral organisms and various types of algae that live inside them.[17] Most land plants and land ecosystems rely on mutualisms between the plants which fix carbon from the air, and Mycorrhyzal fungi which help in extracting minerals from the ground.[18] Another example is the goby fish, which sometimes lives together with a shrimp. The shrimp digs and cleans up a burrow in the sand in which both the shrimp and the goby fish live. The shrimp is almost blind leaving it vulnerable to predators when above ground. In case of danger the goby fish touches the shrimp with its tail to warn it. When that happens both the shrimp and goby fish quickly retract into the burrow.[19] One of the most spectacular examples of obligate mutualism is between the siboglinid tube worms and symbiotic bacteria that live at hydrothermal vents and cold seeps. The worm has no digestive tract and is solely reliant on their internal symbionts for nutrition. The bacteria oxidize either hydrogen sulfide or methane which the host supplies to them. These worms were discovered in the late 1980s at the hydrothermal vents near the Galapagos Islands and have since been found at deep-sea hydrothermal vents and cold seeps in all of the world's oceans.[20] # Commensalism Commensalism describes a relationship between two living organisms where one benefits and the other is not significantly harmed or helped. It is derived from the English word commensal, meaning the sharing of food, and used of human social interaction. The word derives from the Latin com mensa, meaning sharing a table.[21][22] Commensal relationships may involve an organism using another for transportation (phoresy), for housing (inquilinism), or it may also involve an organism using something another created, after the death of the first (metabiosis). An example is the hermit crabs that use gastropod shells to protect their bodies. Further examples include spiders building their webs on trees. # Parasitism A parasitic relationship is one in which one member of the association benefits while the other is harmed.[23] Parasitic symbioses take many forms, from endoparasites that live within the host's body, to ectoparasites that live on its surface. In addition, parasites may be necrotrophic, which is to say they kill their host, or biotrophic, meaning they rely on their host surviving. Biotrophic parasitism is an extremely successful mode of life. Depending on the definition used, as many as half of all animals have at least one parasitic phase in their life cycles, and it is also frequent in plants and fungi. Moreover, almost all free-living animals are host to one or more parasite taxa. # Symbiosis and evolution While historically, symbiosis has received less attention than other interactions such as predation or competition,[24] it is increasingly recognised as an important selective force behind evolution,[25][26] with many species having a long history of interdependent co-evolution.[27] In fact the evolution of all eukaryotes (plants, animals, fungi, protists) is believed to have resulted from a symbiosis between various sorts of bacteria.[28][29][30] ## Symbiogenesis The biologist Lynn Margulis, famous for the work on endosymbiosis, contends that symbiosis is a major driving force behind evolution. She considers Darwin's notion of evolution, driven by competition, as incomplete, and claims evolution is strongly based on co-operation, interaction, and mutual dependence among organisms. According to Margulis and Dorion Sagan, "Life did not take over the globe by combat, but by networking."[31] ## Co-evolution Symbiosis played a major role in the co-evolution of flowering plants and the animals that pollinate them. Many plants that are pollinated by insects, bats or birds, have very specialized flowers modified to promote pollination by a specific pollinator that is also correspondingly adapted. The first flowering plants in the fossil record had relatively simple flowers. Adaptive speciation quickly gave rise to many diverse groups of plants, and at the same time, corresponding speciation occurred in certain insects groups. Some groups of plants developed nectar and large sticky pollen while insects evolved more specialized morphologies to access and collect these rich food sources. In some taxa of plants and insects the relationship has become dependent,[32] where the plant species can only be pollinated by one species of insect. [33] ## Objections Creationists have long claimed that obligate symbioses are evidence against evolution, arguing that since neither organism can survive without the other, they must have come into existence at exactly the same time.[34] This point of view is countered in scientific claims by the extreme variety of symbiotic relationships as well the mutability of species over time: obligate mutualisms could have evolved from facultative relationships in which neither species is fully committed. Many examples of facultative symbioses and multiple theoretical and computational models describing how such a relationship would evolve do in fact exist.[35][36][37][38] # Notes - ↑ Lee 2003 - ↑ Wilkinson 2001 - ↑ Douglas 1994, p. 1 - ↑ Dethlefsen L, McFall-Ngai M, Relman DA (2007). "An ecological and evolutionary perspective on human-microbe mutualism and disease". Nature. 449: 811–808. doi:10.1038/nature06245. PMID 17943117.CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} - ↑ Paszkowski U. (2006). "Mutualism and parasitism: the yin and yang of plant symbioses". Curr Opin Plant Biol. 9: 364–370. doi:10.1016/j.pbi.2006.05.008. PMID 16713732. - ↑ Wilkinson 2001 - ↑ Isaac 1992, p. 266 - ↑ Saffo 1993 - ↑ Moran 2006 - ↑ Ahmadjian & Paracer 2000, p. 12 - ↑ Ahmadjian & Paracer 2000, p. 12 - ↑ Sapp 1994, p. 142 - ↑ Ahmadjian & Paracer 2000, p. 12 - ↑ Nardon & Charles 2002 - ↑ Ahmadjian & Paracer 2000, p. 6 - ↑ Moran 2006 - ↑ Toller, Rowan & Knowlton 2001 - ↑ Harrison 2005 - ↑ Facey, Helfman & Collette 1997 - ↑ Cordes 2005 - ↑ Ahmadjian & Paracer 2000, p. 6 - ↑ Nair 2005 - ↑ Ahmadjian & Paracer 2000, p. 7 - ↑ Townsend, Begon & Harper 1996 - ↑ Wernegreen 2004 - ↑ Moran 2006 - ↑ Ahmadjian & Paracer 2000, p. 3-4 - ↑ Brinkman 2002 - ↑ Golding & Gupta 1995 - ↑ Moran 2006 - ↑ Sagan & Margulis 1986 - ↑ Harrison 2002 - ↑ Danforth & Ascher 1997 - ↑ Isaak 2004 - ↑ Roughgarden 1975 - ↑ Powell 1992 - ↑ Weiblen 2002 - ↑ Boucher 1988	https://www.wikidoc.org/index.php/Mutual_dependence
b0410ef919d99515d8445886360ca5e89a531ed2	wikidoc	Mutualism	Mutualism # Overview Mutualism is a biological interaction between individuals of two different species, where both individuals derive a fitness benefit, for example increased survivorship. Similar interactions within a species are known as co-operation. Mutualism plays a key part in ecology and evolutionary biology. For example, mutualistic interactions are vital for terrestrial ecosystem function as more than 90% of land plants rely on mycorrhizal relationships with fungi to provide them with inorganic compounds and trace elements. In addition, mutualism has driven the evolution of much of the biological diversity we see, such as flower forms (important for pollination mutualisms) and co-evolution between groups of species However mutualism has historically received less attention than other interactions such as predation and parasitism . Measuring the exact fitness benefit to the individuals is not always straightforward, particularly when the individuals can receive benefits from a range of species, for example most plant-pollinator mutualisms. It is therefore common to categorise mutualisms according to the closeness of the association, using terms such as obligate, facultative and symbiotic. Defining "closeness", however, is also problematical. It can refer to mutual dependency (the species cannot live without one another) or the biological intimacy of the relationship in relation to physical closeness (e.g. one species living within the tissues of the other species). Mutualism and symbiosis are sometimes used to refer to the same thing but this is strictly incorrect: the term symbiosis was originally meant to include relationships which were mutualistic, parasitic or commensal. # Types of relationships Mutualistic interactions can be thought of as a form of "biological barter" in which species trade resources (for example carbohydrates or inorganic compounds) or services such as gamete or offspring dispersal, or protection from predators. ## Resource-resource relationships Resource-resource interactions, in which one type of resource is traded for a different resource, are probably the most common form of mutualism; for example mycorrhizal associations between plant roots and fungi, with the plant providing carbohydrates to the fungus in return for nitrogenous compounds and water. Other examples include rhizobia bacteria which fix nitrogen for leguminous plants (family Fabaceae) in return for energy-containing carbohydrates. ## Service-resource relationships Service-resource relationships are also common, for example pollination in which nectar or pollen (food resources) are traded for pollen dispersal (a service) or ant protection of aphids, where the aphids trade sugar-rich honeydew (a by-product of their mode of feeding on plant sap) in return for defence against predators such as ladybird beetles. ## Service-service relationships Strict service-service interactions are very rare, for reasons that are far from clear. One example is the relationship between sea anemones and anemonefish in the family Pomacentridae: the anemones provide the fish with protection from predators (which cannot tolerate the stings of the anemone's tentacles) and the fish defend the anemones against butterfly fish (family Chaetodontidae) which eat anemones. However, in common with many mutualisms, there is more than one aspect to the biological barter: in the anemonefish-anemone mutualism, waste ammonia from the fish feed the symbiotic algae that are found in the anemone's tentacles. Therefore what appears to be a service-service mutualism in fact has a service-resource component. A second example is that of the relationship between some ants and trees in the genus Acacia, such as the Whistling Thorn and Bullhorn Acacia. The ants nest inside the plant's thorns. In exchange for shelter, the ants protect acacias from attack by herbivores (which they frequently eat, introducing a resource component to this service-service relationship) and competition from other plants by trimming back vegetation that would shade the acacia. In addition, another service-resource component is present, as the ants regularly feed on lipid-rich food-bodies called Beltian bodies that are on the Acacia plant. # Humans and mutualism Humans also engage in mutualisms with other species, including our gut flora (without which we would not be able to digest food efficiently) and domesticated animals such as dogs, which provide protection in return for food and shelter. In traditional agriculture, many plants will function mutualistically as companion plants, providing each other with shelter, soil fertility and the repelling of pests. For example, beans may grow up cornstalks as a trellis, while fixing nitrogen in the soil for the corn, as exploited in the Three Sisters gardening technique. The question how and why species might cooperate has been addressed philosophically by a number of writers. Gilles Deleuze, for example, was interested in the way this questioned the conception of evolutionism and the notion of linear historical progress.	Mutualism # Overview Mutualism is a biological interaction between individuals of two different species, where both individuals derive a fitness benefit, for example increased survivorship. Similar interactions within a species are known as co-operation. Mutualism plays a key part in ecology and evolutionary biology. For example, mutualistic interactions are vital for terrestrial ecosystem function as more than 90% of land plants rely on mycorrhizal relationships with fungi to provide them with inorganic compounds and trace elements. In addition, mutualism has driven the evolution of much of the biological diversity we see, such as flower forms (important for pollination mutualisms) and co-evolution between groups of species[1] However mutualism has historically received less attention than other interactions such as predation and parasitism[2] [3]. Measuring the exact fitness benefit to the individuals is not always straightforward, particularly when the individuals can receive benefits from a range of species, for example most plant-pollinator mutualisms. It is therefore common to categorise mutualisms according to the closeness of the association, using terms such as obligate, facultative and symbiotic. Defining "closeness", however, is also problematical. It can refer to mutual dependency (the species cannot live without one another) or the biological intimacy of the relationship in relation to physical closeness (e.g. one species living within the tissues of the other species)[4]. Mutualism and symbiosis are sometimes used to refer to the same thing but this is strictly incorrect: the term symbiosis was originally meant to include relationships which were mutualistic, parasitic or commensal. # Types of relationships Mutualistic interactions can be thought of as a form of "biological barter"[5] in which species trade resources (for example carbohydrates or inorganic compounds) or services such as gamete or offspring dispersal, or protection from predators. ## Resource-resource relationships Resource-resource interactions, in which one type of resource is traded for a different resource, are probably the most common form of mutualism; for example mycorrhizal associations between plant roots and fungi, with the plant providing carbohydrates to the fungus in return for nitrogenous compounds and water. Other examples include rhizobia bacteria which fix nitrogen for leguminous plants (family Fabaceae) in return for energy-containing carbohydrates[6]. ## Service-resource relationships Service-resource relationships are also common, for example pollination in which nectar or pollen (food resources) are traded for pollen dispersal (a service) or ant protection of aphids, where the aphids trade sugar-rich honeydew (a by-product of their mode of feeding on plant sap) in return for defence against predators such as ladybird beetles. ## Service-service relationships Strict service-service interactions are very rare, for reasons that are far from clear[7]. One example is the relationship between sea anemones and anemonefish in the family Pomacentridae: the anemones provide the fish with protection from predators (which cannot tolerate the stings of the anemone's tentacles) and the fish defend the anemones against butterfly fish (family Chaetodontidae) which eat anemones. However, in common with many mutualisms, there is more than one aspect to the biological barter: in the anemonefish-anemone mutualism, waste ammonia from the fish feed the symbiotic algae that are found in the anemone's tentacles[8][9]. Therefore what appears to be a service-service mutualism in fact has a service-resource component. A second example is that of the relationship between some ants and trees in the genus Acacia, such as the Whistling Thorn and Bullhorn Acacia. The ants nest inside the plant's thorns. In exchange for shelter, the ants protect acacias from attack by herbivores (which they frequently eat, introducing a resource component to this service-service relationship) and competition from other plants by trimming back vegetation that would shade the acacia. In addition, another service-resource component is present, as the ants regularly feed on lipid-rich food-bodies called Beltian bodies that are on the Acacia plant. # Humans and mutualism Humans also engage in mutualisms with other species, including our gut flora (without which we would not be able to digest food efficiently) and domesticated animals such as dogs, which provide protection in return for food and shelter. In traditional agriculture, many plants will function mutualistically as companion plants, providing each other with shelter, soil fertility and the repelling of pests. For example, beans may grow up cornstalks as a trellis, while fixing nitrogen in the soil for the corn, as exploited in the Three Sisters gardening technique. The question how and why species might cooperate has been addressed philosophically by a number of writers. Gilles Deleuze, for example, was interested in the way this questioned the conception of evolutionism and the notion of linear historical progress.	https://www.wikidoc.org/index.php/Mutualism
b68264896c929a46e4a43d6720ff2d5e81847d75	wikidoc	Rifabutin	Rifabutin # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Rifabutin is an anti-bacterial, anti-infective agent that is FDA approved for the prophylaxis of disseminated Mycobacterium avium complex (MAC) disease in patients with advanced HIV infection. Common adverse reactions include discoloration of skin, rash, diarrhea, disorder of taste, indigestion, loss of appetite, nausea, vomiting, increased liver aminotransferase level (mild), ocular discoloration, uveitis, abnormal color of body fluid. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - MYCOBUTIN Capsules are indicated for the prevention of disseminated Mycobacterium avium complex (MAC) disease in patients with advanced HIV infection. - Dosing Information - It is recommended that MYCOBUTIN Capsules be administered at a dose of 300 mg once daily. For those patients with propensity to nausea, vomiting, or other gastrointestinal upset, administration of MYCOBUTIN at doses of 150 mg twice daily taken with food may be useful. For patients with severe renal impairment (creatinine clearance less than 30 mL/min), the dose of MYCOBUTIN should be reduced by 50%. No dosage adjustment is required for patients with mild to moderate renal impairment. Reduction of the dose of MYCOBUTIN may also be needed for patients receiving concomitant treatment with certain other drugs. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Rifabutin in adult patients. ### Non–Guideline-Supported Use - Crohn's disease # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Rifabutin FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Rifabutin in pediatric patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Rifabutin in pediatric patients. # Contraindications - MYCOBUTIN Capsules are contraindicated in patients who have had clinically significant hypersensitivity to rifabutin or to any other rifamycins. # Warnings - MYCOBUTIN Capsules must not be administered for MAC prophylaxis to patients with active tuberculosis. Tuberculosis in HIV-positive patients is common and may present with atypical or extrapulmonary findings. Patients are likely to have a nonreactive purified protein derivative (PPD) despite active disease. In addition to chest X-ray and sputum culture, the following studies may be useful in the diagnosis of tuberculosis in the HIV-positive patient: blood culture, urine culture, or biopsy of a suspicious lymph node. - When MYCOBUTIN is used concomitantly with clarithromycin for MAC treatment, a decreased dose of MYCOBUTIN is recommended due to the increase in plasma concentrations of MYCOBUTIN. Due to the possible occurrence of uveitis, patients should also be carefully monitored when MYCOBUTIN is given in combination with clarithromycin (or other macrolides) and/or fluconazole (and related compounds). If uveitis is suspected, the patient should be referred to an ophthalmologist and, if considered necessary, treatment with MYCOBUTIN should be suspended (see also ADVERSE REACTIONS). - Patients who develop complaints consistent with active tuberculosis while on prophylaxis with MYCOBUTIN should be evaluated immediately, so that those with active disease may be given an effective combination regimen of anti-tuberculosis medications. Administration of MYCOBUTIN as a single agent to patients with active tuberculosis is likely to lead to the development of tuberculosis that is resistant both to MYCOBUTIN and to rifampin. - There is no evidence that MYCOBUTIN is effective prophylaxis against M. tuberculosis. Patients requiring prophylaxis against both M. tuberculosis and Mycobacterium avium complex may be given isoniazid and MYCOBUTIN concurrently. - Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including MYCOBUTIN (rifabutin capsules, USP), and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. - C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. - If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. - In accordance with the commonly accepted criteria for the treatment of mycobacterial infections, MYCOBUTIN should always be given in combination with other anti-mycobacterial drugs not belonging to the family of rifamycins. - For patients with severe liver insufficiency a dose reduction should be considered. Mild hepatic impairment does not require a dose modification. - Severe renal impairment (creatinine clearance below 30 mL/min) requires a dosage reduction of 50%. Mild to moderate renal impairment does not require any dosage adjustment. - Protease inhibitors act as substrates or inhibitors of CYP450 IIIA4 mediated metabolism. Therefore, due to significant drug-drug interactions between protease inhibitors and rifabutin, their concomitant use should be based on the overall assessment of the patient and a patient-specific drug profile (see PRECAUTIONS-Drug Interactions). For further recommendations regarding protease inhibitors, please refer to current, official product monographs or contact the specific manufacturer. ### PRECAUTIONS General - Because treatment with MYCOBUTIN Capsules may be associated with neutropenia, and more rarely thrombocytopenia, physicians should consider obtaining hematologic studies periodically in patients receiving prophylaxis with MYCOBUTIN. Information for Patients - Patients should be advised of the signs and symptoms of both MAC and tuberculosis, and should be instructed to consult their physicians if they develop new complaints consistent with either of these diseases. In addition, since MYCOBUTIN may rarely be associated with myositis and uveitis, patients should be advised to notify their physicians if they develop signs or symptoms suggesting either of these disorders. - Urine, feces, saliva, sputum, perspiration, tears, and skin may be colored brown-orange with rifabutin and some of its metabolites. Soft contact lenses may be permanently stained. Patients to be treated with MYCOBUTIN should be made aware of these possibilities. - Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes, after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible. - There is no reason to believe that MYCOBUTIN has any adverse effect on the ability to drive and/or use machines. # Adverse Reactions ## Clinical Trials Experience - MYCOBUTIN Capsules were generally well tolerated in the controlled clinical trials. Discontinuation of therapy due to an adverse event was required in 16% of patients receiving MYCOBUTIN, compared to 8% of patients receiving placebo in these trials. Primary reasons for discontinuation of MYCOBUTIN were rash (4% of treated patients), gastrointestinal intolerance (3%), and neutropenia (2%). - The following table enumerates adverse experiences that occurred at a frequency of 1% or greater, among the patients treated with MYCOBUTIN in studies 023 and 027. CLINICAL ADVERSE EVENTS REPORTED IN <1% OF PATIENTS WHO RECEIVED MYCOBUTIN - Considering data from the 023 and 027 pivotal trials, and from other clinical studies, MYCOBUTIN appears to be a likely cause of the following adverse events which occurred in less than 1% of treated patients: flu-like syndrome, hepatitis, hemolysis, arthralgia, myositis, chest pressure or pain with dyspnea, and skin discoloration. - The following adverse events have occurred in more than one patient receiving MYCOBUTIN, but an etiologic role has not been established: seizure, paresthesia, aphasia, confusion, and non-specific T wave changes on electrocardiogram. - When MYCOBUTIN was administered at doses from 1050 mg/day to 2400 mg/day, generalized arthralgia and uveitis were reported. These adverse experiences abated when MYCOBUTIN was discontinued. - The following table enumerates the changes in laboratory values that were considered as laboratory abnormalities in studies 023 and 027. - The incidence of neutropenia in patients treated with MYCOBUTIN was significantly greater than in patients treated with placebo (p = 0.03). Although thrombocytopenia was not significantly more common among patients treated with MYCOBUTIN in these trials, MYCOBUTIN has been clearly linked to thrombocytopenia in rare cases. One patient in study 023 developed thrombotic thrombocytopenic purpura, which was attributed to MYCOBUTIN. - Uveitis is rare when MYCOBUTIN is used as a single agent at 300 mg/day for prophylaxis of MAC in HIV-infected persons, even with the concomitant use of fluconazole and/or macrolide antibiotics. However, if higher doses of MYCOBUTIN are administered in combination with these agents, the incidence of uveitis is higher. - Patients who developed uveitis had mild to severe symptoms that resolved after treatment with corticosteroids and/or mydriatic eye drops; in some severe cases, however, resolution of symptoms occurred after several weeks. - When uveitis occurs, temporary discontinuance of MYCOBUTIN and ophthalmologic evaluation are recommended. In most mild cases, MYCOBUTIN may be restarted; however, if signs or symptoms recur, use of MYCOBUTIN should be discontinued (Morbidity and Mortality Weekly Report, September 9, 1994). - Adverse reactions identified through clinical trials or post-marketing surveillance by system organ class (SOC) are listed below. - Blood and lymphatic system disorders: Pancytopenia, white blood cell disorders (including agranulocytosis, leukopenia, lymphopenia, granulocytopenia, neutropenia, white blood cell count decreased, neutrophil count decreased), thrombocytopenia, platelet count decreased, anemia. - Immune system disorders: Shock, hypersensitivity, bronchospasm, rash, eosinophilia. - Eye disorders: Uveitis, corneal deposits. - Gastrointestinal disorders: Clostridium difficile colitis , nausea, vomiting. - Hepato-biliary disorders: Jaundice, hepatic enzyme increased. - Skin and subcutaneous tissue disorders: Skin discoloration. - Musculoskeletal and connective tissue disorders: Arthralgia, myalgia. - General disorders and administration site conditions: Pyrexia. - Pyrexia, rash and rarely other hypersensitivity reactions such as eosinophilia, bronchospasm and shock might occur, as has been seen with other antibiotics. A limited number of skin discoloration has been reported. Mild to severe, reversible uveitis has been reported less frequently when MYCOBUTIN is used at 300 mg as monotherapy in MAC prophylaxis versus MYCOBUTIN in combination with clarithromycin for MAC treatment (see also WARNINGS). Corneal deposits have been reported during routine ophthalmologic surveillance of some HIV-positive pediatric patients receiving MYCOBUTIN as part of a multiple drug regimen for MAC prophylaxis. The deposits are tiny, almost transparent, asymptomatic peripheral and central corneal deposits, and do not impair vision. ## Postmarketing Experience - There is limited information regarding Postmarketing Experience of Rifabutin in the drug label. # Drug Interactions - Multiple dosing of rifabutin has been associated with induction of hepatic metabolic enzymes of the CYP450 IIIA subfamily. Rifabutin's predominant metabolite (25-desacetyl rifabutin; LM 565), may also contribute to this effect. Metabolic induction due to rifabutin is likely to produce a decrease in circulating levels of concomitantly administered drugs (especially those metabolized by the CYP450 IIIA pathway). Kinetic data suggest that enzymatic induction by rifabutin is complete within 5 days and is dose-independent over the 300 to 600 mg dose-range. Similarly, concomitant medications that competitively inhibit the CYP450 IIIA activity may increase circulating levels of rifabutin. Malabsorption Gastric pH alteration due to progressing HIV disease has been linked with malabsorption of some drugs used in HIV-positive patients (e.g., rifampin, isoniazid). Drug serum concentration data from AIDS patients with varying disease severity (based on CD4+ counts) suggest that rifabutin absorption is not influenced by progressing HIV disease. Effects on Other Drugs - Rifabutin induces CYP3A enzymes and therefore may reduce the plasma concentrations of drugs metabolized by those enzymes. This effect may reduce the efficacy of standard doses of such drugs, which include itraconazole, clarithromycin, and saquinavir. Effects on Rifabutin - Some drugs that inhibit CYP3A may significantly increase the plasma concentration of rifabutin. Because high plasma levels of rifabutin may increase the risk of adverse reactions, carefully monitor patients receiving coadministration of such drugs, which include fluconazole and clarithromycin. In some cases, the dosage of MYCOBUTIN may need to be reduced when it is coadministered with such a drug (see below). - The following table summarizes the results and magnitude of the pertinent drug interactions assessed with rifabutin. The clinical relevance of these interactions and subsequent dose modifications should be judged in light of the population studied, severity of the disease, patient's drug profile, and the likely impact on the risk/benefit ratio. Other drugs - The structurally similar drug, rifampin, is known to reduce the plasma concentrations of a number of other drugs (see prescribing information for rifampin). Although rifabutin is a weaker enzyme inducer than rifampin, it may be expected to have some effect on those drugs as well. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B - Reproduction studies have been carried out in rats and rabbits given rifabutin using dose levels up to 200 mg/kg (40 times the recommended human daily dose). No teratogenicity was observed in either species. In rats, given 200 mg/kg/day, there was a decrease in fetal viability. In rats, at 40 mg/kg/day (8 times the recommended human daily dose), rifabutin caused an increase in fetal skeletal variants. In rabbits, at 80 mg/kg/day (16 times the recommended human daily dose), rifabutin caused maternotoxicity and increase in fetal skeletal anomalies. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, rifabutin should be used in pregnant women only if the potential benefit justifies the potential risk to the fetus. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category - There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Rifabutin in women who are pregnant. ### Labor and Delivery - There is no FDA guidance on use of Rifabutin during labor and delivery. ### Nursing Mothers - It is not known whether rifabutin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use - Safety and effectiveness of rifabutin for prophylaxis of MAC in children have not been established. Limited safety data are available from treatment use in 22 HIV-positive children with MAC who received MYCOBUTIN in combination with at least two other antimycobacterials for periods from 1 to 183 weeks. Mean doses (mg/kg) for these children were: 18.5 (range 15.0 to 25.0) for infants one year of age, 8.6 (range 4.4 to 18.8) for children 2 to 10 years of age, and 4.0 (range 2.8 to 5.4) for adolescents 14 to 16 years of age. There is no evidence that doses greater than 5 mg/kg daily are useful. Adverse experiences were similar to those observed in the adult population, and included leukopenia, neutropenia, and rash. In addition, corneal deposits have been observed in some patients during routine ophthalmologic surveillance of HIV-positive pediatric patients receiving MYCOBUTIN as part of a multiple-drug regimen for MAC prophylaxis. These are tiny, almost transparent, asymptomatic peripheral and central corneal deposits which do not impair vision. Doses of MYCOBUTIN may be administered mixed with foods such as applesauce. ### Geriatic Use - Clinical studies of MYCOBUTIN did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy (see CLINICAL PHARMACOLOGY). ### Gender - There is no FDA guidance on the use of Rifabutin with respect to specific gender populations. ### Race - There is no FDA guidance on the use of Rifabutin with respect to specific racial populations. ### Renal Impairment - There is no FDA guidance on the use of Rifabutin in patients with renal impairment. ### Hepatic Impairment - There is no FDA guidance on the use of Rifabutin in patients with hepatic impairment. ### Females of Reproductive Potential and Males - There is no FDA guidance on the use of Rifabutin in women of reproductive potentials and males. ### Immunocompromised Patients - There is no FDA guidance one the use of Rifabutin in patients who are immunocompromised. # Administration and Monitoring ### Administration - It is recommended that MYCOBUTIN Capsules be administered at a dose of 300 mg once daily. For those patients with propensity to nausea, vomiting, or other gastrointestinal upset, administration of MYCOBUTIN at doses of 150 mg twice daily taken with food may be useful. For patients with severe renal impairment (creatinine clearance less than 30 mL/min), the dose of MYCOBUTIN should be reduced by 50%. No dosage adjustment is required for patients with mild to moderate renal impairment. Reduction of the dose of MYCOBUTIN may also be needed for patients receiving concomitant treatment with certain other drugs (see PRECAUTIONS-Drug Interactions). ### Monitoring - Due to the possible occurrence of uveitis, patients should be carefully monitored when MYCOBUTIN is given in combination with clarithromycin (or other macrolides) and/or fluconazole (and related compounds). - Some drugs that inhibit CYP3A may significantly increase the plasma concentration of rifabutin. Because high plasma levels of rifabutin may increase the risk of adverse reactions, carefully monitor patients receiving coadministration of such drugs, which include fluconazole and clarithromycin (see PHARMACOLOGY & Drug Interactions). In some cases, the dosage of MYCOBUTIN may need to be reduced when it is coadministered with such a drug (see below). - Amprenavir- A 50% reduction in the rifabutin dose is recommended when combined with amprenavir. Increased monitoring for adverse reactions is warranted. - Lopinavir/ritonavir- Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted. Further dosage reduction of rifabutin may be necessary. - Tipranavir/ritonavir- Therapeutic drug monitoring of rifabutin is recommended. - Posaconazole- If the drugs are co-administered, patients should be monitored for adverse events associated with rifabutin administration. - Voriconazole- If the benefit outweighs the risk, rifabutin may be coadministered with voriconazole if the maintenance dose of voriconazole is increased to 5 mg/kg intravenously every 12 hours or from 200 mg to 350 mg orally, every 12 hours (100 mg to 200 mg orally, every 12 hours in patients less than 40 kg). Careful monitoring of full blood counts and adverse events to rifabutin (e.g. uveitis) is recommended when rifabutin is coadministered with voriconazole. # IV Compatibility - There is limited information regarding IV Compatibility of Rifabutin in the drug label. # Overdosage - No information is available on accidental overdosage in humans. Treatment - While there is no experience in the treatment of overdose with MYCOBUTIN Capsules, clinical experience with rifamycins suggests that gastric lavage to evacuate gastric contents (within a few hours of overdose), followed by instillation of an activated charcoal slurry into the stomach, may help absorb any remaining drug from the gastrointestinal tract. - Rifabutin is 85% protein bound and distributed extensively into tissues (Vss:8 to 9 L/kg). It is not primarily excreted via the urinary route (less than 10% as unchanged drug); therefore, neither hemodialysis nor forced diuresis is expected to enhance the systemic elimination of unchanged rifabutin from the body in a patient with an overdose of MYCOBUTIN. # Pharmacology ## Mechanism of Action - Rifabutin inhibits DNA-dependent RNA polymerase in susceptible strains of Escherichia coli and Bacillus subtilis but not in mammalian cells. In resistant strains of E. coli, rifabutin, like rifampin, did not inhibit this enzyme. It is not known whether rifabutin inhibits DNA-dependent RNA polymerase in Mycobacterium avium or in M. intracellulare which comprise M. avium complex (MAC). ## Structure - MYCOBUTIN Capsules contain the antimycobacterial agent rifabutin, which is a semisynthetic ansamycin antibiotic derived from rifamycin S. MYCOBUTIN Capsules for oral administration contain 150 mg of rifabutin, USP, per capsule, along with the inactive ingredients microcrystalline cellulose, magnesium stearate, red iron oxide, silica gel, sodium lauryl sulfate, titanium dioxide, and edible white ink. - The chemical name for rifabutin is 1',4-didehydro-1-deoxy-1,4-dihydro-5'-(2-methylpropyl)-1-oxorifamycin XIV (Chemical Abstracts Service, 9th Collective Index) or (9S, 12E, 14S, 15R, 16S, 17R, 18R, 19R, 20S, 21S, 22E, 24Z)-6,16,18,20-tetrahydroxy-1'-isobutyl-14-methoxy-7,9,15,17,19,21,25-heptamethyl-spiro trienimino)-2H-furonaphth imidazole-2,4'-piperidine]-5,10,26-(3H,9H)-trione-16-acetate. Rifabutin has a molecular formula of C46H62N4O11, a molecular weight of 847.02 and the following structure: - Rifabutin is a red-violet powder soluble in chloroform and methanol, sparingly soluble in ethanol, and very slightly soluble in water (0.19 mg/mL). Its log P value (the base 10 logarithm of the partition coefficient between n-octanol and water) is 3.2 (n-octanol/water). ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Rifabutin in the drug label. ## Pharmacokinetics Absorption - Following a single oral dose of 300 mg to nine healthy adult volunteers, rifabutin was readily absorbed from the gastrointestinal tract with mean (±SD) peak plasma levels (Cmax) of 375 (±267) ng/mL (range: 141 to 1033 ng/mL) attained in 3.3 (±0.9) hours (Tmax range: 2 to 4 hours). Absolute bioavailability assessed in five HIV-positive patients, who received both oral and intravenous doses, averaged 20%. Total recovery of radioactivity in the urine indicates that at least 53% of the orally administered rifabutin dose is absorbed from the gastrointestinal tract. The bioavailability of rifabutin from the capsule dosage form, relative to an oral solution, was 85% in 12 healthy adult volunteers. High-fat meals slow the rate without influencing the extent of absorption from the capsule dosage form. Plasma concentrations post-Cmax declined in an apparent biphasic manner. Pharmacokinetic dose-proportionality was established over the 300 to 600 mg dose range in nine healthy adult volunteers (crossover design) and in 16 early symptomatic human immunodeficiency virus (HIV)-positive patients over a 300 to 900 mg dose range. Distribution - Due to its high lipophilicity, rifabutin demonstrates a high propensity for distribution and intracellular tissue uptake. Following intravenous dosing, estimates of apparent steady-state distribution volume (9.3 ± 1.5 L/kg) in five HIV-positive patients exceeded total body water by approximately 15-fold. Substantially higher intracellular tissue levels than those seen in plasma have been observed in both rat and man. The lung-to-plasma concentration ratio, obtained at 12 hours, was approximately 6.5 in four surgical patients who received an oral dose. Mean rifabutin steady-state trough levels (Cp,minss; 24-hour post-dose) ranged from 50 to 65 ng/mL in HIV-positive patients and in healthy adult volunteers. About 85% of the drug is bound in a concentration-independent manner to plasma proteins over a concentration range of 0.05 to 1 µg/mL. Binding does not appear to be influenced by renal or hepatic dysfunction. Rifabutin was slowly eliminated from plasma in seven healthy adult volunteers, presumably because of distribution-limited elimination, with a mean terminal half-life of 45 (±17) hours (range: 16 to 69 hours). Although the systemic levels of rifabutin following multiple dosing decreased by 38%, its terminal half-life remained unchanged. Metabolism - Of the five metabolites that have been identified, 25-O-desacetyl and 31-hydroxy are the most predominant, and show a plasma metabolite:parent area under the curve ratio of 0.10 and 0.07, respectively. The former has an activity equal to the parent drug and contributes up to 10% to the total antimicrobial activity. Excretion - A mass-balance study in three healthy adult volunteers with 14C-labeled rifabutin showed that 53% of the oral dose was excreted in the urine, primarily as metabolites. About 30% of the dose is excreted in the feces. Mean systemic clearance (CLs/F) in healthy adult volunteers following a single oral dose was 0.69 (±0.32) L/hr/kg (range: 0.46 to 1.34 L/hr/kg). Renal and biliary clearance of unchanged drug each contribute approximately 5% to CLs/F. Pharmacokinetics in Special Populations Geriatric - Compared to healthy volunteers, steady-state kinetics of MYCOBUTIN are more variable in elderly patients (>70 years). Pediatric - The pharmacokinetics of MYCOBUTIN have not been studied in subjects under 18 years of age. Renal Insufficiency - The disposition of rifabutin (300 mg) was studied in 18 patients with varying degrees of renal function. Area under plasma concentration time curve (AUC) increased by about 71% in patients with severe renal insufficiency (creatinine clearance below 30 mL/min) compared to patients with creatinine clearance (Crcl) between 61–74 mL/min. In patients with mild to moderate renal insufficiency (Crcl between 30–61 mL/min), the AUC increased by about 41%. A reduction in the dosage of rifabutin is recommended for patients with Crcl< 30 mL/min (see DOSAGE AND ADMINISTRATION). Drug-Drug Interactions - (see also PRECAUTIONS-Drug Interactions) - Rifabutin induces the enzymes of the cytochrome P450 3A subfamily (CYP3A) and therefore may reduce the plasma concentrations of drugs that are principally metabolized by those enzymes. Rifabutin is also metabolized by CYP3A. Thus, some drugs that inhibit CYP3A may significantly increase plasma concentrations of rifabutin. Antifungals Fluconazole - Fluconazole (200 mg/day for 2 weeks) increased the AUC of rifabutin (300 mg/day for 2 weeks) by 82% and Cmax by 88% in 12 HIV-infected patients who were on zidovudine (500 mg/day) maintenance therapy (see PRECAUTIONS-Drug Interactions). Rifabutin did not affect the pharmacokinetics of fluconazole. Itraconazole - Coadministration of itraconazole (200 mg/day) with rifabutin (300 mg/day) in six HIV-infected patients reduced both the AUC and Cmax of itraconazole by 70% to 75% (see PRECAUTIONS-Drug Interactions). Antipneumocystis Agents Dapsone - Rifabutin (300 mg/day) decreased the AUC of dapsone (50 mg/day) in HIV-infected patients (n=16) by about 27% to 40%. Sulfamethoxazole-trimethoprim - Coadministration of rifabutin (300 mg/day) and sulfamethoxazole-trimethoprim (double strength) in 12 HIV-infected patients decreased the AUC of sulfamethoxazole-trimethoprim by about 15% to 20%. When trimethoprim was given alone, the AUC of trimethoprim was decreased by 14% and the Cmax by 6%. - Sulfamethoxazole-trimethoprim did not alter the pharmacokinetics of rifabutin. Antiretroviral Agents Delavirdine - In 7 HIV-infected patients, rifabutin (300 mg/day) decreased delavirdine (400 mg q 8h) AUC by about 80%, Cmax by about 75%, and mean trough plasma concentrations by about 95%. Based on comparisons with historical data, delavirdine appeared to increase the AUC of rifabutin by at least 100% (see PRECAUTIONS-Drug Interactions). Didanosine - In 12 HIV-infected patients, coadministration of rifabutin (300 or 600 mg/day) and didanosine (167–375 mg BID) did not alter the pharmacokinetics of either drug. Indinavir - In healthy volunteers, coadministration of indinavir (800 mg q 8h) and rifabutin (300 mg/day) decreased the AUC of indinavir by about 30% and increased the AUC of rifabutin by about 200% (see PRECAUTIONS-Drug Interactions). Nelfinavir - Coadministration of nelfinavir (750 mg q 8h for 8 days) and rifabutin (300 mg/day for 7–8 days) decreased the AUC and Cmax of nelfinavir by about 32% and 25%, respectively, and increased the AUC and Cmax of rifabutin by about 207% and 146%, respectively (see PRECAUTIONS-Drug Interactions). Ritonavir - Coadministration of ritonavir (500 mg q 12h) and rifabutin (150 mg/day) increased the AUC and Cmax of rifabutin by more than 400% and 250%, respectively (see PRECAUTIONS-Drug Interactions). Saquinavir - In 12 HIV-infected patients, rifabutin (300 mg/day) decreased the AUC of saquinavir (600 mg TID) by about 40% (see PRECAUTIONS-Drug Interactions). Zidovudine - In 16 HIV-infected patients on zidovudine (100 or 200 mg q 4h), rifabutin (300 or 450 mg/day) lowered the Cmax and AUC of zidovudine by about 48% and 32%, respectively. However, zidovudine levels remained within the therapeutic range during coadministration of rifabutin. Zidovudine did not affect the pharmacokinetics of rifabutin. Antituberculosis Agents - In studies conducted in healthy volunteers, rifabutin (300 mg) did not alter the pharmacokinetics of ethambutol (n=10) or isoniazid (n=10). Macrolides Clarithromycin - In studies conducted in HIV-infected patients, coadministration of rifabutin (300 mg/day) and clarithromycin (500 mg q 12h) decreased the AUC of clarithromycin by about 50% (n=12) and increased the AUC of rifabutin by about 75% (n=14) (see PRECAUTIONS-Drug Interactions). Other Drugs Methadone - Rifabutin did not alter the pharmacokinetics of methadone in 24 HIV-infected, methadone-maintained, former intravenous drug users. Oral contraceptives - In 22 healthy female volunteers receiving an oral contraceptive (35 mcg ethinylestradiol (EE) and 1 mg norethindrone (NE) daily for 21 days), rifabutin decreased EE (AUC) and Cmax by 35% and 20%, respectively, and NE AUC by 46% (see PRECAUTIONS-Drug Interactions). Theophylline - Rifabutin did not alter the pharmacokinetics of theophylline when coadministered in 11 healthy volunteers. Other drugs - The structurally similar drug, rifampin, is known to reduce the plasma concentrations of a number of other drugs (see prescribing information for rifampin). Although rifabutin is a weaker enzyme inducer than rifampin, rifabutin may be expected to have some effect on those drugs as well. ### MICROBIOLOGY Mechanism of Action - Rifabutin inhibits DNA-dependent RNA polymerase in susceptible strains of Escherichia coli and Bacillus subtilis but not in mammalian cells. In resistant strains of E. coli, rifabutin, like rifampin, did not inhibit this enzyme. It is not known whether rifabutin inhibits DNA-dependent RNA polymerase in Mycobacterium avium or in M. intracellulare which comprise M. avium complex (MAC). Susceptibility Testing - In vitro susceptibility testing methods and diagnostic products used for determining minimum inhibitory concentration (MIC) values against M. avium complex (MAC) organisms have not been standardized. Breakpoints to determine whether clinical isolates of MAC and other mycobacterial species are susceptible or resistant to rifabutin have not been established. In Vitro Studies - Rifabutin has demonstrated in vitro activity against ] (MAC) organisms isolated from both HIV-positive and HIV-negative people. While gene probe techniques may be used to identify these two organisms, many reported studies did not distinguish between these two species. The vast majority of isolates from MAC-infected, HIV-positive people are M. avium, whereas in HIV-negative people, about 40% of the MAC isolates are M. intracellulare. - Various in vitro methodologies employing broth or solid media, with and without polysorbate 80 (Tween 80), have been used to determine rifabutin MIC values for mycobacterial species. In general, MIC values determined in broth are several fold lower than that observed with methods employing solid media. Utilization of Tween 80 in these assays has been shown to further lower MIC values. - However, MIC values were substantially higher for egg-based compared to agar-based solid media. - Rifabutin activity against 211 MAC isolates from HIV-positive people was evaluated in vitro utilizing a radiometric broth and an agar dilution method. Results showed that 78% and 82% of these isolates had MIC99 values of ≤0.25 µg/mL and ≤1.0 µg/mL, respectively, when evaluated by these two methods. Rifabutin was also shown to be active against phagocytized, M. avium complex in a mouse macrophage cell culture model. - Rifabutin has in vitro activity against many strains of Mycobacterium tuberculosis. In one study, utilizing the radiometric broth method, each of 17 and 20 rifampin-naive clinical isolates tested from the United States and Taiwan, respectively, were shown to be susceptible to rifabutin concentrations of ≤0.125 µg/mL. - Cross-resistance between rifampin and rifabutin is commonly observed with M. tuberculosis and M. avium complex isolates. Isolates of M. tuberculosis resistant to rifampin are likely to be resistant to rifabutin. Rifampicin and rifabutin MIC99 values against 523 isolates of M. avium complex were determined utilizing the agar dilution method (Ref. Heifets, Leonid B. and Iseman, Michael D. 1985. Determination of in vitro susceptibility of Mycobacteria to Ansamycin. Am. Rev. Respir. Dis. 132 (3):710–711). - Rifabutin in vitro MIC99 values of ≤0.5 µg/mL, determined by the agar dilution method, for M. kansasii, M. gordonae and M. marinum have been reported; however, the clinical significance of these results is unknown. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility - Long-term carcinogenicity studies were conducted with rifabutin in mice and in rats. Rifabutin was not carcinogenic in mice at doses up to 180 mg/kg/day, or approximately 36 times the recommended human daily dose. Rifabutin was not carcinogenic in the rat at doses up to 60 mg/kg/day, about 12 times the recommended human dose. - Rifabutin was not mutagenic in the bacterial mutation assay (Ames Test) using both rifabutin-susceptible and resistant strains. Rifabutin was not mutagenic in Schizosaccharomyces pombe P1 and was not genotoxic in V-79 Chinese hamster cells, human lymphocytes in vitro, or mouse bone marrow cells in vivo. - Fertility was impaired in male rats given 160 mg/kg (32 times the recommended human daily dose). # Clinical Studies - Two randomized, double-blind clinical trials (study 023 and study 027) compared MYCOBUTIN (300 mg/day) to placebo in patients with CDC-defined AIDS and CD4 counts ≤ 200 cells/µL. These studies accrued patients from 2/90 through 2/92. Study 023 enrolled 590 patients, with a median CD4 cell count at study entry of 42 cells/µL (mean 61). Study 027 enrolled 556 patients with a median CD4 cell count at study entry of 40 cells/µL (mean 58). - Endpoints included the following: - MAC bacteremia, defined as at least one blood culture positive for Mycobacterium avium complex (MAC) bacteria. - Clinically significant disseminated MAC disease, defined as MAC bacteremia accompanied by signs or symptoms of serious MAC infection, including one or more of the following: fever, night sweats, rigors, weight loss, worsening anemia, and/or elevations in alkaline phosphatase. - Survival MAC bacteremia - Participants who received MYCOBUTIN were one-third to one-half as likely to develop MAC bacteremia as were participants who received placebo. These results were statistically significant (study 023: p<0.001; study 027: p = 0.002). - In study 023, the one-year cumulative incidence of MAC bacteremia, on an intent to treat basis, was 9% for patients randomized to MYCOBUTIN and 22% for patients randomized to placebo. In study 027, these rates were 13% and 28% for patients receiving MYCOBUTIN and placebo, respectively. - Most cases of MAC bacteremia (approximately 90% in these studies) occurred among participants whose CD4 count at study entry was ≤100 cells/µL. The median and mean CD4 counts at onset of MAC bacteremia were 13 cells/µL and 24 cells/µL, respectively. These studies did not investigate the optimal time to begin MAC prophylaxis. Clinically significant disseminated MAC disease - In association with the decreased incidence of bacteremia, patients on MYCOBUTIN showed reductions in the signs and symptoms of disseminated MAC disease, including fever, night sweats, weight loss, fatigue, abdominal pain, anemia, and hepatic dysfunction. Survival - The one-year survival rates in study 023 were 77% for the group receiving MYCOBUTIN and 77% for the placebo group. In study 027, the one-year survival rates were 77% for the group receiving MYCOBUTIN and 70% for the placebo group. - These differences were not statistically significant. ANIMAL TOXICOLOGY - Liver abnormalities (increased bilirubin and liver weight) occurred in all species tested, in rats at doses 5 times, in monkeys at doses 8 times, and in mice at doses 6 times the recommended human daily dose. Testicular atrophy occurred in baboons at doses 4 times the recommended human dose, and in rats at doses 40 times the recommended human daily dose. # How Supplied - MYCOBUTIN Capsules (rifabutin capsules, USP) are supplied as hard gelatin capsules having an opaque red-brown cap and body, imprinted with MYCOBUTIN/PHARMACIA & UPJOHN in white ink, each containing 150 mg of rifabutin, USP. - MYCOBUTIN is available as follows: - NDC 0013-5301-17- Bottles of 100 capsules ## Storage - Keep tightly closed and dispense in a tight container as defined in the USP. Store at 25°C (77°F); excursions permitted to 15°–30°C (59°–86°F) . # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be advised of the signs and symptoms of both MAC and tuberculosis, and should be instructed to consult their physicians if they develop new complaints consistent with either of these diseases. In addition, since MYCOBUTIN may rarely be associated with myositis and uveitis, patients should be advised to notify their physicians if they develop signs or symptoms suggesting either of these disorders. - Urine, feces, saliva, sputum, perspiration, tears, and skin may be colored brown-orange with rifabutin and some of its metabolites. Soft contact lenses may be permanently stained. Patients to be treated with MYCOBUTIN should be made aware of these possibilities. - Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes, after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible. - There is no reason to believe that MYCOBUTIN has any adverse effect on the ability to drive and/or use machines. # Precautions with Alcohol - Alcohol-Rifabutin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names Mycobutin # Look-Alike Drug Names - A® — B® # Drug Shortage Status # Price	Rifabutin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Deepika Beereddy, MBBS [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Rifabutin is an anti-bacterial, anti-infective agent that is FDA approved for the prophylaxis of disseminated Mycobacterium avium complex (MAC) disease in patients with advanced HIV infection. Common adverse reactions include discoloration of skin, rash, diarrhea, disorder of taste, indigestion, loss of appetite, nausea, vomiting, increased liver aminotransferase level (mild), ocular discoloration, uveitis, abnormal color of body fluid. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - MYCOBUTIN Capsules are indicated for the prevention of disseminated Mycobacterium avium complex (MAC) disease in patients with advanced HIV infection. - Dosing Information - It is recommended that MYCOBUTIN Capsules be administered at a dose of 300 mg once daily. For those patients with propensity to nausea, vomiting, or other gastrointestinal upset, administration of MYCOBUTIN at doses of 150 mg twice daily taken with food may be useful. For patients with severe renal impairment (creatinine clearance less than 30 mL/min), the dose of MYCOBUTIN should be reduced by 50%. No dosage adjustment is required for patients with mild to moderate renal impairment. Reduction of the dose of MYCOBUTIN may also be needed for patients receiving concomitant treatment with certain other drugs. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Rifabutin in adult patients. ### Non–Guideline-Supported Use - Crohn's disease # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Rifabutin FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Rifabutin in pediatric patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Rifabutin in pediatric patients. # Contraindications - MYCOBUTIN Capsules are contraindicated in patients who have had clinically significant hypersensitivity to rifabutin or to any other rifamycins. # Warnings - MYCOBUTIN Capsules must not be administered for MAC prophylaxis to patients with active tuberculosis. Tuberculosis in HIV-positive patients is common and may present with atypical or extrapulmonary findings. Patients are likely to have a nonreactive purified protein derivative (PPD) despite active disease. In addition to chest X-ray and sputum culture, the following studies may be useful in the diagnosis of tuberculosis in the HIV-positive patient: blood culture, urine culture, or biopsy of a suspicious lymph node. - When MYCOBUTIN is used concomitantly with clarithromycin for MAC treatment, a decreased dose of MYCOBUTIN is recommended due to the increase in plasma concentrations of MYCOBUTIN. Due to the possible occurrence of uveitis, patients should also be carefully monitored when MYCOBUTIN is given in combination with clarithromycin (or other macrolides) and/or fluconazole (and related compounds). If uveitis is suspected, the patient should be referred to an ophthalmologist and, if considered necessary, treatment with MYCOBUTIN should be suspended (see also ADVERSE REACTIONS). - Patients who develop complaints consistent with active tuberculosis while on prophylaxis with MYCOBUTIN should be evaluated immediately, so that those with active disease may be given an effective combination regimen of anti-tuberculosis medications. Administration of MYCOBUTIN as a single agent to patients with active tuberculosis is likely to lead to the development of tuberculosis that is resistant both to MYCOBUTIN and to rifampin. - There is no evidence that MYCOBUTIN is effective prophylaxis against M. tuberculosis. Patients requiring prophylaxis against both M. tuberculosis and Mycobacterium avium complex may be given isoniazid and MYCOBUTIN concurrently. - Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including MYCOBUTIN (rifabutin capsules, USP), and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. - C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. - If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. - In accordance with the commonly accepted criteria for the treatment of mycobacterial infections, MYCOBUTIN should always be given in combination with other anti-mycobacterial drugs not belonging to the family of rifamycins. - For patients with severe liver insufficiency a dose reduction should be considered. Mild hepatic impairment does not require a dose modification. - Severe renal impairment (creatinine clearance below 30 mL/min) requires a dosage reduction of 50%. Mild to moderate renal impairment does not require any dosage adjustment. - Protease inhibitors act as substrates or inhibitors of CYP450 IIIA4 mediated metabolism. Therefore, due to significant drug-drug interactions between protease inhibitors and rifabutin, their concomitant use should be based on the overall assessment of the patient and a patient-specific drug profile (see PRECAUTIONS-Drug Interactions). For further recommendations regarding protease inhibitors, please refer to current, official product monographs or contact the specific manufacturer. ### PRECAUTIONS General - Because treatment with MYCOBUTIN Capsules may be associated with neutropenia, and more rarely thrombocytopenia, physicians should consider obtaining hematologic studies periodically in patients receiving prophylaxis with MYCOBUTIN. Information for Patients - Patients should be advised of the signs and symptoms of both MAC and tuberculosis, and should be instructed to consult their physicians if they develop new complaints consistent with either of these diseases. In addition, since MYCOBUTIN may rarely be associated with myositis and uveitis, patients should be advised to notify their physicians if they develop signs or symptoms suggesting either of these disorders. - Urine, feces, saliva, sputum, perspiration, tears, and skin may be colored brown-orange with rifabutin and some of its metabolites. Soft contact lenses may be permanently stained. Patients to be treated with MYCOBUTIN should be made aware of these possibilities. - Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes, after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible. - There is no reason to believe that MYCOBUTIN has any adverse effect on the ability to drive and/or use machines. # Adverse Reactions ## Clinical Trials Experience - MYCOBUTIN Capsules were generally well tolerated in the controlled clinical trials. Discontinuation of therapy due to an adverse event was required in 16% of patients receiving MYCOBUTIN, compared to 8% of patients receiving placebo in these trials. Primary reasons for discontinuation of MYCOBUTIN were rash (4% of treated patients), gastrointestinal intolerance (3%), and neutropenia (2%). - The following table enumerates adverse experiences that occurred at a frequency of 1% or greater, among the patients treated with MYCOBUTIN in studies 023 and 027. CLINICAL ADVERSE EVENTS REPORTED IN <1% OF PATIENTS WHO RECEIVED MYCOBUTIN - Considering data from the 023 and 027 pivotal trials, and from other clinical studies, MYCOBUTIN appears to be a likely cause of the following adverse events which occurred in less than 1% of treated patients: flu-like syndrome, hepatitis, hemolysis, arthralgia, myositis, chest pressure or pain with dyspnea, and skin discoloration. - The following adverse events have occurred in more than one patient receiving MYCOBUTIN, but an etiologic role has not been established: seizure, paresthesia, aphasia, confusion, and non-specific T wave changes on electrocardiogram. - When MYCOBUTIN was administered at doses from 1050 mg/day to 2400 mg/day, generalized arthralgia and uveitis were reported. These adverse experiences abated when MYCOBUTIN was discontinued. - The following table enumerates the changes in laboratory values that were considered as laboratory abnormalities in studies 023 and 027. - The incidence of neutropenia in patients treated with MYCOBUTIN was significantly greater than in patients treated with placebo (p = 0.03). Although thrombocytopenia was not significantly more common among patients treated with MYCOBUTIN in these trials, MYCOBUTIN has been clearly linked to thrombocytopenia in rare cases. One patient in study 023 developed thrombotic thrombocytopenic purpura, which was attributed to MYCOBUTIN. - Uveitis is rare when MYCOBUTIN is used as a single agent at 300 mg/day for prophylaxis of MAC in HIV-infected persons, even with the concomitant use of fluconazole and/or macrolide antibiotics. However, if higher doses of MYCOBUTIN are administered in combination with these agents, the incidence of uveitis is higher. - Patients who developed uveitis had mild to severe symptoms that resolved after treatment with corticosteroids and/or mydriatic eye drops; in some severe cases, however, resolution of symptoms occurred after several weeks. - When uveitis occurs, temporary discontinuance of MYCOBUTIN and ophthalmologic evaluation are recommended. In most mild cases, MYCOBUTIN may be restarted; however, if signs or symptoms recur, use of MYCOBUTIN should be discontinued (Morbidity and Mortality Weekly Report, September 9, 1994). - Adverse reactions identified through clinical trials or post-marketing surveillance by system organ class (SOC) are listed below. - Blood and lymphatic system disorders: Pancytopenia, white blood cell disorders (including agranulocytosis, leukopenia, lymphopenia, granulocytopenia, neutropenia, white blood cell count decreased, neutrophil count decreased), thrombocytopenia, platelet count decreased, anemia. - Immune system disorders: Shock, hypersensitivity, bronchospasm, rash, eosinophilia. - Eye disorders: Uveitis, corneal deposits. - Gastrointestinal disorders: Clostridium difficile colitis , nausea, vomiting. - Hepato-biliary disorders: Jaundice, hepatic enzyme increased. - Skin and subcutaneous tissue disorders: Skin discoloration. - Musculoskeletal and connective tissue disorders: Arthralgia, myalgia. - General disorders and administration site conditions: Pyrexia. - Pyrexia, rash and rarely other hypersensitivity reactions such as eosinophilia, bronchospasm and shock might occur, as has been seen with other antibiotics. A limited number of skin discoloration has been reported. Mild to severe, reversible uveitis has been reported less frequently when MYCOBUTIN is used at 300 mg as monotherapy in MAC prophylaxis versus MYCOBUTIN in combination with clarithromycin for MAC treatment (see also WARNINGS). Corneal deposits have been reported during routine ophthalmologic surveillance of some HIV-positive pediatric patients receiving MYCOBUTIN as part of a multiple drug regimen for MAC prophylaxis. The deposits are tiny, almost transparent, asymptomatic peripheral and central corneal deposits, and do not impair vision. ## Postmarketing Experience - There is limited information regarding Postmarketing Experience of Rifabutin in the drug label. # Drug Interactions - Multiple dosing of rifabutin has been associated with induction of hepatic metabolic enzymes of the CYP450 IIIA subfamily. Rifabutin's predominant metabolite (25-desacetyl rifabutin; LM 565), may also contribute to this effect. Metabolic induction due to rifabutin is likely to produce a decrease in circulating levels of concomitantly administered drugs (especially those metabolized by the CYP450 IIIA pathway). Kinetic data suggest that enzymatic induction by rifabutin is complete within 5 days and is dose-independent over the 300 to 600 mg dose-range. Similarly, concomitant medications that competitively inhibit the CYP450 IIIA activity may increase circulating levels of rifabutin. Malabsorption Gastric pH alteration due to progressing HIV disease has been linked with malabsorption of some drugs used in HIV-positive patients (e.g., rifampin, isoniazid). Drug serum concentration data from AIDS patients with varying disease severity (based on CD4+ counts) suggest that rifabutin absorption is not influenced by progressing HIV disease. Effects on Other Drugs - Rifabutin induces CYP3A enzymes and therefore may reduce the plasma concentrations of drugs metabolized by those enzymes. This effect may reduce the efficacy of standard doses of such drugs, which include itraconazole, clarithromycin, and saquinavir. Effects on Rifabutin - Some drugs that inhibit CYP3A may significantly increase the plasma concentration of rifabutin. Because high plasma levels of rifabutin may increase the risk of adverse reactions, carefully monitor patients receiving coadministration of such drugs, which include fluconazole and clarithromycin. In some cases, the dosage of MYCOBUTIN may need to be reduced when it is coadministered with such a drug (see below). - The following table summarizes the results and magnitude of the pertinent drug interactions assessed with rifabutin. The clinical relevance of these interactions and subsequent dose modifications should be judged in light of the population studied, severity of the disease, patient's drug profile, and the likely impact on the risk/benefit ratio. Other drugs - The structurally similar drug, rifampin, is known to reduce the plasma concentrations of a number of other drugs (see prescribing information for rifampin). Although rifabutin is a weaker enzyme inducer than rifampin, it may be expected to have some effect on those drugs as well. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B - Reproduction studies have been carried out in rats and rabbits given rifabutin using dose levels up to 200 mg/kg (40 times the recommended human daily dose). No teratogenicity was observed in either species. In rats, given 200 mg/kg/day, there was a decrease in fetal viability. In rats, at 40 mg/kg/day (8 times the recommended human daily dose), rifabutin caused an increase in fetal skeletal variants. In rabbits, at 80 mg/kg/day (16 times the recommended human daily dose), rifabutin caused maternotoxicity and increase in fetal skeletal anomalies. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, rifabutin should be used in pregnant women only if the potential benefit justifies the potential risk to the fetus. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category - There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Rifabutin in women who are pregnant. ### Labor and Delivery - There is no FDA guidance on use of Rifabutin during labor and delivery. ### Nursing Mothers - It is not known whether rifabutin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use - Safety and effectiveness of rifabutin for prophylaxis of MAC in children have not been established. Limited safety data are available from treatment use in 22 HIV-positive children with MAC who received MYCOBUTIN in combination with at least two other antimycobacterials for periods from 1 to 183 weeks. Mean doses (mg/kg) for these children were: 18.5 (range 15.0 to 25.0) for infants one year of age, 8.6 (range 4.4 to 18.8) for children 2 to 10 years of age, and 4.0 (range 2.8 to 5.4) for adolescents 14 to 16 years of age. There is no evidence that doses greater than 5 mg/kg daily are useful. Adverse experiences were similar to those observed in the adult population, and included leukopenia, neutropenia, and rash. In addition, corneal deposits have been observed in some patients during routine ophthalmologic surveillance of HIV-positive pediatric patients receiving MYCOBUTIN as part of a multiple-drug regimen for MAC prophylaxis. These are tiny, almost transparent, asymptomatic peripheral and central corneal deposits which do not impair vision. Doses of MYCOBUTIN may be administered mixed with foods such as applesauce. ### Geriatic Use - Clinical studies of MYCOBUTIN did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy (see CLINICAL PHARMACOLOGY). ### Gender - There is no FDA guidance on the use of Rifabutin with respect to specific gender populations. ### Race - There is no FDA guidance on the use of Rifabutin with respect to specific racial populations. ### Renal Impairment - There is no FDA guidance on the use of Rifabutin in patients with renal impairment. ### Hepatic Impairment - There is no FDA guidance on the use of Rifabutin in patients with hepatic impairment. ### Females of Reproductive Potential and Males - There is no FDA guidance on the use of Rifabutin in women of reproductive potentials and males. ### Immunocompromised Patients - There is no FDA guidance one the use of Rifabutin in patients who are immunocompromised. # Administration and Monitoring ### Administration - It is recommended that MYCOBUTIN Capsules be administered at a dose of 300 mg once daily. For those patients with propensity to nausea, vomiting, or other gastrointestinal upset, administration of MYCOBUTIN at doses of 150 mg twice daily taken with food may be useful. For patients with severe renal impairment (creatinine clearance less than 30 mL/min), the dose of MYCOBUTIN should be reduced by 50%. No dosage adjustment is required for patients with mild to moderate renal impairment. Reduction of the dose of MYCOBUTIN may also be needed for patients receiving concomitant treatment with certain other drugs (see PRECAUTIONS-Drug Interactions). ### Monitoring - Due to the possible occurrence of uveitis, patients should be carefully monitored when MYCOBUTIN is given in combination with clarithromycin (or other macrolides) and/or fluconazole (and related compounds). - Some drugs that inhibit CYP3A may significantly increase the plasma concentration of rifabutin. Because high plasma levels of rifabutin may increase the risk of adverse reactions, carefully monitor patients receiving coadministration of such drugs, which include fluconazole and clarithromycin (see PHARMACOLOGY & Drug Interactions). In some cases, the dosage of MYCOBUTIN may need to be reduced when it is coadministered with such a drug (see below). - Amprenavir- A 50% reduction in the rifabutin dose is recommended when combined with amprenavir. Increased monitoring for adverse reactions is warranted. - Lopinavir/ritonavir- Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted. Further dosage reduction of rifabutin may be necessary. - Tipranavir/ritonavir- Therapeutic drug monitoring of rifabutin is recommended. - Posaconazole- If the drugs are co-administered, patients should be monitored for adverse events associated with rifabutin administration. - Voriconazole- If the benefit outweighs the risk, rifabutin may be coadministered with voriconazole if the maintenance dose of voriconazole is increased to 5 mg/kg intravenously every 12 hours or from 200 mg to 350 mg orally, every 12 hours (100 mg to 200 mg orally, every 12 hours in patients less than 40 kg). Careful monitoring of full blood counts and adverse events to rifabutin (e.g. uveitis) is recommended when rifabutin is coadministered with voriconazole. # IV Compatibility - There is limited information regarding IV Compatibility of Rifabutin in the drug label. # Overdosage - No information is available on accidental overdosage in humans. Treatment - While there is no experience in the treatment of overdose with MYCOBUTIN Capsules, clinical experience with rifamycins suggests that gastric lavage to evacuate gastric contents (within a few hours of overdose), followed by instillation of an activated charcoal slurry into the stomach, may help absorb any remaining drug from the gastrointestinal tract. - Rifabutin is 85% protein bound and distributed extensively into tissues (Vss:8 to 9 L/kg). It is not primarily excreted via the urinary route (less than 10% as unchanged drug); therefore, neither hemodialysis nor forced diuresis is expected to enhance the systemic elimination of unchanged rifabutin from the body in a patient with an overdose of MYCOBUTIN. # Pharmacology ## Mechanism of Action - Rifabutin inhibits DNA-dependent RNA polymerase in susceptible strains of Escherichia coli and Bacillus subtilis but not in mammalian cells. In resistant strains of E. coli, rifabutin, like rifampin, did not inhibit this enzyme. It is not known whether rifabutin inhibits DNA-dependent RNA polymerase in Mycobacterium avium or in M. intracellulare which comprise M. avium complex (MAC). ## Structure - MYCOBUTIN Capsules contain the antimycobacterial agent rifabutin, which is a semisynthetic ansamycin antibiotic derived from rifamycin S. MYCOBUTIN Capsules for oral administration contain 150 mg of rifabutin, USP, per capsule, along with the inactive ingredients microcrystalline cellulose, magnesium stearate, red iron oxide, silica gel, sodium lauryl sulfate, titanium dioxide, and edible white ink. - The chemical name for rifabutin is 1',4-didehydro-1-deoxy-1,4-dihydro-5'-(2-methylpropyl)-1-oxorifamycin XIV (Chemical Abstracts Service, 9th Collective Index) or (9S, 12E, 14S, 15R, 16S, 17R, 18R, 19R, 20S, 21S, 22E, 24Z)-6,16,18,20-tetrahydroxy-1'-isobutyl-14-methoxy-7,9,15,17,19,21,25-heptamethyl-spiro [9,4-(epoxypentadeca[1,11,13]trienimino)-2H-furo[2',3':7,8]naphth[1,2-d] imidazole-2,4'-piperidine]-5,10,26-(3H,9H)-trione-16-acetate. Rifabutin has a molecular formula of C46H62N4O11, a molecular weight of 847.02 and the following structure: - Rifabutin is a red-violet powder soluble in chloroform and methanol, sparingly soluble in ethanol, and very slightly soluble in water (0.19 mg/mL). Its log P value (the base 10 logarithm of the partition coefficient between n-octanol and water) is 3.2 (n-octanol/water). ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Rifabutin in the drug label. ## Pharmacokinetics Absorption - Following a single oral dose of 300 mg to nine healthy adult volunteers, rifabutin was readily absorbed from the gastrointestinal tract with mean (±SD) peak plasma levels (Cmax) of 375 (±267) ng/mL (range: 141 to 1033 ng/mL) attained in 3.3 (±0.9) hours (Tmax range: 2 to 4 hours). Absolute bioavailability assessed in five HIV-positive patients, who received both oral and intravenous doses, averaged 20%. Total recovery of radioactivity in the urine indicates that at least 53% of the orally administered rifabutin dose is absorbed from the gastrointestinal tract. The bioavailability of rifabutin from the capsule dosage form, relative to an oral solution, was 85% in 12 healthy adult volunteers. High-fat meals slow the rate without influencing the extent of absorption from the capsule dosage form. Plasma concentrations post-Cmax declined in an apparent biphasic manner. Pharmacokinetic dose-proportionality was established over the 300 to 600 mg dose range in nine healthy adult volunteers (crossover design) and in 16 early symptomatic human immunodeficiency virus (HIV)-positive patients over a 300 to 900 mg dose range. Distribution - Due to its high lipophilicity, rifabutin demonstrates a high propensity for distribution and intracellular tissue uptake. Following intravenous dosing, estimates of apparent steady-state distribution volume (9.3 ± 1.5 L/kg) in five HIV-positive patients exceeded total body water by approximately 15-fold. Substantially higher intracellular tissue levels than those seen in plasma have been observed in both rat and man. The lung-to-plasma concentration ratio, obtained at 12 hours, was approximately 6.5 in four surgical patients who received an oral dose. Mean rifabutin steady-state trough levels (Cp,minss; 24-hour post-dose) ranged from 50 to 65 ng/mL in HIV-positive patients and in healthy adult volunteers. About 85% of the drug is bound in a concentration-independent manner to plasma proteins over a concentration range of 0.05 to 1 µg/mL. Binding does not appear to be influenced by renal or hepatic dysfunction. Rifabutin was slowly eliminated from plasma in seven healthy adult volunteers, presumably because of distribution-limited elimination, with a mean terminal half-life of 45 (±17) hours (range: 16 to 69 hours). Although the systemic levels of rifabutin following multiple dosing decreased by 38%, its terminal half-life remained unchanged. Metabolism - Of the five metabolites that have been identified, 25-O-desacetyl and 31-hydroxy are the most predominant, and show a plasma metabolite:parent area under the curve ratio of 0.10 and 0.07, respectively. The former has an activity equal to the parent drug and contributes up to 10% to the total antimicrobial activity. Excretion - A mass-balance study in three healthy adult volunteers with 14C-labeled rifabutin showed that 53% of the oral dose was excreted in the urine, primarily as metabolites. About 30% of the dose is excreted in the feces. Mean systemic clearance (CLs/F) in healthy adult volunteers following a single oral dose was 0.69 (±0.32) L/hr/kg (range: 0.46 to 1.34 L/hr/kg). Renal and biliary clearance of unchanged drug each contribute approximately 5% to CLs/F. Pharmacokinetics in Special Populations Geriatric - Compared to healthy volunteers, steady-state kinetics of MYCOBUTIN are more variable in elderly patients (>70 years). Pediatric - The pharmacokinetics of MYCOBUTIN have not been studied in subjects under 18 years of age. Renal Insufficiency - The disposition of rifabutin (300 mg) was studied in 18 patients with varying degrees of renal function. Area under plasma concentration time curve (AUC) increased by about 71% in patients with severe renal insufficiency (creatinine clearance below 30 mL/min) compared to patients with creatinine clearance (Crcl) between 61–74 mL/min. In patients with mild to moderate renal insufficiency (Crcl between 30–61 mL/min), the AUC increased by about 41%. A reduction in the dosage of rifabutin is recommended for patients with Crcl< 30 mL/min (see DOSAGE AND ADMINISTRATION). Drug-Drug Interactions - (see also PRECAUTIONS-Drug Interactions) - Rifabutin induces the enzymes of the cytochrome P450 3A subfamily (CYP3A) and therefore may reduce the plasma concentrations of drugs that are principally metabolized by those enzymes. Rifabutin is also metabolized by CYP3A. Thus, some drugs that inhibit CYP3A may significantly increase plasma concentrations of rifabutin. Antifungals Fluconazole - Fluconazole (200 mg/day for 2 weeks) increased the AUC of rifabutin (300 mg/day for 2 weeks) by 82% and Cmax by 88% in 12 HIV-infected patients who were on zidovudine (500 mg/day) maintenance therapy (see PRECAUTIONS-Drug Interactions). Rifabutin did not affect the pharmacokinetics of fluconazole. Itraconazole - Coadministration of itraconazole (200 mg/day) with rifabutin (300 mg/day) in six HIV-infected patients reduced both the AUC and Cmax of itraconazole by 70% to 75% (see PRECAUTIONS-Drug Interactions). Antipneumocystis Agents Dapsone - Rifabutin (300 mg/day) decreased the AUC of dapsone (50 mg/day) in HIV-infected patients (n=16) by about 27% to 40%. Sulfamethoxazole-trimethoprim - Coadministration of rifabutin (300 mg/day) and sulfamethoxazole-trimethoprim (double strength) in 12 HIV-infected patients decreased the AUC of sulfamethoxazole-trimethoprim by about 15% to 20%. When trimethoprim was given alone, the AUC of trimethoprim was decreased by 14% and the Cmax by 6%. - Sulfamethoxazole-trimethoprim did not alter the pharmacokinetics of rifabutin. Antiretroviral Agents Delavirdine - In 7 HIV-infected patients, rifabutin (300 mg/day) decreased delavirdine (400 mg q 8h) AUC by about 80%, Cmax by about 75%, and mean trough plasma concentrations by about 95%. Based on comparisons with historical data, delavirdine appeared to increase the AUC of rifabutin by at least 100% (see PRECAUTIONS-Drug Interactions). Didanosine - In 12 HIV-infected patients, coadministration of rifabutin (300 or 600 mg/day) and didanosine (167–375 mg BID) did not alter the pharmacokinetics of either drug. Indinavir - In healthy volunteers, coadministration of indinavir (800 mg q 8h) and rifabutin (300 mg/day) decreased the AUC of indinavir by about 30% and increased the AUC of rifabutin by about 200% (see PRECAUTIONS-Drug Interactions). Nelfinavir - Coadministration of nelfinavir (750 mg q 8h for 8 days) and rifabutin (300 mg/day for 7–8 days) decreased the AUC and Cmax of nelfinavir by about 32% and 25%, respectively, and increased the AUC and Cmax of rifabutin by about 207% and 146%, respectively (see PRECAUTIONS-Drug Interactions). Ritonavir - Coadministration of ritonavir (500 mg q 12h) and rifabutin (150 mg/day) increased the AUC and Cmax of rifabutin by more than 400% and 250%, respectively (see PRECAUTIONS-Drug Interactions). Saquinavir - In 12 HIV-infected patients, rifabutin (300 mg/day) decreased the AUC of saquinavir (600 mg TID) by about 40% (see PRECAUTIONS-Drug Interactions). Zidovudine - In 16 HIV-infected patients on zidovudine (100 or 200 mg q 4h), rifabutin (300 or 450 mg/day) lowered the Cmax and AUC of zidovudine by about 48% and 32%, respectively. However, zidovudine levels remained within the therapeutic range during coadministration of rifabutin. Zidovudine did not affect the pharmacokinetics of rifabutin. Antituberculosis Agents - In studies conducted in healthy volunteers, rifabutin (300 mg) did not alter the pharmacokinetics of ethambutol (n=10) or isoniazid (n=10). Macrolides Clarithromycin - In studies conducted in HIV-infected patients, coadministration of rifabutin (300 mg/day) and clarithromycin (500 mg q 12h) decreased the AUC of clarithromycin by about 50% (n=12) and increased the AUC of rifabutin by about 75% (n=14) (see PRECAUTIONS-Drug Interactions). Other Drugs Methadone - Rifabutin did not alter the pharmacokinetics of methadone in 24 HIV-infected, methadone-maintained, former intravenous drug users. Oral contraceptives - In 22 healthy female volunteers receiving an oral contraceptive (35 mcg ethinylestradiol (EE) and 1 mg norethindrone (NE) daily for 21 days), rifabutin decreased EE (AUC) and Cmax by 35% and 20%, respectively, and NE AUC by 46% (see PRECAUTIONS-Drug Interactions). Theophylline - Rifabutin did not alter the pharmacokinetics of theophylline when coadministered in 11 healthy volunteers. Other drugs - The structurally similar drug, rifampin, is known to reduce the plasma concentrations of a number of other drugs (see prescribing information for rifampin). Although rifabutin is a weaker enzyme inducer than rifampin, rifabutin may be expected to have some effect on those drugs as well. ### MICROBIOLOGY Mechanism of Action - Rifabutin inhibits DNA-dependent RNA polymerase in susceptible strains of Escherichia coli and Bacillus subtilis but not in mammalian cells. In resistant strains of E. coli, rifabutin, like rifampin, did not inhibit this enzyme. It is not known whether rifabutin inhibits DNA-dependent RNA polymerase in Mycobacterium avium or in M. intracellulare which comprise M. avium complex (MAC). Susceptibility Testing - In vitro susceptibility testing methods and diagnostic products used for determining minimum inhibitory concentration (MIC) values against M. avium complex (MAC) organisms have not been standardized. Breakpoints to determine whether clinical isolates of MAC and other mycobacterial species are susceptible or resistant to rifabutin have not been established. In Vitro Studies - Rifabutin has demonstrated in vitro activity against [[[M. avium complex]] (MAC) organisms isolated from both HIV-positive and HIV-negative people. While gene probe techniques may be used to identify these two organisms, many reported studies did not distinguish between these two species. The vast majority of isolates from MAC-infected, HIV-positive people are M. avium, whereas in HIV-negative people, about 40% of the MAC isolates are M. intracellulare. - Various in vitro methodologies employing broth or solid media, with and without polysorbate 80 (Tween 80), have been used to determine rifabutin MIC values for mycobacterial species. In general, MIC values determined in broth are several fold lower than that observed with methods employing solid media. Utilization of Tween 80 in these assays has been shown to further lower MIC values. - However, MIC values were substantially higher for egg-based compared to agar-based solid media. - Rifabutin activity against 211 MAC isolates from HIV-positive people was evaluated in vitro utilizing a radiometric broth and an agar dilution method. Results showed that 78% and 82% of these isolates had MIC99 values of ≤0.25 µg/mL and ≤1.0 µg/mL, respectively, when evaluated by these two methods. Rifabutin was also shown to be active against phagocytized, M. avium complex in a mouse macrophage cell culture model. - Rifabutin has in vitro activity against many strains of Mycobacterium tuberculosis. In one study, utilizing the radiometric broth method, each of 17 and 20 rifampin-naive clinical isolates tested from the United States and Taiwan, respectively, were shown to be susceptible to rifabutin concentrations of ≤0.125 µg/mL. - Cross-resistance between rifampin and rifabutin is commonly observed with M. tuberculosis and M. avium complex isolates. Isolates of M. tuberculosis resistant to rifampin are likely to be resistant to rifabutin. Rifampicin and rifabutin MIC99 values against 523 isolates of M. avium complex were determined utilizing the agar dilution method (Ref. Heifets, Leonid B. and Iseman, Michael D. 1985. Determination of in vitro susceptibility of Mycobacteria to Ansamycin. Am. Rev. Respir. Dis. 132 (3):710–711). - Rifabutin in vitro MIC99 values of ≤0.5 µg/mL, determined by the agar dilution method, for M. kansasii, M. gordonae and M. marinum have been reported; however, the clinical significance of these results is unknown. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility - Long-term carcinogenicity studies were conducted with rifabutin in mice and in rats. Rifabutin was not carcinogenic in mice at doses up to 180 mg/kg/day, or approximately 36 times the recommended human daily dose. Rifabutin was not carcinogenic in the rat at doses up to 60 mg/kg/day, about 12 times the recommended human dose. - Rifabutin was not mutagenic in the bacterial mutation assay (Ames Test) using both rifabutin-susceptible and resistant strains. Rifabutin was not mutagenic in Schizosaccharomyces pombe P1 and was not genotoxic in V-79 Chinese hamster cells, human lymphocytes in vitro, or mouse bone marrow cells in vivo. - Fertility was impaired in male rats given 160 mg/kg (32 times the recommended human daily dose). # Clinical Studies - Two randomized, double-blind clinical trials (study 023 and study 027) compared MYCOBUTIN (300 mg/day) to placebo in patients with CDC-defined AIDS and CD4 counts ≤ 200 cells/µL. These studies accrued patients from 2/90 through 2/92. Study 023 enrolled 590 patients, with a median CD4 cell count at study entry of 42 cells/µL (mean 61). Study 027 enrolled 556 patients with a median CD4 cell count at study entry of 40 cells/µL (mean 58). - Endpoints included the following: - MAC bacteremia, defined as at least one blood culture positive for Mycobacterium avium complex (MAC) bacteria. - Clinically significant disseminated MAC disease, defined as MAC bacteremia accompanied by signs or symptoms of serious MAC infection, including one or more of the following: fever, night sweats, rigors, weight loss, worsening anemia, and/or elevations in alkaline phosphatase. - Survival MAC bacteremia - Participants who received MYCOBUTIN were one-third to one-half as likely to develop MAC bacteremia as were participants who received placebo. These results were statistically significant (study 023: p<0.001; study 027: p = 0.002). - In study 023, the one-year cumulative incidence of MAC bacteremia, on an intent to treat basis, was 9% for patients randomized to MYCOBUTIN and 22% for patients randomized to placebo. In study 027, these rates were 13% and 28% for patients receiving MYCOBUTIN and placebo, respectively. - Most cases of MAC bacteremia (approximately 90% in these studies) occurred among participants whose CD4 count at study entry was ≤100 cells/µL. The median and mean CD4 counts at onset of MAC bacteremia were 13 cells/µL and 24 cells/µL, respectively. These studies did not investigate the optimal time to begin MAC prophylaxis. Clinically significant disseminated MAC disease - In association with the decreased incidence of bacteremia, patients on MYCOBUTIN showed reductions in the signs and symptoms of disseminated MAC disease, including fever, night sweats, weight loss, fatigue, abdominal pain, anemia, and hepatic dysfunction. Survival - The one-year survival rates in study 023 were 77% for the group receiving MYCOBUTIN and 77% for the placebo group. In study 027, the one-year survival rates were 77% for the group receiving MYCOBUTIN and 70% for the placebo group. - These differences were not statistically significant. ANIMAL TOXICOLOGY - Liver abnormalities (increased bilirubin and liver weight) occurred in all species tested, in rats at doses 5 times, in monkeys at doses 8 times, and in mice at doses 6 times the recommended human daily dose. Testicular atrophy occurred in baboons at doses 4 times the recommended human dose, and in rats at doses 40 times the recommended human daily dose. # How Supplied - MYCOBUTIN Capsules (rifabutin capsules, USP) are supplied as hard gelatin capsules having an opaque red-brown cap and body, imprinted with MYCOBUTIN/PHARMACIA & UPJOHN in white ink, each containing 150 mg of rifabutin, USP. - MYCOBUTIN is available as follows: - NDC 0013-5301-17- Bottles of 100 capsules ## Storage - Keep tightly closed and dispense in a tight container as defined in the USP. Store at 25°C (77°F); excursions permitted to 15°–30°C (59°–86°F) [see USP Controlled Room Temperature]. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be advised of the signs and symptoms of both MAC and tuberculosis, and should be instructed to consult their physicians if they develop new complaints consistent with either of these diseases. In addition, since MYCOBUTIN may rarely be associated with myositis and uveitis, patients should be advised to notify their physicians if they develop signs or symptoms suggesting either of these disorders. - Urine, feces, saliva, sputum, perspiration, tears, and skin may be colored brown-orange with rifabutin and some of its metabolites. Soft contact lenses may be permanently stained. Patients to be treated with MYCOBUTIN should be made aware of these possibilities. - Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes, after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible. - There is no reason to believe that MYCOBUTIN has any adverse effect on the ability to drive and/or use machines. # Precautions with Alcohol - Alcohol-Rifabutin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names Mycobutin # Look-Alike Drug Names - A® — B®[1] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Mycobutin
54e849b2f82bd37a5793a551d53f4e3e5b32249d	wikidoc	Norovirus	Norovirus # Overview Norovirus is the cause of norovirus infection. Noroviruses (genus Norovirus) are a group of related, single-stranded RNA, nonenveloped viruses that cause acute gastroenteritis in humans. Noroviruses belong to the family Caliciviridae. # Causes ## Common Causes Norovirus is transmitted through person-to-person contact, food and water. Genotype GII.4 is mostly contact transmitted. Non-GII.4 genotypes such as GI.3, GI.6, GI.7, GII.3, GII.6 and GII.12 are mostly food-borne. Genogroup GI strains are more often transmitted through water. This is due to their higher stability in water compared to other strains of the virus. Norovirus is among top ranks of food-borne viruses, globally. Transmission could occur in different stages of pre- and post-production of the food products. For instance, shellfish can be contaminated with fecal discharge in the water, fresh and frozen berries could be contaminated through water contaminated by sewage or contact during harvesting. Viral outbreaks through food-borne transmission can lead to a mixture of the viral strain and increased risk of genetic recombination. Studies show that about 7% of the foodborne outbreaks have a common source. ## Less Common Causes Norovirus also has a nosocomial transition, causing a major burden for health care services. Immunocompromised patients may develop numerous norovirus variations due to the chronic infection. This intra-host viral variation may lead to the appearance of variants not similar to any of the ones of previous outbreaks, thus can escape the herd immunity. To date, animal norovirus strains have not been reported to infect human population, but there has been evidence of intra-species transmission. Human norovirus has been detected in the stools of pigs, cattle and dogs.	Norovirus Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Norovirus is the cause of norovirus infection. Noroviruses (genus Norovirus) are a group of related, single-stranded RNA, nonenveloped viruses that cause acute gastroenteritis in humans. Noroviruses belong to the family Caliciviridae. # Causes ## Common Causes Norovirus is transmitted through person-to-person contact, food and water. Genotype GII.4 is mostly contact transmitted. Non-GII.4 genotypes such as GI.3, GI.6, GI.7, GII.3, GII.6 and GII.12 are mostly food-borne. Genogroup GI strains are more often transmitted through water. This is due to their higher stability in water compared to other strains of the virus.[1][2] Norovirus is among top ranks of food-borne viruses, globally[3]. Transmission could occur in different stages of pre- and post-production of the food products. For instance, shellfish can be contaminated with fecal discharge in the water[4], fresh and frozen berries could be contaminated through water contaminated by sewage or contact during harvesting. Viral outbreaks through food-borne transmission can lead to a mixture of the viral strain and increased risk of genetic recombination. Studies show that about 7% of the foodborne outbreaks have a common source[5]. ## Less Common Causes Norovirus also has a nosocomial transition, causing a major burden for health care services[6]. Immunocompromised patients may develop numerous norovirus variations due to the chronic infection. This intra-host viral variation may lead to the appearance of variants not similar to any of the ones of previous outbreaks, thus can escape the herd immunity.[7][1] To date, animal norovirus strains have not been reported to infect human population, but there has been evidence of intra-species transmission. Human norovirus has been detected in the stools of pigs, cattle and dogs.[1]	https://www.wikidoc.org/index.php/NLV
d509c4519f0df1c4eb4236bc70071189fa429dab	wikidoc	Nafarelin	Nafarelin # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Nafarelin is a fertility agent that is FDA approved for the treatment of endometriosis, including pain relief and reduction of endometriotic lesions, central precocious puberty. Common adverse reactions include acne, hot sweats, decreased bone mineral density, headache, mood swings, abnormal vaginal bleeding, erectile dysfunction, swelling of breast, vaginal dryness. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - SYNAREL is indicated for management of endometriosis, including pain relief and reduction of endometriotic lesions. Experience with SYNAREL for the management of endometriosis has been limited to women 18 years of age and older treated for 6 months. - Dosing Information - For the management of endometriosis, the recommended daily dose of SYNAREL is 400 µg. This is achieved by one spray (200 µg) into one nostril in the morning and one spray into the other nostril in the evening. Treatment should be started between days 2 and 4 of the menstrual cycle. - In an occasional patient, the 400 µg daily dose may not produce amenorrhea. For these patients with persistent regular menstruation after 2 months of treatment, the dose of SYNAREL may be increased to 800 µg daily. The 800 µg dose is administered as one spray into each nostril in the morning (a total of two sprays) and again in the evening. - The recommended duration of administration is six months. Retreatment cannot be recommended since safety data for retreatment are not available. If the symptoms of endometriosis recur after a course of therapy, and further treatment with SYNAREL is contemplated, it is recommended that bone density be assessed before retreatment begins to ensure that values are within normal limits. - There appeared to be no significant effect of rhinitis, i.e., nasal congestion, on the systemic bioavailability of SYNAREL; however, if the use of a nasal decongestant for rhinitis is necessary during treatment with SYNAREL, the decongestant should not be used until at least 2 hours following dosing with SYNAREL. - Sneezing during or immediately after dosing with SYNAREL should be avoided, if possible, since this may impair drug absorption. - At 400 µg/day, a bottle of SYNAREL provides a 30-day (about 60 sprays) supply. If the daily dose is increased, increase the supply to the patient to ensure uninterrupted treatment for the recommended duration of therapy. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Nafarelin in adult patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Nafarelin in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ### CENTRAL PRECOCIOUS PUBERTY - SYNAREL is indicated for treatment of central precocious puberty (CPP) (gonadotropin-dependent precocious puberty) in children of both sexes. - The diagnosis of central precocious puberty (CPP) is suspected when premature development of secondary sexual characteristics occurs at or before the age of 8 years in girls and 9 years in boys, and is accompanied by significant advancement of bone age and/or a poor adult height prediction. The diagnosis should be confirmed by pubertal gonadal sex steroid levels and a pubertal LH response to stimulation by native GnRH. Pelvic ultrasound assessment in girls usually reveals enlarged uterus and ovaries, the latter often with multiple cystic formations. Magnetic resonance imaging or CT-scanning of the brain is recommended to detect hypothalamic or pituitary tumors, or anatomical changes associated with increased intracranial pressure. Other causes of sexual precocity, such as congenital adrenal hyperplasia, testotoxicosis, testicular tumors and/or other autonomous feminizing or masculinizing disorders must be excluded by proper clinical hormonal and diagnostic imaging examinations. - Dosing Information - For the treatment of central precocious puberty (CPP), the recommended daily dose of SYNAREL is 1600 µg. The dose can be increased to 1800 µg daily if adequate suppression cannot be achieved at 1600 µg/day. - The 1600 µg dose is achieved by two sprays (400 µg) into each nostril in the morning (4 sprays) and two sprays into each nostril in the evening (4 sprays), a total of 8 sprays per day. The 1800 µg dose is achieved by 3 sprays (600 µg) into alternating nostrils three times a day, a total of 9 sprays per day. The patient's head should be tilted back slightly, and 30 seconds should elapse between sprays. - If the prescribed therapy has been well tolerated by the patient, treatment of CPP with SYNAREL should continue until resumption of puberty is desired. - There appeared to be no significant effect of rhinitis, i.e., nasal congestion, on the systemic bioavailability of SYNAREL; however, if the use of a nasal decongestant for rhinitis is necessary during treatment with SYNAREL, the decongestant should not be used until at least 2 hours following dosing with SYNAREL. - Sneezing during or immediately after dosing with SYNAREL should be avoided, if possible, since this may impair drug absorption. - At 1600 µg/day, a bottle of SYNAREL provides about a 7-day supply (about 56 sprays). If the daily dose is increased, increase the supply to the patient to ensure uninterrupted treatment for the duration of therapy. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Nafarelin in pediatric patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Nafarelin in pediatric patients. # Contraindications - Hypersensitivity to GnRH, GnRH agonist analogs or any of the excipients in SYNAREL; - Undiagnosed abnormal vaginal bleeding; - Use in pregnancy or in women who may become pregnant while receiving the drug. SYNAREL may cause fetal harm when administered to a pregnant woman. Major fetal abnormalities were observed in rats, but not in mice or rabbits after administration of SYNAREL during the period of organogenesis. There was a dose-related increase in fetal mortality and a decrease in fetal weight in rats (see Pregnancy Section). The effects on rat fetal mortality are expected consequences of the alterations in hormonal levels brought about by the drug. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, she should be apprised of the potential hazard to the fetus; - Use in women who are breast-feeding (see Nursing Mothers Section). # Warnings - The diagnosis of central precocious puberty (CPP) must be established before treatment is initiated. Regular monitoring of CPP patients is needed to assess both patient response as well as compliance. This is particularly important during the first 6 to 8 weeks of treatment to assure that suppression of pituitary-gonadal function is rapid. Testing may include LH response to GnRH stimulation and circulating gonadal sex steroid levels. Assessment of growth velocity and bone age velocity should begin within 3 to 6 months of treatment initiation. - Some patients may not show suppression of the pituitary-gonadal axis by clinical and/or biochemical parameters. This may be due to lack of compliance with the recommended treatment regimen and may be rectified by recommending that the dosing be done by caregivers. If compliance problems are excluded, the possibility of gonadotropin independent sexual precocity should be reconsidered and appropriate examinations should be conducted. If compliance problems are excluded and if gonadotropin independent sexual precocity is not present, the dose of SYNAREL may be increased to 1800 µg/day administered as 600 µg tid. ### Precautions General - As with other drugs that stimulate the release of gonadotropins or that induce ovulation, in adult women with endometriosis ovarian cysts have been reported to occur in the first two months of therapy with SYNAREL. Many, but not all, of these events occurred in women with polycystic ovarian disease. These cystic enlargements may resolve spontaneously, generally by about four to six weeks of therapy, but in some cases may require discontinuation of drug and/or surgical intervention. The relevance, if any, of such events in children is unknown. Information for Patients, Patients' Parents or Guardians - An information pamphlet for patients is included with the product. Patients and their caregivers should be aware of the following information: - Reversibility of the suppressive effects of nafarelin has been demonstrated by the appearance or return of menses, by the return of pubertal gonadotropin and gonadal sex steroid levels, and/or by advancement of secondary sexual development. Semen analysis was normal in the two ejaculated specimens obtained thus far from boys who have been taken off therapy to resume puberty. Fertility has not been documented by pregnancies and the effect of long-term use of the drug on fertility is not known. - Patients and their caregivers should be adequately counseled to assure full compliance; irregular or incomplete daily doses may result in stimulation of the pituitary-gonadal axis. - During the first month of treatment with SYNAREL, some signs of puberty, e.g., vaginal bleeding or breast enlargement, may occur. This is the expected initial effect of the drug. Such changes should resolve soon after the first month. lf such resolution does not occur within the first two months of treatment, this may be due to lack of compliance or the presence of gonadotropin independent sexual precocity. If both possibilities are definitively excluded, the dose of SYNAREL may be increased to 1800 µg/day administered as 600 µg tid. - Patients with intercurrent rhinitis should consult their physician for the use of a topical nasal decongestant. If the use of a topical nasal decongestant is required during treatment with SYNAREL, the decongestant should not be used until at least 2 hours following dosing with SYNAREL. - Sneezing during or immediately after dosing with SYNAREL should be avoided, if possible, since this may impair drug absorption. # Adverse Reactions ## Clinical Trials Experience - In clinical trials of 155 pediatric patients, 2.6% reported symptoms suggestive of drug sensitivity, such as shortness of breath, chest pain, urticaria, rash, and pruritus. - In these 155 patients treated for an average of 41 months and as long as 80 months (6.7 years), adverse events most frequently reported (>3% of patients) consisted largely of episodes occurring during the first 6 weeks of treatment as a result of the transient stimulatory action of nafarelin upon the pituitary-gonadal axis: - acne (10%) - transient breast enlargement (8%) - vaginal bleeding (8%) - emotional lability (6%) - transient increase in pubic hair (5%) - body odor (4%) - seborrhea (3%) - Hot flashes, common in adult women treated for endometriosis, occurred in only 3% of treated children and were transient. Other adverse events thought to be drug-related, and occurring in >3% of patients were rhinitis (5%) and white or brownish vaginal discharge (3%). Approximately 3% of patients withdrew from clinical trials due to adverse events. - In one male patient with concomitant congenital adrenal hyperplasia, and who had discontinued treatment 8 months previously to resume puberty, adrenal rest tumors were found in the left testis. Relationship to SYNAREL is unlikely. - Regular examinations of the pituitary gland by magnetic resonance imaging (MRI) or computer assisted tomography (CT) of children during long-term nafarelin therapy as well as during the post-treatment period has occasionally revealed changes in the shape and size of the pituitary gland. These changes include asymmetry and enlargement of the pituitary gland, and a pituitary microadenoma has been suspected in a few children. The relationship of these findings to SYNAREL is not known. ## Postmarketing Experience Pituitary apoplexy - During post-marketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of gonadotropin-releasing hormone agonists. In a majority of these cases, a pituitary adenoma was diagnosed, with a majority of pituitary apoplexy cases occurring within 2 weeks of the first dose, and some within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required. Central/peripheral nervous adverse events - Convulsion. # Drug Interactions - No pharmacokinetic-based drug-drug interaction studies have been conducted with SYNAREL. However, because nafarelin acetate is a peptide that is primarily degraded by peptidase and not by cytochrome P-450 enzymes, and the drug is only about 80% bound to plasma proteins at 4°C, drug interactions would not be expected to occur. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): X Teratogenic Effects - Pregnancy Category X. See 'CONTRAINDICATIONS.' Intramuscular SYNAREL was administered to rats during the period of organogenesis at 0.4, 1.6, and 6.4 µg/kg/day (about 0.5, 2, and 7 times the maximum recommended human intranasal dose based on the relative bioavailability by the two routes of administration). An increase in major fetal abnormalities was observed in 4/80 fetuses at the highest dose. A similar, repeat study at the same doses in rats and studies in mice and rabbits at doses up to 600 µg/kg/day and 0.18 µg/kg/day, respectively, failed to demonstrate an increase in fetal abnormalities after administration during the period of organogenesis. In rats and rabbits, there was a dose-related increase in fetal mortality and a decrease in fetal weight with the highest dose. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category - There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nafarelin in women who are pregnant. ### Labor and Delivery - There is no FDA guidance on use of Nafarelin during labor and delivery. ### Nursing Mothers - It is not known whether SYNAREL is excreted in human milk. Because many drugs are excreted in human milk, and because the effects of SYNAREL on lactation and/or the breastfed child have not been determined, SYNAREL should not be used by nursing mothers. ### Pediatric Use - There is no FDA guidance on the use of Nafarelin with respect to pediatric patients. ### Geriatic Use - There is no FDA guidance on the use of Nafarelin with respect to geriatric patients. ### Gender - There is no FDA guidance on the use of Nafarelin with respect to specific gender populations. ### Race - There is no FDA guidance on the use of Nafarelin with respect to specific racial populations. ### Renal Impairment - There is no FDA guidance on the use of Nafarelin in patients with renal impairment. ### Hepatic Impairment - There is no FDA guidance on the use of Nafarelin in patients with hepatic impairment. ### Females of Reproductive Potential and Males - There is no FDA guidance on the use of Nafarelin in women of reproductive potentials and males. ### Immunocompromised Patients - There is no FDA guidance one the use of Nafarelin in patients who are immunocompromised. # Administration and Monitoring ### Administration - For the treatment of central precocious puberty (CPP), the recommended daily dose of SYNAREL is 1600 µg. The dose can be increased to 1800 µg daily if adequate suppression cannot be achieved at 1600 µg/day. - The 1600 µg dose is achieved by two sprays (400 µg) into each nostril in the morning (4 sprays) and two sprays into each nostril in the evening (4 sprays), a total of 8 sprays per day. The 1800 µg dose is achieved by 3 sprays (600 µg) into alternating nostrils three times a day, a total of 9 sprays per day. The patient's head should be tilted back slightly, and 30 seconds should elapse between sprays. - If the prescribed therapy has been well tolerated by the patient, treatment of CPP with SYNAREL should continue until resumption of puberty is desired. - There appeared to be no significant effect of rhinitis, i.e., nasal congestion, on the systemic bioavailability of SYNAREL; however, if the use of a nasal decongestant for rhinitis is necessary during treatment with SYNAREL, the decongestant should not be used until at least 2 hours following dosing with SYNAREL. - Sneezing during or immediately after dosing with SYNAREL should be avoided, if possible, since this may impair drug absorption. - At 1600 µg/day, a bottle of SYNAREL provides about a 7-day supply (about 56 sprays). If the daily dose is increased, increase the supply to the patient to ensure uninterrupted treatment for the duration of therapy. - For the management of endometriosis, the recommended daily dose of SYNAREL is 400 µg. This is achieved by one spray (200 µg) into one nostril in the morning and one spray into the other nostril in the evening. Treatment should be started between days 2 and 4 of the menstrual cycle. - In an occasional patient, the 400 µg daily dose may not produce amenorrhea. For these patients with persistent regular menstruation after 2 months of treatment, the dose of SYNAREL may be increased to 800 µg daily. The 800 µg dose is administered as one spray into each nostril in the morning (a total of two sprays) and again in the evening. - The recommended duration of administration is six months. Retreatment cannot be recommended since safety data for retreatment are not available. If the symptoms of endometriosis recur after a course of therapy, and further treatment with SYNAREL is contemplated, it is recommended that bone density be assessed before retreatment begins to ensure that values are within normal limits. - There appeared to be no significant effect of rhinitis, i.e., nasal congestion, on the systemic bioavailability of SYNAREL; however, if the use of a nasal decongestant for rhinitis is necessary during treatment with SYNAREL, the decongestant should not be used until at least 2 hours following dosing with SYNAREL. - Sneezing during or immediately after dosing with SYNAREL should be avoided, if possible, since this may impair drug absorption. - At 400 µg/day, a bottle of SYNAREL provides a 30-day (about 60 sprays) supply. If the daily dose is increased, increase the supply to the patient to ensure uninterrupted treatment for the recommended duration of therapy. ### Monitoring - There is limited information regarding Monitoring of Nafarelin in the drug label. # IV Compatibility - There is limited information regarding IV Compatibility of Nafarelin in the drug label. # Overdosage - In experimental animals, a single subcutaneous administration of up to 60 times the recommended human dose (on a µg/kg basis, not adjusted for bioavailability) had no adverse effects. At present, there is no clinical evidence of adverse effects following overdosage of GnRH analogs. - Based on studies in monkeys, SYNAREL is not absorbed after oral administration. # Pharmacology ## Mechanism of Action - Nafarelin acetate is a potent agonistic analog of gonadotropin-releasing hormone (GnRH). At the onset of administration, nafarelin stimulates the release of the pituitary gonadotropins, LH and FSH, resulting in a temporary increase of gonadal steroidogenesis. Repeated dosing abolishes the stimulatory effect on the pituitary gland. Twice daily administration leads to decreased secretion of gonadal steroids by about 4 weeks; consequently, tissues and functions that depend on gonadal steroids for their maintenance become quiescent. ## Structure - SYNAREL (nafarelin acetate) Nasal Solution is intended for administration as a spray to the nasal mucosa. Nafarelin acetate, the active component of SYNAREL Nasal Solution, is a decapeptide with the chemical name: 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-3-(2-naphthyl)-D-alanyl-L-leucyl-L-arginyl-L-prolyl-glycinamide acetate. Nafarelin acetate is a synthetic analog of the naturally occurring gonadotropin-releasing hormone (GnRH). - Nafarelin acetate has the following chemical structure: - SYNAREL Nasal Solution contains nafarelin acetate (2 mg/mL, content expressed as nafarelin base) in a solution of benzalkonium chloride, glacial acetic acid, sodium hydroxide or hydrochloric acid (to adjust pH), sorbitol, and purified water. - After priming the pump unit for SYNAREL, each actuation of the unit delivers approximately 100 µL of the spray containing approximately 200 µg nafarelin base. The contents of one spray bottle are intended to deliver at least 60 sprays. ## Pharmacodynamics - There is limited information regarding Pharmacodynamics of Nafarelin in the drug label. ## Pharmacokinetics - In children, nafarelin acetate was rapidly absorbed into the systemic circulation after intranasal administration. Maximum serum concentrations (measured by RIA) were achieved between 10 and 45 minutes. Following a single dose of 400 µg base, the observed peak concentration was 2.2 ng/mL, whereas following a single dose of 600 µg base, the observed peak concentration was 6.6 ng/mL. The average serum half-life of nafarelin following intranasal administration of a 400 µg dose was approximately 2.5 hours. It is not known and cannot be predicted what the pharmacokinetics of nafarelin will be in children given a dose above 600 µg. - In adult women, nafarelin acetate was rapidly absorbed into the systemic circulation after intranasal administration. Maximum serum concentrations (measured by RIA) were achieved between 10 and 40 minutes. Following a single dose of 200 µg base, the observed average peak concentration was 0.6 ng/mL (range 0.2 to 1.4 ng/mL), whereas following a single dose of 400 µg base, the observed average peak concentration was 1.8 ng/mL (range 0.5 to 5.3 ng/mL). Bioavailability from a 400 µg dose averaged 2.8% (range 1.2 to 5.6%). The average serum half-life of nafarelin following intranasal administration was approximately 3 hours. About 80% of nafarelin acetate was bound to plasma proteins at 4°C. Twice daily intranasal administration of 200 or 400 µg of SYNAREL in 18 healthy women for 22 days did not lead to significant accumulation of the drug. Based on the mean Cmin levels on Days 15 and 22, there appeared to be dose proportionality across the two dose levels. - After subcutaneous administration of 14C-nafarelin acetate to men, 44–55% of the dose was recovered in urine and 18.5–44.2% was recovered in feces. Approximately 3% of the administered dose appeared as unchanged nafarelin in urine. The 14C serum half-life of the metabolites was about 85.5 hours. Six metabolites of nafarelin have been identified of which the major metabolite is Tyr-D(2)-Nal-Leu-Arg-Pro-Gly-NH2(5-10). The activity of the metabolites, the metabolism of nafarelin by nasal mucosa, and the pharmacokinetics of the drug in hepatically- and renally-impaired patients have not been determined. - There appeared to be no significant effect of rhinitis, i.e., nasal congestion, on the systemic bioavailability of SYNAREL; however, if the use of a nasal decongestant for rhinitis is necessary during treatment with SYNAREL, the decongestant should not be used until at least 2 hours following dosing with SYNAREL. - When used regularly in girls and boys with central precocious puberty (CPP) at the recommended dose, SYNAREL suppresses LH and sex steroid hormone levels to prepubertal levels, affects a corresponding arrest of secondary sexual development, and slows linear growth and skeletal maturation. In some cases, initial estrogen withdrawal bleeding may occur, generally within 6 weeks after initiation of therapy. Thereafter, menstruation should cease. - In clinical studies the peak response of LH to GnRH stimulation was reduced from a pubertal response to a prepubertal response (< 15 mlU/mL) within one month of treatment. - Linear growth velocity, which is commonly pubertal in children with CPP, is reduced in most children within the first year of treatment to values of 5 to 6 cm/year or less. Children with CPP are frequently taller than their chronological age peers; height for chronological age approaches normal in most children during the second or third year of treatment with SYNAREL. Skeletal maturation rate (bone age velocity—change in bone age divided by change in chronological age) is usually abnormal (greater than 1) in children with CPP; in most children, bone age velocity approaches normal (1) during the first year of treatment. This results in a narrowing of the gap between bone age and chronological age, usually by the second or third year of treatment. The mean predicted adult height increases. - In clinical trials, breast development was arrested or regressed in 82% of girls, and genital development was arrested or regressed in 100% of boys. Because pubic hair growth is largely controlled by adrenal androgens, which are unaffected by nafarelin, pubic hair development was arrested or regressed only in 54% of girls and boys. - Reversal of the suppressive effects of SYNAREL has been demonstrated to occur in all children with CPP for whom one-year post-treatment follow-up is available (n=69). This demonstration consisted of the appearance or return of menses, the return of pubertal gonadotropin and gonadal sex steroid levels, and/or the advancement of secondary sexual development. Semen analysis was normal in the two ejaculated specimens obtained thus far from boys who have been taken off therapy to resume puberty. Fertility has not been documented by pregnancies and the effect of long-term use of the drug on fertility is not known. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility - Carcinogenicity studies of nafarelin were conducted in rats (24 months) at doses up to 100 µg/kg/day and mice (18 months) at doses up to 500 µg/kg/day using intramuscular doses (up to 110 times and 560 times the maximum recommended human intranasal dose, respectively). These multiples of the human dose are based on the relative bioavailability of the drug by the two routes of administration. As seen with other GnRH agonists, nafarelin acetate given to laboratory rodents at high doses for prolonged periods induced proliferative responses (hyperplasia and/or neoplasia) of endocrine organs. At 24 months, there was an increase in the incidence of pituitary tumors (adenoma/carcinoma) in high-dose female rats and a dose-related increase in male rats. There was an increase in pancreatic islet cell adenomas in both sexes, and in benign testicular and ovarian tumors in the treated groups. There was a dose-related increase in benign adrenal medullary tumors in treated female rats. In mice, there was a dose-related increase in Harderian gland tumors in males and an increase in pituitary adenomas in high-dose females. No metastases of these tumors were observed. It is known that tumorigenicity in rodents is particularly sensitive to hormonal stimulation. - Mutagenicity studies were performed with nafarelin acetate using bacterial, yeast, and mammalian systems. These studies provided no evidence of mutagenic potential. - Reproduction studies in male and female rats have shown full reversibility of fertility suppression when drug treatment was discontinued after continuous administration for up to 6 months. The effect of treatment of prepubertal rats on the subsequent reproductive performance of mature animals has not been investigated. # Clinical Studies - There is limited information regarding Clinical Studies of Nafarelin in the drug label. # How Supplied - Each 0.5 ounce bottle (NDC 0025-0166-08) contains 8 mL SYNAREL (nafarelin acetate) Nasal Solution 2 mg/mL (as nafarelin base), and is supplied with a metered spray pump that delivers 200 µg of nafarelin per spray. A dust cover and a leaflet of patient instructions are also included. ## Storage - Store upright at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) . Protect from light. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information # Precautions with Alcohol - Alcohol-Nafarelin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Synarel # Look-Alike Drug Names - A® — B® # Drug Shortage Status # Price	Nafarelin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Deepika Beereddy, MBBS [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Nafarelin is a fertility agent that is FDA approved for the treatment of endometriosis, including pain relief and reduction of endometriotic lesions, central precocious puberty. Common adverse reactions include acne, hot sweats, decreased bone mineral density, headache, mood swings, abnormal vaginal bleeding, erectile dysfunction, swelling of breast, vaginal dryness. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - SYNAREL is indicated for management of endometriosis, including pain relief and reduction of endometriotic lesions. Experience with SYNAREL for the management of endometriosis has been limited to women 18 years of age and older treated for 6 months. - Dosing Information - For the management of endometriosis, the recommended daily dose of SYNAREL is 400 µg. This is achieved by one spray (200 µg) into one nostril in the morning and one spray into the other nostril in the evening. Treatment should be started between days 2 and 4 of the menstrual cycle. - In an occasional patient, the 400 µg daily dose may not produce amenorrhea. For these patients with persistent regular menstruation after 2 months of treatment, the dose of SYNAREL may be increased to 800 µg daily. The 800 µg dose is administered as one spray into each nostril in the morning (a total of two sprays) and again in the evening. - The recommended duration of administration is six months. Retreatment cannot be recommended since safety data for retreatment are not available. If the symptoms of endometriosis recur after a course of therapy, and further treatment with SYNAREL is contemplated, it is recommended that bone density be assessed before retreatment begins to ensure that values are within normal limits. - There appeared to be no significant effect of rhinitis, i.e., nasal congestion, on the systemic bioavailability of SYNAREL; however, if the use of a nasal decongestant for rhinitis is necessary during treatment with SYNAREL, the decongestant should not be used until at least 2 hours following dosing with SYNAREL. - Sneezing during or immediately after dosing with SYNAREL should be avoided, if possible, since this may impair drug absorption. - At 400 µg/day, a bottle of SYNAREL provides a 30-day (about 60 sprays) supply. If the daily dose is increased, increase the supply to the patient to ensure uninterrupted treatment for the recommended duration of therapy. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Nafarelin in adult patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Nafarelin in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ### CENTRAL PRECOCIOUS PUBERTY - SYNAREL is indicated for treatment of central precocious puberty (CPP) (gonadotropin-dependent precocious puberty) in children of both sexes. - The diagnosis of central precocious puberty (CPP) is suspected when premature development of secondary sexual characteristics occurs at or before the age of 8 years in girls and 9 years in boys, and is accompanied by significant advancement of bone age and/or a poor adult height prediction. The diagnosis should be confirmed by pubertal gonadal sex steroid levels and a pubertal LH response to stimulation by native GnRH. Pelvic ultrasound assessment in girls usually reveals enlarged uterus and ovaries, the latter often with multiple cystic formations. Magnetic resonance imaging or CT-scanning of the brain is recommended to detect hypothalamic or pituitary tumors, or anatomical changes associated with increased intracranial pressure. Other causes of sexual precocity, such as congenital adrenal hyperplasia, testotoxicosis, testicular tumors and/or other autonomous feminizing or masculinizing disorders must be excluded by proper clinical hormonal and diagnostic imaging examinations. - Dosing Information - For the treatment of central precocious puberty (CPP), the recommended daily dose of SYNAREL is 1600 µg. The dose can be increased to 1800 µg daily if adequate suppression cannot be achieved at 1600 µg/day. - The 1600 µg dose is achieved by two sprays (400 µg) into each nostril in the morning (4 sprays) and two sprays into each nostril in the evening (4 sprays), a total of 8 sprays per day. The 1800 µg dose is achieved by 3 sprays (600 µg) into alternating nostrils three times a day, a total of 9 sprays per day. The patient's head should be tilted back slightly, and 30 seconds should elapse between sprays. - If the prescribed therapy has been well tolerated by the patient, treatment of CPP with SYNAREL should continue until resumption of puberty is desired. - There appeared to be no significant effect of rhinitis, i.e., nasal congestion, on the systemic bioavailability of SYNAREL; however, if the use of a nasal decongestant for rhinitis is necessary during treatment with SYNAREL, the decongestant should not be used until at least 2 hours following dosing with SYNAREL. - Sneezing during or immediately after dosing with SYNAREL should be avoided, if possible, since this may impair drug absorption. - At 1600 µg/day, a bottle of SYNAREL provides about a 7-day supply (about 56 sprays). If the daily dose is increased, increase the supply to the patient to ensure uninterrupted treatment for the duration of therapy. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Nafarelin in pediatric patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Nafarelin in pediatric patients. # Contraindications - Hypersensitivity to GnRH, GnRH agonist analogs or any of the excipients in SYNAREL; - Undiagnosed abnormal vaginal bleeding; - Use in pregnancy or in women who may become pregnant while receiving the drug. SYNAREL may cause fetal harm when administered to a pregnant woman. Major fetal abnormalities were observed in rats, but not in mice or rabbits after administration of SYNAREL during the period of organogenesis. There was a dose-related increase in fetal mortality and a decrease in fetal weight in rats (see Pregnancy Section). The effects on rat fetal mortality are expected consequences of the alterations in hormonal levels brought about by the drug. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, she should be apprised of the potential hazard to the fetus; - Use in women who are breast-feeding (see Nursing Mothers Section). # Warnings - The diagnosis of central precocious puberty (CPP) must be established before treatment is initiated. Regular monitoring of CPP patients is needed to assess both patient response as well as compliance. This is particularly important during the first 6 to 8 weeks of treatment to assure that suppression of pituitary-gonadal function is rapid. Testing may include LH response to GnRH stimulation and circulating gonadal sex steroid levels. Assessment of growth velocity and bone age velocity should begin within 3 to 6 months of treatment initiation. - Some patients may not show suppression of the pituitary-gonadal axis by clinical and/or biochemical parameters. This may be due to lack of compliance with the recommended treatment regimen and may be rectified by recommending that the dosing be done by caregivers. If compliance problems are excluded, the possibility of gonadotropin independent sexual precocity should be reconsidered and appropriate examinations should be conducted. If compliance problems are excluded and if gonadotropin independent sexual precocity is not present, the dose of SYNAREL may be increased to 1800 µg/day administered as 600 µg tid. ### Precautions General - As with other drugs that stimulate the release of gonadotropins or that induce ovulation, in adult women with endometriosis ovarian cysts have been reported to occur in the first two months of therapy with SYNAREL. Many, but not all, of these events occurred in women with polycystic ovarian disease. These cystic enlargements may resolve spontaneously, generally by about four to six weeks of therapy, but in some cases may require discontinuation of drug and/or surgical intervention. The relevance, if any, of such events in children is unknown. Information for Patients, Patients' Parents or Guardians - An information pamphlet for patients is included with the product. Patients and their caregivers should be aware of the following information: - Reversibility of the suppressive effects of nafarelin has been demonstrated by the appearance or return of menses, by the return of pubertal gonadotropin and gonadal sex steroid levels, and/or by advancement of secondary sexual development. Semen analysis was normal in the two ejaculated specimens obtained thus far from boys who have been taken off therapy to resume puberty. Fertility has not been documented by pregnancies and the effect of long-term use of the drug on fertility is not known. - Patients and their caregivers should be adequately counseled to assure full compliance; irregular or incomplete daily doses may result in stimulation of the pituitary-gonadal axis. - During the first month of treatment with SYNAREL, some signs of puberty, e.g., vaginal bleeding or breast enlargement, may occur. This is the expected initial effect of the drug. Such changes should resolve soon after the first month. lf such resolution does not occur within the first two months of treatment, this may be due to lack of compliance or the presence of gonadotropin independent sexual precocity. If both possibilities are definitively excluded, the dose of SYNAREL may be increased to 1800 µg/day administered as 600 µg tid. - Patients with intercurrent rhinitis should consult their physician for the use of a topical nasal decongestant. If the use of a topical nasal decongestant is required during treatment with SYNAREL, the decongestant should not be used until at least 2 hours following dosing with SYNAREL. - Sneezing during or immediately after dosing with SYNAREL should be avoided, if possible, since this may impair drug absorption. # Adverse Reactions ## Clinical Trials Experience - In clinical trials of 155 pediatric patients, 2.6% reported symptoms suggestive of drug sensitivity, such as shortness of breath, chest pain, urticaria, rash, and pruritus. - In these 155 patients treated for an average of 41 months and as long as 80 months (6.7 years), adverse events most frequently reported (>3% of patients) consisted largely of episodes occurring during the first 6 weeks of treatment as a result of the transient stimulatory action of nafarelin upon the pituitary-gonadal axis: - acne (10%) - transient breast enlargement (8%) - vaginal bleeding (8%) - emotional lability (6%) - transient increase in pubic hair (5%) - body odor (4%) - seborrhea (3%) - Hot flashes, common in adult women treated for endometriosis, occurred in only 3% of treated children and were transient. Other adverse events thought to be drug-related, and occurring in >3% of patients were rhinitis (5%) and white or brownish vaginal discharge (3%). Approximately 3% of patients withdrew from clinical trials due to adverse events. - In one male patient with concomitant congenital adrenal hyperplasia, and who had discontinued treatment 8 months previously to resume puberty, adrenal rest tumors were found in the left testis. Relationship to SYNAREL is unlikely. - Regular examinations of the pituitary gland by magnetic resonance imaging (MRI) or computer assisted tomography (CT) of children during long-term nafarelin therapy as well as during the post-treatment period has occasionally revealed changes in the shape and size of the pituitary gland. These changes include asymmetry and enlargement of the pituitary gland, and a pituitary microadenoma has been suspected in a few children. The relationship of these findings to SYNAREL is not known. ## Postmarketing Experience Pituitary apoplexy - During post-marketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of gonadotropin-releasing hormone agonists. In a majority of these cases, a pituitary adenoma was diagnosed, with a majority of pituitary apoplexy cases occurring within 2 weeks of the first dose, and some within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required. Central/peripheral nervous adverse events - Convulsion. # Drug Interactions - No pharmacokinetic-based drug-drug interaction studies have been conducted with SYNAREL. However, because nafarelin acetate is a peptide that is primarily degraded by peptidase and not by cytochrome P-450 enzymes, and the drug is only about 80% bound to plasma proteins at 4°C, drug interactions would not be expected to occur. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): X Teratogenic Effects - Pregnancy Category X. See 'CONTRAINDICATIONS.' Intramuscular SYNAREL was administered to rats during the period of organogenesis at 0.4, 1.6, and 6.4 µg/kg/day (about 0.5, 2, and 7 times the maximum recommended human intranasal dose based on the relative bioavailability by the two routes of administration). An increase in major fetal abnormalities was observed in 4/80 fetuses at the highest dose. A similar, repeat study at the same doses in rats and studies in mice and rabbits at doses up to 600 µg/kg/day and 0.18 µg/kg/day, respectively, failed to demonstrate an increase in fetal abnormalities after administration during the period of organogenesis. In rats and rabbits, there was a dose-related increase in fetal mortality and a decrease in fetal weight with the highest dose. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category - There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nafarelin in women who are pregnant. ### Labor and Delivery - There is no FDA guidance on use of Nafarelin during labor and delivery. ### Nursing Mothers - It is not known whether SYNAREL is excreted in human milk. Because many drugs are excreted in human milk, and because the effects of SYNAREL on lactation and/or the breastfed child have not been determined, SYNAREL should not be used by nursing mothers. ### Pediatric Use - There is no FDA guidance on the use of Nafarelin with respect to pediatric patients. ### Geriatic Use - There is no FDA guidance on the use of Nafarelin with respect to geriatric patients. ### Gender - There is no FDA guidance on the use of Nafarelin with respect to specific gender populations. ### Race - There is no FDA guidance on the use of Nafarelin with respect to specific racial populations. ### Renal Impairment - There is no FDA guidance on the use of Nafarelin in patients with renal impairment. ### Hepatic Impairment - There is no FDA guidance on the use of Nafarelin in patients with hepatic impairment. ### Females of Reproductive Potential and Males - There is no FDA guidance on the use of Nafarelin in women of reproductive potentials and males. ### Immunocompromised Patients - There is no FDA guidance one the use of Nafarelin in patients who are immunocompromised. # Administration and Monitoring ### Administration - For the treatment of central precocious puberty (CPP), the recommended daily dose of SYNAREL is 1600 µg. The dose can be increased to 1800 µg daily if adequate suppression cannot be achieved at 1600 µg/day. - The 1600 µg dose is achieved by two sprays (400 µg) into each nostril in the morning (4 sprays) and two sprays into each nostril in the evening (4 sprays), a total of 8 sprays per day. The 1800 µg dose is achieved by 3 sprays (600 µg) into alternating nostrils three times a day, a total of 9 sprays per day. The patient's head should be tilted back slightly, and 30 seconds should elapse between sprays. - If the prescribed therapy has been well tolerated by the patient, treatment of CPP with SYNAREL should continue until resumption of puberty is desired. - There appeared to be no significant effect of rhinitis, i.e., nasal congestion, on the systemic bioavailability of SYNAREL; however, if the use of a nasal decongestant for rhinitis is necessary during treatment with SYNAREL, the decongestant should not be used until at least 2 hours following dosing with SYNAREL. - Sneezing during or immediately after dosing with SYNAREL should be avoided, if possible, since this may impair drug absorption. - At 1600 µg/day, a bottle of SYNAREL provides about a 7-day supply (about 56 sprays). If the daily dose is increased, increase the supply to the patient to ensure uninterrupted treatment for the duration of therapy. - For the management of endometriosis, the recommended daily dose of SYNAREL is 400 µg. This is achieved by one spray (200 µg) into one nostril in the morning and one spray into the other nostril in the evening. Treatment should be started between days 2 and 4 of the menstrual cycle. - In an occasional patient, the 400 µg daily dose may not produce amenorrhea. For these patients with persistent regular menstruation after 2 months of treatment, the dose of SYNAREL may be increased to 800 µg daily. The 800 µg dose is administered as one spray into each nostril in the morning (a total of two sprays) and again in the evening. - The recommended duration of administration is six months. Retreatment cannot be recommended since safety data for retreatment are not available. If the symptoms of endometriosis recur after a course of therapy, and further treatment with SYNAREL is contemplated, it is recommended that bone density be assessed before retreatment begins to ensure that values are within normal limits. - There appeared to be no significant effect of rhinitis, i.e., nasal congestion, on the systemic bioavailability of SYNAREL; however, if the use of a nasal decongestant for rhinitis is necessary during treatment with SYNAREL, the decongestant should not be used until at least 2 hours following dosing with SYNAREL. - Sneezing during or immediately after dosing with SYNAREL should be avoided, if possible, since this may impair drug absorption. - At 400 µg/day, a bottle of SYNAREL provides a 30-day (about 60 sprays) supply. If the daily dose is increased, increase the supply to the patient to ensure uninterrupted treatment for the recommended duration of therapy. ### Monitoring - There is limited information regarding Monitoring of Nafarelin in the drug label. # IV Compatibility - There is limited information regarding IV Compatibility of Nafarelin in the drug label. # Overdosage - In experimental animals, a single subcutaneous administration of up to 60 times the recommended human dose (on a µg/kg basis, not adjusted for bioavailability) had no adverse effects. At present, there is no clinical evidence of adverse effects following overdosage of GnRH analogs. - Based on studies in monkeys, SYNAREL is not absorbed after oral administration. # Pharmacology ## Mechanism of Action - Nafarelin acetate is a potent agonistic analog of gonadotropin-releasing hormone (GnRH). At the onset of administration, nafarelin stimulates the release of the pituitary gonadotropins, LH and FSH, resulting in a temporary increase of gonadal steroidogenesis. Repeated dosing abolishes the stimulatory effect on the pituitary gland. Twice daily administration leads to decreased secretion of gonadal steroids by about 4 weeks; consequently, tissues and functions that depend on gonadal steroids for their maintenance become quiescent. ## Structure - SYNAREL (nafarelin acetate) Nasal Solution is intended for administration as a spray to the nasal mucosa. Nafarelin acetate, the active component of SYNAREL Nasal Solution, is a decapeptide with the chemical name: 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-3-(2-naphthyl)-D-alanyl-L-leucyl-L-arginyl-L-prolyl-glycinamide acetate. Nafarelin acetate is a synthetic analog of the naturally occurring gonadotropin-releasing hormone (GnRH). - Nafarelin acetate has the following chemical structure: - SYNAREL Nasal Solution contains nafarelin acetate (2 mg/mL, content expressed as nafarelin base) in a solution of benzalkonium chloride, glacial acetic acid, sodium hydroxide or hydrochloric acid (to adjust pH), sorbitol, and purified water. - After priming the pump unit for SYNAREL, each actuation of the unit delivers approximately 100 µL of the spray containing approximately 200 µg nafarelin base. The contents of one spray bottle are intended to deliver at least 60 sprays. ## Pharmacodynamics - There is limited information regarding Pharmacodynamics of Nafarelin in the drug label. ## Pharmacokinetics - In children, nafarelin acetate was rapidly absorbed into the systemic circulation after intranasal administration. Maximum serum concentrations (measured by RIA) were achieved between 10 and 45 minutes. Following a single dose of 400 µg base, the observed peak concentration was 2.2 ng/mL, whereas following a single dose of 600 µg base, the observed peak concentration was 6.6 ng/mL. The average serum half-life of nafarelin following intranasal administration of a 400 µg dose was approximately 2.5 hours. It is not known and cannot be predicted what the pharmacokinetics of nafarelin will be in children given a dose above 600 µg. - In adult women, nafarelin acetate was rapidly absorbed into the systemic circulation after intranasal administration. Maximum serum concentrations (measured by RIA) were achieved between 10 and 40 minutes. Following a single dose of 200 µg base, the observed average peak concentration was 0.6 ng/mL (range 0.2 to 1.4 ng/mL), whereas following a single dose of 400 µg base, the observed average peak concentration was 1.8 ng/mL (range 0.5 to 5.3 ng/mL). Bioavailability from a 400 µg dose averaged 2.8% (range 1.2 to 5.6%). The average serum half-life of nafarelin following intranasal administration was approximately 3 hours. About 80% of nafarelin acetate was bound to plasma proteins at 4°C. Twice daily intranasal administration of 200 or 400 µg of SYNAREL in 18 healthy women for 22 days did not lead to significant accumulation of the drug. Based on the mean Cmin levels on Days 15 and 22, there appeared to be dose proportionality across the two dose levels. - After subcutaneous administration of 14C-nafarelin acetate to men, 44–55% of the dose was recovered in urine and 18.5–44.2% was recovered in feces. Approximately 3% of the administered dose appeared as unchanged nafarelin in urine. The 14C serum half-life of the metabolites was about 85.5 hours. Six metabolites of nafarelin have been identified of which the major metabolite is Tyr-D(2)-Nal-Leu-Arg-Pro-Gly-NH2(5-10). The activity of the metabolites, the metabolism of nafarelin by nasal mucosa, and the pharmacokinetics of the drug in hepatically- and renally-impaired patients have not been determined. - There appeared to be no significant effect of rhinitis, i.e., nasal congestion, on the systemic bioavailability of SYNAREL; however, if the use of a nasal decongestant for rhinitis is necessary during treatment with SYNAREL, the decongestant should not be used until at least 2 hours following dosing with SYNAREL. - When used regularly in girls and boys with central precocious puberty (CPP) at the recommended dose, SYNAREL suppresses LH and sex steroid hormone levels to prepubertal levels, affects a corresponding arrest of secondary sexual development, and slows linear growth and skeletal maturation. In some cases, initial estrogen withdrawal bleeding may occur, generally within 6 weeks after initiation of therapy. Thereafter, menstruation should cease. - In clinical studies the peak response of LH to GnRH stimulation was reduced from a pubertal response to a prepubertal response (< 15 mlU/mL) within one month of treatment. - Linear growth velocity, which is commonly pubertal in children with CPP, is reduced in most children within the first year of treatment to values of 5 to 6 cm/year or less. Children with CPP are frequently taller than their chronological age peers; height for chronological age approaches normal in most children during the second or third year of treatment with SYNAREL. Skeletal maturation rate (bone age velocity—change in bone age divided by change in chronological age) is usually abnormal (greater than 1) in children with CPP; in most children, bone age velocity approaches normal (1) during the first year of treatment. This results in a narrowing of the gap between bone age and chronological age, usually by the second or third year of treatment. The mean predicted adult height increases. - In clinical trials, breast development was arrested or regressed in 82% of girls, and genital development was arrested or regressed in 100% of boys. Because pubic hair growth is largely controlled by adrenal androgens, which are unaffected by nafarelin, pubic hair development was arrested or regressed only in 54% of girls and boys. - Reversal of the suppressive effects of SYNAREL has been demonstrated to occur in all children with CPP for whom one-year post-treatment follow-up is available (n=69). This demonstration consisted of the appearance or return of menses, the return of pubertal gonadotropin and gonadal sex steroid levels, and/or the advancement of secondary sexual development. Semen analysis was normal in the two ejaculated specimens obtained thus far from boys who have been taken off therapy to resume puberty. Fertility has not been documented by pregnancies and the effect of long-term use of the drug on fertility is not known. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility - Carcinogenicity studies of nafarelin were conducted in rats (24 months) at doses up to 100 µg/kg/day and mice (18 months) at doses up to 500 µg/kg/day using intramuscular doses (up to 110 times and 560 times the maximum recommended human intranasal dose, respectively). These multiples of the human dose are based on the relative bioavailability of the drug by the two routes of administration. As seen with other GnRH agonists, nafarelin acetate given to laboratory rodents at high doses for prolonged periods induced proliferative responses (hyperplasia and/or neoplasia) of endocrine organs. At 24 months, there was an increase in the incidence of pituitary tumors (adenoma/carcinoma) in high-dose female rats and a dose-related increase in male rats. There was an increase in pancreatic islet cell adenomas in both sexes, and in benign testicular and ovarian tumors in the treated groups. There was a dose-related increase in benign adrenal medullary tumors in treated female rats. In mice, there was a dose-related increase in Harderian gland tumors in males and an increase in pituitary adenomas in high-dose females. No metastases of these tumors were observed. It is known that tumorigenicity in rodents is particularly sensitive to hormonal stimulation. - Mutagenicity studies were performed with nafarelin acetate using bacterial, yeast, and mammalian systems. These studies provided no evidence of mutagenic potential. - Reproduction studies in male and female rats have shown full reversibility of fertility suppression when drug treatment was discontinued after continuous administration for up to 6 months. The effect of treatment of prepubertal rats on the subsequent reproductive performance of mature animals has not been investigated. # Clinical Studies - There is limited information regarding Clinical Studies of Nafarelin in the drug label. # How Supplied - Each 0.5 ounce bottle (NDC 0025-0166-08) contains 8 mL SYNAREL (nafarelin acetate) Nasal Solution 2 mg/mL (as nafarelin base), and is supplied with a metered spray pump that delivers 200 µg of nafarelin per spray. A dust cover and a leaflet of patient instructions are also included. ## Storage - Store upright at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature]. Protect from light. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information # Precautions with Alcohol - Alcohol-Nafarelin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Synarel # Look-Alike Drug Names - A® — B®[1] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Nafarelin
2bf0b6a9a5ebd8ce855bf956c7761cc3aeff1866	wikidoc	Nafovanny	Nafovanny Nafovanny in Vietnam is the largest captive-breeding non-human primate facility in the world, supplying long-tailed macaques (Macaca Fascicularis) to animal testing laboratories, including Huntingdon Life Sciences in the UK and Covance in Germany. # Location and size Located in Long Thanh, Vietnam close to the Cambodian border, Nafovanny consists of two main farms with a total area of 90,000 square meters, able to hold 30,000 monkeys. According to the British Union for the Abolition of Vivisection (BUAV), the facility also maintains secret breeding farms on the Cambodian border, in which the BUAV alleges wild monkeys may also be held. The existence of these satellite farms is not referenced in the company's brochure, according to the BUAV. # Customers The British government approved Nafovanny to export primates to British laboratories in 1999. The British Animal Scientific Procedures Inspectorate visited Nafovanny in March 2005, and identified "shortcomings in animal accommodation and care," but since then the government has "received assurances and evidence that significant improvements have been made." According to Viet Nam News, 3,000 Nafovanny macaques were exported to the U.S. for testing purposes in 2000. Around 50,000 non-human primates are used each year in the U.S. and 10,000 in Europe, 3,000 of them in the UK.	Nafovanny Nafovanny in Vietnam is the largest captive-breeding non-human primate facility in the world, supplying long-tailed macaques (Macaca Fascicularis) to animal testing laboratories, including Huntingdon Life Sciences in the UK and Covance in Germany. [2] # Location and size Located in Long Thanh, Vietnam [3] close to the Cambodian border, Nafovanny consists of two main farms with a total area of 90,000 square meters, able to hold 30,000 monkeys. According to the British Union for the Abolition of Vivisection (BUAV), the facility also maintains secret breeding farms on the Cambodian border, in which the BUAV alleges wild monkeys may also be held. The existence of these satellite farms is not referenced in the company's brochure, according to the BUAV. [2] # Customers Template:Animal testing The British government approved Nafovanny to export primates to British laboratories in 1999. [2] The British Animal Scientific Procedures Inspectorate visited Nafovanny in March 2005, and identified "shortcomings in animal accommodation and care," but since then the government has "received assurances and evidence that significant improvements have been made." [4] According to Viet Nam News, 3,000 Nafovanny macaques were exported to the U.S. for testing purposes in 2000. [5] Around 50,000 non-human primates are used each year in the U.S. [6] and 10,000 in Europe, [7][8] 3,000 of them in the UK. [9]	https://www.wikidoc.org/index.php/Nafovanny
abef164484130372123b3c4c6fab48d740062dc9	wikidoc	Naftifine	Naftifine # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Naftifine is a allylamine , antifungal and dermatological agent that is FDA approved for the treatment of interdigital tinea pedis, tinea cruris, and tinea corporis caused by the organism Trichophyton rubrum. Common adverse reactions include dry skin, erythema, pruritus, sensation of burning of skin, skin irritation, stinging of skin. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) NAFTIN Cream is an allylamine antifungal indicated for the treatment of interdigital tinea pedis, tinea cruris, and tinea corporis caused by the organism Trichophyton rubrum. ### Dosing Information - For topical use only. NAFTIN Cream is not for ophthalmic, oral or intravaginal use. Apply a thin layer of NAFTIN Cream once-daily to the affected areas plus a ½ inch margin of healthy surrounding skin for 2 weeks. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Naftifine in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Naftifine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Naftifine in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Naftifine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Naftifine in pediatric patients. # Contraindications - None # Warnings - If irritation or sensitivity develops with the use of NAFTIN Cream, treatment should be discontinued. Patients should be directed to contact their physician if these conditions develop following use of NAFTIN Cream. # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. - During clinical trials, 760 subjects were exposed to naftifine 1% and 2% cream formulations. A total of 421 subjects with interdigital tinea pedis and/or tinea cruris were treated with NAFTIN Cream. - In two randomized, vehicle-controlled trials (400 patients were treated with NAFTIN Cream). The population was 12 to 88 years old, primarily male (79%), 48% Caucasian, 36% Black or African American, 40% Hispanic or Latino and had either predominantly interdigital tinea pedis or tinea cruris. Most subjects received doses once-daily, topically, for 2 weeks to cover the affected skin areas plus a ½ inch margin of surrounding healthy skin. In the two vehicle-controlled trials, 17.5% of NAFTIN Cream treated subjects experienced an adverse reaction compared with 19.3% of vehicle subjects. The most common adverse reaction (≥1%) is pruritus. Most adverse reactions were mild in severity. The incidence of Adverse Reactions in the NAFTIN Cream treated population were not significantly different than the vehicle treated population. - In an open-label pediatric pharmacokinetics and safety trial, 22 pediatric subjects 13-17 years of age with interdigital tinea pedis and tinea cruris received NAFTIN Cream. The incidence of adverse reactions in the pediatric population was similar to that observed in the adult population. ## Postmarketing Experience - The following adverse reactions have been identified during post-approval use of (naftifine hydrochloride): redness/irritation, inflammation, maceration, swelling, burning, blisters, serous drainage, crusting, headache, dizziness, leukopenia, agranulocytosis. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. # Drug Interactions There is limited information regarding Drug Interactions of Naftifine in pediatric patients. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B - There are no adequate and well-controlled studies of NAFTIN Cream in pregnant women. Because animal reproduction studies are not always predictive of human response, NAFTIN Cream should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - The animal multiples of human exposure calculations were based on daily dose body surface area comparison (mg/m2) for the reproductive toxicology studies described in this section and in Section 13.1. The Maximum Recommended Human Dose (MRHD) was set at 8 g 2% cream per day (2.67 mg/kg/day for a 60 kg individual). - Systemic embryofetal development studies were conducted in rats and rabbits. Oral doses of 30, 100 and 300 mg/kg/day naftifine hydrochloride were administered during the period of organogenesis (gestational days 6 – 15) to pregnant female rats. No treatment-related effects on embryofetal toxicity or teratogenicity were noted at doses up to 300 mg/kg/day (18.2× MRHD). Subcutaneous doses of 10 and 30 mg/kg/day naftifine hydrochloride were administered during the period of organogenesis (gestational days 6 – 15) to pregnant female rats. No treatment-related effects on embryofetal toxicity or teratogenicity were noted at 30 mg/kg/day (1.8× MRHD). Subcutaneous doses of 3, 10 and 30 mg/kg/day naftifine hydrochloride were administered during the period of organogenesis (gestational days 6 – 18) to pregnant female rabbits. No treatment related effects on embryofetal toxicity or teratogenicity were noted at 30 mg/kg/day (3.6× MRHD). - A peri- and post-natal development study was conducted in rats. Oral doses of 30, 100 and 300 mg/kg/day naftifine hydrochloride were administered to female rats from gestational day 14 to lactation day 21. Reduced body weight gain of females during gestation and of the offspring during lactation was noted at 300 mg/kg/day (18.2× MRHD). No developmental toxicity was noted at 100 mg/kg/day (6.1× MRHD). Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Naftifine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Naftifine during labor and delivery. ### Nursing Mothers - It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when NAFTIN Cream is administered to a nursing woman. ### Pediatric Use - The safety and effectiveness of NAFTIN Cream have been established in the age group 12-17 with interdigital tinea pedis and tinea cruris. - Use of NAFTIN Cream in this age group is supported by evidence from adequate and well controlled studies in adults with additional safety and PK data from an open label trial, conducted in 22 adolescents ≥12 years of age who were exposed to Naftin Cream at a dose of approximately 8 g/day. - Safety and effectiveness in pediatric patients < 12 years of age have not been established. ### Geriatic Use - Clinical studies of NAFTIN Cream did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. ### Gender There is no FDA guidance on the use of Naftifine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Naftifine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Naftifine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Naftifine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Naftifine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Naftifine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Topical ### Monitoring There is limited information regarding Monitoring of Naftifine in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Naftifine in the drug label. # Overdosage There is limited information regarding Chronic Overdose of Naftifine in the drug label. # Pharmacology ## Mechanism of Action - To date, a mechanism of resistance to naftifine has not been identified. - Naftifine has been shown to be active against most isolates of the following fungi, both in vitro and in clinical infections, as described in the INDICATIONS AND USAGE section: - Trichophyton rubrum ## Structure - NAFTIN Cream is a white to off-white cream for topical use only. Each gram of (naftifine hydrochloride) Cream contains 20 mg of naftifine hydrochloride, a synthetic allylamine antifungal compound. - Chemically, naftifine HCl is (E)-N-Cinnamyl-N-methyl-1-napthalenemethylamine hydrochloride. - The molecular formula is C21H21NHCl with a molecular weight of 323.86. - The structural formula of naftifine hydrochloride is: ## Pharmacodynamics - The pharmacodynamics of NAFTIN Cream have not been established. ## Pharmacokinetics - In vitro and in vivo bioavailability studies have demonstrated that naftifine penetrates the stratum corneum in sufficient concentration to inhibit the growth of dermatophytes. - The pharmacokinetics of NAFTIN Cream was evaluated following once-daily topical application for 2 weeks to twenty one adult subjects, both males and females, with both tinea pedis and tinea cruris. The median total amount of cream applied was 6.4 g (range 5.3-7.5 g) per day. The results showed that the systemic exposure (i.e., maximum concentration (Cmax) and area under the curve (AUC)) to naftifine increased over the 2 week treatment period in all the 21 subjects. Geometric Mean (CV%) AUC0-24 was 117 (41.2) nghr/mL on Day 1, and 204 (28.5) nghr/mL on Day 14. Geometric Mean (CV %) Cmax was 7 ng/mL (55.6) on Day 1 and 11 ng/mL (29.3) on day 14. Median Tmax was 8.0 hours on Day 1 (range: 4 to 24) and 6.0 hours on Day 14 (range: 0 to 16). Accumulation after 14 days of topical application was less than two fold. Trough concentrations generally increased throughout the 14 day study period. Naftifine continued to be detected in plasma in 13/21 (62%) subjects on day 28, the mean (SD) plasma concentrations were 1.6 ± 0.5 ng/mL (range below limit of quantitation (BLQ) to 3 ng/mL). - In the same pharmacokinetic trial conducted in patients with tinea pedis and tinea cruris, median fraction of the dose excreted in urine during the treatment period was 0.0016% on Day 1 versus 0.0020% on Day 14. - In a second trial, that enrolled 22 subjects the pharmacokinetics of NAFTIN Cream was evaluated in 20 pediatric subjects 13 – 17 years of age with both tinea pedis and tinea cruris. Subjects were treated with a median dose of 8.1 g (range 6.6-10.1 g) applied to the affected areas once daily for 14 days. The results showed that the systemic exposure increased over the treatment period. Geometric Mean (CV%) AUC0-24 was 138 (50.2) nghr/mL on Day 1, and 192 (74.9) nghr/mL on Day 14. Geometric Mean (CV %) Cmax was 9.21 ng/mL (48.4) on Day 1 and 12.7 ng/mL (67.2) on day 14. Median fraction of the dose excreted in urine during the treatment period was 0.0030% on Day 1 and 0.0033% on Day 14. ## Nonclinical Toxicology - Long-term studies to evaluate the carcinogenic potential of NAFTIN Cream have not been performed. - Naftifine hydrochloride revealed no evidence of mutagenic or clastogenic potential based on the results of two in vitro genotoxicity tests (Ames assay and Chinese hamster ovary cell chromosome aberration assay) and one in vivo genotoxicity test (mouse bone marrow micronucleus assay). - Oral administration of naftifine hydrochloride to rats, throughout mating, gestation, parturition and lactation, demonstrated no effects on growth, fertility or reproduction, at doses up to 100 mg/kg/day (6.1× MRHD). # Clinical Studies - NAFTIN Cream has been investigated for safety and efficacy in a randomized, double-blind, vehicle-controlled, multi-center study in 146 subjects with symptomatic and dermatophyte culture positive tinea cruris. Subjects were randomized to receive (naftifine hydrochloride) Cream or vehicle. Subjects applied the study agent (naftifine hydrochloride) Cream or vehicle to the affected area plus a ½-inch margin of healthy skin surrounding the affected area once-daily for 2 weeks. Signs and symptoms of tinea cruris (presence or absence of erythema, pruritus, and scaling) were assessed, and KOH examination and dermatophyte culture were performed at the primary efficacy endpoint at week 4. - The mean age of the study population was 47 years and 87% were male and 43% were white. At baseline, subjects were confirmed to have signs and symptoms of tinea cruris, positive KOH exam, and confirmed dermatophyte presence based on culture results from a central mycology laboratory. The analysis of the intent-to-treat population was a comparison of the proportions of subjects with a complete cure at the week 4 visit (see Table 1). Complete cure was defined as both clinical cure (absence of erythema, pruritus, and scaling) and mycological cure (negative KOH and dermatophyte culture). - The percentage of subjects experiencing clinical cure and the percentage of subjects experiencing mycological cure at week 4 are presented individually in Table 1 below. - NAFTIN Cream has been investigated for efficacy in a randomized, double-blind, vehicle-controlled, multi-center study in 217 subjects with symptomatic and dermatophyte culture positive interdigital tinea pedis. Subjects were randomized to receive NAFTIN Cream or vehicle. Subjects applied the study agent (naftifine hydrochloride) Cream or vehicle to the affected area of the foot plus a ½-inch margin of healthy skin surrounding the affected area once-daily for 2 weeks. Signs and symptoms of interdigital tinea pedis (presence or absence of erythema, pruritus, and scaling) were assessed and KOH examination and dermatophyte culture was performed at the primary efficacy endpoint at week 6. - The mean age of the study population was 42 years and 71% were male and 57% were white. At baseline, subjects were confirmed to have signs and symptoms of interdigital tinea pedis, positive KOH exam, and confirmed dermatophyte culture. The primary efficacy endpoint was the proportions of subjects with a complete cure at the week 6 visit (see Table 2). Complete cure was defined as both a clinical cure (absence of erythema, pruritus, and scaling) and mycological cure (negative KOH and dermatophyte culture). - The efficacy results at week 6, four weeks following the end of treatment, are presented in Table 2 below. Naftin Cream demonstrated complete cure in subjects with interdigital tinea pedis, but complete cure in subjects with only moccasin type tinea pedis was not demonstrated. # How Supplied NAFTIN Cream is a white to off-white cream supplied in collapsible tubes in the following sizes: 30g – NDC 0259-1102-30 45g – NDC 0259-1102-45 60g – NDC 0259-1102-60 ## Storage - Store NAFTIN Cream at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) # Images ## Drug Images ## Package and Label Display Panel NDC 0259-1102-45 NAFTIN® (Naftifine Hydrochloride) Cream, 2% MERZ For Topical Use Only Not for Ophthalmic Use, Oral or Intravaginal Use 45g Rx Only # Patient Counseling Information - Inform patients that NAFTIN Cream is for topical use only. NAFTIN Cream is not intended for oral, intravaginal or ophthalmic use. - If irritation or sensitivity develops with the use of NAFTIN Cream treatment should be discontinued and appropriate therapy instituted. Patients should be directed to contact their physician if these conditions develop following use of NAFTIN Cream. # Precautions with Alcohol - Alcohol-Naftifine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Naftin® - Naftin-MP® # Look-Alike Drug Names There is limited information regarding Naftifine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Naftifine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Adeel Jamil, M.D. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Naftifine is a allylamine , antifungal and dermatological agent that is FDA approved for the treatment of interdigital tinea pedis, tinea cruris, and tinea corporis caused by the organism Trichophyton rubrum. Common adverse reactions include dry skin, erythema, pruritus, sensation of burning of skin, skin irritation, stinging of skin. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) NAFTIN Cream is an allylamine antifungal indicated for the treatment of interdigital tinea pedis, tinea cruris, and tinea corporis caused by the organism Trichophyton rubrum. ### Dosing Information - For topical use only. NAFTIN Cream is not for ophthalmic, oral or intravaginal use. Apply a thin layer of NAFTIN Cream once-daily to the affected areas plus a ½ inch margin of healthy surrounding skin for 2 weeks. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Naftifine in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Naftifine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Naftifine in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Naftifine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Naftifine in pediatric patients. # Contraindications - None # Warnings - If irritation or sensitivity develops with the use of NAFTIN Cream, treatment should be discontinued. Patients should be directed to contact their physician if these conditions develop following use of NAFTIN Cream. # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. - During clinical trials, 760 subjects were exposed to naftifine 1% and 2% cream formulations. A total of 421 subjects with interdigital tinea pedis and/or tinea cruris were treated with NAFTIN Cream. - In two randomized, vehicle-controlled trials (400 patients were treated with NAFTIN Cream). The population was 12 to 88 years old, primarily male (79%), 48% Caucasian, 36% Black or African American, 40% Hispanic or Latino and had either predominantly interdigital tinea pedis or tinea cruris. Most subjects received doses once-daily, topically, for 2 weeks to cover the affected skin areas plus a ½ inch margin of surrounding healthy skin. In the two vehicle-controlled trials, 17.5% of NAFTIN Cream treated subjects experienced an adverse reaction compared with 19.3% of vehicle subjects. The most common adverse reaction (≥1%) is pruritus. Most adverse reactions were mild in severity. The incidence of Adverse Reactions in the NAFTIN Cream treated population were not significantly different than the vehicle treated population. - In an open-label pediatric pharmacokinetics and safety trial, 22 pediatric subjects 13-17 years of age with interdigital tinea pedis and tinea cruris received NAFTIN Cream. The incidence of adverse reactions in the pediatric population was similar to that observed in the adult population. ## Postmarketing Experience - The following adverse reactions have been identified during post-approval use of (naftifine hydrochloride): redness/irritation, inflammation, maceration, swelling, burning, blisters, serous drainage, crusting, headache, dizziness, leukopenia, agranulocytosis. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. # Drug Interactions There is limited information regarding Drug Interactions of Naftifine in pediatric patients. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B - There are no adequate and well-controlled studies of NAFTIN Cream in pregnant women. Because animal reproduction studies are not always predictive of human response, NAFTIN Cream should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - The animal multiples of human exposure calculations were based on daily dose body surface area comparison (mg/m2) for the reproductive toxicology studies described in this section and in Section 13.1. The Maximum Recommended Human Dose (MRHD) was set at 8 g 2% cream per day (2.67 mg/kg/day for a 60 kg individual). - Systemic embryofetal development studies were conducted in rats and rabbits. Oral doses of 30, 100 and 300 mg/kg/day naftifine hydrochloride were administered during the period of organogenesis (gestational days 6 – 15) to pregnant female rats. No treatment-related effects on embryofetal toxicity or teratogenicity were noted at doses up to 300 mg/kg/day (18.2× MRHD). Subcutaneous doses of 10 and 30 mg/kg/day naftifine hydrochloride were administered during the period of organogenesis (gestational days 6 – 15) to pregnant female rats. No treatment-related effects on embryofetal toxicity or teratogenicity were noted at 30 mg/kg/day (1.8× MRHD). Subcutaneous doses of 3, 10 and 30 mg/kg/day naftifine hydrochloride were administered during the period of organogenesis (gestational days 6 – 18) to pregnant female rabbits. No treatment related effects on embryofetal toxicity or teratogenicity were noted at 30 mg/kg/day (3.6× MRHD). - A peri- and post-natal development study was conducted in rats. Oral doses of 30, 100 and 300 mg/kg/day naftifine hydrochloride were administered to female rats from gestational day 14 to lactation day 21. Reduced body weight gain of females during gestation and of the offspring during lactation was noted at 300 mg/kg/day (18.2× MRHD). No developmental toxicity was noted at 100 mg/kg/day (6.1× MRHD). Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Naftifine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Naftifine during labor and delivery. ### Nursing Mothers - It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when NAFTIN Cream is administered to a nursing woman. ### Pediatric Use - The safety and effectiveness of NAFTIN Cream have been established in the age group 12-17 with interdigital tinea pedis and tinea cruris. - Use of NAFTIN Cream in this age group is supported by evidence from adequate and well controlled studies in adults with additional safety and PK data from an open label trial, conducted in 22 adolescents ≥12 years of age who were exposed to Naftin Cream at a dose of approximately 8 g/day. - Safety and effectiveness in pediatric patients < 12 years of age have not been established. ### Geriatic Use - Clinical studies of NAFTIN Cream did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. ### Gender There is no FDA guidance on the use of Naftifine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Naftifine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Naftifine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Naftifine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Naftifine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Naftifine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Topical ### Monitoring There is limited information regarding Monitoring of Naftifine in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Naftifine in the drug label. # Overdosage There is limited information regarding Chronic Overdose of Naftifine in the drug label. # Pharmacology ## Mechanism of Action - To date, a mechanism of resistance to naftifine has not been identified. - Naftifine has been shown to be active against most isolates of the following fungi, both in vitro and in clinical infections, as described in the INDICATIONS AND USAGE section: - Trichophyton rubrum ## Structure - NAFTIN Cream is a white to off-white cream for topical use only. Each gram of (naftifine hydrochloride) Cream contains 20 mg of naftifine hydrochloride, a synthetic allylamine antifungal compound. - Chemically, naftifine HCl is (E)-N-Cinnamyl-N-methyl-1-napthalenemethylamine hydrochloride. - The molecular formula is C21H21N•HCl with a molecular weight of 323.86. - The structural formula of naftifine hydrochloride is: ## Pharmacodynamics - The pharmacodynamics of NAFTIN Cream have not been established. ## Pharmacokinetics - In vitro and in vivo bioavailability studies have demonstrated that naftifine penetrates the stratum corneum in sufficient concentration to inhibit the growth of dermatophytes. - The pharmacokinetics of NAFTIN Cream was evaluated following once-daily topical application for 2 weeks to twenty one adult subjects, both males and females, with both tinea pedis and tinea cruris. The median total amount of cream applied was 6.4 g (range 5.3-7.5 g) per day. The results showed that the systemic exposure (i.e., maximum concentration (Cmax) and area under the curve (AUC)) to naftifine increased over the 2 week treatment period in all the 21 subjects. Geometric Mean (CV%) AUC0-24 was 117 (41.2) nghr/mL on Day 1, and 204 (28.5) nghr/mL on Day 14. Geometric Mean (CV %) Cmax was 7 ng/mL (55.6) on Day 1 and 11 ng/mL (29.3) on day 14. Median Tmax was 8.0 hours on Day 1 (range: 4 to 24) and 6.0 hours on Day 14 (range: 0 to 16). Accumulation after 14 days of topical application was less than two fold. Trough concentrations generally increased throughout the 14 day study period. Naftifine continued to be detected in plasma in 13/21 (62%) subjects on day 28, the mean (SD) plasma concentrations were 1.6 ± 0.5 ng/mL (range below limit of quantitation (BLQ) to 3 ng/mL). - In the same pharmacokinetic trial conducted in patients with tinea pedis and tinea cruris, median fraction of the dose excreted in urine during the treatment period was 0.0016% on Day 1 versus 0.0020% on Day 14. - In a second trial, that enrolled 22 subjects the pharmacokinetics of NAFTIN Cream was evaluated in 20 pediatric subjects 13 – 17 years of age with both tinea pedis and tinea cruris. Subjects were treated with a median dose of 8.1 g (range 6.6-10.1 g) applied to the affected areas once daily for 14 days. The results showed that the systemic exposure increased over the treatment period. Geometric Mean (CV%) AUC0-24 was 138 (50.2) nghr/mL on Day 1, and 192 (74.9) nghr/mL on Day 14. Geometric Mean (CV %) Cmax was 9.21 ng/mL (48.4) on Day 1 and 12.7 ng/mL (67.2) on day 14. Median fraction of the dose excreted in urine during the treatment period was 0.0030% on Day 1 and 0.0033% on Day 14. ## Nonclinical Toxicology - Long-term studies to evaluate the carcinogenic potential of NAFTIN Cream have not been performed. - Naftifine hydrochloride revealed no evidence of mutagenic or clastogenic potential based on the results of two in vitro genotoxicity tests (Ames assay and Chinese hamster ovary cell chromosome aberration assay) and one in vivo genotoxicity test (mouse bone marrow micronucleus assay). - Oral administration of naftifine hydrochloride to rats, throughout mating, gestation, parturition and lactation, demonstrated no effects on growth, fertility or reproduction, at doses up to 100 mg/kg/day (6.1× MRHD). # Clinical Studies - NAFTIN Cream has been investigated for safety and efficacy in a randomized, double-blind, vehicle-controlled, multi-center study in 146 subjects with symptomatic and dermatophyte culture positive tinea cruris. Subjects were randomized to receive (naftifine hydrochloride) Cream or vehicle. Subjects applied the study agent (naftifine hydrochloride) Cream or vehicle to the affected area plus a ½-inch margin of healthy skin surrounding the affected area once-daily for 2 weeks. Signs and symptoms of tinea cruris (presence or absence of erythema, pruritus, and scaling) were assessed, and KOH examination and dermatophyte culture were performed at the primary efficacy endpoint at week 4. - The mean age of the study population was 47 years and 87% were male and 43% were white. At baseline, subjects were confirmed to have signs and symptoms of tinea cruris, positive KOH exam, and confirmed dermatophyte presence based on culture results from a central mycology laboratory. The analysis of the intent-to-treat population was a comparison of the proportions of subjects with a complete cure at the week 4 visit (see Table 1). Complete cure was defined as both clinical cure (absence of erythema, pruritus, and scaling) and mycological cure (negative KOH and dermatophyte culture). - The percentage of subjects experiencing clinical cure and the percentage of subjects experiencing mycological cure at week 4 are presented individually in Table 1 below. - NAFTIN Cream has been investigated for efficacy in a randomized, double-blind, vehicle-controlled, multi-center study in 217 subjects with symptomatic and dermatophyte culture positive interdigital tinea pedis. Subjects were randomized to receive NAFTIN Cream or vehicle. Subjects applied the study agent (naftifine hydrochloride) Cream or vehicle to the affected area of the foot plus a ½-inch margin of healthy skin surrounding the affected area once-daily for 2 weeks. Signs and symptoms of interdigital tinea pedis (presence or absence of erythema, pruritus, and scaling) were assessed and KOH examination and dermatophyte culture was performed at the primary efficacy endpoint at week 6. - The mean age of the study population was 42 years and 71% were male and 57% were white. At baseline, subjects were confirmed to have signs and symptoms of interdigital tinea pedis, positive KOH exam, and confirmed dermatophyte culture. The primary efficacy endpoint was the proportions of subjects with a complete cure at the week 6 visit (see Table 2). Complete cure was defined as both a clinical cure (absence of erythema, pruritus, and scaling) and mycological cure (negative KOH and dermatophyte culture). - The efficacy results at week 6, four weeks following the end of treatment, are presented in Table 2 below. Naftin Cream demonstrated complete cure in subjects with interdigital tinea pedis, but complete cure in subjects with only moccasin type tinea pedis was not demonstrated. # How Supplied NAFTIN Cream is a white to off-white cream supplied in collapsible tubes in the following sizes: 30g – NDC 0259-1102-30 45g – NDC 0259-1102-45 60g – NDC 0259-1102-60 ## Storage - Store NAFTIN Cream at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) # Images ## Drug Images ## Package and Label Display Panel NDC 0259-1102-45 NAFTIN® (Naftifine Hydrochloride) Cream, 2% MERZ For Topical Use Only Not for Ophthalmic Use, Oral or Intravaginal Use 45g Rx Only # Patient Counseling Information - Inform patients that NAFTIN Cream is for topical use only. NAFTIN Cream is not intended for oral, intravaginal or ophthalmic use. - If irritation or sensitivity develops with the use of NAFTIN Cream treatment should be discontinued and appropriate therapy instituted. Patients should be directed to contact their physician if these conditions develop following use of NAFTIN Cream. # Precautions with Alcohol - Alcohol-Naftifine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Naftin® - Naftin-MP® # Look-Alike Drug Names There is limited information regarding Naftifine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Naftifine
a6b490cfa6b85cae139bc21008220329052d53cc	wikidoc	Nalmefene	Nalmefene # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Nalmefene is an opioid antagonist that is FDA approved for the {{{indicationType}}} of opioid drug effects, including respiratory depression and opiod overdose. Common adverse reactions include drowsiness, hypertension, tachycardia, dizziness, nausea, and vomiting. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - REVEX is supplied in two concentrations that can be identified by their color coded container labels: a concentration suitable for postoperative use (100 µg/mL) in a blue labeled ampul containing ONE (1) mL and a concentration suitable for the management of overdose (1 mg/mL, 10 times as concentrated, 20 times as much drug) in a green labeled ampul containing TWO (2) mL. Proper steps should be taken to prevent use of the incorrect concentration. - General Principles - REVEX should be titrated to reverse the undesired effects of opioids. Once adequate reversal has been established, additional administration is not required and may actually be harmful due to unwanted reversal of analgesia or precipitated withdrawal. - Duration of Action - The duration of action of REVEX is as long as most opioid analgesics. The apparent duration of action of REVEX will vary, however, depending on the half-life and plasma concentration of the narcotic being reversed, the presence or absence of other drugs affecting the brain or muscles of respiration, and the dose of REVEX administered. Partially reversing doses of REVEX (1 µg/kg) lose their effect as the drug is redistributed through the body, and the effects of these low doses may not last more than 30-60 minutes in the presence of persistent opioid effects. Fully reversing doses (1 mg/70 kg) have been shown to last many hours in both experimental and clinical studies, but may complicate the management of patients who are in pain, at high cardiovascular risk, or who are physically dependent on opioids. - The recommended doses represent a compromise between a desirable controlled reversal and the need for prompt response and adequate duration of action. Using higher dosages or shorter intervals between incremental doses is likely to increase the incidence and severity of symptoms related to acute withdrawal such as nausea, vomiting, elevated blood pressure, and anxiety. - REVEX may cause acute withdrawal symptoms in individuals who have some degree of tolerance to and dependence on opioids. These patients should be closely observed for symptoms of withdrawal following administration of the initial and subsequent injections of REVEX. Subsequent doses should be administered with intervals of at least 2-5 minutes between doses to allow the full effect of each incremental dose of REVEX to be reached. - Use 100µg/mL dosage strength (blue label) and see Table 2 for initial doses. - The goal of treatment with REVEX in the postoperative setting is to achieve reversal of excessive opioid effects without inducing a complete reversal and acute pain. This is best accomplished with an initial dose of 0.25 µg/kg followed by 0.25µg/kg incremental doses at 2-5 minute intervals, stopping as soon as the desired degree of opioid reversal is obtained. A cumulative total dose above 1.0 µg/kg does not provide additional therapeutic effect. - Use 1.0 mg/mL dosage strength (green label). - The recommended initial dose of REVEX for non-opioid dependent patients is 0.5 mg/70 kg. If needed, this may be followed by a second dose of 1.0 mg/70 kg, 2-5 minutes later. If a total dose of 1.5 mg /70 kg has been administered without clinical response, additional REVEX (nalmefene hydrochloride injection) is unlikely to have an effect. Patients should not be given more REVEX than is required to restore the respiratory rate to normal, thus minimizing the likelihood of cardiovascular stress and precipitated withdrawal syndrome. - If there is a reasonable suspicion of opioid dependency, a challenge dose of REVEX 0.1 mg/70 kg should be administered initially. If there is no evidence of withdrawal in 2 minutes, the recommended dosing should be followed. - REVEX had no effect in cases where opioids were not responsible for sedation and hypoventilation. Therefore, patients should only be treated with REVEX when the likelihood of an opioid overdose is high, based on a history of opioid overdose or the clinical presentation of respiratory depression with concurrent pupillary constriction. - Repeated Dosing - REVEX is the longest acting of the currently available parenteral opioid antagonists. If recurrence of respiratory depression does occur, the dose should again be titrated to clinical effect using incremental doses to avoid over-reversal. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Nalmefene in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Nalmefene in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Nalmefene in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Nalmefene in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Nalmefene in pediatric patients. # Contraindications - REVEX is contraindicated in patients with a known hypersensitivity to the product. # Warnings - Use of REVEX in Emergencies - REVEX, like all drugs in this class, is not the primary treatment for ventilatory failure. In most emergency settings, treatment with REVEX should follow, not precede, the establishment of a patent airway, ventilatory assistance, administration of oxygen, and establishment of circulatory access. - Risk of Recurrent Respiratory Depression - Accidental overdose with long acting opioids may result in prolonged respiratory depression. Respiratory depression in both the postoperative and overdose setting may be complex and involve the effects of anesthetic agents, neuromuscular blockers, and other drugs. While REVEX has a longer duration of action than naloxone in fully reversing doses, the physician should be aware that a recurrence of respiratory depression is possible, even after an apparently adequate initial response to REVEX treatment. - Patients treated with REVEX should be observed until, in the opinion of the physician, there is no reasonable risk of recurrent respiratory depression. ### Precautions - General - Cardiovascular Risks with Narcotic Antagonists - Pulmonary edema, cardiovascular instability, hypotension, hypertension, ventricular tachycardia, and ventricular fibrillation have been reported in connection with opioid reversal in both postoperative and emergency department settings. In many cases, these effects appear to be the result of abrupt reversal of opioid effects. - Although REVEX has been used safely in patients with pre-existing cardiac disease, all drugs of this class should be used with caution in patients at high cardiovascular risk or who have received potentially cardiotoxic drugs. - Risk of Precipitated Withdrawal - REVEX, like other opioid antagonists, is known to produce acute withdrawal symptoms and, therefore, should be used with extreme caution in patients with known physical dependence on opioids or following surgery involving high doses of opioids. Imprudent use or excessive doses of opioid antagonists in the postoperative setting has been associated with hypertension, tachycardia, and excessive mortality in patients at high risk for cardiovascular complications. - Incomplete Reversal of Buprenorphine - Preclinical studies have shown that nalmefene at doses up to 10 mg/kg (437 times the maximum recommended human dose) produced incomplete reversal of buprenorphine-induced analgesia in animal models. This appears to be a consequence of a high affinity and slow displacement of buprenorphine from the opioid receptors. Hence, REVEX may not completely reverse buprenorphine-induced respiratory depression. # Adverse Reactions ## Clinical Trials Experience - Adverse event information was obtained following administration of REVEX to 152 normal volunteers and in controlled clinical trials to 1127 patients for the treatment of opioid overdose or for postoperative opioid reversal. - Nalmefene was well tolerated and showed no serious toxicity during experimental administration to healthy individuals, even when given at 15 times the highest recommended dose. In a small number of subjects, at doses exceeding the recommended REVEX dose, nalmefene produced symptoms suggestive of reversal of endogenous opioids, such as have been reported for other narcotic antagonist drugs. These symptoms (nausea, chills, myalgia, dysphoria, abdominal cramps, and joint pain) were usually transient and occurred at very low frequency. - Such symptoms of precipitated opioid withdrawal at the recommended clinical doses were seen in both postoperative and overdose patients who were later found to have had histories of covert opioid use. Symptoms of precipitated withdrawal were similar to those seen with other opioid antagonists, were transient following the lower doses used in the postoperative setting, and more prolonged following the administration of the larger doses used in the treatment of overdose. - Tachycardia and nausea following the use of nalmefene in the postoperative setting were reported at the same frequencies as for naloxone at equivalent doses. The risk of both these adverse events was low at doses giving partial opioid reversal and increased with increases in dose. Thus, total doses larger than 1.0 µg/kg in the postoperative setting and 1.5 mg/70 kg in the treatment of overdose are not recommended. - Incidence less than 1% Bradycardia, arrhythmia Diarrhea, dry mouth Somnolence, depression, agitation, nervousness, tremor, confusion, withdrawal syndrome, myoclonus Pharyngitis Pruritus Urinary retention - The incidence of adverse events was highest in patients who received more than the recommended dose of REVEX. - Laboratory findings - Transient increases in CPK were reported as adverse events in 0.5% of the postoperative patients studied. These increases were believed to be related to surgery and not believed to be related to the administration of REVEX. Increases in AST were reported as adverse events in 0.3% of the patients receiving either nalmefene or naloxone. The clinical significance of this finding is unknown. No cases of hepatitis or hepatic injury due to either nalmefene or naloxone were observed in the clinical trials. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Nalmefene in the drug label. # Drug Interactions - REVEX has been administered after benzodiazepines, inhalational anesthetics, muscle relaxants, and muscle relaxant antagonists administered in conjunction with general anesthesia. It also has been administered in outpatient settings, both in trials in conscious sedation and in the emergency management of overdose following a wide variety of agents. No deleterious interactions have been observed. - Preclinical studies have shown that both flumazenil and nalmefene can induce seizures in animals. The coadministration of both flumazenil and nalmefene produced fewer seizures than expected in a study in rodents, based on the expected effects of each drug alone. Based on these data, an adverse interaction from the coadministration of the two drugs is not expected, but physicians should remain aware of the potential risk of seizures from agents in these classes. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category B - Reproduction studies have been performed in rats (up to 1200 mg/m 2/day) and rabbits (up to 2400 mg/m2/day) by oral administration of nalmefene and in rabbits by intravenous administration up to 96 mg/m2/day (114 times the human dose). There was no evidence of impaired fertility or harm to the fetus. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nalmefene in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Nalmefene during labor and delivery. ### Nursing Mothers - Nalmefene and its metabolites were secreted into rat milk, reaching concentrations approximately three times those in plasma at one hour and decreasing to about half the corresponding plasma concentrations by 24 hours following bolus administration. As no clinical information is available, caution should be exercised when REVEX is administered to a nursing woman. ### Pediatric Use - Safety and effectiveness of REVEX in pediatric patients have not been established. ### Geriatic Use - Clinical studies of REVEX (nalmefene hydrochloride injection) did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. ### Gender There is no FDA guidance on the use of Nalmefene with respect to specific gender populations. ### Race There is no FDA guidance on the use of Nalmefene with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Nalmefene in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Nalmefene in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Nalmefene in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Nalmefene in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous - Intramuscular - Subcutaneous ### Monitoring There is limited information regarding Monitoring of Nalmefene in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Nalmefene in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - Intravenous doses of up to 24 mg of nalmefene, administered to healthy volunteers in the absence of opioid agonists, produced no serious adverse reactions, severe signs or symptoms, or clinically significant laboratory abnormalities. As with all opioid antagonists, use in patients physically dependent on opioids can result in precipitated withdrawal reactions that may result in symptoms that require medical attention. ### Management - Treatment of such cases should be symptomatic and supportive. Administration of large amounts of opioids to patients receiving opioid antagonists in an attempt to overcome a full blockade has resulted in adverse respiratory and circulatory reactions. ## Chronic Overdose There is limited information regarding Chronic Overdose of Nalmefene in the drug label. # Pharmacology ## Mechanism of Action - *REVEX prevents or reverses the effects of opioids, including respiratory depression, sedation, and hypotension. REVEX has no opioid agonist activity. ## Structure - REVEX (nalmefene hydrochloride injection), an opioid antagonist, is a 6-methylene analogue of naltrexone. The chemical structure is shown below: - Molecular Weight: 375.9, CAS # 58895-64-0 - Chemical Name: 17-(Cyclopropylmethyl)-4,5α-epoxy-6-methylenemorphinan-3,14-diol, hydrochloride salt. - Nalmefene hydrochloride is a white to off-white crystalline powder which is freely soluble in water up to 130 mg/mL and slightly soluble in chloroform up to 0.13 mg/mL, with a pK a of 7.6. - REVEX is available as a sterile solution for intravenous, intramuscular, and subcutaneous administration in two concentrations, containing 100 µg or 1.0 mg of nalmefene free base per mL. The 100 µg/mL concentration contains 110.8 µg of nalmefene hydrochloride and the 1.0 mg/mL concentration contains 1.108 mg of nalmefene hydrochloride per mL. Both concentrations contain 9.0 mg of sodium chloride per mL and the pH is adjusted to 3.9 with hydrochloric acid. - Concentrations and dosages of REVEX are expressed as the free base equivalent of nalmefene. ## Pharmacodynamics - REVEX is not known to produce respiratory depression, psychotomimetic effects, or pupillary constriction. No pharmacological activity was observed when REVEX was administered in the absence of opioid agonists. - REVEX has not been shown to produce tolerance, physical dependence, or abuse potential. - REVEX can produce acute withdrawal symptoms in individuals who are opioid dependent. ## Pharmacokinetics - Nalmefene exhibited dose proportional pharmacokinetics following intravenous administration of 0.5 mg to 2.0 mg. Pharmacokinetic parameters for nalmefene after a 1 mg intravenous administration in adult male volunteers are listed in Table 1. - Absorption - Nalmefene was completely bioavailable following intramuscular or subcutaneous administration in 12 male volunteers relative to intravenous nalmefene. The relative bioavailabilities of intramuscular and subcutaneous routes of administration were 101.5%± 8.1% (Mean ± SD) and 99.7%± 6.9%, respectively. Nalmefene will be administered primarily as an intravenous bolus, however, nalmefene can be given intra-muscularly (IM) or subcutaneously (SC) if venous access cannot be established. While the time to maximum plasma nalmefene concentration was 2.3 ± 1.1 hours following intramuscular and 1.5 ± 1.2 hours following subcutaneous administrations, therapeutic plasma concentrations are likely to be reached within 5-15 minutes after a 1 mg dose in an emergency. Because of the variability in the speed of absorption for IM& SC dosing, and the inability to titrate to effect, great care should be taken if repeated doses must be given by these routes. - Distribution - Following a 1 mg parenteral dose, nalmefene was rapidly distributed. In a study of brain receptor occupancy, a 1 mg dose of nalmefene blocked over 80% of brain opioid receptors within 5 minutes after administration. The apparent volumes of distribution centrally (Vc) and at steady-state (Vdss) are 3.9 ± 1.1 L/kg and 8.6 ± 1.7 L/kg, respectively. Ultrafiltration studies of nalmefene have demonstrated that 45% (CV 4.1%) is bound to plasma proteins over a concentration range of 0.1 to 2µg/mL. An in vitro determination of the distribution of nalmefene in human blood demonstrated that nalmefene distributed 67% (CV 8.7%) into red blood cells and 39% (CV 6.4%) into plasma. The whole blood to plasma ratio was 1.3 (CV 6.6%) over the nominal concentration range in whole blood from 0.376 to 30 ng/mL. - Metabolism - Nalmefene is metabolized by the liver, primarily by glucuronide conjugation, and excreted in the urine. Nalmefene is also metabolized to trace amounts of an N-dealkylated metabolite. Nalmefene glucuronide is inactive and the N-dealkylated metabolite has minimal pharmacological activity. Less than 5% of nalmefene is excreted in the urine unchanged. Seventeen percent (17%) of the nalmefene dose is excreted in the feces. The plasma concentration-time profile in some subjects suggests that nalmefene undergoes enterohepatic recycling. - Elimination - After intravenous administration of 1 mg REVEX to normal males (ages 19-32), plasma concentrations declined biexponentially with a redistribution and a terminal elimination half-life of 41 ± 34 minutes and 10.8 ± 5.2 hours, respectively. The systemic clearance of nalmefene is 0.8 ± 0.2 L/hr/kg and the renal clearance is 0.08 ± 0.04 L/hr/kg. - Special Populations - Elderly - Dose proportionality was observed in nalmefene AUC0-inf following 0.5 to 2 mg intravenous administration to elderly male subjects. Following a 1 mg intravenous nalmefene dose, there were no significant differences between young (19-32 years) and elderly (62-80 years) adult male subjects with respect to plasma clearance, steady-state volume of distribution, or half-life. There was an apparent age-related decrease in the central volume of distribution (young: 3.9± 1.1 L/kg, elderly: 2.8 ± 1.1 L/kg) that resulted in a greater initial nalmefene concentration in the elderly group. While initial nalmefene plasma concentrations were transiently higher in the elderly, it would not be anticipated that this population would require dosing adjustment. No clinical adverse events were noted in the elderly following the 1 mg intravenous nalmefene dose. - Patients with Hepatic Impairment - Subjects with hepatic disease, when compared to matched normal controls, had a 28.3% decrease in plasma clearance of nalmefene (0.56 ± 0.21 L/hr/kg versus 0.78 ± 0.24 L/hr/kg, respectively). Elimination half-life increased from 10.2 ± 2.2 hours to 11.9 ± 2.0 hours in the hepatically impaired. No dosage adjustment is recommended since nalmefene will be administered as an acute course of therapy. - Patients with Renal Impairment - There was a statistically significant 27% decrease in plasma clearance of nalmefene in the end-stage renal disease (ESRD) population during interdialysis (0.57± 0.20 L/hr/kg) and a 25% decreased plasma clearance in the ESRD population during intradialysis (0.59 ± 0.18 L/hr/kg) compared to normals (0.79± 0.24 L/hr/kg). The elimination half-life was prolonged in ESRD patients from 10.2 ± 2.2 hours in normals to 26.1 ± 9.9 hours. - Gender Differences - There has not been sufficient pharmacokinetic study to make a definitive statement as to whether the pharmacokinetics of nalmefene differs between the genders. ## Nonclinical Toxicology - Nalmefene did not have mutagenic activity in the Ames test with five bacterial strains or the mouse lymphoma assay. Clastogenic activity was not observed in the mouse micronucleus test or in the cytogenic bone marrow assay in rats. However, nalmefene did exhibit a weak but significant clastogenic activity in the human lymphocyte metaphase assay in the absence but not in the presence of exogenous metabolic activation. Oral administration of nalmefene up to 1200 mg/m 2/day did not affect fertility, reproductive performance, and offspring survival in rats. # Clinical Studies - REVEX has been administered to reverse the effects of opioids after general anesthesia and in the treatment of overdose. It has also been used to reverse the systemic effects of intrathecal opioids. - Reversal of Postoperative Opioid Depression - REVEX (nalmefene hydrochloride injection) (N=326) was studied in 5 controlled trials in patients who had received morphine or fentanyl intraoperatively. The primary efficacy criterion was the reversal of respiratory depression. A positive reversal was defined as both an increase in respiratory rate by 5 breaths per minute and a minimum respiratory rate of 12 breaths per minute. Five minutes after administration, initial single REVEX doses of 0.1, 0.25, 0.5, or 1.0 µg/kg had effectively reversed respiratory depression in a dose-dependent manner. Twenty minutes after initial administration, respiratory depression had been effectively reversed in most patients receiving cumulative doses within the recommended range (0.1 to 1.0 µg/kg). Total doses of REVEX above 1.0 µg/kg did not increase the therapeutic response. The postoperative administration of REVEX at the recommended doses did not prevent the analgesic response to subsequently administered opioids. - Reversal of the Effect of Intrathecally Administered Opioids - Intravenous REVEX at doses of 0.5 and 1.0 µg/kg was administered to 47 patients given intrathecal morphine. One to 2 doses of 0.5 and 1.0 µg/kg REVEX reversed respiratory depression in most patients. The administration of REVEX at the recommended doses did not prevent the analgesic response to subsequently administered opioids. - Management of Known or Suspected Opioid Overdose - REVEX (N=284) at doses of 0.5 mg to 2.0 mg was studied in 4 trials of patients who were presumed to have taken an opioid overdose. REVEX doses of 0.5 mg to 1.0 mg effectively reversed respiratory depression within 2 to 5 minutes in most patients subsequently confirmed to have opioid overdose. A total dose greater than 1.5 mg did not increase the therapeutic response. # How Supplied - REVEX (nalmefene hydrochloride injection) is available in the following presentations: - An ampul containing 1 mL of 100 µg/mL nalmefene base (Blue Label) Box of 10 (NDC 10019-315-21) - An ampul containing 2 mL of 1 mg/mL nalmefene base (Green Label) Box of 10 (NDC 10019-311-22) - Store at controlled room temperature. ## Storage There is limited information regarding Nalmefene Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Nalmefene in the drug label. # Precautions with Alcohol - Alcohol-Nalmefene interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - REVEX® # Look-Alike Drug Names There is limited information regarding Nalmefene Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Nalmefene Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Nalmefene is an opioid antagonist that is FDA approved for the {{{indicationType}}} of opioid drug effects, including respiratory depression and opiod overdose. Common adverse reactions include drowsiness, hypertension, tachycardia, dizziness, nausea, and vomiting. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - REVEX is supplied in two concentrations that can be identified by their color coded container labels: a concentration suitable for postoperative use (100 µg/mL) in a blue labeled ampul containing ONE (1) mL and a concentration suitable for the management of overdose (1 mg/mL, 10 times as concentrated, 20 times as much drug) in a green labeled ampul containing TWO (2) mL. Proper steps should be taken to prevent use of the incorrect concentration. - General Principles - REVEX should be titrated to reverse the undesired effects of opioids. Once adequate reversal has been established, additional administration is not required and may actually be harmful due to unwanted reversal of analgesia or precipitated withdrawal. - Duration of Action - The duration of action of REVEX is as long as most opioid analgesics. The apparent duration of action of REVEX will vary, however, depending on the half-life and plasma concentration of the narcotic being reversed, the presence or absence of other drugs affecting the brain or muscles of respiration, and the dose of REVEX administered. Partially reversing doses of REVEX (1 µg/kg) lose their effect as the drug is redistributed through the body, and the effects of these low doses may not last more than 30-60 minutes in the presence of persistent opioid effects. Fully reversing doses (1 mg/70 kg) have been shown to last many hours in both experimental and clinical studies, but may complicate the management of patients who are in pain, at high cardiovascular risk, or who are physically dependent on opioids. - The recommended doses represent a compromise between a desirable controlled reversal and the need for prompt response and adequate duration of action. Using higher dosages or shorter intervals between incremental doses is likely to increase the incidence and severity of symptoms related to acute withdrawal such as nausea, vomiting, elevated blood pressure, and anxiety. - REVEX may cause acute withdrawal symptoms in individuals who have some degree of tolerance to and dependence on opioids. These patients should be closely observed for symptoms of withdrawal following administration of the initial and subsequent injections of REVEX. Subsequent doses should be administered with intervals of at least 2-5 minutes between doses to allow the full effect of each incremental dose of REVEX to be reached. - Use 100µg/mL dosage strength (blue label) and see Table 2 for initial doses. - The goal of treatment with REVEX in the postoperative setting is to achieve reversal of excessive opioid effects without inducing a complete reversal and acute pain. This is best accomplished with an initial dose of 0.25 µg/kg followed by 0.25µg/kg incremental doses at 2-5 minute intervals, stopping as soon as the desired degree of opioid reversal is obtained. A cumulative total dose above 1.0 µg/kg does not provide additional therapeutic effect. - Use 1.0 mg/mL dosage strength (green label). - The recommended initial dose of REVEX for non-opioid dependent patients is 0.5 mg/70 kg. If needed, this may be followed by a second dose of 1.0 mg/70 kg, 2-5 minutes later. If a total dose of 1.5 mg /70 kg has been administered without clinical response, additional REVEX (nalmefene hydrochloride injection) is unlikely to have an effect. Patients should not be given more REVEX than is required to restore the respiratory rate to normal, thus minimizing the likelihood of cardiovascular stress and precipitated withdrawal syndrome. - If there is a reasonable suspicion of opioid dependency, a challenge dose of REVEX 0.1 mg/70 kg should be administered initially. If there is no evidence of withdrawal in 2 minutes, the recommended dosing should be followed. - REVEX had no effect in cases where opioids were not responsible for sedation and hypoventilation. Therefore, patients should only be treated with REVEX when the likelihood of an opioid overdose is high, based on a history of opioid overdose or the clinical presentation of respiratory depression with concurrent pupillary constriction. - Repeated Dosing - REVEX is the longest acting of the currently available parenteral opioid antagonists. If recurrence of respiratory depression does occur, the dose should again be titrated to clinical effect using incremental doses to avoid over-reversal. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Nalmefene in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Nalmefene in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Nalmefene in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Nalmefene in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Nalmefene in pediatric patients. # Contraindications - REVEX is contraindicated in patients with a known hypersensitivity to the product. # Warnings - Use of REVEX in Emergencies - REVEX, like all drugs in this class, is not the primary treatment for ventilatory failure. In most emergency settings, treatment with REVEX should follow, not precede, the establishment of a patent airway, ventilatory assistance, administration of oxygen, and establishment of circulatory access. - Risk of Recurrent Respiratory Depression - Accidental overdose with long acting opioids [such as methadone and levo-alpha-acetylmethadol (LAAM)] may result in prolonged respiratory depression. Respiratory depression in both the postoperative and overdose setting may be complex and involve the effects of anesthetic agents, neuromuscular blockers, and other drugs. While REVEX has a longer duration of action than naloxone in fully reversing doses, the physician should be aware that a recurrence of respiratory depression is possible, even after an apparently adequate initial response to REVEX treatment. - Patients treated with REVEX should be observed until, in the opinion of the physician, there is no reasonable risk of recurrent respiratory depression. ### Precautions - General - Cardiovascular Risks with Narcotic Antagonists - Pulmonary edema, cardiovascular instability, hypotension, hypertension, ventricular tachycardia, and ventricular fibrillation have been reported in connection with opioid reversal in both postoperative and emergency department settings. In many cases, these effects appear to be the result of abrupt reversal of opioid effects. - Although REVEX has been used safely in patients with pre-existing cardiac disease, all drugs of this class should be used with caution in patients at high cardiovascular risk or who have received potentially cardiotoxic drugs. - Risk of Precipitated Withdrawal - REVEX, like other opioid antagonists, is known to produce acute withdrawal symptoms and, therefore, should be used with extreme caution in patients with known physical dependence on opioids or following surgery involving high doses of opioids. Imprudent use or excessive doses of opioid antagonists in the postoperative setting has been associated with hypertension, tachycardia, and excessive mortality in patients at high risk for cardiovascular complications. - Incomplete Reversal of Buprenorphine - Preclinical studies have shown that nalmefene at doses up to 10 mg/kg (437 times the maximum recommended human dose) produced incomplete reversal of buprenorphine-induced analgesia in animal models. This appears to be a consequence of a high affinity and slow displacement of buprenorphine from the opioid receptors. Hence, REVEX may not completely reverse buprenorphine-induced respiratory depression. # Adverse Reactions ## Clinical Trials Experience - Adverse event information was obtained following administration of REVEX to 152 normal volunteers and in controlled clinical trials to 1127 patients for the treatment of opioid overdose or for postoperative opioid reversal. - Nalmefene was well tolerated and showed no serious toxicity during experimental administration to healthy individuals, even when given at 15 times the highest recommended dose. In a small number of subjects, at doses exceeding the recommended REVEX dose, nalmefene produced symptoms suggestive of reversal of endogenous opioids, such as have been reported for other narcotic antagonist drugs. These symptoms (nausea, chills, myalgia, dysphoria, abdominal cramps, and joint pain) were usually transient and occurred at very low frequency. - Such symptoms of precipitated opioid withdrawal at the recommended clinical doses were seen in both postoperative and overdose patients who were later found to have had histories of covert opioid use. Symptoms of precipitated withdrawal were similar to those seen with other opioid antagonists, were transient following the lower doses used in the postoperative setting, and more prolonged following the administration of the larger doses used in the treatment of overdose. - Tachycardia and nausea following the use of nalmefene in the postoperative setting were reported at the same frequencies as for naloxone at equivalent doses. The risk of both these adverse events was low at doses giving partial opioid reversal and increased with increases in dose. Thus, total doses larger than 1.0 µg/kg in the postoperative setting and 1.5 mg/70 kg in the treatment of overdose are not recommended. - Incidence less than 1% Bradycardia, arrhythmia Diarrhea, dry mouth Somnolence, depression, agitation, nervousness, tremor, confusion, withdrawal syndrome, myoclonus Pharyngitis Pruritus Urinary retention - The incidence of adverse events was highest in patients who received more than the recommended dose of REVEX. - Laboratory findings - Transient increases in CPK were reported as adverse events in 0.5% of the postoperative patients studied. These increases were believed to be related to surgery and not believed to be related to the administration of REVEX. Increases in AST were reported as adverse events in 0.3% of the patients receiving either nalmefene or naloxone. The clinical significance of this finding is unknown. No cases of hepatitis or hepatic injury due to either nalmefene or naloxone were observed in the clinical trials. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Nalmefene in the drug label. # Drug Interactions - REVEX has been administered after benzodiazepines, inhalational anesthetics, muscle relaxants, and muscle relaxant antagonists administered in conjunction with general anesthesia. It also has been administered in outpatient settings, both in trials in conscious sedation and in the emergency management of overdose following a wide variety of agents. No deleterious interactions have been observed. - Preclinical studies have shown that both flumazenil and nalmefene can induce seizures in animals. The coadministration of both flumazenil and nalmefene produced fewer seizures than expected in a study in rodents, based on the expected effects of each drug alone. Based on these data, an adverse interaction from the coadministration of the two drugs is not expected, but physicians should remain aware of the potential risk of seizures from agents in these classes. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category B - Reproduction studies have been performed in rats (up to 1200 mg/m 2/day) and rabbits (up to 2400 mg/m2/day) by oral administration of nalmefene and in rabbits by intravenous administration up to 96 mg/m2/day (114 times the human dose). There was no evidence of impaired fertility or harm to the fetus. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nalmefene in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Nalmefene during labor and delivery. ### Nursing Mothers - Nalmefene and its metabolites were secreted into rat milk, reaching concentrations approximately three times those in plasma at one hour and decreasing to about half the corresponding plasma concentrations by 24 hours following bolus administration. As no clinical information is available, caution should be exercised when REVEX is administered to a nursing woman. ### Pediatric Use - Safety and effectiveness of REVEX in pediatric patients have not been established. ### Geriatic Use - Clinical studies of REVEX (nalmefene hydrochloride injection) did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. ### Gender There is no FDA guidance on the use of Nalmefene with respect to specific gender populations. ### Race There is no FDA guidance on the use of Nalmefene with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Nalmefene in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Nalmefene in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Nalmefene in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Nalmefene in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous - Intramuscular - Subcutaneous ### Monitoring There is limited information regarding Monitoring of Nalmefene in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Nalmefene in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - Intravenous doses of up to 24 mg of nalmefene, administered to healthy volunteers in the absence of opioid agonists, produced no serious adverse reactions, severe signs or symptoms, or clinically significant laboratory abnormalities. As with all opioid antagonists, use in patients physically dependent on opioids can result in precipitated withdrawal reactions that may result in symptoms that require medical attention. ### Management - Treatment of such cases should be symptomatic and supportive. Administration of large amounts of opioids to patients receiving opioid antagonists in an attempt to overcome a full blockade has resulted in adverse respiratory and circulatory reactions. ## Chronic Overdose There is limited information regarding Chronic Overdose of Nalmefene in the drug label. # Pharmacology ## Mechanism of Action - *REVEX prevents or reverses the effects of opioids, including respiratory depression, sedation, and hypotension. REVEX has no opioid agonist activity. ## Structure - REVEX (nalmefene hydrochloride injection), an opioid antagonist, is a 6-methylene analogue of naltrexone. The chemical structure is shown below: - Molecular Weight: 375.9, CAS # 58895-64-0 - Chemical Name: 17-(Cyclopropylmethyl)-4,5α-epoxy-6-methylenemorphinan-3,14-diol, hydrochloride salt. - Nalmefene hydrochloride is a white to off-white crystalline powder which is freely soluble in water up to 130 mg/mL and slightly soluble in chloroform up to 0.13 mg/mL, with a pK a of 7.6. - REVEX is available as a sterile solution for intravenous, intramuscular, and subcutaneous administration in two concentrations, containing 100 µg or 1.0 mg of nalmefene free base per mL. The 100 µg/mL concentration contains 110.8 µg of nalmefene hydrochloride and the 1.0 mg/mL concentration contains 1.108 mg of nalmefene hydrochloride per mL. Both concentrations contain 9.0 mg of sodium chloride per mL and the pH is adjusted to 3.9 with hydrochloric acid. - Concentrations and dosages of REVEX are expressed as the free base equivalent of nalmefene. ## Pharmacodynamics - REVEX is not known to produce respiratory depression, psychotomimetic effects, or pupillary constriction. No pharmacological activity was observed when REVEX was administered in the absence of opioid agonists. - REVEX has not been shown to produce tolerance, physical dependence, or abuse potential. - REVEX can produce acute withdrawal symptoms in individuals who are opioid dependent. ## Pharmacokinetics - Nalmefene exhibited dose proportional pharmacokinetics following intravenous administration of 0.5 mg to 2.0 mg. Pharmacokinetic parameters for nalmefene after a 1 mg intravenous administration in adult male volunteers are listed in Table 1. - Absorption - Nalmefene was completely bioavailable following intramuscular or subcutaneous administration in 12 male volunteers relative to intravenous nalmefene. The relative bioavailabilities of intramuscular and subcutaneous routes of administration were 101.5%± 8.1% (Mean ± SD) and 99.7%± 6.9%, respectively. Nalmefene will be administered primarily as an intravenous bolus, however, nalmefene can be given intra-muscularly (IM) or subcutaneously (SC) if venous access cannot be established. While the time to maximum plasma nalmefene concentration was 2.3 ± 1.1 hours following intramuscular and 1.5 ± 1.2 hours following subcutaneous administrations, therapeutic plasma concentrations are likely to be reached within 5-15 minutes after a 1 mg dose in an emergency. Because of the variability in the speed of absorption for IM& SC dosing, and the inability to titrate to effect, great care should be taken if repeated doses must be given by these routes. - Distribution - Following a 1 mg parenteral dose, nalmefene was rapidly distributed. In a study of brain receptor occupancy, a 1 mg dose of nalmefene blocked over 80% of brain opioid receptors within 5 minutes after administration. The apparent volumes of distribution centrally (Vc) and at steady-state (Vdss) are 3.9 ± 1.1 L/kg and 8.6 ± 1.7 L/kg, respectively. Ultrafiltration studies of nalmefene have demonstrated that 45% (CV 4.1%) is bound to plasma proteins over a concentration range of 0.1 to 2µg/mL. An in vitro determination of the distribution of nalmefene in human blood demonstrated that nalmefene distributed 67% (CV 8.7%) into red blood cells and 39% (CV 6.4%) into plasma. The whole blood to plasma ratio was 1.3 (CV 6.6%) over the nominal concentration range in whole blood from 0.376 to 30 ng/mL. - Metabolism - Nalmefene is metabolized by the liver, primarily by glucuronide conjugation, and excreted in the urine. Nalmefene is also metabolized to trace amounts of an N-dealkylated metabolite. Nalmefene glucuronide is inactive and the N-dealkylated metabolite has minimal pharmacological activity. Less than 5% of nalmefene is excreted in the urine unchanged. Seventeen percent (17%) of the nalmefene dose is excreted in the feces. The plasma concentration-time profile in some subjects suggests that nalmefene undergoes enterohepatic recycling. - Elimination - After intravenous administration of 1 mg REVEX to normal males (ages 19-32), plasma concentrations declined biexponentially with a redistribution and a terminal elimination half-life of 41 ± 34 minutes and 10.8 ± 5.2 hours, respectively. The systemic clearance of nalmefene is 0.8 ± 0.2 L/hr/kg and the renal clearance is 0.08 ± 0.04 L/hr/kg. - Special Populations - Elderly - Dose proportionality was observed in nalmefene AUC0-inf following 0.5 to 2 mg intravenous administration to elderly male subjects. Following a 1 mg intravenous nalmefene dose, there were no significant differences between young (19-32 years) and elderly (62-80 years) adult male subjects with respect to plasma clearance, steady-state volume of distribution, or half-life. There was an apparent age-related decrease in the central volume of distribution (young: 3.9± 1.1 L/kg, elderly: 2.8 ± 1.1 L/kg) that resulted in a greater initial nalmefene concentration in the elderly group. While initial nalmefene plasma concentrations were transiently higher in the elderly, it would not be anticipated that this population would require dosing adjustment. No clinical adverse events were noted in the elderly following the 1 mg intravenous nalmefene dose. - Patients with Hepatic Impairment - Subjects with hepatic disease, when compared to matched normal controls, had a 28.3% decrease in plasma clearance of nalmefene (0.56 ± 0.21 L/hr/kg versus 0.78 ± 0.24 L/hr/kg, respectively). Elimination half-life increased from 10.2 ± 2.2 hours to 11.9 ± 2.0 hours in the hepatically impaired. No dosage adjustment is recommended since nalmefene will be administered as an acute course of therapy. - Patients with Renal Impairment - There was a statistically significant 27% decrease in plasma clearance of nalmefene in the end-stage renal disease (ESRD) population during interdialysis (0.57± 0.20 L/hr/kg) and a 25% decreased plasma clearance in the ESRD population during intradialysis (0.59 ± 0.18 L/hr/kg) compared to normals (0.79± 0.24 L/hr/kg). The elimination half-life was prolonged in ESRD patients from 10.2 ± 2.2 hours in normals to 26.1 ± 9.9 hours. - Gender Differences - There has not been sufficient pharmacokinetic study to make a definitive statement as to whether the pharmacokinetics of nalmefene differs between the genders. ## Nonclinical Toxicology - Nalmefene did not have mutagenic activity in the Ames test with five bacterial strains or the mouse lymphoma assay. Clastogenic activity was not observed in the mouse micronucleus test or in the cytogenic bone marrow assay in rats. However, nalmefene did exhibit a weak but significant clastogenic activity in the human lymphocyte metaphase assay in the absence but not in the presence of exogenous metabolic activation. Oral administration of nalmefene up to 1200 mg/m 2/day did not affect fertility, reproductive performance, and offspring survival in rats. # Clinical Studies - REVEX has been administered to reverse the effects of opioids after general anesthesia and in the treatment of overdose. It has also been used to reverse the systemic effects of intrathecal opioids. - Reversal of Postoperative Opioid Depression - REVEX (nalmefene hydrochloride injection) (N=326) was studied in 5 controlled trials in patients who had received morphine or fentanyl intraoperatively. The primary efficacy criterion was the reversal of respiratory depression. A positive reversal was defined as both an increase in respiratory rate by 5 breaths per minute and a minimum respiratory rate of 12 breaths per minute. Five minutes after administration, initial single REVEX doses of 0.1, 0.25, 0.5, or 1.0 µg/kg had effectively reversed respiratory depression in a dose-dependent manner. Twenty minutes after initial administration, respiratory depression had been effectively reversed in most patients receiving cumulative doses within the recommended range (0.1 to 1.0 µg/kg). Total doses of REVEX above 1.0 µg/kg did not increase the therapeutic response. The postoperative administration of REVEX at the recommended doses did not prevent the analgesic response to subsequently administered opioids. - Reversal of the Effect of Intrathecally Administered Opioids - Intravenous REVEX at doses of 0.5 and 1.0 µg/kg was administered to 47 patients given intrathecal morphine. One to 2 doses of 0.5 and 1.0 µg/kg REVEX reversed respiratory depression in most patients. The administration of REVEX at the recommended doses did not prevent the analgesic response to subsequently administered opioids. - Management of Known or Suspected Opioid Overdose - REVEX (N=284) at doses of 0.5 mg to 2.0 mg was studied in 4 trials of patients who were presumed to have taken an opioid overdose. REVEX doses of 0.5 mg to 1.0 mg effectively reversed respiratory depression within 2 to 5 minutes in most patients subsequently confirmed to have opioid overdose. A total dose greater than 1.5 mg did not increase the therapeutic response. # How Supplied - REVEX (nalmefene hydrochloride injection) is available in the following presentations: - An ampul containing 1 mL of 100 µg/mL nalmefene base (Blue Label) Box of 10 (NDC 10019-315-21) - An ampul containing 2 mL of 1 mg/mL nalmefene base (Green Label) Box of 10 (NDC 10019-311-22) - Store at controlled room temperature. ## Storage There is limited information regarding Nalmefene Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Nalmefene in the drug label. # Precautions with Alcohol - Alcohol-Nalmefene interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - REVEX®[1] # Look-Alike Drug Names There is limited information regarding Nalmefene Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Nalmefene
959c85f7ce8419d587b5c703c2daec7d45d195ef	wikidoc	Nanometre	Nanometre # Overview A nanometre (American spelling: nanometer, symbol nm) (Greek: νάνος, nanos, dwarf; μετρώ, metrό, count) is a unit of length in the metric system, equal to one billionth of a metre (i.e., one millionth of a millimetre), which is the current SI base unit of length. It can be written in scientific notations as 1×10−9 m (engineering notation) or 1 E-9 m (exponential notation) — both meaning 1/1,000,000,000 metres. femtometre <<< picometre <<< nanometre <<< micrometre <<< millimetre < centimetre < decimetre < metre < decametre < hectometre < kilometre It is one of the more often used units for very small lengths, and equals ten Ångström, an internationally recognized non-SI unit of length. It is often associated with the field of nanotechnology. Formerly, millimicron (symbol mµ) was used for the nanometre. It is also the most common unit used to describe the manufacturing technology used in the semiconductor industry. It is the most common unit to describe the wavelength of light, with visible light falling in the region of 400-700nm. # Similar terms Nanometry is the science of counting and measuring particles on the scale of nanometres. The term nanoscale is used to refer to objects with dimensions on the order 1-100 nm. The term is often heard in relation to nanotechnology.	Nanometre # Overview A nanometre (American spelling: nanometer, symbol nm) (Greek: νάνος, nanos, dwarf; μετρώ, metrό, count) is a unit of length in the metric system, equal to one billionth of a metre (i.e., one millionth of a millimetre), which is the current SI base unit of length. It can be written in scientific notations as 1×10−9 m (engineering notation) or 1 E-9 m (exponential notation) — both meaning 1/1,000,000,000 metres. femtometre <<< picometre <<< nanometre <<< micrometre <<< millimetre < centimetre < decimetre < metre < decametre < hectometre < kilometre It is one of the more often used units for very small lengths, and equals ten Ångström, an internationally recognized non-SI unit of length. It is often associated with the field of nanotechnology. Formerly, millimicron (symbol mµ) was used for the nanometre. It is also the most common unit used to describe the manufacturing technology used in the semiconductor industry. It is the most common unit to describe the wavelength of light, with visible light falling in the region of 400-700nm. # Similar terms Nanometry is the science of counting and measuring particles on the scale of nanometres. The term nanoscale is used to refer to objects with dimensions on the order 1-100 nm. The term is often heard in relation to nanotechnology.	https://www.wikidoc.org/index.php/Nanometer
76f565a36ef31a262e6266ebd2f95d95963f1c4c	wikidoc	Tetracene	Tetracene Tetracene, also called naphthacene, benzanthracene and 2,3-benzanthracene, is a polycyclic aromatic hydrocarbon. It has the appearance of a pale yellow powder. Tetracene is used as a sensitiser in chemoluminescence. It is a molecular organic semiconductor, used in OFETs and OLEDs. In May 2007, researchers from two Japanese universities, Tohoku University in Sendai, and Osaka University, have reported an ambipolar light-emitting transistor made of a tetracene single crystal . Ambipolar means that the electric charge is transported by both, positively charged molecular cations and negatively charged molecular anions. Tetracene can be also used as a gain medium in dye lasers. Jan Hendrik Schön during his time at Bell Labs (1997-2002) claimed to have developed an electrically pumped laser based on tetracene. However his results could not be reproduced and it is considered scientific fraud. Tetracene is the four ringed member of the series of acenes, the previous one being anthracene (tricene) and the next one being pentacene.	Tetracene Template:Chembox new Tetracene, also called naphthacene, benz[b]anthracene and 2,3-benzanthracene, is a polycyclic aromatic hydrocarbon. It has the appearance of a pale yellow powder. Tetracene is used as a sensitiser in chemoluminescence. It is a molecular organic semiconductor, used in OFETs and OLEDs. In May 2007, researchers from two Japanese universities, Tohoku University in Sendai, and Osaka University, have reported an ambipolar light-emitting transistor made of a tetracene single crystal [1]. Ambipolar means that the electric charge is transported by both, positively charged molecular cations and negatively charged molecular anions. Tetracene can be also used as a gain medium in dye lasers. Jan Hendrik Schön during his time at Bell Labs (1997-2002) claimed to have developed an electrically pumped laser based on tetracene. However his results could not be reproduced and it is considered scientific fraud. Tetracene is the four ringed member of the series of acenes, the previous one being anthracene (tricene) and the next one being pentacene. # External links Template:Hydrocarbon-stub de:Tetracen Template:WH Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Naphthacene
32bb6ee1f8c987747bd4b1ba2a04597a034db2fb	wikidoc	Noscapine	Noscapine # Overview Noscapine (also known as Narcotine, Nectodon, Nospen, Anarcotine and (archaic) Opiane) is a benzylisoquinoline alkaloid from plants of the poppy family, without painkilling properties. This agent is primarily used for its antitussive (cough-suppressing) effects. # Medical uses Noscapine is often used as an antitussive medication. A 2012 Dutch guideline; however, does not recommend its use for coughing. # Side effects - Loss of coordination - Hallucinations (auditory and visual) - Loss of sexual drive - Swelling of prostate - Loss of appetite - Dilated pupils - Increased heart rate - Shaking and muscle spasms - Chest pains - Increased alertness - Loss of any sleepiness - Loss of stereoscopic vision # Interactions Noscapine can increase the effects of centrally sedating substances such as alcohol and hypnotics. The drug should not be taken with any MAOIs (monoamine oxidase inhibitors), as unknown and potentially fatal effects may occur. Noscapine should not be taken in conjunction with warfarin as the anticoagulant effects of warfarin may be increased. # Mechanism of action Noscapine's antitussive effects appear to be primarily mediated by its σ–receptor agonist activity. Evidence for this mechanism is suggested by experimental evidence in rats. Pretreatment with rimcazole, a σ- specific antagonist, causes a dose-dependent reduction in antitussive activity of noscapine. # Structure analysis The lactone ring is unstable and opens in basic media. The opposite reaction is presented in acidic media. The bond C1-C3' is also unstable. This is the bond connecting the two optically active carbon atoms. In aqueous solution of sulfuric acid and heating it dissociates into cotarnine (4-methoxy-6-methyl-5,6,7,8-tetrahydro-dioxoloisoquinoline) and opic acid (6-formyl-2,3-dimethoxybenzoic acid). When noscapine is reduced with zinc/HCl, the bond C1-C3' saturates and the molecule dissociates into hydrocotarnine (2-hydroxycotarnine) and meconine (6,7-dimethoxyisobenzofuran-1(3H)-one). # History Noscapine was first isolated and characterized in chemical breakdown and properties in 1817 under the denomination of "Narcotine" by Pierre Robiquet, a French chemist in Paris. Robiquet conducted over 20 years between 1815 and 1835 a series of studies in the enhancement of methods for the isolation of morphine, and also isolated in 1832 another very important component of raw opium, that he called codeine, currently a widely used opium-derived compound. # Society and culture ## Recreational use There are anecdotal reports of the recreational use of over-the-counter drugs in several countries, being readily available from local pharmacies without a prescription. The effects, beginning around 45 to 120 mins after consumption, are similar to dextromethorphan and alcohol intoxication. Unlike dextromethorphan, noscapine is not an NMDA receptor antagonist. ## Noscapine in heroin Noscapine can survive the manufacturing processes of heroin and can be found in street heroin. This is useful for law enforcement agencies, as the amounts of contaminants can identify the source of seized drugs. In 2005 in Liège, Belgium, the average noscapine concentration was around 8%. Noscapine has also been used to identify drug users who are taking street heroin at the same time as prescribed diamorphine. Since the diamorphine in street heroin is the same as the pharmaceutical diamorphine, examination of the contaminants is the only way to test whether street heroin has been used. Other contaminants used in urine samples alongside noscapine include papaverine and acetylcodeine. Noscapine is metabolised by the body, and is itself rarely found in urine, instead being present as the primary metabolites, cotarnine and meconine. Detection is performed by gas chromatography-mass spectrometry or liquid chromatography-mass spectrometry (LCMS) but can also use a variety of other analytical techniques. # Research Noscapine is currently being investigated as an antitumor agent in animal models of several human cancers.	Noscapine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Noscapine (also known as Narcotine, Nectodon, Nospen, Anarcotine and (archaic) Opiane) is a benzylisoquinoline alkaloid from plants of the poppy family, without painkilling properties. This agent is primarily used for its antitussive (cough-suppressing) effects. # Medical uses Noscapine is often used as an antitussive medication.[1] A 2012 Dutch guideline; however, does not recommend its use for coughing.[2] # Side effects - Loss of coordination - Hallucinations (auditory and visual) - Loss of sexual drive - Swelling of prostate - Loss of appetite - Dilated pupils - Increased heart rate - Shaking and muscle spasms - Chest pains - Increased alertness - Loss of any sleepiness - Loss of stereoscopic vision # Interactions Noscapine can increase the effects of centrally sedating substances such as alcohol and hypnotics.[3] The drug should not be taken with any MAOIs (monoamine oxidase inhibitors), as unknown and potentially fatal effects may occur.[citation needed] Noscapine should not be taken in conjunction with warfarin as the anticoagulant effects of warfarin may be increased.[4] # Mechanism of action Noscapine's antitussive effects appear to be primarily mediated by its σ–receptor agonist activity. Evidence for this mechanism is suggested by experimental evidence in rats. Pretreatment with rimcazole, a σ- specific antagonist, causes a dose-dependent reduction in antitussive activity of noscapine.[5] # Structure analysis The lactone ring is unstable and opens in basic media. The opposite reaction is presented in acidic media. The bond C1-C3' is also unstable. This is the bond connecting the two optically active carbon atoms. In aqueous solution of sulfuric acid and heating it dissociates into cotarnine (4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline) and opic acid (6-formyl-2,3-dimethoxybenzoic acid). When noscapine is reduced with zinc/HCl, the bond C1-C3' saturates and the molecule dissociates into hydrocotarnine (2-hydroxycotarnine) and meconine (6,7-dimethoxyisobenzofuran-1(3H)-one). # History Noscapine was first isolated and characterized in chemical breakdown and properties in 1817 under the denomination of "Narcotine"[6] by Pierre Robiquet, a French chemist in Paris. Robiquet conducted over 20 years between 1815 and 1835 a series of studies in the enhancement of methods for the isolation of morphine, and also isolated in 1832 another very important component of raw opium, that he called codeine, currently a widely used opium-derived compound. # Society and culture ## Recreational use There are anecdotal reports of the recreational use of over-the-counter drugs in several countries, being readily available from local pharmacies without a prescription. The effects, beginning around 45 to 120 mins after consumption, are similar to dextromethorphan and alcohol intoxication. Unlike dextromethorphan, noscapine is not an NMDA receptor antagonist.[7] ## Noscapine in heroin Noscapine can survive the manufacturing processes of heroin and can be found in street heroin. This is useful for law enforcement agencies, as the amounts of contaminants can identify the source of seized drugs. In 2005 in Liège, Belgium, the average noscapine concentration was around 8%.[8] Noscapine has also been used to identify drug users who are taking street heroin at the same time as prescribed diamorphine.[9] Since the diamorphine in street heroin is the same as the pharmaceutical diamorphine, examination of the contaminants is the only way to test whether street heroin has been used. Other contaminants used in urine samples alongside noscapine include papaverine and acetylcodeine. Noscapine is metabolised by the body, and is itself rarely found in urine, instead being present as the primary metabolites, cotarnine and meconine. Detection is performed by gas chromatography-mass spectrometry or liquid chromatography-mass spectrometry (LCMS) but can also use a variety of other analytical techniques. # Research Noscapine is currently being investigated as an antitumor agent in animal models of several human cancers.	https://www.wikidoc.org/index.php/Narcotine
9e9debdf76a3d9fc3edd3ba85bacd103b76877f9	wikidoc	Natamycin	Natamycin # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Natamycin is an antifungal polyene that is FDA approved for the treatment of fungal blepharitis, conjunctivitis, and keratitis caused by susceptible organisms including Fusarium solani keratitis. Common adverse reactions include Eye irritation. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Fungal Keratitis, Blepharitis and Conjunctivitis - One drop natamycin ophthalmic suspension 5% instilled in the conjunctival sac at hourly or two-hourly intervals. - The frequency of application can usually be reduced to one drop 6 to 8 times daily after the first 3 to 4 days. - Therapy should generally be continued for 14 to 21 days or until there is resolution of active fungal keratitis. In many cases, it may be helpful to reduce the dosage gradually at 4 to 7 day intervals to assure that the replicating organism has been eliminated. - Less frequent initial dosage (4 to 6 daily applications) may be sufficient in fungal blepharitis and conjunctivitis. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Natamycin in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Natamycin in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Natamycin FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Natamycin in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Natamycin in pediatric patients. # Contraindications - Contraindicated in individuals with a history of hypersensitivity to any of its components. # Warnings - FOR TOPICAL OPHTHALMIC USE ONLY — NOT FOR INJECTION. - Failure of improvement of keratitis following 7-10 days of administration of the drug suggests that the infection may be caused by a microorganism not susceptible to natamycin. - Continuation of therapy should be based on clinical re-evaluation and additional laboratory studies. - Adherence of the suspension to areas of epithelial ulceration or retention of the suspension in the fornices occurs regularly. - Use only if the container is undamaged. # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Natamycin Clinical Trials Experience in the drug label. ## Postmarketing Experience - The following events have been identified during post-marketing use of natamycin in clinical practice. - Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. - The events, which have been chosen for inclusion due to their seriousness, frequency of reporting, possible causal connection to natamycin, or a combination of these factors include: - Allergic reaction - Change in vision, - Chest pain - Corneal opacity - Dyspnea - Eye discomfort - Eye edema - Eye hyperemia - Eye irritation - Eye pain - Foreign body sensation - Parethesia - Tearing # Drug Interactions There is limited information regarding Natamycin Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C Animal reproduction studies have not been conducted with natamycin. It is also not known whether natamycin can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Natamycin (natamycin ophthalmic suspension) 5% should be given to a pregnant woman only if clearly needed. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Natamycin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Natamycin during labor and delivery. ### Nursing Mothers It is not known whether these drugs are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when natamycin is administered to a nursing woman. ### Pediatric Use Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use No overall differences in safety or effectiveness have been observed between elderly and younger patients. ### Gender There is no FDA guidance on the use of Natamycin with respect to specific gender populations. ### Race There is no FDA guidance on the use of Natamycin with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Natamycin in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Natamycin in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Natamycin in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Natamycin in patients who are immunocompromised. # Administration and Monitoring ### Administration - Ophthalmic ### Monitoring There is limited information regarding Natamycin Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Natamycin and IV administrations. # Overdosage There is limited information regarding Natamycin overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action Natamycin is a tetraene polyene antibiotic derived from Streptomyces natalensis. It possesses in vitro activity against a variety of yeast and filamentous fungi, including Candida, Aspergillus, Cephalosporium, Fusarium and Penicillium. The mechanism of action appears to be through binding of the molecule to the sterol moiety of the fungal cell membrane. The polyenesterol complex alters the permeability of the membrane to produce depletion of essential cellular constituents. Although the activity against fungi is dose-related, natamycin is predominantly fungicidal. Natamycin is not effective in vitro against gram-positive or gram-negative bacteria. ## Structure - Natamycin ophthalmic suspension) 5% is a sterile, antifungal drug for topical ophthalmic administration. - Each mL of the suspension contains: - Active: natamycin 5% (50 mg). - Preservative: benzalkonium chloride 0.02%. - Inactive: sodium hydroxide and/or hydrochloric acid (neutralized to adjust the pH), purified water. - The active ingredient is represented by the chemical structure: - Established name: Natamycin - Molecular Formula: C33H47NO13 - Molecular Weight: 665.73 - Chemical name: Stereoisomer of 22--1,3,26- trihydroxy-12- methyl-10-oxo-6,11,28- trioxatricyclo octacosa-8,14,16,18,20-pentaene-25- carboxylic acid. - Other: Pimaricin - The pH range is 5.0 - 7.5. ## Pharmacodynamics There is limited information regarding Natamycin Pharmacodynamics in the drug label. ## Pharmacokinetics Topical administration appears to produce effective concentrations of natamycin within the corneal stroma but not in intraocular fluid. Systemic absorption should not be expected following topical administration of natamycin (natamycin ophthalmic suspension) 5%. As with other polyene antibiotics, absorption from the gastrointestinal tract is very poor. Studies in rabbits receiving topical natamycin revealed no measurable compound in the aqueous humor or sera, but the sensitivity of the measurement was no greater than 2 mg/mL. ## Nonclinical Toxicology There have been no long term studies done using natamycin in animals to evaluate carcinogenesis, mutagenesis, or impairment of fertility. # Clinical Studies There is limited information regarding Natamycin Clinical Studies in the drug label. # How Supplied - Natamycin ophthalmic suspension 5% is a 15mL fill packaged in a 15mL amber glass bottle with a black phenolic closure. - A flint glass dropper with a red plastic closure and a black rubber bulb are packaged separately in a clear plastic blister with Tyvek backing. - NDC 0065-0645-15 ## Storage - Store between 2-24°C (36-75°F). - Do not freeze. - Avoid exposure to light and excessive heat. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Do not touch dropper tip to any surface, as this may contaminate the suspension. *Patients should be advised not to wear contact lenses if they have signs and symptoms of fungal blepharitis, conjunctivitis, and keratitis. # Precautions with Alcohol Alcohol-Natamycin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Natacyn # Look-Alike Drug Names There is limited information regarding Natamycin Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Natamycin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Stefano Giannoni [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Natamycin is an antifungal polyene that is FDA approved for the treatment of fungal blepharitis, conjunctivitis, and keratitis caused by susceptible organisms including Fusarium solani keratitis. Common adverse reactions include Eye irritation. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Fungal Keratitis, Blepharitis and Conjunctivitis - One drop natamycin ophthalmic suspension 5% instilled in the conjunctival sac at hourly or two-hourly intervals. - The frequency of application can usually be reduced to one drop 6 to 8 times daily after the first 3 to 4 days. - Therapy should generally be continued for 14 to 21 days or until there is resolution of active fungal keratitis. In many cases, it may be helpful to reduce the dosage gradually at 4 to 7 day intervals to assure that the replicating organism has been eliminated. - Less frequent initial dosage (4 to 6 daily applications) may be sufficient in fungal blepharitis and conjunctivitis. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Natamycin in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Natamycin in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Natamycin FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Natamycin in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Natamycin in pediatric patients. # Contraindications - Contraindicated in individuals with a history of hypersensitivity to any of its components. # Warnings - FOR TOPICAL OPHTHALMIC USE ONLY — NOT FOR INJECTION. - Failure of improvement of keratitis following 7-10 days of administration of the drug suggests that the infection may be caused by a microorganism not susceptible to natamycin. - Continuation of therapy should be based on clinical re-evaluation and additional laboratory studies. - Adherence of the suspension to areas of epithelial ulceration or retention of the suspension in the fornices occurs regularly. - Use only if the container is undamaged. # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Natamycin Clinical Trials Experience in the drug label. ## Postmarketing Experience - The following events have been identified during post-marketing use of natamycin in clinical practice. - Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. - The events, which have been chosen for inclusion due to their seriousness, frequency of reporting, possible causal connection to natamycin, or a combination of these factors include: - Allergic reaction - Change in vision, - Chest pain - Corneal opacity - Dyspnea - Eye discomfort - Eye edema - Eye hyperemia - Eye irritation - Eye pain - Foreign body sensation - Parethesia - Tearing # Drug Interactions There is limited information regarding Natamycin Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C Animal reproduction studies have not been conducted with natamycin. It is also not known whether natamycin can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Natamycin (natamycin ophthalmic suspension) 5% should be given to a pregnant woman only if clearly needed. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Natamycin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Natamycin during labor and delivery. ### Nursing Mothers It is not known whether these drugs are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when natamycin is administered to a nursing woman. ### Pediatric Use Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use No overall differences in safety or effectiveness have been observed between elderly and younger patients. ### Gender There is no FDA guidance on the use of Natamycin with respect to specific gender populations. ### Race There is no FDA guidance on the use of Natamycin with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Natamycin in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Natamycin in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Natamycin in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Natamycin in patients who are immunocompromised. # Administration and Monitoring ### Administration - Ophthalmic ### Monitoring There is limited information regarding Natamycin Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Natamycin and IV administrations. # Overdosage There is limited information regarding Natamycin overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action Natamycin is a tetraene polyene antibiotic derived from Streptomyces natalensis. It possesses in vitro activity against a variety of yeast and filamentous fungi, including Candida, Aspergillus, Cephalosporium, Fusarium and Penicillium. The mechanism of action appears to be through binding of the molecule to the sterol moiety of the fungal cell membrane. The polyenesterol complex alters the permeability of the membrane to produce depletion of essential cellular constituents. Although the activity against fungi is dose-related, natamycin is predominantly fungicidal. Natamycin is not effective in vitro against gram-positive or gram-negative bacteria. ## Structure - Natamycin ophthalmic suspension) 5% is a sterile, antifungal drug for topical ophthalmic administration. - Each mL of the suspension contains: - Active: natamycin 5% (50 mg). - Preservative: benzalkonium chloride 0.02%. - Inactive: sodium hydroxide and/or hydrochloric acid (neutralized to adjust the pH), purified water. - The active ingredient is represented by the chemical structure: - Established name: Natamycin - Molecular Formula: C33H47NO13 - Molecular Weight: 665.73 - Chemical name: Stereoisomer of 22-[(3-amino-3,6-dideoxy- β-D-mannopyranosyl)oxy]-1,3,26- trihydroxy-12- methyl-10-oxo-6,11,28- trioxatricyclo[22.3.1.05,7] octacosa-8,14,16,18,20-pentaene-25- carboxylic acid. - Other: Pimaricin - The pH range is 5.0 - 7.5. ## Pharmacodynamics There is limited information regarding Natamycin Pharmacodynamics in the drug label. ## Pharmacokinetics Topical administration appears to produce effective concentrations of natamycin within the corneal stroma but not in intraocular fluid. Systemic absorption should not be expected following topical administration of natamycin (natamycin ophthalmic suspension) 5%. As with other polyene antibiotics, absorption from the gastrointestinal tract is very poor. Studies in rabbits receiving topical natamycin revealed no measurable compound in the aqueous humor or sera, but the sensitivity of the measurement was no greater than 2 mg/mL. ## Nonclinical Toxicology There have been no long term studies done using natamycin in animals to evaluate carcinogenesis, mutagenesis, or impairment of fertility. # Clinical Studies There is limited information regarding Natamycin Clinical Studies in the drug label. # How Supplied - Natamycin ophthalmic suspension 5% is a 15mL fill packaged in a 15mL amber glass bottle with a black phenolic closure. - A flint glass dropper with a red plastic closure and a black rubber bulb are packaged separately in a clear plastic blister with Tyvek backing. - NDC 0065-0645-15 ## Storage - Store between 2-24°C (36-75°F). - Do not freeze. - Avoid exposure to light and excessive heat. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Do not touch dropper tip to any surface, as this may contaminate the suspension. *Patients should be advised not to wear contact lenses if they have signs and symptoms of fungal blepharitis, conjunctivitis, and keratitis. # Precautions with Alcohol Alcohol-Natamycin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Natacyn[1] # Look-Alike Drug Names There is limited information regarding Natamycin Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Natacyn
59c9c563d2360e5dd9b349c612167104d2e68352	wikidoc	Nebulette	Nebulette Nebulette is a cardiac-specific isoform belonging to the nebulin family of proteins. It is encoded by the NEBL gene. This family is composed of 5 members: nebulette, nebulin, N-RAP, LASP-1 and LASP-2. Nebulette localizes to Z-discs of cardiac muscle and appears to regulate the length of actin thin filaments. # Structure Nebulette is a 116.4 kDa protein composed of 1014 amino acids. As a member of the nebulin family of proteins, nebulette is characterized by 35 amino acid stretches of ‘‘nebulin repeats’’, which are actin binding domains containing a conserved SDxxYK motif. Like nebulin, nebulette has an acidic region with unknown structure at its N-terminus, and a serine-rich region adjacent to an SH3 domain at its C-terminus. Though nebulette shares structural features with nebulin, nebulin is expressed preferentially in skeletal muscle and has an enormous size (600-900 kDa), while nebulette is expressed in cardiac muscle at Z-disc regions and is significantly smaller (roughly 1/6 of the size). Nebulette interacts with actin, tropomyosin, alpha-actinin. Xin, and XIRP2. # Function Nebulette was identified in 1995 by Moncman and Wang using primary cultures of chicken embryonic cardiomyocytes by immunoprecipitations with certain anti-nebulin monoclonal antibodies. Normal expression of nebulette is essential for the assembly and contractile function of myofibrils. Specifically, nebulette appears to regulate the stability and length of actin thin filaments, as well as beating frequencies of cardiomyocytes; reduction of full-length nebulette protein in cardiomyocytes resulted in reduced thin filament lengths, depressed beating frequencies and loss of thin filament regulatory proteins troponin I and tropomyosin. # Clinical significance Mutations in the NEBL gene have been associated with dilated cardiomyopathy. Studies in transgenic mice have supported their causative role in endocardial fibroelastosis and dilated cardiomyopathy. # Further reading - "Mass spectrometry characterization of NEBL at COPaKB". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB)..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}	Nebulette Nebulette is a cardiac-specific isoform belonging to the nebulin family of proteins. It is encoded by the NEBL gene. This family is composed of 5 members: nebulette, nebulin, N-RAP, LASP-1 and LASP-2. Nebulette localizes to Z-discs of cardiac muscle and appears to regulate the length of actin thin filaments. # Structure Nebulette is a 116.4 kDa protein composed of 1014 amino acids.[1][2] As a member of the nebulin family of proteins, nebulette is characterized by 35 amino acid stretches of ‘‘nebulin repeats’’, which are actin binding domains containing a conserved SDxxYK motif.[3] Like nebulin, nebulette has an acidic region with unknown structure at its N-terminus, and a serine-rich region adjacent to an SH3 domain at its C-terminus.[4] Though nebulette shares structural features with nebulin, nebulin is expressed preferentially in skeletal muscle and has an enormous size (600-900 kDa), while nebulette is expressed in cardiac muscle at Z-disc regions and is significantly smaller (roughly 1/6 of the size).[5] Nebulette interacts with actin, tropomyosin, alpha-actinin.[6] Xin, and XIRP2.[7] # Function Nebulette was identified in 1995 by Moncman and Wang using primary cultures of chicken embryonic cardiomyocytes by immunoprecipitations with certain anti-nebulin monoclonal antibodies.[8] Normal expression of nebulette is essential for the assembly and contractile function of myofibrils.[9] Specifically, nebulette appears to regulate the stability and length of actin thin filaments, as well as beating frequencies of cardiomyocytes; reduction of full-length nebulette protein in cardiomyocytes resulted in reduced thin filament lengths, depressed beating frequencies and loss of thin filament regulatory proteins troponin I and tropomyosin.[10][11] # Clinical significance Mutations in the NEBL gene have been associated with dilated cardiomyopathy.[12] Studies in transgenic mice have supported their causative role in endocardial fibroelastosis and dilated cardiomyopathy.[13] # Further reading - "Mass spectrometry characterization of NEBL at COPaKB". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB)..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}[14]	https://www.wikidoc.org/index.php/Nebulette
095e71fa2dd395b02a090a57746f703374281ad4	wikidoc	Nebulizer	Nebulizer # Overview In medicine, a nebulizer is a device used to administer medication to people in forms of a liquid mist to the airways. It is commonly used in treating cystic fibrosis, asthma, and other respiratory diseases. Also called "atomizers", they pump air or oxygen through a liquid medicine to turn it into a vapor, which is then inhaled by the patient. As a general rule, doctors generally prefer to prescribe inhalers for their patients, not only because these are cheaper and more portable, but are often less potent and carry less risk of side effects. Nebulizers, for that reason, are usually reserved only for serious cases of respiratory disease, or severe attacks. Newer, compact ultrasonic nebulizers are also available. These nebulizers, such as the Omron MicroAir series, use vibrating micro-mesh to produce the vapor. Nebulizers of this variety are rather expensive, and the micro-mesh is very delicate and sensitive to dust and debris. # Use and attachments Nebulizers usually accept their medicine in the form of a concentrated liquid, sometimes viscous. These medicines are frequently steroids, and the reason they are inhaled instead of ingested is to limit their effect to the lungs and respiratory system only. Otherwise, that amount of steroid saturated throughout the body would be toxic. This liquid is loaded into the machine for use. Bronchodilators such as Albuterol are often used. Usually, the vaporized medicine is inhaled through a tube-like mouthpiece, similar to that of an inhaler. This has the added benefit of increasing portability, as well as allowing surrounding air to mix with the medicine, decreasing the unpleasantness of the vapor. The inhaling apparatus, however, is sometimes replaced with a standard rubber face mask, similar to that use for inhaled anaesthesia, for ease of use with young children or the elderly. After use with steroids, the person who used the nebulizer must rinse his or her mouth because those steroids can cause yeast infection of the mouth (thrush). This is not true for bronchodilators; however, patients may still wish to rinse their mouths due to the unpleasant taste of many bronchdilating drugs.	Nebulizer Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview In medicine, a nebulizer is a device used to administer medication to people in forms of a liquid mist to the airways. It is commonly used in treating cystic fibrosis, asthma, and other respiratory diseases. Also called "atomizers", they pump air or oxygen through a liquid medicine to turn it into a vapor, which is then inhaled by the patient. As a general rule, doctors generally prefer to prescribe inhalers for their patients, not only because these are cheaper and more portable, but are often less potent and carry less risk of side effects. Nebulizers, for that reason, are usually reserved only for serious cases of respiratory disease, or severe attacks. Newer, compact ultrasonic nebulizers are also available. These nebulizers, such as the Omron MicroAir series, use vibrating micro-mesh to produce the vapor. Nebulizers of this variety are rather expensive, and the micro-mesh is very delicate and sensitive to dust and debris. # Use and attachments Nebulizers usually accept their medicine in the form of a concentrated liquid, sometimes viscous. These medicines are frequently steroids, and the reason they are inhaled instead of ingested is to limit their effect to the lungs and respiratory system only. Otherwise, that amount of steroid saturated throughout the body would be toxic. This liquid is loaded into the machine for use. Bronchodilators such as Albuterol are often used. Usually, the vaporized medicine is inhaled through a tube-like mouthpiece, similar to that of an inhaler. This has the added benefit of increasing portability, as well as allowing surrounding air to mix with the medicine, decreasing the unpleasantness of the vapor. The inhaling apparatus, however, is sometimes replaced with a standard rubber face mask, similar to that use for inhaled anaesthesia, for ease of use with young children or the elderly. After use with steroids, the person who used the nebulizer must rinse his or her mouth because those steroids can cause yeast infection of the mouth (thrush). This is not true for bronchodilators; however, patients may still wish to rinse their mouths due to the unpleasant taste of many bronchdilating drugs. Template:WH Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Nebuliser
7dd8487863060715caf347aaa5269e8fe49ff364	wikidoc	RNA virus	RNA virus # Overview An RNA virus is a virus that has ribonucleic acid (RNA) as its genetic material and does not replicate using a DNA intermediate. RNA viruses belong to either Group III, Group IV or Group V of the Baltimore classification system of classifying viruses. Their nucleic acid is usually single-stranded RNA (ssRNA) but may be double-stranded RNA (dsRNA). Notable human pathogenic RNA viruses include SARS, Influenza and Hepatitis C. # Characteristics ## Single-stranded RNA viruses and RNA Sense RNA viruses can be further classified according to the sense or polarity of their RNA into negative-sense and positive-sense, or ambisense RNA viruses. Positive-sense viral RNA is identical to viral mRNA and thus can be immediately translated by the host cell. Negative-sense viral RNA is complementary to mRNA and thus must be converted to positive-sense RNA by an RNA polymerase before translation. As such, purified RNA of a positive-sense virus can directly cause infection though it may be less infectious than the whole virus particle. Purified RNA of a negative-sense virus is not infectious by itself as it needs to be transcribed into positive-sense RNA. Ambisense RNA viruses transcribe genes from both the positive or negative strand. ## Double-stranded RNA viruses The double-stranded (ds)RNA viruses represent a diverse group of viruses that vary widely in host range (humans, animals, plants, fungi, and bacteria), genome segment number (one to twelve), and virion organization (T-number, capsid layers, or turrets). Members of this group include the rotaviruses, renowned globally as the commonest cause of gastroenteritis in young children, and bluetongue virus , an economically important pathogen of cattle and sheep. In recent years, remarkable progress has been made in determining, at atomic and subnanometeric levels, the structures of a number of key viral proteins and of the virion capsids of several dsRNA viruses, highlighting the significant parallels in the structure and replicative processes of many of these viruses. ## Mutation rates RNA viruses generally have very high mutation rates as they lack DNA polymerases which can find and fix mistakes, and are therefore unable to conduct DNA repair of damaged genetic material. DNA viruses have considerably lower mutation rates due to the proof-reading ability of DNA polymerases within the host cell. Retroviruses integrate a DNA intermediate of their RNA genome into the host genome, and therefore have a higher chance of correcting any mistakes in their genome thanks to the action of proof-reading DNA polymerases belonging to the host cell. Although RNA usually mutates rapidly, recent work found that the SARS virus and related RNA viruses contain a gene that mutates very slowly. The gene in question has a complex three-dimensional structure which is hypothesized to provide a chemical function necessary for viral propagation, perhaps as a ribozyme. If so, most mutations would render it unfit for that purpose and would not propagate. # Replication Animal RNA viruses can be placed into about four different groups depending on their mode of replication. - Positive-sense viruses have their genome directly utilized as if it were mRNA, producing a single protein which is modified by host and viral proteins to form the various proteins needed for replication. One of these includes RNA replicase, which copies the viral RNA to form a double-stranded replicative form, in turn this directs the formation of new virions. - Negative-sense viruses must have their genome copied by an RNA polymerase or transcriptase to form positive-sense RNA. This means that the virus must bring along with it the RNA-dependent RNA polymerase enzyme. The positive-sense RNA molecule then acts as viral mRNA, which is translated into proteins by the host ribosomes. The resultant protein goes on to direct the synthesis of new virions, such as capsid proteins and RNA replicase, which is used to produce new negative-sense RNA molecules. - Double-stranded reoviruses contain up to a dozen different RNA molecules which each code for an mRNA. These all associate with proteins to form a single large complex which is replicated using virally-encoded replicase to form new virions. - Retroviruses are single-stranded but unlike other single-stranded RNA viruses they use DNA intermediates to replicate. Reverse transcriptase, a viral enzyme that comes from the virus itself after it is uncoated, converts the viral RNA into a complementary strand of DNA, which is copied to produce a double stranded molecule of viral DNA. This DNA goes on to direct the formation of new virions. # Group III - dsRNA viruses - Family Birnaviridae - Family Chrysoviridae - Family Cystoviridae - Family Hypoviridae - Family Partitiviridae - Family Reoviridae - includes Rotavirus - Family Totiviridae - Unassigned genera Endornavirus - Endornavirus # Group IV - positive-sense ssRNA viruses - Order Nidovirales Family Arteriviridae Family Coronaviridae - includes Coronavirus, SARS Family Roniviridae - Family Arteriviridae - Family Coronaviridae - includes Coronavirus, SARS - Family Roniviridae - Unassigned Family Astroviridae Family Barnaviridae Family Bromoviridae Family Caliciviridae - includes Norwalk virus Family Closteroviridae Family Comoviridae Family Dicistroviridae Family Flaviviridae - includes Yellow fever virus, West Nile virus, Hepatitis C virus, Dengue fever virus Family Flexiviridae Family Leviviridae Family Luteoviridae - includes Barley yellow dwarf virus Family Marnaviridae Family Narnaviridae Family Nodaviridae Family Picornaviridae - includes Poliovirus, the common cold virus, Hepatitis A virus Family Potyviridae Family Sequiviridae Family Tetraviridae Family Togaviridae - includes Rubella virus, Ross River virus, Sindbis virus Family Tombusviridae Family Tymoviridae Unassigned genera Genus Benyvirus Genus Cheravirus Genus Furovirus Genus Hepevirus - includes Hepatitis E virus Genus Hordeivirus Genus Idaeovirus Genus Ourmiavirus Genus Pecluvirus Genus Pomovirus Genus Sadwavirus Genus Sobemovirus Genus Tobamovirus - includes tobacco mosaic virus Genus Tobravirus Genus Umbravirus - Family Astroviridae - Family Barnaviridae - Family Bromoviridae - Family Caliciviridae - includes Norwalk virus - Family Closteroviridae - Family Comoviridae - Family Dicistroviridae - Family Flaviviridae - includes Yellow fever virus, West Nile virus, Hepatitis C virus, Dengue fever virus - Family Flexiviridae - Family Leviviridae - Family Luteoviridae - includes Barley yellow dwarf virus - Family Marnaviridae - Family Narnaviridae - Family Nodaviridae - Family Picornaviridae - includes Poliovirus, the common cold virus, Hepatitis A virus - Family Potyviridae - Family Sequiviridae - Family Tetraviridae - Family Togaviridae - includes Rubella virus, Ross River virus, Sindbis virus - Family Tombusviridae - Family Tymoviridae - Unassigned genera Genus Benyvirus Genus Cheravirus Genus Furovirus Genus Hepevirus - includes Hepatitis E virus Genus Hordeivirus Genus Idaeovirus Genus Ourmiavirus Genus Pecluvirus Genus Pomovirus Genus Sadwavirus Genus Sobemovirus Genus Tobamovirus - includes tobacco mosaic virus Genus Tobravirus Genus Umbravirus - Genus Benyvirus - Genus Cheravirus - Genus Furovirus - Genus Hepevirus - includes Hepatitis E virus - Genus Hordeivirus - Genus Idaeovirus - Genus Ourmiavirus - Genus Pecluvirus - Genus Pomovirus - Genus Sadwavirus - Genus Sobemovirus - Genus Tobamovirus - includes tobacco mosaic virus - Genus Tobravirus - Genus Umbravirus # Group V - negative-sense ssRNA viruses - Order Mononegavirales Family Bornaviridae - Borna disease virus Family Filoviridae - includes Ebola virus, Marburg virus Family Paramyxoviridae - includes Measles virus, Mumps virus, Nipah virus, Hendra virus Family Rhabdoviridae - includes Rabies virus - Family Bornaviridae - Borna disease virus - Family Filoviridae - includes Ebola virus, Marburg virus - Family Paramyxoviridae - includes Measles virus, Mumps virus, Nipah virus, Hendra virus - Family Rhabdoviridae - includes Rabies virus - Unassigned Family Arenaviridae - includes Lassa virus Family Bunyaviridae - includes Hantavirus Family Orthomyxoviridae - includes Influenza viruses Unassigned genera: Genus Deltavirus Genus Ophiovirus Genus Tenuivirus Genus Varicosavirus - Family Arenaviridae - includes Lassa virus - Family Bunyaviridae - includes Hantavirus - Family Orthomyxoviridae - includes Influenza viruses - Unassigned genera: Genus Deltavirus Genus Ophiovirus Genus Tenuivirus Genus Varicosavirus - Genus Deltavirus - Genus Ophiovirus - Genus Tenuivirus - Genus Varicosavirus	RNA virus Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview An RNA virus is a virus that has ribonucleic acid (RNA) as its genetic material and does not replicate using a DNA intermediate. RNA viruses belong to either Group III, Group IV or Group V of the Baltimore classification system of classifying viruses. Their nucleic acid is usually single-stranded RNA (ssRNA) but may be double-stranded RNA (dsRNA).[1] Notable human pathogenic RNA viruses include SARS, Influenza and Hepatitis C. # Characteristics ## Single-stranded RNA viruses and RNA Sense RNA viruses can be further classified according to the sense or polarity of their RNA into negative-sense and positive-sense, or ambisense RNA viruses. Positive-sense viral RNA is identical to viral mRNA and thus can be immediately translated by the host cell. Negative-sense viral RNA is complementary to mRNA and thus must be converted to positive-sense RNA by an RNA polymerase before translation. As such, purified RNA of a positive-sense virus can directly cause infection though it may be less infectious than the whole virus particle. Purified RNA of a negative-sense virus is not infectious by itself as it needs to be transcribed into positive-sense RNA. Ambisense RNA viruses transcribe genes from both the positive or negative strand. ## Double-stranded RNA viruses The double-stranded (ds)RNA viruses represent a diverse group of viruses that vary widely in host range (humans, animals, plants, fungi, and bacteria), genome segment number (one to twelve), and virion organization (T-number, capsid layers, or turrets). Members of this group include the rotaviruses, renowned globally as the commonest cause of gastroenteritis in young children, and bluetongue virus [2] [3], an economically important pathogen of cattle and sheep. In recent years, remarkable progress has been made in determining, at atomic and subnanometeric levels, the structures of a number of key viral proteins and of the virion capsids of several dsRNA viruses, highlighting the significant parallels in the structure and replicative processes of many of these viruses. [1] ## Mutation rates RNA viruses generally have very high mutation rates as they lack DNA polymerases which can find and fix mistakes, and are therefore unable to conduct DNA repair of damaged genetic material. DNA viruses have considerably lower mutation rates due to the proof-reading ability of DNA polymerases within the host cell. Retroviruses integrate a DNA intermediate of their RNA genome into the host genome, and therefore have a higher chance of correcting any mistakes in their genome thanks to the action of proof-reading DNA polymerases belonging to the host cell. Although RNA usually mutates rapidly, recent work found that the SARS virus and related RNA viruses contain a gene that mutates very slowly.[4] The gene in question has a complex three-dimensional structure which is hypothesized to provide a chemical function necessary for viral propagation, perhaps as a ribozyme. If so, most mutations would render it unfit for that purpose and would not propagate. # Replication Animal RNA viruses can be placed into about four different groups depending on their mode of replication. - Positive-sense viruses have their genome directly utilized as if it were mRNA, producing a single protein which is modified by host and viral proteins to form the various proteins needed for replication. One of these includes RNA replicase, which copies the viral RNA to form a double-stranded replicative form, in turn this directs the formation of new virions. - Negative-sense viruses must have their genome copied by an RNA polymerase or transcriptase to form positive-sense RNA. This means that the virus must bring along with it the RNA-dependent RNA polymerase enzyme. The positive-sense RNA molecule then acts as viral mRNA, which is translated into proteins by the host ribosomes. The resultant protein goes on to direct the synthesis of new virions, such as capsid proteins and RNA replicase, which is used to produce new negative-sense RNA molecules. - Double-stranded reoviruses contain up to a dozen different RNA molecules which each code for an mRNA. These all associate with proteins to form a single large complex which is replicated using virally-encoded replicase to form new virions. - Retroviruses are single-stranded but unlike other single-stranded RNA viruses they use DNA intermediates to replicate. Reverse transcriptase, a viral enzyme that comes from the virus itself after it is uncoated, converts the viral RNA into a complementary strand of DNA, which is copied to produce a double stranded molecule of viral DNA. This DNA goes on to direct the formation of new virions. # Group III - dsRNA viruses - Family Birnaviridae - Family Chrysoviridae - Family Cystoviridae - Family Hypoviridae - Family Partitiviridae - Family Reoviridae - includes Rotavirus - Family Totiviridae - Unassigned genera Endornavirus - Endornavirus # Group IV - positive-sense ssRNA viruses - Order Nidovirales Family Arteriviridae Family Coronaviridae - includes Coronavirus, SARS Family Roniviridae - Family Arteriviridae - Family Coronaviridae - includes Coronavirus, SARS - Family Roniviridae - Unassigned Family Astroviridae Family Barnaviridae Family Bromoviridae Family Caliciviridae - includes Norwalk virus Family Closteroviridae Family Comoviridae Family Dicistroviridae Family Flaviviridae - includes Yellow fever virus, West Nile virus, Hepatitis C virus, Dengue fever virus Family Flexiviridae Family Leviviridae Family Luteoviridae - includes Barley yellow dwarf virus Family Marnaviridae Family Narnaviridae Family Nodaviridae Family Picornaviridae - includes Poliovirus, the common cold virus, Hepatitis A virus Family Potyviridae Family Sequiviridae Family Tetraviridae Family Togaviridae - includes Rubella virus, Ross River virus, Sindbis virus Family Tombusviridae Family Tymoviridae Unassigned genera Genus Benyvirus Genus Cheravirus Genus Furovirus Genus Hepevirus - includes Hepatitis E virus Genus Hordeivirus Genus Idaeovirus Genus Ourmiavirus Genus Pecluvirus Genus Pomovirus Genus Sadwavirus Genus Sobemovirus Genus Tobamovirus - includes tobacco mosaic virus Genus Tobravirus Genus Umbravirus - Family Astroviridae - Family Barnaviridae - Family Bromoviridae - Family Caliciviridae - includes Norwalk virus - Family Closteroviridae - Family Comoviridae - Family Dicistroviridae - Family Flaviviridae - includes Yellow fever virus, West Nile virus, Hepatitis C virus, Dengue fever virus - Family Flexiviridae - Family Leviviridae - Family Luteoviridae - includes Barley yellow dwarf virus - Family Marnaviridae - Family Narnaviridae - Family Nodaviridae - Family Picornaviridae - includes Poliovirus, the common cold virus, Hepatitis A virus - Family Potyviridae - Family Sequiviridae - Family Tetraviridae - Family Togaviridae - includes Rubella virus, Ross River virus, Sindbis virus - Family Tombusviridae - Family Tymoviridae - Unassigned genera Genus Benyvirus Genus Cheravirus Genus Furovirus Genus Hepevirus - includes Hepatitis E virus Genus Hordeivirus Genus Idaeovirus Genus Ourmiavirus Genus Pecluvirus Genus Pomovirus Genus Sadwavirus Genus Sobemovirus Genus Tobamovirus - includes tobacco mosaic virus Genus Tobravirus Genus Umbravirus - Genus Benyvirus - Genus Cheravirus - Genus Furovirus - Genus Hepevirus - includes Hepatitis E virus - Genus Hordeivirus - Genus Idaeovirus - Genus Ourmiavirus - Genus Pecluvirus - Genus Pomovirus - Genus Sadwavirus - Genus Sobemovirus - Genus Tobamovirus - includes tobacco mosaic virus - Genus Tobravirus - Genus Umbravirus # Group V - negative-sense ssRNA viruses - Order Mononegavirales Family Bornaviridae - Borna disease virus Family Filoviridae - includes Ebola virus, Marburg virus Family Paramyxoviridae - includes Measles virus, Mumps virus, Nipah virus, Hendra virus Family Rhabdoviridae - includes Rabies virus - Family Bornaviridae - Borna disease virus - Family Filoviridae - includes Ebola virus, Marburg virus - Family Paramyxoviridae - includes Measles virus, Mumps virus, Nipah virus, Hendra virus - Family Rhabdoviridae - includes Rabies virus - Unassigned Family Arenaviridae - includes Lassa virus Family Bunyaviridae - includes Hantavirus Family Orthomyxoviridae - includes Influenza viruses Unassigned genera: Genus Deltavirus Genus Ophiovirus Genus Tenuivirus Genus Varicosavirus - Family Arenaviridae - includes Lassa virus - Family Bunyaviridae - includes Hantavirus - Family Orthomyxoviridae - includes Influenza viruses - Unassigned genera: Genus Deltavirus Genus Ophiovirus Genus Tenuivirus Genus Varicosavirus - Genus Deltavirus - Genus Ophiovirus - Genus Tenuivirus - Genus Varicosavirus	https://www.wikidoc.org/index.php/Negative-sense_ssRNA_virus
0b7c24a69e22f55a75a2dd1bf6a26701205209cf	wikidoc	Neisseria	Neisseria # Overview Neisseria is a genus of bacteria included among the proteobacteria, a large group of Gram-negative forms. Neisseria are diplococci that resemble coffee beans when viewed microscopically. The genus includes the species N. gonorrhoeae (also called the gonococcus), which causes gonorrhoea, and N. meningitidis (also called the meningococcus), one of the most common causes of bacterial meningitis and the causative agent of meningococcal septicaemia. This genus also contains several, believed to be nonpathogenic species, like: - Neisseria cinerea - Neisseria elongata - Neisseria flavescens - Neisseria lactamica - Neisseria mucosa - Neisseria polysaccharea - Neisseria sicca - Neisseria subflava # History The genus Neisseria is named after the German bacteriologist Albert Neisser, who discovered its first example, Neisseria gonorrheae, the pathogen which causes the human disease gonorrhea. Neisser also co-discovered the pathogen that causes leprosy, Mycobacterium leprae. These discoveries were made possible by the development of new staining techniques which he helped to develop. # Biochemical Indentification All the medically significant species of Neisseria are positive for both catalase and oxidase. Different Neisseria species can be identified by the sets of sugars from which they will produce acid. For example, N. gonorrheae makes acid from only glucose, however N. meningitidis produces acid from both glucose and maltose.	Neisseria Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Neisseria is a genus of bacteria included among the proteobacteria, a large group of Gram-negative forms. Neisseria are diplococci that resemble coffee beans when viewed microscopically.[1] The genus includes the species N. gonorrhoeae (also called the gonococcus), which causes gonorrhoea, and N. meningitidis (also called the meningococcus), one of the most common causes of bacterial meningitis and the causative agent of meningococcal septicaemia. This genus also contains several, believed to be nonpathogenic species, like: - Neisseria cinerea - Neisseria elongata - Neisseria flavescens - Neisseria lactamica - Neisseria mucosa - Neisseria polysaccharea - Neisseria sicca - Neisseria subflava # History The genus Neisseria is named after the German bacteriologist Albert Neisser, who discovered its first example, Neisseria gonorrheae, the pathogen which causes the human disease gonorrhea. Neisser also co-discovered the pathogen that causes leprosy, Mycobacterium leprae. These discoveries were made possible by the development of new staining techniques which he helped to develop. # Biochemical Indentification All the medically significant species of Neisseria are positive for both catalase and oxidase. Different Neisseria species can be identified by the sets of sugars from which they will produce acid. For example, N. gonorrheae makes acid from only glucose, however N. meningitidis produces acid from both glucose and maltose.	https://www.wikidoc.org/index.php/Neisseria
6b54acc0e44b26f1d834d26beb446bc442bd05b6	wikidoc	Neocortex	Neocortex The neocortex (Latin for "new bark" or "new rind") is a part of the brain of mammals. It is the top layer of the cerebral hemispheres, 2-4 mm thick, and made up of six layers, labelled I to VI (with VI being the innermost and I being the outermost). The neocortex is part of the cerebral cortex (along with the archicortex and paleocortex — which are cortical parts of the limbic system). It is involved in higher functions such as sensory perception, generation of motor commands, spatial reasoning, conscious thought, and in humans, language. Other names for the neocortex include neopallium ("new mantle") and isocortex ("equal rind"). # Anatomy The neocortex consists of grey matter surrounding the deeper white matter of the cerebrum. While the neocortex is smooth in rats and some other small mammals, it has deep grooves (sulci) and wrinkles (gyri) in primates and several other mammals. These folds increase the surface area of the neocortex considerably. The female neocortex contains approximately 19 billion neurons while the male neocortex has 23 billion. It is unknown what effect, if any, results from this difference. The structure of the cortex is relatively uniform (whence the names "iso" and "homotypical"): it consists of six horizontal layers segregated by cell type, neuronal input, or cell density. The neurons are arranged in structures called neocortical columns. These are patches of the neocortex with a diameter of about 0.5 mm (and a depth of 2 mm). Each column typically responds to a sensory stimulus representing a certain body part or region of sound or vision. These columns are similar and can be thought of as the basic repeating functional units of the neocortex. In humans, the neocortex consists of about half million of these columns, each of which contains approximately 60,000 neurons. The neocortex is divided into several lobes, and different regions of the neocortex have different functions. (See Cerebral cortex and Cerebrum.) # Evolution With respect to evolution, the neocortex is the newest part of the cerebral cortex (hence the name "neo"); the other parts of the cerebral cortex are the paleocortex and archicortex, collectively known as the allocortex. The cellular organization of the allocortex is different from the six-layer structure mentioned above. In humans, 90% of the cerebral cortex is neopallium. The six-layer cortex appears to be a distinguishing feature of mammals: It has been found in the brains of all mammals but not in any other animals. There is some debate , however, as to the cross-species nomenclature for neocortex. In avians, for instance, there are clear examples of cognitive processes that are thought to be neocortical in nature, despite the lack of the distinctive six-layer neocortical structure. In a similar manner, reptiles, such as turtles, have primary sensory cortices. A consistent, alternative name has yet to be agreed upon.	Neocortex Template:Otheruses4 Template:Infobox Brain The neocortex (Latin for "new bark" or "new rind") is a part of the brain of mammals. It is the top layer of the cerebral hemispheres, 2-4 mm thick, and made up of six layers, labelled I to VI (with VI being the innermost and I being the outermost). The neocortex is part of the cerebral cortex (along with the archicortex and paleocortex — which are cortical parts of the limbic system). It is involved in higher functions such as sensory perception, generation of motor commands, spatial reasoning, conscious thought, and in humans, language. Other names for the neocortex include neopallium ("new mantle") and isocortex ("equal rind"). # Anatomy The neocortex consists of grey matter surrounding the deeper white matter of the cerebrum. While the neocortex is smooth in rats and some other small mammals, it has deep grooves (sulci) and wrinkles (gyri) in primates and several other mammals. These folds increase the surface area of the neocortex considerably. The female neocortex contains approximately 19 billion neurons while the male neocortex has 23 billion. It is unknown what effect, if any, results from this difference. The structure of the cortex is relatively uniform (whence the names "iso" and "homotypical"): it consists of six horizontal layers segregated by cell type, neuronal input, or cell density. The neurons are arranged in structures called neocortical columns. These are patches of the neocortex with a diameter of about 0.5 mm (and a depth of 2 mm). Each column typically responds to a sensory stimulus representing a certain body part or region of sound or vision. These columns are similar and can be thought of as the basic repeating functional units of the neocortex. In humans, the neocortex consists of about half million of these columns, each of which contains approximately 60,000 neurons. The neocortex is divided into several lobes, and different regions of the neocortex have different functions. (See Cerebral cortex and Cerebrum.) # Evolution With respect to evolution, the neocortex is the newest part of the cerebral cortex (hence the name "neo"); the other parts of the cerebral cortex are the paleocortex and archicortex, collectively known as the allocortex. The cellular organization of the allocortex is different from the six-layer structure mentioned above. In humans, 90% of the cerebral cortex is neopallium. The six-layer cortex appears to be a distinguishing feature of mammals: It has been found in the brains of all mammals but not in any other animals. There is some debate [1][2], however, as to the cross-species nomenclature for neocortex. In avians, for instance, there are clear examples of cognitive processes that are thought to be neocortical in nature, despite the lack of the distinctive six-layer neocortical structure. In a similar manner, reptiles, such as turtles, have primary sensory cortices. A consistent, alternative name has yet to be agreed upon.	https://www.wikidoc.org/index.php/Neocortex
ceec625eab3f9926f8bc2831136fbf5feaa01aea	wikidoc	Neologism	Neologism A neologism is a word, term, or phrase that has been recently created (or "coined"), often to apply to new concepts, to synthesize pre-existing concepts, or to make older terminology sound more contemporary. Neologisms are especially useful in identifying inventions, new phenomena, or old ideas that have taken on a new cultural context. The term e-mail, as used today, is an example of a neologism. Neologisms are by definition "new", and as such are often directly attributable to a specific individual, publication, period, or event. The term "neologism" was itself coined around 1800, so in the early 19th century, the word "neologism" was itself a neologism. In psychiatry, the term is used to describe the use of words that only have meaning to the person who uses them, independent of their common meaning. It is considered normal in children, but a symptom of thought disorder (indicative of a psychotic mental illness, such as schizophrenia) in adults. Use of neologisms may also be related to aphasia acquired after brain damage resulting from a stroke or head injury. People with autism may also create neologisms. In theology, a neologism is a relatively new doctrine (for example, rationalism). In this sense, a neologist is an innovator in the area of a doctrine or belief system, and is often considered heretical or subversive by the mainstream clergy or religious institution(s). # Changing culture Neologisms tend to occur more often in cultures which are rapidly changing, and also in situations where there is easy and fast propagation of information. They are often created by combining existing words (see compound noun and adjective) or by giving words new and unique suffixes or prefixes. Those which are portmanteaux are shortened. Neologisms can also be created through abbreviation or acronym, by intentionally rhyming with existing words, or simply through playing with sounds. Neologisms often become popular through memetics – by way of mass media, the Internet, word of mouth (including academic discourse, renowned for its jargon, with recent coinages such as Fordism, Taylorism, Disneyfication and McDonaldization now in everyday use). (See also Wiktionary's Neologisms:unstable or Protologism pages for a wiki venue of popularizing newly coined words). Every word in a language was, at some time, a neologism, ceasing to be such through time and acceptance. Neologisms often become accepted parts of the language. Other times, however, they disappear from common usage. Whether a neologism continues as part of the language depends on many factors, probably the most important of which is acceptance by the public. Acceptance by linguistic experts and incorporation into dictionaries also plays a part, as does whether the phenomenon described by a neologism remains current, thus continuing to need a descriptor. It is unusual, however, for a word to enter common use if it does not resemble another word or words in an identifiable way. (In some cases, however, strange new words succeed because the idea behind them is especially memorable or exciting; for example, the word 'quiz', which Richard Daly brought into the English language by writing it on walls all around Dublin.) When a word or phrase is no longer "new", it is no longer a neologism. Neologisms may take decades to become "old", however. Opinions differ on exactly how old a word must be to no longer be considered a neologism; cultural acceptance probably plays a more important role than time in this regard. # Evolution of neologisms Newly created words entering a language tend to pass through stages that can be described as: - Unstable - Extremely new, being proposed, or being used only by a small subculture (also known as protologisms). - Diffused - Having reached a significant audience, but not yet having gained widespread acceptance. - Stable - Having gained recognizable and probably lasting acceptance. - Dated - The point where the word has ceased holding novelty and has passed into cliché, formal linguistic acceptance, or become culturally dated in its use. # Sources of neologism For a list of topically arranged protologisms (very-recently-coined terms), see Wiktionary:List of protologisms by topic. ## Science Words or phrases created to describe new scientific hypotheses, discoveries, or inventions. Examples: - radar (1941) - laser (1960) - black hole (1968) - meme (1976) - prion (1982) - beetle bank (early 1990s) ## Science fiction Concepts created to describe new, futuristic ideas. Examples: - hyperspace (1934) - robotics (1941) - waldo (1942) - Dyson sphere (circa 1960) - ansible (1966) - phaser (1966) - ringworld (1971) - replicant (1982) - xenocide (1991) - metaverse (1992) ## Literature more generally See "Neologisms in literature" topic below. ## Politics Words or phrases created to make some kind of political or rhetorical point, sometimes perhaps with an eye to the Sapir-Whorf hypothesis. Examples: - genocide (1943) - Dixiecrat (1948) - meritocracy (1958) - pro-life (1961) - homophobia (1969) - political correctness (1970) - Californication (1970s) - pro-choice (1975) - heterosexism (1979) - glocalisation (1980s) - sie and hir (pronouns) (1981) - Republicrat (1985) - astroturfing (1986) - dog-whistle politics (1990) - Islamophobia (1991) - soccer mom (1992) - blue state/red state/swing state (c. 2000) - corporatocracy (2000s) - Islamofascism (2001) - santorum (2003) - Chindia (2004) - NASCAR dad (2004) - fauxtography (2005) ## Popular culture Words or phrases evolved from mass media content or used to describe popular culture phenomena (these may be considered a variety of slang as well as neologisms). Examples: - moin (early 20th century) - prequel (1958) - Internet (1974) - jumping the shark (late 1970s) - posterized (ca. 1980s) ("posterize" has also existed for some time as a term for an image-editing technique; its neologistic sports usage is completely unrelated.) - queercore (mid 1980s) - plus-size (1990s) - blog (late 1990s) - chav (early 2000s) - webinar (early 2000s) - wardrobe malfunction (2004) - truthiness (2005) (already existed as an obscure word previously recorded by the Oxford English Dictionary, but its 2005 usage on the Colbert Report was a neologistic one, with a new definition) - From "d'oh" to "cromulent" - many culturally-significant phrases from The Simpsons (1989–) are now in common use. ## Commerce and advertising Genericised trademarks. Examples: - aspirin - crock pot - laundromat - linoleum - affluenza ## Linguistics Words or phrases created to describe new language constructs. Examples: - retronym (popularized in 1980) - backronym (1983) - aptronym (2003; popularized by Franklin Pierce Adams) - snowclone (2004) - protologism (2005) ## Other Miscellaneous sources. Examples: - nonce words — words coined and used only for a particular occasion, usually for a special literary effect. # Neologisms in literature Many neologisms have come from popular literature, and tend to appear in different forms. Most commonly, they are simply taken from a word used in the narrative of a book; a few representative examples are: "grok" (to achieve complete intuitive understanding), from Stranger in a Strange Land by Robert A. Heinlein; "McJob", from Generation X: Tales for an Accelerated Culture by Douglas Coupland; "cyberspace", from Neuromancer by William Gibson. Sometimes the title of the book will become the neologism, for instance, Catch-22 (from the title of Joseph Heller's novel). Also worthy of note is the case in which the author's name becomes the neologism, although the term is sometimes based on only one work of that author. This includes such words as "Orwellian" (from George Orwell, referring to his novel Nineteen Eighty-Four) and "Ballardesque" or "Ballardian" (from J.G. Ballard, author of Crash). Kurt Vonnegut's Cat's Cradle was the container of the Bokononism family of nonce words. Another category is words derived from famous characters in literature, such as "quixotic" (referring to the titular character in Don Quixote de la Mancha by Cervantes), a "scrooge" (from the main character in Dickens's A Christmas Carol), or a "pollyanna" (from Eleanor H. Porter's book of the same name). James Joyce's Finnegans Wake, composed in a uniquely complex linguistic style, coined the words monomyth and quark. Lewis Carroll's poem "Jabberwocky" has been calledTemplate:Who "the king of neologistic poems" because it incorporated dozens of invented words. The early modern English prose writings of Sir Thomas Browne are the source of many neologisms as recorded by the OED. # Quotation	Neologism Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] A neologism is a word, term, or phrase that has been recently created (or "coined"), often to apply to new concepts, to synthesize pre-existing concepts, or to make older terminology sound more contemporary. Neologisms are especially useful in identifying inventions, new phenomena, or old ideas that have taken on a new cultural context. The term e-mail, as used today, is an example of a neologism. Neologisms are by definition "new", and as such are often directly attributable to a specific individual, publication, period, or event. The term "neologism" was itself coined around 1800, so in the early 19th century, the word "neologism" was itself a neologism. In psychiatry, the term is used to describe the use of words that only have meaning to the person who uses them, independent of their common meaning. It is considered normal in children, but a symptom of thought disorder (indicative of a psychotic mental illness, such as schizophrenia) in adults. Use of neologisms may also be related to aphasia acquired after brain damage resulting from a stroke or head injury.[1] People with autism may also create neologisms.[2] In theology, a neologism is a relatively new doctrine (for example, rationalism). In this sense, a neologist is an innovator in the area of a doctrine or belief system, and is often considered heretical or subversive by the mainstream clergy or religious institution(s). # Changing culture Neologisms tend to occur more often in cultures which are rapidly changing, and also in situations where there is easy and fast propagation of information.[citation needed] They are often created by combining existing words (see compound noun and adjective) or by giving words new and unique suffixes or prefixes. Those which are portmanteaux are shortened. Neologisms can also be created through abbreviation or acronym, by intentionally rhyming with existing words, or simply through playing with sounds. Neologisms often become popular through memetics – by way of mass media, the Internet, word of mouth (including academic discourse, renowned for its jargon, with recent coinages such as Fordism, Taylorism, Disneyfication and McDonaldization now in everyday use).[citation needed] (See also Wiktionary's Neologisms:unstable or Protologism pages for a wiki venue of popularizing newly coined words). Every word in a language was, at some time, a neologism[citation needed], ceasing to be such through time and acceptance. Neologisms often become accepted parts of the language. Other times, however, they disappear from common usage. Whether a neologism continues as part of the language depends on many factors, probably the most important of which is acceptance by the public. Acceptance by linguistic experts and incorporation into dictionaries also plays a part, as does whether the phenomenon described by a neologism remains current, thus continuing to need a descriptor.[citation needed] It is unusual, however, for a word to enter common use if it does not resemble another word or words in an identifiable way. (In some cases, however, strange new words succeed because the idea behind them is especially memorable or exciting; for example, the word 'quiz', which Richard Daly brought into the English language by writing it on walls all around Dublin[citation needed].) When a word or phrase is no longer "new", it is no longer a neologism. Neologisms may take decades to become "old", however. Opinions differ on exactly how old a word must be to no longer be considered a neologism; cultural acceptance probably plays a more important role than time in this regard. # Evolution of neologisms Newly created words entering a language tend to pass through stages that can be described as:[citation needed] - Unstable - Extremely new, being proposed, or being used only by a small subculture (also known as protologisms). - Diffused - Having reached a significant audience, but not yet having gained widespread acceptance. - Stable - Having gained recognizable and probably lasting acceptance. - Dated - The point where the word has ceased holding novelty and has passed into cliché, formal linguistic acceptance, or become culturally dated in its use. # Sources of neologism For a list of topically arranged protologisms (very-recently-coined terms), see Wiktionary:List of protologisms by topic. ## Science Words or phrases created to describe new scientific hypotheses, discoveries, or inventions. Examples: - radar (1941) - laser (1960) - black hole (1968) - meme (1976) - prion (1982) - beetle bank (early 1990s) ## Science fiction Concepts created to describe new, futuristic ideas. Examples: - hyperspace (1934) - robotics (1941) - waldo (1942) - Dyson sphere (circa 1960) - ansible (1966) - phaser (1966) - ringworld (1971) - replicant (1982) - xenocide (1991) - metaverse (1992) ## Literature more generally See "Neologisms in literature" topic below. ## Politics Words or phrases created to make some kind of political or rhetorical point, sometimes perhaps with an eye to the Sapir-Whorf hypothesis. Examples: - genocide (1943) - Dixiecrat (1948) - meritocracy (1958) - pro-life (1961) - homophobia (1969) - political correctness (1970) - Californication (1970s) - pro-choice (1975) - heterosexism (1979) - glocalisation (1980s) - sie and hir (pronouns) (1981) - Republicrat (1985) - astroturfing (1986) - dog-whistle politics (1990) - Islamophobia (1991) - soccer mom (1992) - blue state/red state/swing state (c. 2000) - corporatocracy (2000s) - Islamofascism (2001) - santorum (2003) - Chindia (2004) - NASCAR dad (2004) - fauxtography (2005) ## Popular culture Words or phrases evolved from mass media content or used to describe popular culture phenomena (these may be considered a variety of slang as well as neologisms). Examples: - moin (early 20th century) - prequel (1958) - Internet (1974) - jumping the shark (late 1970s) - posterized (ca. 1980s) ("posterize" has also existed for some time as a term for an image-editing technique; its neologistic sports usage is completely unrelated.) - queercore (mid 1980s) - plus-size (1990s) - blog (late 1990s) - chav (early 2000s) - webinar (early 2000s) - wardrobe malfunction (2004) - truthiness (2005) (already existed as an obscure word previously recorded by the Oxford English Dictionary, but its 2005 usage on the Colbert Report was a neologistic one, with a new definition) - From "d'oh" to "cromulent" - many culturally-significant phrases from The Simpsons (1989–) are now in common use. ## Commerce and advertising Genericised trademarks. Examples: - aspirin - crock pot - laundromat - linoleum - affluenza ## Linguistics Words or phrases created to describe new language constructs. Examples: - retronym (popularized in 1980) - backronym (1983) - aptronym (2003; popularized by Franklin Pierce Adams) - snowclone (2004) - protologism (2005) ## Other Miscellaneous sources. Examples: - nonce words — words coined and used only for a particular occasion, usually for a special literary effect. # Neologisms in literature Many neologisms have come from popular literature, and tend to appear in different forms. Most commonly, they are simply taken from a word used in the narrative of a book; a few representative examples are: "grok" (to achieve complete intuitive understanding), from Stranger in a Strange Land by Robert A. Heinlein; "McJob", from Generation X: Tales for an Accelerated Culture by Douglas Coupland; "cyberspace", from Neuromancer by William Gibson. Sometimes the title of the book will become the neologism, for instance, Catch-22 (from the title of Joseph Heller's novel). Also worthy of note is the case in which the author's name becomes the neologism, although the term is sometimes based on only one work of that author. This includes such words as "Orwellian" (from George Orwell, referring to his novel Nineteen Eighty-Four) and "Ballardesque" or "Ballardian" (from J.G. Ballard, author of Crash). Kurt Vonnegut's Cat's Cradle was the container of the Bokononism family of nonce words. Another category is words derived from famous characters in literature, such as "quixotic" (referring to the titular character in Don Quixote de la Mancha by Cervantes), a "scrooge" (from the main character in Dickens's A Christmas Carol), or a "pollyanna" (from Eleanor H. Porter's book of the same name). James Joyce's Finnegans Wake, composed in a uniquely complex linguistic style, coined the words monomyth and quark. Lewis Carroll's poem "Jabberwocky" has been calledTemplate:Who "the king of neologistic poems" because it incorporated dozens of invented words. The early modern English prose writings of Sir Thomas Browne are the source of many neologisms as recorded by the OED. # Quotation	https://www.wikidoc.org/index.php/Neologism
841842c2446623dd76343ebdc6b2aa800ecbd5ca	wikidoc	Neophilia	Neophilia Neophilia is defined as a love of novelty and new things. A neophiliac or neophile is an individual who is unusually accepting of new things and excited by novelty. The word has particular significance in Internet and hacker culture. The New Hacker's Dictionary gave the following definition to neophilia - Recent research uncovered a possible link between certain predisposition to some kind of neophilia and increased levels of the enzyme monoamine oxidase A.	Neophilia Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Neophilia is defined as a love of novelty and new things. A neophiliac or neophile is an individual who is unusually accepting of new things and excited by novelty. The word has particular significance in Internet and hacker culture. The New Hacker's Dictionary gave the following definition to neophilia - Recent research uncovered a possible link between certain predisposition to some kind of neophilia and increased levels of the enzyme monoamine oxidase A.[1]	https://www.wikidoc.org/index.php/Neophilia
57f9fa4fac8cb44bfa67a6f524ca1f1c88f57ab3	wikidoc	Neophobia	Neophobia # Overview Neophobia, cainotophobia or cainophobia is the fear of anything new, especially a persistent and abnormal Fear processing in the brain\|fear. In its milder form, it can manifest as the unwillingness to try new things or break from routine. Mild manifestations are often present in young children (who want the small portion of the world that they "know" to remain constant) and elderly people (who often cope using long established habits and don't want to learn "new tricks"). But neophobia could also be fear of losing what one has -- e.g., the fear that if anything changes, one might never be happy again. In biomedical research, neophobia is often associated with the study of taste. Food neophobia is an important concern in pediatric psychology. Norway rats and house mice are thought to have evolved increased levels of neophobia as they became commensals\|commensal with humans because humans were routinely devising new methods (e.g., mousetraps) to eradicate them. Neophobia is also a common finding in aging animals, although apathy could also explain, or contribute to explain, the lack of exploratory drive systematically observed in aging. Researchers argued that the lack of exploratory drive was likely due neurophysiologically to the dysfunction of neural pathways connected to the prefrontal cortex observed during aging. Robert Anton Wilson theorized in his book Prometheus Rising that neophobia is instinctual in people after they begin to raise children. Wilson's views on neophobia are mostly negative, believing that it is the reason human culture and ideas do not advance as quickly as our technology. His model includes an idea from Thomas Kuhn's The Structure of Scientific Revolutions, which is that new ideas, however well proven and evident, are implemented only when the generations who consider them "new" die and are replaced by generations who consider the ideas accepted and old. The word neophobia comes from the Greek νέος, neos, meaning "new, young", and φόβος, phobos, for "fear". Cainophobia comes from the Greek καινός, kainos, meaning "new, fresh". # Food neophobia Food neophobia is the fear of eating new or unfamiliar foods. It differs from selective eating disorder. Food neophobia is particularly common in toddlers and young children. It is often related to an individual’s level of sensation-seeking, meaning a person’s willingness to try new things and take risks. (See Sensation-seeking.) Not only do people with high food neophobia resist trying new food, they also rate new foods that they do try as lower than neophilics. It is very typical for people to generally have a fear of new things and to prefer things that are familiar and common. Most people experience food neophobia to a certain extent, though some people are more neophobic than others. A measure of individual differences in food neophobia is the Food Neophobia Scale (FNS), which consists of a 10-item survey that requires self-reported responses on a seven-point Likert scale. There is also a separate scale geared towards children called the Food Neophobia Scale for Children (FNSC), in which the parents actually do the reporting for the survey. Food neophobia relates to the Omnivore’s Dilemma, a phenomenon that explains the choice that omnivores, and humans in particular, have between eating a new food and risking danger or avoiding it and potentially missing out on a valuable food source. Having at least some degree of food neophobia has been noted to be evolutionarily advantageous as it can help people to avoid eating potentially poisonous foods. Food neophobia differs from picky or “fussy” eating in that picky eaters will often reject familiar foods as well as unfamiliar foods, whereas food neophobia signifies rejecting only unfamiliar foods. Also, while food neophobic individuals will often accept novel foods after repeated exposure to them, picky eaters will continue to reject them. ## Causes Genetics seem to play a role in both food neophobia and general neophobia. Research shows that about two-thirds of the variation in food neophobia is due to genetics. A study done on twin pairs showed an even higher correlation, indicating that genetics does play a factor in food neophobia. Psychosocial factors can also increase a child's chances of developing food neophobia. Young children carefully watch parental food preferences, and this may produce neophobic tendencies with regard to eating if parents tend to avoid some foods. Another cause includes being more sensitive than average to bitter tastes, which may be associated with a significant history of middle ear infection or an increased perception of bitter foods, known as a supertaster. Sometimes food neophobia is more directly caused by an environmental occurrence. For example, with poison-induced neophobia, a food-poisoning experience can lead to people not only avoiding the flavor(s) they associate with creating their illness but also to avoid all novel flavors during the period directly following the poisoning experience. This can be seen as the body’s attempt to prevent any new and risky food items from entering the body. Another environmental factor influencing levels of food neophobia is the current arousal level of the individual. Trying a new food is an arousing experience, and if the person prefers to maintain a lower arousal level in general, then he or she might avoid new foods as a method of managing his or her current arousal level. Also, if people are currently experiencing situations with a lot of novelty and are therefore more aroused, they might be reluctant to try new foods as doing so would increase their arousal level to an uncomfortable level. This example can help explain why Americans visiting a foreign country might be less likely to try a new food item and instead gravitate towards the familiar McDonald’s food. ## Treatment Some efforts to address this situation, such as pressuring the child to eat a disliked food or threatening punishment for not eating it, tend to exacerbate the problem. Effective solutions include offering non-food rewards, such as a small sticker, for tasting a new or disliked food, and for parents to model the behavior they want to see by cheerfully eating the new or disliked foods in front of the children. Exposing someone to a new food increases the chances of liking that food item. However, it is not enough to merely look at a new food. Novel food must be repeatedly tasted in order to increase preference for eating it. It can take as many as 15 tries of a novel food item before a child accepts it. There also appears to be a critical period for lowering later food neophobia in children during the weaning process. The variety of solid foods first exposed to children can lower later food refusal. Some researchers believe that even the food variety of a nursing mother and the consequent variety of flavors in her breastmilk can lead to greater acceptance of novel food items later on in life. Food neophobia does tend to naturally decrease as people age.	Neophobia Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Neophobia, cainotophobia or cainophobia is the fear of anything new, especially a persistent and abnormal Fear processing in the brain\|fear. In its milder form, it can manifest as the unwillingness to try new things or break from routine. Mild manifestations are often present in young children (who want the small portion of the world that they "know" to remain constant) and elderly people (who often cope using long established habits and don't want to learn "new tricks").[citation needed] But neophobia could also be fear of losing what one has -- e.g., the fear that if anything changes, one might never be happy again. In biomedical research, neophobia is often associated with the study of taste. Food neophobia is an important concern in pediatric psychology. Norway rats and house mice are thought to have evolved increased levels of neophobia as they became commensals\|commensal with humans because humans were routinely devising new methods (e.g., mousetraps) to eradicate them.[1] Neophobia is also a common finding in aging animals, although apathy could also explain, or contribute to explain, the lack of exploratory drive systematically observed in aging. Researchers argued that the lack of exploratory drive was likely due neurophysiologically to the dysfunction of neural pathways connected to the prefrontal cortex observed during aging.[2] Robert Anton Wilson theorized in his book Prometheus Rising that neophobia is instinctual in people after they begin to raise children. Wilson's views on neophobia are mostly negative, believing that it is the reason human culture and ideas do not advance as quickly as our technology. His model includes an idea from Thomas Kuhn's The Structure of Scientific Revolutions, which is that new ideas, however well proven and evident, are implemented only when the generations who consider them "new" die and are replaced by generations who consider the ideas accepted and old. The word neophobia comes from the Greek νέος, neos, meaning "new, young",[3] and φόβος, phobos, for "fear".[4] Cainophobia comes from the Greek καινός, kainos, meaning "new, fresh".[5][6] # Food neophobia Food neophobia is the fear of eating new or unfamiliar foods. It differs from selective eating disorder. Food neophobia is particularly common in toddlers and young children. It is often related to an individual’s level of sensation-seeking, meaning a person’s willingness to try new things and take risks. (See Sensation-seeking.) Not only do people with high food neophobia resist trying new food, they also rate new foods that they do try as lower than neophilics.[7] It is very typical for people to generally have a fear of new things and to prefer things that are familiar and common. Most people experience food neophobia to a certain extent, though some people are more neophobic than others. A measure of individual differences in food neophobia is the Food Neophobia Scale (FNS), which consists of a 10-item survey that requires self-reported responses on a seven-point Likert scale.[8] There is also a separate scale geared towards children called the Food Neophobia Scale for Children (FNSC), in which the parents actually do the reporting for the survey.[9] Food neophobia relates to the Omnivore’s Dilemma, a phenomenon that explains the choice that omnivores, and humans in particular, have between eating a new food and risking danger or avoiding it and potentially missing out on a valuable food source. Having at least some degree of food neophobia has been noted to be evolutionarily advantageous as it can help people to avoid eating potentially poisonous foods.[10] Food neophobia differs from picky or “fussy” eating in that picky eaters will often reject familiar foods as well as unfamiliar foods, whereas food neophobia signifies rejecting only unfamiliar foods. Also, while food neophobic individuals will often accept novel foods after repeated exposure to them, picky eaters will continue to reject them. ## Causes Genetics seem to play a role in both food neophobia and general neophobia. Research shows that about two-thirds of the variation in food neophobia is due to genetics. A study done on twin pairs showed an even higher correlation, indicating that genetics does play a factor in food neophobia.[9] Psychosocial factors can also increase a child's chances of developing food neophobia. Young children carefully watch parental food preferences, and this may produce neophobic tendencies with regard to eating if parents tend to avoid some foods.[11] Another cause includes being more sensitive than average to bitter tastes, which may be associated with a significant history of middle ear infection or an increased perception of bitter foods, known as a supertaster.[11] Sometimes food neophobia is more directly caused by an environmental occurrence. For example, with poison-induced neophobia, a food-poisoning experience can lead to people not only avoiding the flavor(s) they associate with creating their illness but also to avoid all novel flavors during the period directly following the poisoning experience. This can be seen as the body’s attempt to prevent any new and risky food items from entering the body. Another environmental factor influencing levels of food neophobia is the current arousal level of the individual. Trying a new food is an arousing experience, and if the person prefers to maintain a lower arousal level in general, then he or she might avoid new foods as a method of managing his or her current arousal level. Also, if people are currently experiencing situations with a lot of novelty and are therefore more aroused, they might be reluctant to try new foods as doing so would increase their arousal level to an uncomfortable level. This example can help explain why Americans visiting a foreign country might be less likely to try a new food item and instead gravitate towards the familiar McDonald’s food. ## Treatment Some efforts to address this situation, such as pressuring the child to eat a disliked food or threatening punishment for not eating it, tend to exacerbate the problem.[11] Effective solutions include offering non-food rewards, such as a small sticker, for tasting a new or disliked food, and for parents to model the behavior they want to see by cheerfully eating the new or disliked foods in front of the children.[11] Exposing someone to a new food increases the chances of liking that food item. However, it is not enough to merely look at a new food. Novel food must be repeatedly tasted in order to increase preference for eating it.[7] It can take as many as 15 tries of a novel food item before a child accepts it. There also appears to be a critical period for lowering later food neophobia in children during the weaning process. The variety of solid foods first exposed to children can lower later food refusal. Some researchers believe that even the food variety of a nursing mother and the consequent variety of flavors in her breastmilk can lead to greater acceptance of novel food items later on in life. Food neophobia does tend to naturally decrease as people age.[10]	https://www.wikidoc.org/index.php/Neophobia
17af2d885053c97c072ccfad86f4da0c9be426a0	wikidoc	Neoplasia	Neoplasia # Overview Neoplasia (new growth in Greek) is abnormal and purposeless proliferation of cells in a tissue or organ. A neoplastic growth is called a neoplasm. Most neoplasms proliferate to form distinct masses, or tumors, but there are also many examples of neoplastic processes which are not grossly apparent, a commonly diagnosed example being cervical intraepithelial neoplasia, a pre-cancerous lesion of the uterine cervix. It is important to note that the term "neoplasm" is not synonymous with cancer, since neoplasms can be either benign or malignant. Leiomyoma (fibroids of the uterus) and melanocytic nevi (moles) are the most common types of neoplasms - both are benign. On the other hand, cancer is a typical example of malignant neoplasia or tumor. Hence, it is important to be able to differentiate between neoplasia, tumor and cancer. Interestingly, there is not a complete consensus in the biomedical community as to the exact biological definition of a neoplasm, although the statement of the British oncologist R.A. Willis is widely cited: Neoplastic tumors often contain more than one type of cell, but their initiation and continued growth is usually dependent on a single population of neoplastic cells. These cells are clonal - that is, they are descended from a single progenitor cell. The neoplastic cells typically bear common genetic or epigenetic abnormalities which are not seen in the non-neoplastic stromal cells and blood-vessel forming cells, whose growth is dependent on molecular stimuli from the neoplastic cells. The demonstration of clonality is now considered by many to be necessary (though not sufficient) to define a cellular proliferation as neoplastic. # Other uses Neoplasia is also the name of a scientific journal for oncology research or a name of a Computer Demo Group, formed in 1995 (NPL). There is also a movie (Link), inspired by the releases of the demogroup.	Neoplasia Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Neoplasia (new growth in Greek) is abnormal and purposeless proliferation of cells in a tissue or organ. A neoplastic growth is called a neoplasm. Most neoplasms proliferate to form distinct masses, or tumors, but there are also many examples of neoplastic processes which are not grossly apparent, a commonly diagnosed example being cervical intraepithelial neoplasia, a pre-cancerous lesion of the uterine cervix. It is important to note that the term "neoplasm" is not synonymous with cancer, since neoplasms can be either benign or malignant. Leiomyoma (fibroids of the uterus) and melanocytic nevi (moles) are the most common types of neoplasms - both are benign. On the other hand, cancer is a typical example of malignant neoplasia or tumor. Hence, it is important to be able to differentiate between neoplasia, tumor and cancer. Interestingly, there is not a complete consensus in the biomedical community as to the exact biological definition of a neoplasm, although the statement of the British oncologist R.A. Willis is widely cited: Neoplastic tumors often contain more than one type of cell, but their initiation and continued growth is usually dependent on a single population of neoplastic cells. These cells are clonal - that is, they are descended from a single progenitor cell. The neoplastic cells typically bear common genetic or epigenetic abnormalities which are not seen in the non-neoplastic stromal cells and blood-vessel forming cells, whose growth is dependent on molecular stimuli from the neoplastic cells. The demonstration of clonality is now considered by many to be necessary (though not sufficient) to define a cellular proliferation as neoplastic. # Other uses Neoplasia is also the name of a scientific journal for oncology research or a name of a Computer Demo Group, formed in 1995 (NPL). There is also a movie (Link), inspired by the releases of the demogroup.	https://www.wikidoc.org/index.php/Neoplasia
037e2a5b28182f3a522e8dd6d7218283146ea2dd	wikidoc	Neosporin	Neosporin # Overview Neosporin (from Neo, (Greek) new + Sporos, (Greek) seed) is the product name of an antibiotic ointment produced by Pfizer (later sold to Johnson & Johnson) used in the prevention of infection and speeding the healing of wounds. The original ointment contains three different antibiotics: bacitracin, neomycin, and polymyxin B. Other brand names for this mixture include Mycitracin and Topisporin. Neomycin and polymyxin are effective in killing gram-negative bacteria, while bacitracin targets gram-positive bacteria; hence, this 'triple antibiotic' ointment covers for a wide range of bacteria which may infect wounds. However, these antibiotics are generally only used topically, because they are known for causing serious side effects (such as nephrotoxicity) when used parenterally. Even when used topically, the antibiotic ointment may cause side effects; in particular, neomycin is well-known for causing allergic reactions such as allergic contact dermatitis. Commonly, though harmlessly, Neosporin tends to exaggerate the pain of abrasions and external injuries. Neosporin is also used as a brand name for several other U.S. products that do not contain neomycin. Pfizer also produces a related mixture of bacitracin and polymyxin, branded Polysporin. Because neomycin is not included in Polysporin, Polysporin may be safely used in individuals with allergies to neomycin. Recently, Pfizer also introduced "Neosporin + Pain Relief," ointment and cream, containing pramoxine, a topical analgesic. In addition to its pain relieving properties, the cream (which omits the bacitracin zinc, as it is not stable in the cream base) appears useful in individuals sensitive to bacitracin, as well as those sensitive to zinc. In Canada, the Neosporin brand is not sold at all, but Polysporin is sold in several varieties. The "original" ointments contain polymyxin B and bacitracin, while the creams and eye/ear drops contain polymyxin B and gramicidin. A "triple" ointment is also available containing all three of the above antibiotics.	Neosporin # Overview Neosporin (from Neo, (Greek) new + Sporos, (Greek) seed) is the product name of an antibiotic ointment produced by Pfizer (later sold to Johnson & Johnson) used in the prevention of infection and speeding the healing of wounds. The original ointment contains three different antibiotics: bacitracin, neomycin, and polymyxin B. Other brand names for this mixture include Mycitracin and Topisporin. Neomycin and polymyxin are effective in killing gram-negative bacteria, while bacitracin targets gram-positive bacteria; hence, this 'triple antibiotic' ointment covers for a wide range of bacteria which may infect wounds. However, these antibiotics are generally only used topically, because they are known for causing serious side effects (such as nephrotoxicity) when used parenterally. Even when used topically, the antibiotic ointment may cause side effects; in particular, neomycin is well-known for causing allergic reactions such as allergic contact dermatitis. Commonly, though harmlessly, Neosporin tends to exaggerate the pain of abrasions and external injuries. Neosporin is also used as a brand name for several other U.S. products that do not contain neomycin. Pfizer also produces a related mixture of bacitracin and polymyxin, branded Polysporin. Because neomycin is not included in Polysporin, Polysporin may be safely used in individuals with allergies to neomycin. Recently, Pfizer also introduced "Neosporin + Pain Relief," ointment and cream, containing pramoxine, a topical analgesic. In addition to its pain relieving properties, the cream (which omits the bacitracin zinc, as it is not stable in the cream base) appears useful in individuals sensitive to bacitracin, as well as those sensitive to zinc. In Canada, the Neosporin brand is not sold at all, but Polysporin is sold in several varieties. The "original" ointments contain polymyxin B and bacitracin, while the creams and eye/ear drops contain polymyxin B and gramicidin. A "triple" ointment is also available containing all three of the above antibiotics. # External links - Neosporin Website Template:WH Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Neosporin
314a6943baca5adaed05a40db3ad2594d1c68204	wikidoc	Nepafenac	Nepafenac # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Nepafenac is an antiinflammatory that is FDA approved for the treatment of pain and inflammation associated with cataract surgery. Common adverse reactions include discharge from eye, disorder of lens capsule, foreign body sensation, raised intraocular pressure, reduced visual acuity. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Nepafenac ophthalmic suspension, 0.3% is indicated for the treatment of pain and inflammation associated with cataract surgery. - One drop of ILEVRO- (nepafenac ophthalmic suspension), 0.3% should be applied to the affected eye one-time-daily beginning 1 day prior to cataract surgery, continued on the day of surgery and through the first 2 weeks of the postoperative period. An additional drop should be administered 30 to 120 minutes prior to surgery. - ILEVRO- (nepafenac ophthalmic suspension), 0.3% may be administered in conjunction with other topical ophthalmic medications such as beta-blockers, carbonic anhydrase inhibitors, alpha-agonists, cycloplegics, and mydriatics. - If more than one topical ophthalmic medication is being used, the medicines must be administered at least 5 minutes apart. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Nepafenac in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Nepafenac in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Nepafenac in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Nepafenac in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Nepafenac in pediatric patients. # Contraindications - ILEVRO- (nepafenac ophthalmic suspension), 0.3% is contraindicated in patients with previously demonstrated hypersensitivity to any of the ingredients in the formula or to other NSAIDs. # Warnings - With some nonsteroidal anti-inflammatory drugs including ILEVRO- (nepafenac ophthalmic suspension), 0.3%, there exists the potential for increased bleeding time due to interference with thrombocyte aggregation. There have been reports that ocularly applied nonsteroidal anti-inflammatory drugs may cause increased bleeding of ocular tissues (including hyphema) in conjunction with ocular surgery. - It is recommended that ILEVRO- (nepafenac ophthalmic suspension), 0.3% be used with caution in patients with known bleeding tendencies or who are receiving other medications which may prolong bleeding time. - Topical nonsteroidal anti-inflammatory drugs (NSAIDs) including ILEVRO- (nepafenac ophthalmic suspension), 0.3%, may slow or delay healing. Topical corticosteroids are also known to slow or delay healing. Concomitant use of topical NSAIDs and topical steroids may increase the potential for healing problems. - Use of topical NSAIDs may result in keratitis. In some susceptible patients, continued use of topical NSAIDs may result in epithelial breakdown, corneal thinning, corneal erosion, corneal ulceration or corneal perforation. These events may be sight threatening. Patients with evidence of corneal epithelial breakdown should immediately discontinue use of topical NSAIDs including ILEVRO- (nepafenac ophthalmic suspension), 0.3% and should be closely monitored for corneal health. - Postmarketing experience with topical NSAIDs suggests that patients with complicated ocular surgeries, corneal denervation, corneal epithelial defects, diabetes mellitus, ocular surface diseases (e.g., dry eye syndrome), rheumatoid arthritis, or repeat ocular surgeries within a short period of time may be at increased risk for corneal adverse events which may become sight threatening. Topical NSAIDs should be used with caution in these patients. - Postmarketing experience with topical NSAIDs also suggests that use more than 1 day prior to surgery or use beyond 14 days post-surgery may increase patient risk and severity of corneal adverse events. - ILEVRO- (nepafenac ophthalmic suspension), 0.3% should not be administered while using contact lenses. # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Nepafenac Clinical Trials Experience in the drug label. ## Postmarketing Experience - Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to the rates in the clinical studies of another drug and may not reflect the rates observed in practice. - The following adverse reactions are discussed in greater detail in other sections of labeling. - Increased Bleeding Time - Delayed Healing - Corneal Effects - The most frequently reported ocular adverse reactions following cataract surgery were capsular opacity, decreased visual acuity, foreign body sensation, increased intraocular pressure, and sticky sensation. These reactions occurred in approximately 5 to 10% of patients. - Other ocular adverse reactions occurring at an incidence of approximately 1 to 5% included conjunctival edema, corneal edema, dry eye, lid margin crusting, ocular discomfort, ocular hyperemia, ocular pain, ocular pruritus, photophobia, tearing and vitreous detachment. - Some of these reactions may be the consequence of the cataract surgical procedure. - Non-ocular adverse reactions reported at an incidence of 1 to 4% included headache, hypertension, nausea/vomiting, and sinusitis. # Drug Interactions There is limited information regarding Nepafenac Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Reproduction studies performed with nepafenac in rabbits and rats at oral doses up to 10 mg/kg/day have revealed no evidence of teratogenicity due to nepafenac, despite the induction of maternal toxicity. At this dose, the animal plasma exposure to nepafenac and amfenac was approximately 70 and 630 times human plasma exposure at the recommended human topical ophthalmic dose for rats and 20 and 180 times human plasma exposure for rabbits, respectively. In rats, maternally toxic doses ≥ 10 mg/kg were associated with dystocia, increased postimplantation loss, reduced fetal weights and growth, and reduced fetal survival. - Nepafenac has been shown to cross the placental barrier in rats. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, ILEVRO- (nepafenac ophthalmic suspension), 0.3% should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - Because of the known effects of prostaglandin biosynthesis inhibiting drugs on the fetal cardiovascular system (closure of the ductus arteriosus), the use of ILEVRO- (nepafenac ophthalmic suspension), 0.3% during late pregnancy should be avoided. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nepafenac in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Nepafenac during labor and delivery. ### Nursing Mothers - Nepafenac is excreted in the milk of lactating rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ILEVRO- (nepafenac ophthalmic suspension), 0.3% is administered to a nursing woman. ### Pediatric Use The safety and effectiveness of ILEVRO- (nepafenac ophthalmic suspension), 0.3% in pediatric patients below the age of 10 years have not been established. ### Geriatic Use No overall differences in safety and effectiveness have been observed between elderly and younger patients. ### Gender There is no FDA guidance on the use of Nepafenac with respect to specific gender populations. ### Race There is no FDA guidance on the use of Nepafenac with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Nepafenac in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Nepafenac in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Nepafenac in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Nepafenac in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral - Topical ### Monitoring - Patients with evidence of corneal epithelial breakdown should immediately discontinue use of topical NSAIDs including ILEVRO- (nepafenac ophthalmic suspension), 0.3% and should be closely monitored for corneal health. # IV Compatibility There is limited information regarding IV Compatibility of Nepafenac in the drug label. # Overdosage There is limited information regarding Nepafenac overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action - After topical ocular dosing, nepafenac penetrates the cornea and is converted by ocular tissue hydrolases to amfenac, a nonsteroidal anti-inflammatory drug. Nepafenac and amfenac are thought to inhibit the action of prostaglandin H synthase (cyclooxygenase), an enzyme required for prostaglandin production. ## Structure ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Nepafenac in the drug label. ## Pharmacokinetics - Following bilateral topical ocular once-daily dosing of ILEVRO- (nepafenac ophthalmic suspension), 0.3%, the concentrations of nepafenac and amfenac peaked at a median time of 0.5 hour and 0.75 hour, respectively on both Day 1 and Day 4. The mean steady-state Cmax for nepafenac and for amfenac were 0.847 ± 0.269 ng/mL and 1.13 ± 0.491 ng/mL, respectively. - Nepafenac at concentrations up to 3000 ng/mL and amfenac at concentrations up to 1000 ng/mL did not inhibit the in vitro metabolism of 6 specific marker substrates of cytochrome P450 (CYP) isozymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4). Therefore, drug-drug interactions involving CYP mediated metabolism of concomitantly administered drugs are unlikely. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Nepafenac in the drug label. # Clinical Studies - In two double masked, randomized clinical trials in which patients were dosed daily beginning one day prior to cataract surgery, continued on the day of surgery and for the first two weeks of the postoperative period, ILEVRO- (nepafenac ophthalmic suspension), 0.3% demonstrated superior clinical efficacy compared to its vehicle in treating postoperative pain and inflammation. - Treatment effect over vehicle for resolution of ocular pain occurred as early as day 1 post-surgery. Treatment effect over vehicle for resolution of inflammation was significantly better than vehicle in both studies at day 7 and day 14 post-surgery. # How Supplied - LEVRO- (nepafenac ophthalmic suspension), 0.3% is supplied in a white, oval, low density polyethylene DROP-TAINER® dispenser with a natural low density polyethylene dispensing plug and gray polypropylene cap presented in an overwrap. Tamper evidence is provided with a shrink band around the closure and neck area of the package. - 1.7 mL in 4 mL bottle NDC 0065-1750-07 - 3 mL in a 4 mL bottle NDC 0065-1750-14 ## Storage - Storage: Store at 2 - 25˚C (36 - 77˚F). - Protect from light. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Nepafenac in the drug label. # Precautions with Alcohol - Alcohol-Nepafenac interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - ILEVRO ® # Look-Alike Drug Names There is limited information regarding Nepafenac Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Nepafenac Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Nepafenac is an antiinflammatory that is FDA approved for the treatment of pain and inflammation associated with cataract surgery. Common adverse reactions include discharge from eye, disorder of lens capsule, foreign body sensation, raised intraocular pressure, reduced visual acuity. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Nepafenac ophthalmic suspension, 0.3% is indicated for the treatment of pain and inflammation associated with cataract surgery. - One drop of ILEVRO* (nepafenac ophthalmic suspension), 0.3% should be applied to the affected eye one-time-daily beginning 1 day prior to cataract surgery, continued on the day of surgery and through the first 2 weeks of the postoperative period. An additional drop should be administered 30 to 120 minutes prior to surgery. - ILEVRO* (nepafenac ophthalmic suspension), 0.3% may be administered in conjunction with other topical ophthalmic medications such as beta-blockers, carbonic anhydrase inhibitors, alpha-agonists, cycloplegics, and mydriatics. - If more than one topical ophthalmic medication is being used, the medicines must be administered at least 5 minutes apart. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Nepafenac in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Nepafenac in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Nepafenac in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Nepafenac in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Nepafenac in pediatric patients. # Contraindications - ILEVRO* (nepafenac ophthalmic suspension), 0.3% is contraindicated in patients with previously demonstrated hypersensitivity to any of the ingredients in the formula or to other NSAIDs. # Warnings - With some nonsteroidal anti-inflammatory drugs including ILEVRO* (nepafenac ophthalmic suspension), 0.3%, there exists the potential for increased bleeding time due to interference with thrombocyte aggregation. There have been reports that ocularly applied nonsteroidal anti-inflammatory drugs may cause increased bleeding of ocular tissues (including hyphema) in conjunction with ocular surgery. - It is recommended that ILEVRO* (nepafenac ophthalmic suspension), 0.3% be used with caution in patients with known bleeding tendencies or who are receiving other medications which may prolong bleeding time. - Topical nonsteroidal anti-inflammatory drugs (NSAIDs) including ILEVRO* (nepafenac ophthalmic suspension), 0.3%, may slow or delay healing. Topical corticosteroids are also known to slow or delay healing. Concomitant use of topical NSAIDs and topical steroids may increase the potential for healing problems. - Use of topical NSAIDs may result in keratitis. In some susceptible patients, continued use of topical NSAIDs may result in epithelial breakdown, corneal thinning, corneal erosion, corneal ulceration or corneal perforation. These events may be sight threatening. Patients with evidence of corneal epithelial breakdown should immediately discontinue use of topical NSAIDs including ILEVRO* (nepafenac ophthalmic suspension), 0.3% and should be closely monitored for corneal health. - Postmarketing experience with topical NSAIDs suggests that patients with complicated ocular surgeries, corneal denervation, corneal epithelial defects, diabetes mellitus, ocular surface diseases (e.g., dry eye syndrome), rheumatoid arthritis, or repeat ocular surgeries within a short period of time may be at increased risk for corneal adverse events which may become sight threatening. Topical NSAIDs should be used with caution in these patients. - Postmarketing experience with topical NSAIDs also suggests that use more than 1 day prior to surgery or use beyond 14 days post-surgery may increase patient risk and severity of corneal adverse events. - ILEVRO* (nepafenac ophthalmic suspension), 0.3% should not be administered while using contact lenses. # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Nepafenac Clinical Trials Experience in the drug label. ## Postmarketing Experience - Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to the rates in the clinical studies of another drug and may not reflect the rates observed in practice. - The following adverse reactions are discussed in greater detail in other sections of labeling. - Increased Bleeding Time - Delayed Healing - Corneal Effects - The most frequently reported ocular adverse reactions following cataract surgery were capsular opacity, decreased visual acuity, foreign body sensation, increased intraocular pressure, and sticky sensation. These reactions occurred in approximately 5 to 10% of patients. - Other ocular adverse reactions occurring at an incidence of approximately 1 to 5% included conjunctival edema, corneal edema, dry eye, lid margin crusting, ocular discomfort, ocular hyperemia, ocular pain, ocular pruritus, photophobia, tearing and vitreous detachment. - Some of these reactions may be the consequence of the cataract surgical procedure. - Non-ocular adverse reactions reported at an incidence of 1 to 4% included headache, hypertension, nausea/vomiting, and sinusitis. # Drug Interactions There is limited information regarding Nepafenac Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Reproduction studies performed with nepafenac in rabbits and rats at oral doses up to 10 mg/kg/day have revealed no evidence of teratogenicity due to nepafenac, despite the induction of maternal toxicity. At this dose, the animal plasma exposure to nepafenac and amfenac was approximately 70 and 630 times human plasma exposure at the recommended human topical ophthalmic dose for rats and 20 and 180 times human plasma exposure for rabbits, respectively. In rats, maternally toxic doses ≥ 10 mg/kg were associated with dystocia, increased postimplantation loss, reduced fetal weights and growth, and reduced fetal survival. - Nepafenac has been shown to cross the placental barrier in rats. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, ILEVRO* (nepafenac ophthalmic suspension), 0.3% should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - Because of the known effects of prostaglandin biosynthesis inhibiting drugs on the fetal cardiovascular system (closure of the ductus arteriosus), the use of ILEVRO* (nepafenac ophthalmic suspension), 0.3% during late pregnancy should be avoided. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nepafenac in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Nepafenac during labor and delivery. ### Nursing Mothers - Nepafenac is excreted in the milk of lactating rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ILEVRO* (nepafenac ophthalmic suspension), 0.3% is administered to a nursing woman. ### Pediatric Use The safety and effectiveness of ILEVRO* (nepafenac ophthalmic suspension), 0.3% in pediatric patients below the age of 10 years have not been established. ### Geriatic Use No overall differences in safety and effectiveness have been observed between elderly and younger patients. ### Gender There is no FDA guidance on the use of Nepafenac with respect to specific gender populations. ### Race There is no FDA guidance on the use of Nepafenac with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Nepafenac in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Nepafenac in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Nepafenac in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Nepafenac in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral - Topical ### Monitoring - Patients with evidence of corneal epithelial breakdown should immediately discontinue use of topical NSAIDs including ILEVRO* (nepafenac ophthalmic suspension), 0.3% and should be closely monitored for corneal health. # IV Compatibility There is limited information regarding IV Compatibility of Nepafenac in the drug label. # Overdosage There is limited information regarding Nepafenac overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action - After topical ocular dosing, nepafenac penetrates the cornea and is converted by ocular tissue hydrolases to amfenac, a nonsteroidal anti-inflammatory drug. Nepafenac and amfenac are thought to inhibit the action of prostaglandin H synthase (cyclooxygenase), an enzyme required for prostaglandin production. ## Structure ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Nepafenac in the drug label. ## Pharmacokinetics - Following bilateral topical ocular once-daily dosing of ILEVRO* (nepafenac ophthalmic suspension), 0.3%, the concentrations of nepafenac and amfenac peaked at a median time of 0.5 hour and 0.75 hour, respectively on both Day 1 and Day 4. The mean steady-state Cmax for nepafenac and for amfenac were 0.847 ± 0.269 ng/mL and 1.13 ± 0.491 ng/mL, respectively. - Nepafenac at concentrations up to 3000 ng/mL and amfenac at concentrations up to 1000 ng/mL did not inhibit the in vitro metabolism of 6 specific marker substrates of cytochrome P450 (CYP) isozymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4). Therefore, drug-drug interactions involving CYP mediated metabolism of concomitantly administered drugs are unlikely. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Nepafenac in the drug label. # Clinical Studies - In two double masked, randomized clinical trials in which patients were dosed daily beginning one day prior to cataract surgery, continued on the day of surgery and for the first two weeks of the postoperative period, ILEVRO* (nepafenac ophthalmic suspension), 0.3% demonstrated superior clinical efficacy compared to its vehicle in treating postoperative pain and inflammation. - Treatment effect over vehicle for resolution of ocular pain occurred as early as day 1 post-surgery. Treatment effect over vehicle for resolution of inflammation was significantly better than vehicle in both studies at day 7 and day 14 post-surgery. # How Supplied - LEVRO* (nepafenac ophthalmic suspension), 0.3% is supplied in a white, oval, low density polyethylene DROP-TAINER® dispenser with a natural low density polyethylene dispensing plug and gray polypropylene cap presented in an overwrap. Tamper evidence is provided with a shrink band around the closure and neck area of the package. - 1.7 mL in 4 mL bottle NDC 0065-1750-07 - 3 mL in a 4 mL bottle NDC 0065-1750-14 ## Storage - Storage: Store at 2 - 25˚C (36 - 77˚F). - Protect from light. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Nepafenac in the drug label. # Precautions with Alcohol - Alcohol-Nepafenac interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - ILEVRO ®[1] # Look-Alike Drug Names There is limited information regarding Nepafenac Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Nepafenac
e83b997db48a9c5f8af8db506ec2c8d6bca1f63e	wikidoc	Neratinib	Neratinib # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Neratinib is a kinase inhibitor that is FDA approved for the extended adjuvant treatment of adult patients with early stage HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy. Common adverse reactions include diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, AST or ALT increase, nail disorder, dry skin, abdominal distention, weight decreased and urinary tract infection. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Neratinib is indicated for the extended adjuvant treatment of adult patients with early stage HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab based therapy. - Antidiarrheal prophylaxis is recommended during the first 2 cycles (56 days) of treatment and should be initiated with the first dose of neratinib. - Instruct patients to take loperamide as directed in TABLE 1, titrating to 1-2 bowel movements per day. - Additional antidiarrheal agents may be required to manage diarrhea in patients with loperamide-refractory diarrhea. Neratinib dose interruptions and dose reductions may also be required to manage diarrhea. - The recommended dose of neratinib is 240 mg (six tablets) given orally once daily with food, continuously for one year. - Instruct patients to take neratinib at approximately the same time every day. Neratinib tablets should be swallowed whole (tablets should not be chewed, crushed, or split prior to swallowing). - If a patient misses a dose, do not replace missed dose, and instruct the patient to resume neratinib with the next scheduled daily dose. - Neratinib dose modification is recommended based on individual safety and tolerability. Management of some adverse reactions may require dose interruption and/or dose reduction as shown in TABLE 2 to TABLE 5. Discontinue neratinib for patients who fail to recover to Grade 0-1 from treatment-related toxicity, for toxicities that result in a treatment delay > 3 weeks, or for patients that are unable to tolerate 120 mg daily. Additional clinical situations may result in dose adjustments as clinically indicated (e.g. intolerable toxicities, persistent Grade 2 adverse reactions, etc.). - Diarrhea management requires the correct use of antidiarrheal medication, dietary changes, and appropriate dose modifications of neratinib. Guidelines for adjusting doses of neratinib in the setting of diarrhea are shown in TABLE 4. - Reduce the neratinib starting dose to 80 mg in patients with severe hepatic impairment (Child Pugh C). No dose modifications are recommended for patients with mild to moderate hepatic impairment (Child Pugh A or B). - Guidelines for dose adjustment of neratinib in the event of liver toxicity are shown in TABLE 5. Patients who experience ≥ Grade 3 diarrhea requiring IV fluid treatment or any signs or symptoms of hepatotoxicity, such as worsening of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia, should be evaluated for changes in liver function tests. Fractionated bilirubin and prothrombin time should also be collected during hepatotoxicity evaluation. - Proton pump inhibitors (PPI): Avoid concomitant use with neratinib. - H2-receptor antagonists: Take neratinib at least 2 hours before the next dose of the H 2-receptor antagonist or 10 hours after the H2-receptor antagonist. - Antacids: Separate dosing of neratinib by 3 hours after antacids. - Tablets: 40 mg neratinib (equivalent to 48.31 mg of neratinib maleate). - Film-coated, red, oval shaped and debossed with ‘W104’ on one side and plain on the other side. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding neratinib Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding neratinib Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Neratinib FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding neratinib Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding neratinib Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications - None. # Warnings - Severe diarrhea and sequelae, such as dehydration, hypotension, and renal failure, have been reported during treatment with neratinib. Diarrhea was reported in 95% of neratinib-treated patients in ExteNET, a randomized placebo controlled trial. In the neratinib arm, Grade 3 diarrhea occurred in 40% and Grade 4 diarrhea occurred in 0.1% of patients. The majority of patients (93%) had diarrhea in the first month of treatment, the median time to first onset of Grade ≥ 3 diarrhea was 8 days (range, 1-350), and the median cumulative duration of Grade ≥ 3 diarrhea was 5 days (range, 1-139). - Antidiarrheal prophylaxis with loperamide has been shown to lower the incidence and severity of diarrhea. Instruct patients to initiate antidiarrheal prophylaxis with loperamide along with the first dose of neratinib and continue during the first two cycles (56 days) of treatment. - Monitor patients for diarrhea and treat with additional antidiarrheals as needed. When severe diarrhea with dehydration occurs, administer fluid and electrolytes as needed, interrupt neratinib, and reduce subsequent doses. Perform stool cultures as clinically indicated to exclude infectious causes of Grade 3 or 4 diarrhea or diarrhea of any grade with complicating features (dehydration, fever, neutropenia). - Neratinib has been associated with hepatotoxicity characterized by increased liver enzymes. In ExteNET, 9.7% of patients experienced an alanine aminotransferase (ALT) increase ≥ 2 x ULN, 5.1% of patients experienced an aspartate aminotransferase (AST) increase ≥ 2 x ULN, and 1.7% of patients experienced an AST or ALT elevation > 5 x ULN (≥ Grade 3). Hepatotoxicity or increases in liver transaminases led to drug discontinuation in 1.7% of neratinib-treated patients. - Total bilirubin, AST, ALT, and alkaline phosphatase should be measured prior to starting treatment with neratinib monthly for the first 3 months of treatment, then every 3 months while on treatment and as clinically indicated. These tests should also be performed in patients experiencing Grade 3 diarrhea or any signs or symptoms of hepatotoxicity, such as worsening of fatigue, nausea, vomiting, right upper quadrant tenderness, fever, rash, or eosinophilia. - Based on findings from animal studies and its mechanism of action, neratinib can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of neratinib to pregnant rabbits during organogenesis caused abortions, embryo-fetal death and fetal abnormalities in rabbits at maternal AUCs approximately 0.2 times the AUC in patients receiving the recommended dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 1 month after the last dose. # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. - The data described below reflect exposure of neratinib as a single agent in ExteNET, a multicenter, randomized, double-blind, placebo-controlled study of neratinib within 2 years after completion of adjuvant treatment with trastuzumab-based therapy in women with HER2-positive early-stage breast cancer. Patients who received neratinib in this trial were not required to receive any prophylaxis with antidiarrheal agents to prevent the neratinib-related diarrhea. The median duration of treatment was 11.6 months in the neratinib arm and 11.8 months in the placebo arm. The median age was 52 years (60% were ≥ 50 years old, 12% were ≥ 65 years old); 81% were Caucasian, 3% Black or African American, 14% Asian and 3% other. A total of 1408 patients were treated with neratinib. - Neratinib dose reduction due to an adverse reaction of any grade occurred in 31.2% of patients receiving neratinib compared to 2.6% of patients receiving placebo. Permanent discontinuation due to any adverse reaction was reported in 27.6% of neratinib-treated patients. The most common adverse reaction leading to discontinuation was diarrhea, accounting for 16.8% of neratinib-treated patients. - The most common adverse reactions (>5%) were diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, AST or ALT increase, nail disorder, dry skin, abdominal distention, weight decreased and urinary tract infection. The most frequently reported Grade 3 or 4 adverse reactions were diarrhea, vomiting, nausea, and abdominal pain. - Serious adverse reactions in the neratinib arm included diarrhea (1.6%), vomiting (0.9%), dehydration (0.6%), cellulitis (0.4%), renal failure (0.4%), erysipelas (0.4%), alanine aminotransferase increased (0.3%), aspartate aminotransferase increased (0.3%), nausea (0.3%), fatigue (0.2%), and abdominal pain (0.2%). - TABLE 6 summarizes the adverse reactions in ExteNET. ## Postmarketing Experience There is limited information regarding Neratinib Postmarketing Experience in the drug label. # Drug Interactions - Effect of Other Drugs on Neratinib - Effect of Neratinib on Other Drugs - TABLE 7 includes drug interactions that affect the pharmacokinetics of neratinib. - Concomitant use of neratinib with digoxin, a P-gp substrate, increased digoxin concentrations. Increased concentrations of digoxin may lead to increased risk of adverse reactions including cardiac toxicity. Refer to the digoxin prescribing information for dosage adjustment recommendations due to drug interactions. neratinib may inhibit the transport of other P-gp substrates (e.g., dabigatran, fexofenadine). # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Based on findings from animal studies and the mechanism of action, neratinib can cause fetal harm when administered to a pregnant woman. - There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of neratinib to pregnant rabbits during organogenesis resulted in abortions, embryo-fetal death and fetal abnormalities in rabbits at maternal exposures (AUC) approximately 0.2 times exposures in patients at the recommended dose. Advise pregnant women of the potential risk to a fetus. - The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies in the U.S. general population. - In a fertility and early embryonic development study in female rats, neratinib was administered orally for 15 days before mating to Day 7 of pregnancy, which did not cause embryonic toxicity at doses up to 12 mg/kg/day in the presence of maternal toxicity. A dose of 12 mg/kg/day in rats is approximately 0.5 times the maximum recommended dose of 240 mg/day in patients on a mg/m2 basis. - In an embryo-fetal development study in rats, pregnant animals received oral doses of neratinib up to 15 mg/kg/day during the period of organogenesis. No effects on embryo-fetal development or survival were observed. Maternal toxicity was evident at 15 mg/kg/day (approximately 0.6 times the AUC in patients receiving the maximum recommended dose of 240 mg/day). - In an embryo-fetal development study in rabbits, pregnant animals received oral doses of neratinib up to 9 mg/kg/day during the period of organogenesis. Administration of neratinib at doses ≥ 6 mg/kg/day resulted in maternal toxicity, abortions and embryo-fetal death (increased resorptions). Neratinib administration resulted in increased incidence of fetal gross external (domed head), soft tissue (dilation of the brain ventricles and ventricular septal defect), and skeletal (misshapen anterior fontanelles and enlarged anterior and/or posterior fontanelles) abnormalities at ≥ 3 mg/kg/day. The AUC(0-t) at 6 mg/kg/day and 9 mg/kg/day in rabbits were approximately 0.5 and 0.8 times, respectively, the AUCs in patients receiving the maximum recommended dose of 240 mg/day. - In a peri and postnatal development study in rats, oral administration of neratinib from gestation day 7 until lactation day 20 resulted in maternal toxicity at ≥ 10 mg/kg/day (approximately 0.4 times the maximum recommended dose of 240 mg/day in patients on a mg/m2 basis) including decreased body weights, body weight gains, and food consumption. Effects on long-term memory were observed in male offspring at maternal doses ≥ 5 mg/kg/day (approximately 0.2 times the maximum recommended dose of 240 mg/day in patients on a mg/m2 basis). Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Neratinib in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Neratinib during labor and delivery. ### Nursing Mothers - No data are available regarding the presence of neratinib or its metabolites in human milk or its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in breastfed infants from neratinib, advise lactating women not to breastfeed while taking neratinib and for at least 1 month after the last dose. ### Pediatric Use - The safety and efficacy of neratinib in pediatric patients has not been established. ### Geriatic Use - In the ExteNET trial, the mean age was 52 years in the neratinib arm; 1236 patients were < 65 years, 172 patients were ≥ 65 years, of whom 25 patients were 75 years or older. - There was a higher frequency of treatment discontinuations due to adverse reactions in the ≥ 65 years age group than in the < 65 years age group; in the neratinib arm, the percentages were 44.8% compared with 25.2%, respectively, and in the placebo arm 6.4% and 5.3%, respectively. - The incidence of serious adverse reactions in the neratinib arm vs. placebo arm was 7.0% vs. 5.7% (< 65 years-old) and 9.9% vs. 8.1% (≥ 65 years-old). The serious adverse reactions most frequently reported in the ≥ 65 years-old group were vomiting (2.3%), diarrhea (1.7%), renal failure (1.7%), and dehydration (1.2%). ### Gender There is no FDA guidance on the use of Neratinib with respect to specific gender populations. ### Race There is no FDA guidance on the use of Neratinib with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Neratinib in patients with renal impairment. ### Hepatic Impairment - No dose modifications are recommended for patients with mild to moderate hepatic impairment (Child Pugh A or B). Patients with severe, pre-existing hepatic impairment (Child Pugh Class C) experienced a reduction in neratinib clearance and an increase in Cmax and AUC. Reduce the neratinib dosage for patients with severe hepatic impairment. ### Females of Reproductive Potential and Males - Based on animal studies, neratinib can cause fetal harm when administered to a pregnant woman. Females of reproductive potential should have a pregnancy test prior to starting treatment with neratinib. Females - Based on animal studies, neratinib can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with neratinib and for at least 1 month after the last dose. Males - Based on findings in animal reproduction studies, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of neratinib. ### Immunocompromised Patients There is no FDA guidance one the use of Neratinib in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring - Disease response or stabilization may indicate efficacy. - FTL3 mutation: Prior to initiation, with an FDA-approved companion diagnostic test available at . - Pregnancy status (women of reproductive potential): Within 7 days prior to initiation of therapy. - CBC: At least weekly for the first 4 weeks, every other week for the next 8 weeks, and monthly thereafter during therapy; include a differential. - Toxicities, including nausea, vomiting, and other non-hematologic toxicities: At least weekly for the first 4 weeks, every other week for the next 8 weeks, and monthly thereafter during therapy. - Pulmonary symptoms of interstitial lung disease or pneumonitis. # IV Compatibility There is limited information regarding the compatibility of Neratinib and IV administrations. # Overdosage - There is no specific antidote, and the benefit of hemodialysis in the treatment of neratinib overdose is unknown. In the event of an overdose, administration should be withheld and general supportive measures undertaken. - In the clinical trial setting, a limited number of patients reported overdose. The adverse reactions experienced by these patients were diarrhea, nausea, vomiting, and dehydration. The frequency and severity of gastrointestinal disorders (diarrhea, abdominal pain, nausea and vomiting) appear to be dose related. # Pharmacology ## Mechanism of Action - Neratinib is a kinase inhibitor that irreversibly binds to Epidermal Growth Factor Receptor (EGFR), Human Epidermal Growth Factor Receptor 2 (HER2), and HER4. In vitro, neratinib reduces EGFR and HER2 autophosphorylation, downstream MAPK and AKT signaling pathways, and showed antitumor activity in EGFR and/or HER2 expressing carcinoma cell lines. Neratinib human metabolites M3, M6, M7 and M11 inhibited the activity of EGFR, HER2 and HER4 in vitro. In vivo, oral administration of neratinib inhibited tumor growth in mouse xenograft models with tumor cell lines expressing HER2 and EGFR. ## Structure ## Pharmacodynamics - The effect of neratinib on the QTc interval was evaluated in a randomized, placebo and positive controlled, double-blind, single-dose, crossover study in 60 healthy subjects. At 2.4-fold the therapeutic exposures of neratinib, there was no clinically relevant effect on the QTc interval. ## Pharmacokinetics - Neratinib exhibits a non-linear PK profile with less than dose proportional increase of AUC with the increasing daily dose over the range of 40 to 400 mg. - The neratinib and major active metabolites M3, M6 and M7 peak concentrations are reached in the range of 2 to 8 hours after oral administration. Effect of Food - The food-effect assessment was conducted in healthy volunteers who received neratinib 240 mg under fasting conditions and with high fat food (approximately 55% fat, 31% carbohydrate, and 14% protein) or standard breakfast (approximately 50% carbohydrate, 35% fat, and 15% protein). A high fat meal increased neratinib Cmax and AUCinf by 1.7-fold (90% CI: 1.1- 2.7) and 2.2-fold (90% CI: 1.4- 3.5), respectively. A standard breakfast increased the Cmax and AUCinf by 1.2-fold (90% CI: 0.97- 1.42) and 1.1-fold (90% CI: 1.02- 1.24), respectively. - In patients, following multiple doses of neratinib, the mean (%CV) apparent volume of distribution at steady-state (Vss/F) was 6433 (19%) L. In vitro protein binding of neratinib in human plasma was greater than 99% and independent of concentration. Neratinib bound predominantly to human serum albumin and human alpha-1 acid glycoprotein. - Following 7 days of daily 240 mg oral doses of neratinib in healthy subjects, the mean (%CV) plasma half-life of neratinib, M3, M6, and M7 was 14.6 (38%), 21.6 (77%), 13.8 (50%) and 10.4 (33%) hours, respectively. The mean elimination half-life of neratinib ranged from 7 to 17 hours following a single oral dose in patients. Following multiple doses of neratinib at once-daily 240 mg in cancer patients, the mean (%CV) CL/F after first dose and at steady state (day 21) were 216 (34%) and 281 (40%) L/hour, respectively. Metabolism - Neratinib is metabolized primarily in the liver by CYP3A4 and to a lesser extent by flavin-containing monooxygenase (FMO). - After oral administration of neratinib, neratinib represents the most prominent component in plasma. At steady state after 240 mg daily oral doses of neratinib in a healthy subject study (n=25), the systemic exposures (AUC) of the active metabolites M3, M6, M7 and M11were 15%, 33%, 22% and 4% of the systemic neratinib exposure (AUC) respectively. Excretion - After oral administration of 200 mg (0.83 times of approved recommended dosage) radiolabeled neratinib oral formulation, fecal excretion accounted for approximately 97.1% and urinary excretion accounted for 1.13% of the total dose. Sixty-one percent of the excreted radioactivity was recovered within 96 hours and 98% was recovered after 10 days. - Age, gender, race and renal function do not have a clinically significant effect on neratinib pharmacokinetics. Patients with Hepatic Impairment - Neratinib is mainly metabolized in the liver. Single doses of 120 mg neratinib were evaluated in non-cancer patients with chronic hepatic impairment (n=6 each in Child Pugh Class A, B, and C) and in healthy subjects (n=9) with normal hepatic function. Neratinib exposures in the patients with Child Pugh Class A (mild impairment) and Child Pugh Class B (moderate impairment) were similar to that in normal healthy volunteers. Patients with severe hepatic impairment (Child Pugh Class C) had neratinib Cmax and AUC increased by 273% and 281%, respectively, as compared to the normal hepatic function controls. - Gastric Acid Reducing Agents: neratinib solubility decreases with increasing GI tract pH values. Drugs that alter the pH values of the GI tract may alter the solubility of neratinib and hence its absorption and systemic exposure. When multiple doses of lansoprazole (30 mg daily), a proton pump inhibitor, were co-administered with a single 240 mg oral doses of neratinib, the neratinib Cmax and AUC decreased by 71% and 65%, respectively. When a single oral dose of 240 mg neratinib was administered 2 hours following a daily dose of 300 mg ranitidine, an H-2 receptor antagonist, the neratinib Cmax and AUC were reduced by 57% and 48%, respectively. When a single oral dose of 240 mg neratinib was administered 2 hours prior to 150 mg ranitidine twice daily (administered in the morning and evening, approximately 12 hours apart), the neratinib Cmaxand AUC were reduced by 44% and 32%, respectively. - Strong and Moderate CYP3A4 Inhibitors: Concomitant use of ketoconazole (400 mg once-daily for 5 days), a strong inhibitor of CYP3A4, with a single oral 240 mg neratinib dose in healthy subjects (n=24) increased neratinib Cmax by 321% and AUC by 481%. - The effect of moderate CYP3A4 inhibition has not been studied. Given neratinib is predominantly metabolized by the CYP3A4 pathway and had a significant exposure change with strong CYP3A4 inhibition, the potential impact on neratinib safety from concomitant use with moderate CYP3A4 inhibitors warrants consideration. - Strong and Moderate CYP3A4 Inducers: Concomitant use of rifampin, a strong inducer of CYP3A4, with a single oral 240 mg neratinib dose in healthy subjects (n=24) reduced neratinib Cmax by 76% and AUC by 87%. The AUC of active metabolites M6 and M7 were also reduced by 37-49% when compared to neratinib administered alone. - The effect of moderate CYP3A4 induction has not been studied. Given neratinib is predominantly metabolized by the CYP3A4 pathway and had a significant exposure change with strong CYP3A4 induction, the potential impact on neratinib efficacy from concomitant use with moderate CYP3A4 inducers warrants consideration. - Effect of neratinib on P-gp Transporters: Concomitant use of digoxin (a single 0.5 mg oral dose), a P-gp substrate, with multiple oral doses of neratinib 240 mg in healthy subjects (n=18) increased the mean digoxin Cmax by 54% and AUC by 32%. ## Nonclinical Toxicology - A two-year carcinogenicity study was conducted in rats at oral neratinib doses of 1, 3, and 10 mg/kg/day. Neratinib was not carcinogenic in male and female rats at exposure levels > 25 times the AUC in patients receiving the maximum recommended dose of 240 mg/day. Neratinib was not carcinogenic in a 26-week study in Tg.rasH2 transgenic mice when administered daily by oral gavage at doses up to 50 mg/kg/day in males and 125 mg/kg/day in females. - Neratinib was not mutagenic in an in vitro bacterial reverse mutation (AMES) assay or clastogenic in an in vitro human lymphocyte chromosomal aberration assay or an in vivo rat bone marrow micronucleus assay. - In a fertility study in rats, neratinib administration up to 12 mg/kg/day (approximately 0.5 times the maximum recommended dose of 240 mg/day in patients on a mg/m2 basis) caused no effects on mating or the ability of animals to become pregnant. In repeat-dose toxicity studies in dogs with oral administration of neratinib daily for up to 39 weeks, tubular hypoplasia of the testes was observed at ≥ 0.5 mg/kg/day. This finding was observed at AUCs that were approximately 0.4 times the AUC in patients at the maximum recommended dose of 240 mg. # Clinical Studies - The safety and efficacy of neratinib were investigated in the ExteNET trial (NCT00878709), a multicenter, randomized, double-blind, placebo-controlled study of neratinib after adjuvant treatment with trastuzumab in women with HER2-positive breast cancer. - A total of 2840 patients with early-stage HER2-positive breast cancer within two years of completing treatment with adjuvant trastuzumab was randomized to receive either neratinib (n=1420) or placebo (n=1420). Randomization was stratified by the following factors: hormone receptor status, nodal status (0, 1-3 vs 4 or more positive nodes) and whether trastuzumab was given sequentially versus concurrently with chemotherapy. Neratinib 240 mg or placebo was given orally once daily for one year. The major efficacy outcome measure was invasive disease-free survival (iDFS) defined as the time between the date of randomization to the first occurrence of invasive recurrence (local/regional, ipsilateral, or contralateral breast cancer), distant recurrence, or death from any cause, with 2 years and 28 days of follow-up. - Patient demographics and tumor characteristics were generally balanced between treatment arms. Patients had a median age of 52 years (range 23 to 83) and 12% of patients were 65 or older. The majority of patients were White (81%), and most patients (99.7%) had an ECOG performance status of 0 or 1. Fifty-seven percent (57%) had hormone receptor positive disease (defined as ER-positive and/or PgR-positive), 24% were node negative, 47% had one to three positive nodes and 30% had four or more positive nodes. Ten percent (10%) of patients had Stage I disease, 41% had Stage II disease and 31% had Stage III disease. The majority of patients (81%) were enrolled within one year of completion of trastuzumab treatment. Median time from the last adjuvant trastuzumab treatment to randomization was 4.4 months in the neratinib arm vs. 4.6 months in the placebo arm. Median duration of treatment was 11.6 months in the neratinib arm vs. 11.8 months in the placebo arm. - The efficacy results from the ExteNET trial are summarized in TABLE 8 and FIGURE 1. - Approximately 75% of patients were re-consented for extended follow-up beyond 24 months. Observations with missing data were censored at the last date of assessment. This exploratory analysis suggests that the iDFS results at 5 years are consistent with the 2-year iDFS results observed in ExteNET. At the time of the iDFS analysis, 2% of patients had died, and Overall Survival data were immature. # How Supplied - Neratinib 40 mg film-coated tablets are red, oval shaped and debossed with ‘W104’ on one side and plain on the other side. - Neratinib is available in: - Bottles of 180 tablets: NDC 70437-240-18 - Bottles of 126 tablets: NDC 70437-240-26 ## Storage - Store at controlled room temperature, 20°C to 25°C (68°F to 77°F); excursions permitted to 15-30°C (59–86°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise the patient to read the FDA-approved patient labeling - Inform patients that neratinib has been associated with diarrhea which may be severe in some cases. - Instruct patients to maintain 1-2 bowel movements per day and on how to use anti-diarrheal treatment regimens. - Advise patients to inform their healthcare provider immediately if severe (≥Grade 3) diarrhea or diarrhea associated with weakness, dizziness, or fever occurs during treatment with neratinib. - Inform patients that neratinib has been associated with hepatotoxicity which may be severe in some cases. Inform patients that they should report signs and symptoms of liver dysfunction to their healthcare provider immediately. - Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the risk to a fetus and potential loss of the pregnancy. - Advise females of reproductive potential to use effective contraception during treatment and for 1 month after receiving the last dose of neratinib. - Advise lactating women not to breastfeed during treatment with neratinib and for at least 1 month after the last dose. - Neratinib may interact with many drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products. - Neratinib may interact with gastric acid reducing agents. Advise patients to avoid concomitant use of proton pump inhibitors. When patients require gastric acid reducing agents, use an H 2-receptor antagonist or antacid. Advise patients to separate the dosing of neratinib by 3 hours after antacid medicine, and to take neratinib at least 2 hours before or 10 hours after a H 2-receptor antagonist. - Neratinib may interact with grapefruit. Advise patients to avoid taking neratinib with grapefruit products. - Instruct patients to take neratinib with food at approximately the same time each day consecutively for one year. - If a patient misses a dose, instruct the patient not to replace the missed dose, and to resume neratinib with the next scheduled daily dose. # Precautions with Alcohol Alcohol-Neratinib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names - Nerlynx # Look-Alike Drug Names There is limited information regarding Neratinib Look-Alike Drug Names in the drug label. # Drug Shortage Status Drug Shortage # Price	Neratinib Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sonya Gelfand # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Neratinib is a kinase inhibitor that is FDA approved for the extended adjuvant treatment of adult patients with early stage HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy. Common adverse reactions include diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, AST or ALT increase, nail disorder, dry skin, abdominal distention, weight decreased and urinary tract infection. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Neratinib is indicated for the extended adjuvant treatment of adult patients with early stage HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab based therapy. - Antidiarrheal prophylaxis is recommended during the first 2 cycles (56 days) of treatment and should be initiated with the first dose of neratinib. - Instruct patients to take loperamide as directed in TABLE 1, titrating to 1-2 bowel movements per day. - Additional antidiarrheal agents may be required to manage diarrhea in patients with loperamide-refractory diarrhea. Neratinib dose interruptions and dose reductions may also be required to manage diarrhea. - The recommended dose of neratinib is 240 mg (six tablets) given orally once daily with food, continuously for one year. - Instruct patients to take neratinib at approximately the same time every day. Neratinib tablets should be swallowed whole (tablets should not be chewed, crushed, or split prior to swallowing). - If a patient misses a dose, do not replace missed dose, and instruct the patient to resume neratinib with the next scheduled daily dose. - Neratinib dose modification is recommended based on individual safety and tolerability. Management of some adverse reactions may require dose interruption and/or dose reduction as shown in TABLE 2 to TABLE 5. Discontinue neratinib for patients who fail to recover to Grade 0-1 from treatment-related toxicity, for toxicities that result in a treatment delay > 3 weeks, or for patients that are unable to tolerate 120 mg daily. Additional clinical situations may result in dose adjustments as clinically indicated (e.g. intolerable toxicities, persistent Grade 2 adverse reactions, etc.). - Diarrhea management requires the correct use of antidiarrheal medication, dietary changes, and appropriate dose modifications of neratinib. Guidelines for adjusting doses of neratinib in the setting of diarrhea are shown in TABLE 4. - Reduce the neratinib starting dose to 80 mg in patients with severe hepatic impairment (Child Pugh C). No dose modifications are recommended for patients with mild to moderate hepatic impairment (Child Pugh A or B). - Guidelines for dose adjustment of neratinib in the event of liver toxicity are shown in TABLE 5. Patients who experience ≥ Grade 3 diarrhea requiring IV fluid treatment or any signs or symptoms of hepatotoxicity, such as worsening of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia, should be evaluated for changes in liver function tests. Fractionated bilirubin and prothrombin time should also be collected during hepatotoxicity evaluation. - Proton pump inhibitors (PPI): Avoid concomitant use with neratinib. - H2-receptor antagonists: Take neratinib at least 2 hours before the next dose of the H 2-receptor antagonist or 10 hours after the H2-receptor antagonist. - Antacids: Separate dosing of neratinib by 3 hours after antacids. - Tablets: 40 mg neratinib (equivalent to 48.31 mg of neratinib maleate). - Film-coated, red, oval shaped and debossed with ‘W104’ on one side and plain on the other side. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding neratinib Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding neratinib Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Neratinib FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding neratinib Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding neratinib Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications - None. # Warnings - Severe diarrhea and sequelae, such as dehydration, hypotension, and renal failure, have been reported during treatment with neratinib. Diarrhea was reported in 95% of neratinib-treated patients in ExteNET, a randomized placebo controlled trial. In the neratinib arm, Grade 3 diarrhea occurred in 40% and Grade 4 diarrhea occurred in 0.1% of patients. The majority of patients (93%) had diarrhea in the first month of treatment, the median time to first onset of Grade ≥ 3 diarrhea was 8 days (range, 1-350), and the median cumulative duration of Grade ≥ 3 diarrhea was 5 days (range, 1-139). - Antidiarrheal prophylaxis with loperamide has been shown to lower the incidence and severity of diarrhea. Instruct patients to initiate antidiarrheal prophylaxis with loperamide along with the first dose of neratinib and continue during the first two cycles (56 days) of treatment. - Monitor patients for diarrhea and treat with additional antidiarrheals as needed. When severe diarrhea with dehydration occurs, administer fluid and electrolytes as needed, interrupt neratinib, and reduce subsequent doses. Perform stool cultures as clinically indicated to exclude infectious causes of Grade 3 or 4 diarrhea or diarrhea of any grade with complicating features (dehydration, fever, neutropenia). - Neratinib has been associated with hepatotoxicity characterized by increased liver enzymes. In ExteNET, 9.7% of patients experienced an alanine aminotransferase (ALT) increase ≥ 2 x ULN, 5.1% of patients experienced an aspartate aminotransferase (AST) increase ≥ 2 x ULN, and 1.7% of patients experienced an AST or ALT elevation > 5 x ULN (≥ Grade 3). Hepatotoxicity or increases in liver transaminases led to drug discontinuation in 1.7% of neratinib-treated patients. - Total bilirubin, AST, ALT, and alkaline phosphatase should be measured prior to starting treatment with neratinib monthly for the first 3 months of treatment, then every 3 months while on treatment and as clinically indicated. These tests should also be performed in patients experiencing Grade 3 diarrhea or any signs or symptoms of hepatotoxicity, such as worsening of fatigue, nausea, vomiting, right upper quadrant tenderness, fever, rash, or eosinophilia. - Based on findings from animal studies and its mechanism of action, neratinib can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of neratinib to pregnant rabbits during organogenesis caused abortions, embryo-fetal death and fetal abnormalities in rabbits at maternal AUCs approximately 0.2 times the AUC in patients receiving the recommended dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 1 month after the last dose. # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. - The data described below reflect exposure of neratinib as a single agent in ExteNET, a multicenter, randomized, double-blind, placebo-controlled study of neratinib within 2 years after completion of adjuvant treatment with trastuzumab-based therapy in women with HER2-positive early-stage breast cancer. Patients who received neratinib in this trial were not required to receive any prophylaxis with antidiarrheal agents to prevent the neratinib-related diarrhea. The median duration of treatment was 11.6 months in the neratinib arm and 11.8 months in the placebo arm. The median age was 52 years (60% were ≥ 50 years old, 12% were ≥ 65 years old); 81% were Caucasian, 3% Black or African American, 14% Asian and 3% other. A total of 1408 patients were treated with neratinib. - Neratinib dose reduction due to an adverse reaction of any grade occurred in 31.2% of patients receiving neratinib compared to 2.6% of patients receiving placebo. Permanent discontinuation due to any adverse reaction was reported in 27.6% of neratinib-treated patients. The most common adverse reaction leading to discontinuation was diarrhea, accounting for 16.8% of neratinib-treated patients. - The most common adverse reactions (>5%) were diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, AST or ALT increase, nail disorder, dry skin, abdominal distention, weight decreased and urinary tract infection. The most frequently reported Grade 3 or 4 adverse reactions were diarrhea, vomiting, nausea, and abdominal pain. - Serious adverse reactions in the neratinib arm included diarrhea (1.6%), vomiting (0.9%), dehydration (0.6%), cellulitis (0.4%), renal failure (0.4%), erysipelas (0.4%), alanine aminotransferase increased (0.3%), aspartate aminotransferase increased (0.3%), nausea (0.3%), fatigue (0.2%), and abdominal pain (0.2%). - TABLE 6 summarizes the adverse reactions in ExteNET. ## Postmarketing Experience There is limited information regarding Neratinib Postmarketing Experience in the drug label. # Drug Interactions - Effect of Other Drugs on Neratinib - Effect of Neratinib on Other Drugs - TABLE 7 includes drug interactions that affect the pharmacokinetics of neratinib. - Concomitant use of neratinib with digoxin, a P-gp substrate, increased digoxin concentrations. Increased concentrations of digoxin may lead to increased risk of adverse reactions including cardiac toxicity. Refer to the digoxin prescribing information for dosage adjustment recommendations due to drug interactions. neratinib may inhibit the transport of other P-gp substrates (e.g., dabigatran, fexofenadine). # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Based on findings from animal studies and the mechanism of action, neratinib can cause fetal harm when administered to a pregnant woman. - There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of neratinib to pregnant rabbits during organogenesis resulted in abortions, embryo-fetal death and fetal abnormalities in rabbits at maternal exposures (AUC) approximately 0.2 times exposures in patients at the recommended dose. Advise pregnant women of the potential risk to a fetus. - The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies in the U.S. general population. - In a fertility and early embryonic development study in female rats, neratinib was administered orally for 15 days before mating to Day 7 of pregnancy, which did not cause embryonic toxicity at doses up to 12 mg/kg/day in the presence of maternal toxicity. A dose of 12 mg/kg/day in rats is approximately 0.5 times the maximum recommended dose of 240 mg/day in patients on a mg/m2 basis. - In an embryo-fetal development study in rats, pregnant animals received oral doses of neratinib up to 15 mg/kg/day during the period of organogenesis. No effects on embryo-fetal development or survival were observed. Maternal toxicity was evident at 15 mg/kg/day (approximately 0.6 times the AUC in patients receiving the maximum recommended dose of 240 mg/day). - In an embryo-fetal development study in rabbits, pregnant animals received oral doses of neratinib up to 9 mg/kg/day during the period of organogenesis. Administration of neratinib at doses ≥ 6 mg/kg/day resulted in maternal toxicity, abortions and embryo-fetal death (increased resorptions). Neratinib administration resulted in increased incidence of fetal gross external (domed head), soft tissue (dilation of the brain ventricles and ventricular septal defect), and skeletal (misshapen anterior fontanelles and enlarged anterior and/or posterior fontanelles) abnormalities at ≥ 3 mg/kg/day. The AUC(0-t) at 6 mg/kg/day and 9 mg/kg/day in rabbits were approximately 0.5 and 0.8 times, respectively, the AUCs in patients receiving the maximum recommended dose of 240 mg/day. - In a peri and postnatal development study in rats, oral administration of neratinib from gestation day 7 until lactation day 20 resulted in maternal toxicity at ≥ 10 mg/kg/day (approximately 0.4 times the maximum recommended dose of 240 mg/day in patients on a mg/m2 basis) including decreased body weights, body weight gains, and food consumption. Effects on long-term memory were observed in male offspring at maternal doses ≥ 5 mg/kg/day (approximately 0.2 times the maximum recommended dose of 240 mg/day in patients on a mg/m2 basis). Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Neratinib in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Neratinib during labor and delivery. ### Nursing Mothers - No data are available regarding the presence of neratinib or its metabolites in human milk or its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in breastfed infants from neratinib, advise lactating women not to breastfeed while taking neratinib and for at least 1 month after the last dose. ### Pediatric Use - The safety and efficacy of neratinib in pediatric patients has not been established. ### Geriatic Use - In the ExteNET trial, the mean age was 52 years in the neratinib arm; 1236 patients were < 65 years, 172 patients were ≥ 65 years, of whom 25 patients were 75 years or older. - There was a higher frequency of treatment discontinuations due to adverse reactions in the ≥ 65 years age group than in the < 65 years age group; in the neratinib arm, the percentages were 44.8% compared with 25.2%, respectively, and in the placebo arm 6.4% and 5.3%, respectively. - The incidence of serious adverse reactions in the neratinib arm vs. placebo arm was 7.0% vs. 5.7% (< 65 years-old) and 9.9% vs. 8.1% (≥ 65 years-old). The serious adverse reactions most frequently reported in the ≥ 65 years-old group were vomiting (2.3%), diarrhea (1.7%), renal failure (1.7%), and dehydration (1.2%). ### Gender There is no FDA guidance on the use of Neratinib with respect to specific gender populations. ### Race There is no FDA guidance on the use of Neratinib with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Neratinib in patients with renal impairment. ### Hepatic Impairment - No dose modifications are recommended for patients with mild to moderate hepatic impairment (Child Pugh A or B). Patients with severe, pre-existing hepatic impairment (Child Pugh Class C) experienced a reduction in neratinib clearance and an increase in Cmax and AUC. Reduce the neratinib dosage for patients with severe hepatic impairment. ### Females of Reproductive Potential and Males - Based on animal studies, neratinib can cause fetal harm when administered to a pregnant woman. Females of reproductive potential should have a pregnancy test prior to starting treatment with neratinib. Females - Based on animal studies, neratinib can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with neratinib and for at least 1 month after the last dose. Males - Based on findings in animal reproduction studies, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of neratinib. ### Immunocompromised Patients There is no FDA guidance one the use of Neratinib in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring - Disease response or stabilization may indicate efficacy. - FTL3 mutation: Prior to initiation, with an FDA-approved companion diagnostic test available at http://www.fda/gov/CompanionDiagnostics. - Pregnancy status (women of reproductive potential): Within 7 days prior to initiation of therapy. - CBC: At least weekly for the first 4 weeks, every other week for the next 8 weeks, and monthly thereafter during therapy; include a differential. - Toxicities, including nausea, vomiting, and other non-hematologic toxicities: At least weekly for the first 4 weeks, every other week for the next 8 weeks, and monthly thereafter during therapy. - Pulmonary symptoms of interstitial lung disease or pneumonitis. # IV Compatibility There is limited information regarding the compatibility of Neratinib and IV administrations. # Overdosage - There is no specific antidote, and the benefit of hemodialysis in the treatment of neratinib overdose is unknown. In the event of an overdose, administration should be withheld and general supportive measures undertaken. - In the clinical trial setting, a limited number of patients reported overdose. The adverse reactions experienced by these patients were diarrhea, nausea, vomiting, and dehydration. The frequency and severity of gastrointestinal disorders (diarrhea, abdominal pain, nausea and vomiting) appear to be dose related. # Pharmacology ## Mechanism of Action - Neratinib is a kinase inhibitor that irreversibly binds to Epidermal Growth Factor Receptor (EGFR), Human Epidermal Growth Factor Receptor 2 (HER2), and HER4. In vitro, neratinib reduces EGFR and HER2 autophosphorylation, downstream MAPK and AKT signaling pathways, and showed antitumor activity in EGFR and/or HER2 expressing carcinoma cell lines. Neratinib human metabolites M3, M6, M7 and M11 inhibited the activity of EGFR, HER2 and HER4 in vitro. In vivo, oral administration of neratinib inhibited tumor growth in mouse xenograft models with tumor cell lines expressing HER2 and EGFR. ## Structure ## Pharmacodynamics - The effect of neratinib on the QTc interval was evaluated in a randomized, placebo and positive controlled, double-blind, single-dose, crossover study in 60 healthy subjects. At 2.4-fold the therapeutic exposures of neratinib, there was no clinically relevant effect on the QTc interval. ## Pharmacokinetics - Neratinib exhibits a non-linear PK profile with less than dose proportional increase of AUC with the increasing daily dose over the range of 40 to 400 mg. - The neratinib and major active metabolites M3, M6 and M7 peak concentrations are reached in the range of 2 to 8 hours after oral administration. Effect of Food - The food-effect assessment was conducted in healthy volunteers who received neratinib 240 mg under fasting conditions and with high fat food (approximately 55% fat, 31% carbohydrate, and 14% protein) or standard breakfast (approximately 50% carbohydrate, 35% fat, and 15% protein). A high fat meal increased neratinib Cmax and AUCinf by 1.7-fold (90% CI: 1.1- 2.7) and 2.2-fold (90% CI: 1.4- 3.5), respectively. A standard breakfast increased the Cmax and AUCinf by 1.2-fold (90% CI: 0.97- 1.42) and 1.1-fold (90% CI: 1.02- 1.24), respectively. - In patients, following multiple doses of neratinib, the mean (%CV) apparent volume of distribution at steady-state (Vss/F) was 6433 (19%) L. In vitro protein binding of neratinib in human plasma was greater than 99% and independent of concentration. Neratinib bound predominantly to human serum albumin and human alpha-1 acid glycoprotein. - Following 7 days of daily 240 mg oral doses of neratinib in healthy subjects, the mean (%CV) plasma half-life of neratinib, M3, M6, and M7 was 14.6 (38%), 21.6 (77%), 13.8 (50%) and 10.4 (33%) hours, respectively. The mean elimination half-life of neratinib ranged from 7 to 17 hours following a single oral dose in patients. Following multiple doses of neratinib at once-daily 240 mg in cancer patients, the mean (%CV) CL/F after first dose and at steady state (day 21) were 216 (34%) and 281 (40%) L/hour, respectively. Metabolism - Neratinib is metabolized primarily in the liver by CYP3A4 and to a lesser extent by flavin-containing monooxygenase (FMO). - After oral administration of neratinib, neratinib represents the most prominent component in plasma. At steady state after 240 mg daily oral doses of neratinib in a healthy subject study (n=25), the systemic exposures (AUC) of the active metabolites M3, M6, M7 and M11were 15%, 33%, 22% and 4% of the systemic neratinib exposure (AUC) respectively. Excretion - After oral administration of 200 mg (0.83 times of approved recommended dosage) radiolabeled neratinib oral formulation, fecal excretion accounted for approximately 97.1% and urinary excretion accounted for 1.13% of the total dose. Sixty-one percent of the excreted radioactivity was recovered within 96 hours and 98% was recovered after 10 days. - Age, gender, race and renal function do not have a clinically significant effect on neratinib pharmacokinetics. Patients with Hepatic Impairment - Neratinib is mainly metabolized in the liver. Single doses of 120 mg neratinib were evaluated in non-cancer patients with chronic hepatic impairment (n=6 each in Child Pugh Class A, B, and C) and in healthy subjects (n=9) with normal hepatic function. Neratinib exposures in the patients with Child Pugh Class A (mild impairment) and Child Pugh Class B (moderate impairment) were similar to that in normal healthy volunteers. Patients with severe hepatic impairment (Child Pugh Class C) had neratinib Cmax and AUC increased by 273% and 281%, respectively, as compared to the normal hepatic function controls. - Gastric Acid Reducing Agents: neratinib solubility decreases with increasing GI tract pH values. Drugs that alter the pH values of the GI tract may alter the solubility of neratinib and hence its absorption and systemic exposure. When multiple doses of lansoprazole (30 mg daily), a proton pump inhibitor, were co-administered with a single 240 mg oral doses of neratinib, the neratinib Cmax and AUC decreased by 71% and 65%, respectively. When a single oral dose of 240 mg neratinib was administered 2 hours following a daily dose of 300 mg ranitidine, an H-2 receptor antagonist, the neratinib Cmax and AUC were reduced by 57% and 48%, respectively. When a single oral dose of 240 mg neratinib was administered 2 hours prior to 150 mg ranitidine twice daily (administered in the morning and evening, approximately 12 hours apart), the neratinib Cmaxand AUC were reduced by 44% and 32%, respectively. - Strong and Moderate CYP3A4 Inhibitors: Concomitant use of ketoconazole (400 mg once-daily for 5 days), a strong inhibitor of CYP3A4, with a single oral 240 mg neratinib dose in healthy subjects (n=24) increased neratinib Cmax by 321% and AUC by 481%. - The effect of moderate CYP3A4 inhibition has not been studied. Given neratinib is predominantly metabolized by the CYP3A4 pathway and had a significant exposure change with strong CYP3A4 inhibition, the potential impact on neratinib safety from concomitant use with moderate CYP3A4 inhibitors warrants consideration. - Strong and Moderate CYP3A4 Inducers: Concomitant use of rifampin, a strong inducer of CYP3A4, with a single oral 240 mg neratinib dose in healthy subjects (n=24) reduced neratinib Cmax by 76% and AUC by 87%. The AUC of active metabolites M6 and M7 were also reduced by 37-49% when compared to neratinib administered alone. - The effect of moderate CYP3A4 induction has not been studied. Given neratinib is predominantly metabolized by the CYP3A4 pathway and had a significant exposure change with strong CYP3A4 induction, the potential impact on neratinib efficacy from concomitant use with moderate CYP3A4 inducers warrants consideration. - Effect of neratinib on P-gp Transporters: Concomitant use of digoxin (a single 0.5 mg oral dose), a P-gp substrate, with multiple oral doses of neratinib 240 mg in healthy subjects (n=18) increased the mean digoxin Cmax by 54% and AUC by 32%. ## Nonclinical Toxicology - A two-year carcinogenicity study was conducted in rats at oral neratinib doses of 1, 3, and 10 mg/kg/day. Neratinib was not carcinogenic in male and female rats at exposure levels > 25 times the AUC in patients receiving the maximum recommended dose of 240 mg/day. Neratinib was not carcinogenic in a 26-week study in Tg.rasH2 transgenic mice when administered daily by oral gavage at doses up to 50 mg/kg/day in males and 125 mg/kg/day in females. - Neratinib was not mutagenic in an in vitro bacterial reverse mutation (AMES) assay or clastogenic in an in vitro human lymphocyte chromosomal aberration assay or an in vivo rat bone marrow micronucleus assay. - In a fertility study in rats, neratinib administration up to 12 mg/kg/day (approximately 0.5 times the maximum recommended dose of 240 mg/day in patients on a mg/m2 basis) caused no effects on mating or the ability of animals to become pregnant. In repeat-dose toxicity studies in dogs with oral administration of neratinib daily for up to 39 weeks, tubular hypoplasia of the testes was observed at ≥ 0.5 mg/kg/day. This finding was observed at AUCs that were approximately 0.4 times the AUC in patients at the maximum recommended dose of 240 mg. # Clinical Studies - The safety and efficacy of neratinib were investigated in the ExteNET trial (NCT00878709), a multicenter, randomized, double-blind, placebo-controlled study of neratinib after adjuvant treatment with trastuzumab in women with HER2-positive breast cancer. - A total of 2840 patients with early-stage HER2-positive breast cancer within two years of completing treatment with adjuvant trastuzumab was randomized to receive either neratinib (n=1420) or placebo (n=1420). Randomization was stratified by the following factors: hormone receptor status, nodal status (0, 1-3 vs 4 or more positive nodes) and whether trastuzumab was given sequentially versus concurrently with chemotherapy. Neratinib 240 mg or placebo was given orally once daily for one year. The major efficacy outcome measure was invasive disease-free survival (iDFS) defined as the time between the date of randomization to the first occurrence of invasive recurrence (local/regional, ipsilateral, or contralateral breast cancer), distant recurrence, or death from any cause, with 2 years and 28 days of follow-up. - Patient demographics and tumor characteristics were generally balanced between treatment arms. Patients had a median age of 52 years (range 23 to 83) and 12% of patients were 65 or older. The majority of patients were White (81%), and most patients (99.7%) had an ECOG performance status of 0 or 1. Fifty-seven percent (57%) had hormone receptor positive disease (defined as ER-positive and/or PgR-positive), 24% were node negative, 47% had one to three positive nodes and 30% had four or more positive nodes. Ten percent (10%) of patients had Stage I disease, 41% had Stage II disease and 31% had Stage III disease. The majority of patients (81%) were enrolled within one year of completion of trastuzumab treatment. Median time from the last adjuvant trastuzumab treatment to randomization was 4.4 months in the neratinib arm vs. 4.6 months in the placebo arm. Median duration of treatment was 11.6 months in the neratinib arm vs. 11.8 months in the placebo arm. - The efficacy results from the ExteNET trial are summarized in TABLE 8 and FIGURE 1. - Approximately 75% of patients were re-consented for extended follow-up beyond 24 months. Observations with missing data were censored at the last date of assessment. This exploratory analysis suggests that the iDFS results at 5 years are consistent with the 2-year iDFS results observed in ExteNET. At the time of the iDFS analysis, 2% of patients had died, and Overall Survival data were immature. # How Supplied - Neratinib 40 mg film-coated tablets are red, oval shaped and debossed with ‘W104’ on one side and plain on the other side. - Neratinib is available in: - Bottles of 180 tablets: NDC 70437-240-18 - Bottles of 126 tablets: NDC 70437-240-26 ## Storage - Store at controlled room temperature, 20°C to 25°C (68°F to 77°F); excursions permitted to 15-30°C (59–86°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise the patient to read the FDA-approved patient labeling - Inform patients that neratinib has been associated with diarrhea which may be severe in some cases. - Instruct patients to maintain 1-2 bowel movements per day and on how to use anti-diarrheal treatment regimens. - Advise patients to inform their healthcare provider immediately if severe (≥Grade 3) diarrhea or diarrhea associated with weakness, dizziness, or fever occurs during treatment with neratinib. - Inform patients that neratinib has been associated with hepatotoxicity which may be severe in some cases. Inform patients that they should report signs and symptoms of liver dysfunction to their healthcare provider immediately. - Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the risk to a fetus and potential loss of the pregnancy. - Advise females of reproductive potential to use effective contraception during treatment and for 1 month after receiving the last dose of neratinib. - Advise lactating women not to breastfeed during treatment with neratinib and for at least 1 month after the last dose. - Neratinib may interact with many drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products. - Neratinib may interact with gastric acid reducing agents. Advise patients to avoid concomitant use of proton pump inhibitors. When patients require gastric acid reducing agents, use an H 2-receptor antagonist or antacid. Advise patients to separate the dosing of neratinib by 3 hours after antacid medicine, and to take neratinib at least 2 hours before or 10 hours after a H 2-receptor antagonist. - Neratinib may interact with grapefruit. Advise patients to avoid taking neratinib with grapefruit products. - Instruct patients to take neratinib with food at approximately the same time each day consecutively for one year. - If a patient misses a dose, instruct the patient not to replace the missed dose, and to resume neratinib with the next scheduled daily dose. # Precautions with Alcohol Alcohol-Neratinib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names - Nerlynx # Look-Alike Drug Names There is limited information regarding Neratinib Look-Alike Drug Names in the drug label. # Drug Shortage Status Drug Shortage # Price	https://www.wikidoc.org/index.php/Neratinib
3119feeaaaae6f7581ee6895ad4fa01323b8b28f	wikidoc	Neurology	Neurology Neurology is a medical speciality dealing with disorders of the nervous system. Specifically, it deals with the diagnosis and treatment of all categories of disease involving the central, peripheral, and autonomic nervous systems, including their coverings, blood vessels, and all effector tissue, such as muscle. Physicians who specialize in neurology are called neurologists, and are trained to investigate, or diagnose and treat, neurological disorders. Pediatric neurologists treat neurological disease in children. Neurologists may also be involved in clinical research, clinical trials, as well as basic research, and translational research. In the United Kingdom, contributions to the field of Neurology stem from various professions; saliently, several biomedical research scientists are choosing to specialise in the technical/laboratory aspects of one of neurology's subdisciplines. # Field of work Neurological disorders are disorders that affect the central nervous system (brain and spinal cord), the peripheral nervous system, or the autonomic nervous system. Major conditions include: - Behavioral/cognitive syndromes - Headache disorders such as migraine, cluster headache, and tension headache - Seizure disorders - Neurodegenerative disorders including - Alzheimer's disease - Parkinson's disease - Huntington's disease - Amyotrophic lateral sclerosis (Lou Gehrig's disease) - Cerebrovascular disease such as - Transient ischemic attack - Stroke - Sleep disorders - Cerebral palsy - Infections of the brain (encephalitis), brain meninges (meningitis), and spinal cord (myelitis) - Infections of the peripheral nervous system - Neoplasms - tumors of the brain and its meninges (brain tumors), spinal cord tumors, tumors of the peripheral nerves (neuroma) - Movement disorders such as - Parkinson's disease - Huntington's disease - Hemiballismus - Tic disorder - Gilles de la Tourette syndrome - Demyelinating diseases of the - Central nervous system such as multiple sclerosis - Peripheral nervous system such as Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy (CIDP) - Spinal cord disorders - tumors, infections, trauma, and malformations (e.g., myelocele, meningomyelocele, tethered cord) - Disorders of peripheral nerves, muscle (myopathy), and neuromuscular junctions - Traumatic injuries to the brain, spinal cord, and peripheral nerves - Altered mental status, encephalopathy, stupor, and coma - Speech and language disorders # Educational requirements A neurologist's educational background and medical training varies with the country of training. In the United States and Canada, neurologists are physicians who have completed postgraduate training in neurology after the completion of medical school and attainment of the allopathic (MD, MBBS, MBChB, etc) or osteopathic (DO) degree. Neurologists complete a minimum of 10 years of post secondary education and clinical training. In the majority of cases this training includes obtaining an undergraduate degree (a few medical schools will admit students with as little as two years of undergraduate education), a medical degree (4 years), and then completing a four-year residency in neurology. The four-year residency consists of one year of internal medicine training followed by three years of training in neurology. Many neurologists also have additional subspecialty training (fellowships) after completing their residency in one area of neurology such as stroke, epilepsy, neuromuscular, sleep medicine, pain management, neuroimmunology, clinical neurophysiology, or movement disorders. # Testing examinations During a neurological examination, the neurologist reviews the patient's health history with special attention to the current condition. The patient then takes a neurological exam. Typically, the exam tests mental status, function of the cranial nerves (including vision), strength, coordination, reflexes, and sensation. This information helps the neurologist determine if the problem exists in the nervous system and the clinical localization. Localization of the pathology is the key process by which neurologists develop their differential diagnosis. Further tests may be needed to confirm a diagnosis and ultimately guide therapy and appropriate management. # Clinical tasks ## General caseload Neurologists are responsible for the diagnosis, treatment, and management of all the above conditions. When surgical intervention is required, the neurologist may refer the patient to a neurosurgeon, an interventional neuroradiologist, or a neurointerventionalist. In some countries, additional legal responsibilities of a neurologist may include making a finding of brain death when it is suspected that a patient is deceased. Neurologists frequently care for people with hereditary (genetic) diseases when the major manifestations are neurological, as is frequently the case. Lumbar punctures are frequently performed by neurologists. Some neurologists may develop an interest in particular subfields, such as dementia, movement disorders, headaches, epilepsy, sleep disorders, chronic pain management, multiple sclerosis or neuromuscular diseases. ## Overlapping areas There is some overlap with other specialties, varying from country to country and even within a local geographic area. Acute head trauma is most often treated by neurosurgeons, whereas sequela of head trauma may be treated by neurologists or specialists in rehabilitation medicine. Although stroke cases have been traditionally managed by internal medicine or hospitalists, the emergence of vascular neurology and endovascular neurosurgery as disciplines have created a demand for stroke specialists. The establishment of JCAHO stroke centers have increased the role of neurologists in stroke care in many primary as well as tertiary hospitals. Some cases of nervous system infectious diseases are treated by infectious disease specialists. Most cases of headache are diagnosed and treated primarily by general practitioners, at least the less severe cases. Similarly, most cases of sciatica and other mechanical radiculopathies are treated by general practitioners, though they may be referred to neurologists or a surgeon (neurosurgeons or orthopedic surgeons). Sleep disorders are also treated by pulmonologists. Cerebral palsy is initially treated by pediatricians, but care may be transferred to an adult neurologist after the patient reaches a certain age. Clinical neuropsychologists are often called upon to evaluate brain-behavior relationships for the purpose of assisting with differential diagnosis, planning rehabilitation strategies, documenting cognitive strengths and weaknesses, and measuring change over time (e.g., for identifying abnormal aging or tracking the progression of a dementia). ## Relationship to clinical neurophysiology In some countries, e.g. USA and Germany, neurologists may specialize in clinical neurophysiology, the field responsible for EEG, nerve conduction studies, EMG, and evoked potentials. In other countries, this is an autonomous specialty (e.g. United Kingdom, Sweden). ## Overlap with psychiatry Although many mental illnesses are believed to be neurological disorders affecting the central nervous system, traditionally they are classified separately, and treated by psychiatrists. In a 2002 review article in the American Journal of Psychiatry, Professor Joseph B. Martin, Dean of Harvard Medical School and a neurologist by training, wrote that 'the separation of the two categories is arbitrary, often influenced by beliefs rather than proven scientific observations. And the fact that the brain and mind are one makes the separation artificial anyway.' (Martin JB. The integration of neurology, psychiatry and neuroscience in the 21st century. Am J Psychiatry 2002; 159:695-704) There are strong indications that neuro-chemical mechanisms play an important role in the development of, for instance, bipolar disorder and schizophrenia. As well, 'neurological' diseases often have 'psychiatric' manifestations, such as post-stroke depression, depression and dementia associated with Parkinson's disease, mood and cognitive dysfunctions in Alzheimer's disease, to name a few. Hence, there is no sharp distinction between neurology and psychiatry on a biological basis - this distinction has mainly practical reasons and strong historical roots. (such as the dominance of Freud's psychoanalytic theory in psychiatric thinking in the first three quarters of the 20th century - which has since then been largely replaced by the focus on neurosciences - aided by the tremendous advances in genetics and neuroimaging recently.)	Neurology Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Neurology is a medical speciality dealing with disorders of the nervous system. Specifically, it deals with the diagnosis and treatment of all categories of disease involving the central, peripheral, and autonomic nervous systems, including their coverings, blood vessels, and all effector tissue, such as muscle.[1] Physicians who specialize in neurology are called neurologists, and are trained to investigate, or diagnose and treat, neurological disorders. Pediatric neurologists treat neurological disease in children. Neurologists may also be involved in clinical research, clinical trials, as well as basic research, and translational research. In the United Kingdom, contributions to the field of Neurology stem from various professions; saliently, several biomedical research scientists are choosing to specialise in the technical/laboratory aspects of one of neurology's subdisciplines. # Field of work Neurological disorders are disorders that affect the central nervous system (brain and spinal cord), the peripheral nervous system, or the autonomic nervous system. Major conditions include: - Behavioral/cognitive syndromes - Headache disorders such as migraine, cluster headache, and tension headache - Seizure disorders - Neurodegenerative disorders including - Alzheimer's disease - Parkinson's disease - Huntington's disease - Amyotrophic lateral sclerosis (Lou Gehrig's disease) - Cerebrovascular disease such as - Transient ischemic attack - Stroke - Sleep disorders - Cerebral palsy - Infections of the brain (encephalitis), brain meninges (meningitis), and spinal cord (myelitis) - Infections of the peripheral nervous system - Neoplasms - tumors of the brain and its meninges (brain tumors), spinal cord tumors, tumors of the peripheral nerves (neuroma) - Movement disorders such as - Parkinson's disease - Huntington's disease - Hemiballismus - Tic disorder - Gilles de la Tourette syndrome - Demyelinating diseases of the - Central nervous system such as multiple sclerosis - Peripheral nervous system such as Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy (CIDP) - Spinal cord disorders - tumors, infections, trauma, and malformations (e.g., myelocele, meningomyelocele, tethered cord) - Disorders of peripheral nerves, muscle (myopathy), and neuromuscular junctions - Traumatic injuries to the brain, spinal cord, and peripheral nerves - Altered mental status, encephalopathy, stupor, and coma - Speech and language disorders # Educational requirements A neurologist's educational background and medical training varies with the country of training. In the United States and Canada, neurologists are physicians who have completed postgraduate training in neurology after the completion of medical school and attainment of the allopathic (MD, MBBS, MBChB, etc) or osteopathic (DO) degree. Neurologists complete a minimum of 10 years of post secondary education and clinical training. In the majority of cases this training includes obtaining an undergraduate degree (a few medical schools will admit students with as little as two years of undergraduate education), a medical degree (4 years), and then completing a four-year residency in neurology. The four-year residency consists of one year of internal medicine training followed by three years of training in neurology. Many neurologists also have additional subspecialty training (fellowships) after completing their residency in one area of neurology such as stroke, epilepsy, neuromuscular, sleep medicine, pain management, neuroimmunology, clinical neurophysiology, or movement disorders. # Testing examinations During a neurological examination, the neurologist reviews the patient's health history with special attention to the current condition. The patient then takes a neurological exam. Typically, the exam tests mental status, function of the cranial nerves (including vision), strength, coordination, reflexes, and sensation. This information helps the neurologist determine if the problem exists in the nervous system and the clinical localization. Localization of the pathology is the key process by which neurologists develop their differential diagnosis. Further tests may be needed to confirm a diagnosis and ultimately guide therapy and appropriate management. # Clinical tasks ## General caseload Neurologists are responsible for the diagnosis, treatment, and management of all the above conditions. When surgical intervention is required, the neurologist may refer the patient to a neurosurgeon, an interventional neuroradiologist, or a neurointerventionalist. In some countries, additional legal responsibilities of a neurologist may include making a finding of brain death when it is suspected that a patient is deceased. Neurologists frequently care for people with hereditary (genetic) diseases when the major manifestations are neurological, as is frequently the case. Lumbar punctures are frequently performed by neurologists. Some neurologists may develop an interest in particular subfields, such as dementia, movement disorders, headaches, epilepsy, sleep disorders, chronic pain management, multiple sclerosis or neuromuscular diseases. ## Overlapping areas There is some overlap with other specialties, varying from country to country and even within a local geographic area. Acute head trauma is most often treated by neurosurgeons, whereas sequela of head trauma may be treated by neurologists or specialists in rehabilitation medicine. Although stroke cases have been traditionally managed by internal medicine or hospitalists, the emergence of vascular neurology and endovascular neurosurgery as disciplines have created a demand for stroke specialists. The establishment of JCAHO stroke centers have increased the role of neurologists in stroke care in many primary as well as tertiary hospitals. Some cases of nervous system infectious diseases are treated by infectious disease specialists. Most cases of headache are diagnosed and treated primarily by general practitioners, at least the less severe cases. Similarly, most cases of sciatica and other mechanical radiculopathies are treated by general practitioners, though they may be referred to neurologists or a surgeon (neurosurgeons or orthopedic surgeons). Sleep disorders are also treated by pulmonologists. Cerebral palsy is initially treated by pediatricians, but care may be transferred to an adult neurologist after the patient reaches a certain age. Clinical neuropsychologists are often called upon to evaluate brain-behavior relationships for the purpose of assisting with differential diagnosis, planning rehabilitation strategies, documenting cognitive strengths and weaknesses, and measuring change over time (e.g., for identifying abnormal aging or tracking the progression of a dementia). ## Relationship to clinical neurophysiology In some countries, e.g. USA and Germany, neurologists may specialize in clinical neurophysiology, the field responsible for EEG, nerve conduction studies, EMG, and evoked potentials. In other countries, this is an autonomous specialty (e.g. United Kingdom, Sweden). ## Overlap with psychiatry Although many mental illnesses are believed to be neurological disorders affecting the central nervous system, traditionally they are classified separately, and treated by psychiatrists. In a 2002 review article in the American Journal of Psychiatry, Professor Joseph B. Martin, Dean of Harvard Medical School and a neurologist by training, wrote that 'the separation of the two categories is arbitrary, often influenced by beliefs rather than proven scientific observations. And the fact that the brain and mind are one makes the separation artificial anyway.' (Martin JB. The integration of neurology, psychiatry and neuroscience in the 21st century. Am J Psychiatry 2002; 159:695-704) There are strong indications that neuro-chemical mechanisms play an important role in the development of, for instance, bipolar disorder and schizophrenia. As well, 'neurological' diseases often have 'psychiatric' manifestations, such as post-stroke depression, depression and dementia associated with Parkinson's disease, mood and cognitive dysfunctions in Alzheimer's disease, to name a few. Hence, there is no sharp distinction between neurology and psychiatry on a biological basis - this distinction has mainly practical reasons and strong historical roots. (such as the dominance of Freud's psychoanalytic theory in psychiatric thinking in the first three quarters of the 20th century - which has since then been largely replaced by the focus on neurosciences - aided by the tremendous advances in genetics and neuroimaging recently.)	https://www.wikidoc.org/index.php/Neurologic
7dd599df574fa0611fcc57f81be378d95c74ebf3	wikidoc	Neurturin	Neurturin Neurturin (NRTN) is a protein. Neurturin belongs to the glial cell-line derived neurotrophic factor (GDNF) family of neurotrophic factors, which regulate the survival and function of neurons. Neurturin’s role as a growth factor places it in the TGF-beta (transforming growth factor) subfamily along with its homologs persephin, artemin, and GDNF. It is also considered a trophic factor and critical in the development and growth of neurons in the brain. Neurotrophic factors like neurturin have been tested in several clinical trial setting for the potential treatment of neurodegenerative diseases, specifically Parkinsons Disease. # Function Neurturin is encoded for by the NRTN gene located on chromosome 19 in humans and has been shown to promote potent effects on survival and function of developing and mature midbrain dopaminergic neurons (DA) in vitro. In vivo the direct administration of neurturin into substantia nigra of mice models also shows mature DA neuron protection. In addition, Neurturin has also been shown to support the survival of several other neurons including sympathetic and sensory neurons of the dorsal root ganglia. Knockout mice have shown that neurturin does not appear essential for survival. However, evidence shows retarded growth of enteric, sensory and parasympathetic neurons in mice upon the removal of neurturin receptors. # Mechanism of activation Neurturin signaling is mediated by the activation of a multi-component receptor system including the Ret tyrosine kinase (RET), a cell-surface bound GDNF family receptor-α (GFRα) protein, and a glycosyl phosphatidylinositol (GPI)-linked protein. Neurturin preferentially binds to the GFRα2 co-receptor. Upon assembly of the complex, specific tyrosine residues are phosphorylated within two molecules of RET that are brought together to initiate signal transduction and the MAP kinase signaling pathway. # Interactions Neurturin has been shown to upregulate B1 (bradykinin) receptors in neurons of mice, indicating a possible influence on pain and inflammation pathways. In addition knockout mice have shown that in the absence of neurturin an increased acetylcholine response is observed. The exact role and function of neurturin in multiple signaling pathways is widely unknown. # Role in disease The most studied is neurturin’s role in neurodegenerative disease like Parkinsons disease and Huntingtons, where several rat studies have implicated neurturin’s role in rescuing neurons. However, these results have never been observed in humans. Hirschsprung disease, a autosomal dominant genetic disorder, is characterized by complete absence of neuronal ganglion cells from the intestinal tract. Previous studies indicate a role of NRTN gene mutations in the disease. One study showed evidence that a mutation in the NRTN gene was not enough along to cause onset of the disease, however when coupled with a mutation in the RET gene, disease was present in family members as well as the individual. A more recent study showed NRTN variants present in individuals with Hirschsprung disease. However, RET associated mutations were not found and in one variant, RET phosphorylation levels were reduced, which has the potential to have downstream effects on the proliferation and differentiation of neuronal crests. Also, high levels of expression of neurturin were found to be associated with nephroblastoma indicating the possible that the growth factor could be influencing differentiation. Lastly, a study also associated neurturin deficiency in mice with keratoconjunctivitis and dry eye. # Therapeutic potential Evidence showing Neurturin’s role in neuron survival and management has made it a popular candidate for the potential treatment or reversal of neurodegeneration. In addition, mice models have shown the dying neurons exposed to trophic factors can be rescued. Neurturin is an example of a trophic factor that is difficult to utilize clinically because of its inability to cross the blood-brain barrier of the CNS (central nervous system). Ceregene sponsored a double-blind phase II clinical trial of CERE-120, a viral vector mediated gene transfer drug that allows for the continuous delivery of neurturin to the nigrostratial system. The hope was to reverse damaged and diseased tissue in Parkinsons patients and overall slow the progression of the disease. However, results were inconclusive and showed that while the drug appears to be relatively safe, there was no statistically significant data supporting the improvement of motor function or neuronal health. Neurturin’s therapeutic potential is unknown and future studies aim to improve delivery of the drug.	Neurturin Neurturin (NRTN) is a protein. Neurturin belongs to the glial cell-line derived neurotrophic factor (GDNF) family of neurotrophic factors, which regulate the survival and function of neurons. Neurturin’s role as a growth factor places it in the TGF-beta (transforming growth factor) subfamily along with its homologs persephin, artemin, and GDNF.[1] It is also considered a trophic factor and critical in the development and growth of neurons in the brain.[2] Neurotrophic factors like neurturin have been tested in several clinical trial setting for the potential treatment of neurodegenerative diseases, specifically Parkinsons Disease.[3] # Function Neurturin is encoded for by the NRTN gene located on chromosome 19 in humans and has been shown to promote potent effects on survival and function of developing and mature midbrain dopaminergic neurons (DA) in vitro.[4] In vivo the direct administration of neurturin into substantia nigra of mice models also shows mature DA neuron protection.[4] In addition, Neurturin has also been shown to support the survival of several other neurons including sympathetic and sensory neurons of the dorsal root ganglia.[5] Knockout mice have shown that neurturin does not appear essential for survival. However, evidence shows retarded growth of enteric, sensory and parasympathetic neurons in mice upon the removal of neurturin receptors.[5] # Mechanism of activation Neurturin signaling is mediated by the activation of a multi-component receptor system including the Ret tyrosine kinase (RET), a cell-surface bound GDNF family receptor-α (GFRα) protein, and a glycosyl phosphatidylinositol (GPI)-linked protein. Neurturin preferentially binds to the GFRα2 co-receptor. Upon assembly of the complex, specific tyrosine residues are phosphorylated within two molecules of RET that are brought together to initiate signal transduction and the MAP kinase signaling pathway.[6] # Interactions Neurturin has been shown to upregulate B1 (bradykinin) receptors in neurons of mice, indicating a possible influence on pain and inflammation pathways.[7] In addition knockout mice have shown that in the absence of neurturin an increased acetylcholine response is observed.[8] The exact role and function of neurturin in multiple signaling pathways is widely unknown. # Role in disease The most studied is neurturin’s role in neurodegenerative disease like Parkinsons disease and Huntingtons, where several rat studies have implicated neurturin’s role in rescuing neurons.[4] However, these results have never been observed in humans. Hirschsprung disease, a autosomal dominant genetic disorder, is characterized by complete absence of neuronal ganglion cells from the intestinal tract. Previous studies indicate a role of NRTN gene mutations in the disease. One study showed evidence that a mutation in the NRTN gene was not enough along to cause onset of the disease, however when coupled with a mutation in the RET gene, disease was present in family members as well as the individual.[9] A more recent study showed NRTN variants present in individuals with Hirschsprung disease.[10] However, RET associated mutations were not found and in one variant, RET phosphorylation levels were reduced, which has the potential to have downstream effects on the proliferation and differentiation of neuronal crests. Also, high levels of expression of neurturin were found to be associated with nephroblastoma indicating the possible that the growth factor could be influencing differentiation.[11] Lastly, a study also associated neurturin deficiency in mice with keratoconjunctivitis and dry eye.[12] # Therapeutic potential Evidence showing Neurturin’s role in neuron survival and management has made it a popular candidate for the potential treatment or reversal of neurodegeneration. In addition, mice models have shown the dying neurons exposed to trophic factors can be rescued. Neurturin is an example of a trophic factor that is difficult to utilize clinically because of its inability to cross the blood-brain barrier of the CNS (central nervous system). Ceregene sponsored a double-blind phase II clinical trial of CERE-120, a viral vector mediated gene transfer drug that allows for the continuous delivery of neurturin to the nigrostratial system.[13] The hope was to reverse damaged and diseased tissue in Parkinsons patients and overall slow the progression of the disease. However, results were inconclusive and showed that while the drug appears to be relatively safe, there was no statistically significant data supporting the improvement of motor function or neuronal health. Neurturin’s therapeutic potential is unknown and future studies aim to improve delivery of the drug.[14]	https://www.wikidoc.org/index.php/Neurturin
47bada567abdcdf30188a4558af6d4272ac1844c	wikidoc	Neuticles	Neuticles Neuticles are prosthetic testicular implants for neutered dogs and other domestic animals. Creator Gregg Miller won the Ig Nobel Prize, a parody of the genuine Nobel Prizes, for medicine for this invention. Miller states he has sold more than 230,000 of this product in 49 countries. Miller thought of Neuticles in 1993 when his Bloodhound named Buck disappeared and was located days later over 20 miles away. Buck had picked up the scent of a female dog in heat. "It was either neuter Buck or go through the nightmare of him taking off again and the next time I most likely wouldn't find him." He asked his Missouri veterinarian if implants were available so Buck would look the same as before being altered. Dr RD Holder of the Independence Animal Hospital in Independence, MO remarked, "I've been a vet for over 45 years and no one has asked for such a thing." Miller discounted the idea and termed himself a "neurotic pet owner". A week later when Buck went back to have his stitches removed Dr Holder brought up the idea to Miller. "The more you think about implants for pets the more sense it makes," Dr Holder told Miller. This convinced Miller decided to start development. Two years later the first commercially Neuticled pet was implanted. Worldwide publicity followed and interest continues to this day. According to their wesbite, over 230,000 pets have received Neuticle implants since they became available in 1995. Neuticles are made from FDA medically approved materials and are crafted to replicate the weight and feel of the animal's natural testicle. They are made of solid silicone and are not gel-filled and therefore cannot leak. Miller says "Neutering is traumatic. It's traumatic for the pet and for the pet's owner." Until Neuticles were invented pet owners had no options. Miller maintains "With Neuticles it's like nothing ever changed and this is important to caring pet owners." Miller also said that his product encourages pet owners to neuter that simply would not before and as a result pet overpopulation is being reduced and "Neuticled" pets are living happier, healthier and longer lives. Neuticles have proved popular enough that several companies have tried to copy the patented prosthetic. In a June 2000 press release CTI Corporation, which manufactures Neuticles, cited an investigation which revealed companies in New York and California were making knock-off Neuticles. CTI warned of potential health risks to the animals getting the fake product and reminded the public of the years of research that went into the product's creation and the development of the surgical technique used to implant them. Neuticles have been endorsed by a number of national, state and regional humane societies including ASPCA. "Who can argue with a perfectly safe surgical procedure that encourages pet owners to neuter?" (ASPCA Animal Watch Spring, 1997) The Spay/Neuter Incentive Project & Sanctuary praises Neuticles as eliminating one of the last reasons people are reluctant to neuter their male pets. The demand for such a product is more common than previously thought. Talking to The Houston Press News, Veterinarian Kenneth Williams says that for every 200 dogs neutered he gets one inquiry or request for implants. Miller has also written a book which details how Neuticles were invented. Entitled Going Going NUTS! the book was published by Publish America. His company's newest product is an eye implant for pets who have lost an eye. They are available in sizes suitable for dogs, cats and horses. Miller and Neuticles were featured on an episode of the Penn & Teller series Bullshit! which featured the extremes people will go to in order to pamper their pets. A 2007 article for the Scottsdale Times in Arizona covered similar ground including the issues of Neuticles, lavish spending on posh pet wardrobes, heated dog bowls and other creature comforts. Responding to critiscism of such pampering, Gregg Miller said: "But why not? What’s the harm? Who’s it hurting? If people don’t like it, tough cheese.”	Neuticles Neuticles are prosthetic testicular implants for neutered dogs and other domestic animals. Creator Gregg Miller won the Ig Nobel Prize, a parody of the genuine Nobel Prizes, for medicine for this invention.[1] [2] Miller states he has sold more than 230,000 of this product in 49 countries.[3] Miller thought of Neuticles in 1993 when his Bloodhound named Buck disappeared and was located days later over 20 miles away. Buck had picked up the scent of a female dog in heat. "It was either neuter Buck or go through the nightmare of him taking off again and the next time I most likely wouldn't find him." He asked his Missouri veterinarian if implants were available so Buck would look the same as before being altered. Dr RD Holder of the Independence Animal Hospital in Independence, MO remarked, "I've been a vet for over 45 years and no one has asked for such a thing." Miller discounted the idea and termed himself a "neurotic pet owner". A week later when Buck went back to have his stitches removed Dr Holder brought up the idea to Miller. "The more you think about implants for pets the more sense it makes," Dr Holder told Miller. This convinced Miller decided to start development. Two years later the first commercially Neuticled pet was implanted. Worldwide publicity followed and interest continues to this day. According to their wesbite, over 230,000 pets have received Neuticle implants since they became available in 1995. Neuticles are made from FDA medically approved materials and are crafted to replicate the weight and feel of the animal's natural testicle. They are made of solid silicone and are not gel-filled and therefore cannot leak.[4] Miller says "Neutering is traumatic. It's traumatic for the pet and for the pet's owner." Until Neuticles were invented pet owners had no options. Miller maintains "With Neuticles it's like nothing ever changed and this is important to caring pet owners." Miller also said that his product encourages pet owners to neuter that simply would not before and as a result pet overpopulation is being reduced and "Neuticled" pets are living happier, healthier and longer lives.[citation needed] Neuticles have proved popular enough that several companies have tried to copy the patented prosthetic. In a June 2000 press release CTI Corporation, which manufactures Neuticles, cited an investigation which revealed companies in New York and California were making knock-off Neuticles. CTI warned of potential health risks to the animals getting the fake product and reminded the public of the years of research that went into the product's creation and the development of the surgical technique used to implant them. [5] Neuticles have been endorsed by a number of national, state and regional humane societies including ASPCA. "Who can argue with a perfectly safe surgical procedure that encourages pet owners to neuter?" (ASPCA Animal Watch Spring, 1997)[citation needed] The Spay/Neuter Incentive Project & Sanctuary praises Neuticles as eliminating one of the last reasons people are reluctant to neuter their male pets.[6] The demand for such a product is more common than previously thought. Talking to The Houston Press News, Veterinarian Kenneth Williams says that for every 200 dogs neutered he gets one inquiry or request for implants.[7] Miller has also written a book which details how Neuticles were invented. Entitled Going Going NUTS! the book was published by Publish America. His company's newest product is an eye implant for pets who have lost an eye.[4] They are available in sizes suitable for dogs, cats and horses. Miller and Neuticles were featured on an episode of the Penn & Teller series Bullshit! which featured the extremes people will go to in order to pamper their pets.[8] A 2007 article for the Scottsdale Times in Arizona covered similar ground including the issues of Neuticles, lavish spending on posh pet wardrobes, heated dog bowls and other creature comforts. Responding to critiscism of such pampering, Gregg Miller said: "But why not? What’s the harm? Who’s it hurting? If people don’t like it, tough cheese.” [9]	https://www.wikidoc.org/index.php/Neuticles
765ab1a19f78e5c15f7c4d22d1c9d22ba39787b9	wikidoc	Typhlitis	Typhlitis Synonyms and keywords: Neutropenic colitis; Neutropenic enterocolitis; cecitis # Overview Typhlitis is most commonly seen in neutropenic patients receiving chemotherapy for a cancer. It is also been seen in people with aplastic anemia, lymphoma, acquired immunodeficiency syndrome, as well as people who have had a kidney transplant. Typhlitis is distinguished by edema and inflammation of the cecum, ascending colon, and, in some cases, terminal ileum. Transmural necrosis, perforation, and mortality can occur as a result of the inflammation. The exact cause of the condition is unknown, but it is most likely caused by a combination of ischemia, infection (particularly with cytomegalovirus), mucosal hemorrhage, and possibly neoplastic infiltration. The treatment includes bowel rest, parenteral nutrition, antibiotics, and intensive fluid and electrolyte replacement. # Historical Perspective - In 1970, Wagner et al found and described typhlitis as necrotizing colitis after autopsy of 191 leukemic children with terminal illness at the Texas Children's Hospital, Baylor College of Medicine, Houston, between 1958 and 1970. # Classification - There is no established system for the classification of Typhlitis. # Pathophysiology - The precise pathophysiology of Neutropenic enterocolitis is unknown. - The primary variables in illness beginning appear to be intestinal mucosal injury, neutropenia, and the immunocompromised status of the patients. - Gram-negative rods, gram-positive cocci, enterococci, fungi, and viruses have all been blamed for the outbreak. - These early circumstances cause intestinal edema, engorged veins, and a disrupted mucosal surface, making the mucosa more susceptible to bacterial intramural invasion. - The distension and necrosis generated by chemotherapy drugs directly influence intestinal motility. - Superimposed infections caused by bacteria,fungi and viruses can also disrupts the already damaged mucosa leading further intestinal edema, distension and necrosis of intestinal layer which lead to intestinal perforation. # Causes ## Causes by Organ System # Differentiating Typhlitis from other Diseases Typhlitis must be distinguished from other diseases that exhibit symptoms such as fever, abdominal pain, and diarrhea. - 1. Clostridium difficile infection - 2. Cytomegalovirus colitis - 3. Norovirus infection - 4. Graft versus host disease - 5. Acute appendicitis - 6. Ischemic colitis # Epidemiology and Demographics - The prevalence of Neutropenic enterocolitis varies between studies. Gorschlüter et al. conducted a systematic review and found that the incidence rate from 21 studies was 5.3 percent in patients hospitalized for hematological malignancies, high-dose chemotherapy for solid tumors, or aplastic anemia. Another cohort study discovered it in 3.5% of 317 severely neutropenic patients. The prevalence of neutropenic enterocolitis has been increasing in tandem with the increased use of chemotherapy, especially the agents known for causing mucositis. - Patients with hematologic malignancies are more likely to develop Neutropenic enterocolitis as a result of their underlying malignancy as well as their treatment regimens. Neutropenic enterocolitis has also been reported in patients taking immunosuppressive medications, patients diagnosed with solid tumors and autoimmune conditions. # Risk Factors Common risk factors in the development of Typhlitis include hematological, solid tumors, neutropenic and Immunocompromised individuals. # Screening There is insufficient evidence to recommend routine screening for Neutropenic enterocolitis. # Natural History, Complications, and Prognosis - Common complications of Neutropenic enterocolitis include perforation, peritonitis, sepsis, and abscess formation, which are all caused by the pathology (bowel wall inflammation). Other risks are related to pancytopenia include thrombocytopenia-related extreme bleeding and delayed healing. - Neutrophilic enterocolitis has documented mortality rates as high as 50%, especially in patients with transmural inflammation or intestinal rupture. # Diagnosis Neutropenic enterocolitis is typically diagnosed based on a combination of clinical and radiological findings. ## Diagnostic Study of Choice There are no established criteria for the diagnosis of typhlitis. ## History and Symptoms The most common symptoms of typhlitis include fever, abdominal pain, and diarrhea. In severe cases, diarrhea can be bloody. Abdominal distension and paralytic ileus may also occur in patients. ## Physical Examination Common physical examination of patients with Neutropenic enterocolitis is usually remarkable for Abdominal discomfort which can be diffuse or localized, with the right lower quadrant being the most common location. A rigid abdomen could be an indication of bowel perforation. ## Laboratory Findings Laboratory findings consistent with the diagnosis of typhlitis include neutropenia with absolute neutrophil count <500 cells/microL, thrombocytopenia ranged from 4000/pl to 120,000/pl. ## Ultrasound - Ultrasound (US) may be helpful in the diagnosis of Neutropenic enterocolitis. Findings on an ultrasound suggestive of Neutropenic enterocolitis include circumferential wall thickening and prominent submucosa . ## X-ray An x-ray may be helpful in the diagnosis of Typhlitis but nonspecific. Findings on an x-ray suggestive of Neutropenic enterocolitis include inflated cecum with dilated small bowel loops, can detect free air. ## CT Scan - A computed tomography (CT) scan of the abdomen may be helpful in the diagnosis of Neutropenic enterocolitis. Findings on CT scan suggestive of Neutropenic enterocolitis include Intestinal wall thickening, mesenteric stranding, intestinal dilatation, pneumatosis, distention and circumferential thickening of the cecal wall. # Treatment ## Medical Therapy - The mainstay of treatment for Neutropenic enterocolitis consists of both supportive therapy and antimicrobials - Supportive therapy for Neutropenic colitis include bowel rest with nasogastric suction, intravenous fluids, and, if necessary, parenteral nutrition. - Empiric therapy for Neutropenic colitis depends on antimicrobial exposure, bacteremia and local resistance pattern. - Pipericillin-tazobactum, carbapenam, or an antipseudomonal cephalosporin is recommended among patients who develop neutropenic colitis and vancomycin is considered in case of mucositis is suspected, which is against gram positive bacteria. ## Surgery - All individuals with Neutropenic enterocolitis should seek surgical advice as soon as possible. - Surgery is usually reserved for patients with either bowel perforation, pneumoperitoneum, or persistent gastrointestinal bleeding. ## Primary Prevention Effective measures for the primary prevention of Neutropenic enterocolitis include early detection and treatment can help to avoid problems and improve outcomes in patients who have undergone intensive chemotherapy or a stem cell transplant.Treatment with G-CSF not only speeds recovery from neutropenia episodes that occur during chemotherapy, but it also reduces the risk of consequences including mucositis. ## Secondary Prevention Effective measures for the secondary prevention include early surgical evaluation in the management of this condition, as it can be life-saving for some patients who present with a complicated Neutropenic enterocolitis	Typhlitis Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Shameera Shaik Masthan MBBS, DLO, DNB[2] Synonyms and keywords: Neutropenic colitis; Neutropenic enterocolitis; cecitis # Overview Typhlitis is most commonly seen in neutropenic patients receiving chemotherapy for a cancer. It is also been seen in people with aplastic anemia, lymphoma, acquired immunodeficiency syndrome, as well as people who have had a kidney transplant. Typhlitis is distinguished by edema and inflammation of the cecum, ascending colon, and, in some cases, terminal ileum. Transmural necrosis, perforation, and mortality can occur as a result of the inflammation. The exact cause of the condition is unknown, but it is most likely caused by a combination of ischemia, infection (particularly with cytomegalovirus), mucosal hemorrhage, and possibly neoplastic infiltration. The treatment includes bowel rest, parenteral nutrition, antibiotics, and intensive fluid and electrolyte replacement. # Historical Perspective - In 1970, Wagner et al found and described typhlitis as necrotizing colitis after autopsy of 191 leukemic children with terminal illness at the Texas Children's Hospital, Baylor College of Medicine, Houston, between 1958 and 1970.[1] # Classification - There is no established system for the classification of Typhlitis. # Pathophysiology - The precise pathophysiology of Neutropenic enterocolitis is unknown.[2] - The primary variables in illness beginning appear to be intestinal mucosal injury, neutropenia, and the immunocompromised status of the patients.[3] - Gram-negative rods, gram-positive cocci, enterococci, fungi, and viruses have all been blamed for the outbreak.[4][5] - These early circumstances cause intestinal edema, engorged veins, and a disrupted mucosal surface, making the mucosa more susceptible to bacterial intramural invasion. - The distension and necrosis generated by chemotherapy drugs directly influence intestinal motility. - Superimposed infections caused by bacteria,fungi and viruses can also disrupts the already damaged mucosa leading further intestinal edema, distension and necrosis of intestinal layer which lead to intestinal perforation. # Causes ## Causes by Organ System # Differentiating Typhlitis from other Diseases Typhlitis must be distinguished from other diseases that exhibit symptoms such as fever, abdominal pain, and diarrhea.[10] - 1. Clostridium difficile infection[11] - 2. Cytomegalovirus colitis[12] - 3. Norovirus infection[13] - 4. Graft versus host disease[14] - 5. Acute appendicitis[15] - 6. Ischemic colitis[16] - # Epidemiology and Demographics - The prevalence of Neutropenic enterocolitis varies between studies. Gorschlüter et al. conducted a systematic review and found that the incidence rate from 21 studies was 5.3 percent in patients hospitalized for hematological malignancies, high-dose chemotherapy for solid tumors, or aplastic anemia. Another cohort study discovered it in 3.5% of 317 severely neutropenic patients. The prevalence of neutropenic enterocolitis has been increasing in tandem with the increased use of chemotherapy, especially the agents known for causing mucositis.[17][18] - Patients with hematologic malignancies are more likely to develop Neutropenic enterocolitis as a result of their underlying malignancy as well as their treatment regimens. Neutropenic enterocolitis has also been reported in patients taking immunosuppressive medications, patients diagnosed with solid tumors and autoimmune conditions.[19] # Risk Factors Common risk factors in the development of Typhlitis include hematological, solid tumors, neutropenic and Immunocompromised individuals.[20] # Screening There is insufficient evidence to recommend routine screening for Neutropenic enterocolitis. # Natural History, Complications, and Prognosis - Common complications of Neutropenic enterocolitis include perforation, peritonitis, sepsis, and abscess formation, which are all caused by the pathology (bowel wall inflammation). Other risks are related to pancytopenia include thrombocytopenia-related extreme bleeding and delayed healing.[21][22] - Neutrophilic enterocolitis has documented mortality rates as high as 50%, especially in patients with transmural inflammation or intestinal rupture. # Diagnosis Neutropenic enterocolitis is typically diagnosed based on a combination of clinical and radiological findings.[23] ## Diagnostic Study of Choice There are no established criteria for the diagnosis of typhlitis. ## History and Symptoms The most common symptoms of typhlitis include fever, abdominal pain, and diarrhea. In severe cases, diarrhea can be bloody. Abdominal distension and paralytic ileus may also occur in patients.[24] ## Physical Examination Common physical examination of patients with Neutropenic enterocolitis is usually remarkable for Abdominal discomfort which can be diffuse or localized, with the right lower quadrant being the most common location. A rigid abdomen could be an indication of bowel perforation.[25] ## Laboratory Findings Laboratory findings consistent with the diagnosis of typhlitis include neutropenia with absolute neutrophil count <500 cells/microL, thrombocytopenia ranged from 4000/pl to 120,000/pl.[26] ## Ultrasound - Ultrasound (US) may be helpful in the diagnosis of Neutropenic enterocolitis. Findings on an ultrasound suggestive of Neutropenic enterocolitis include circumferential wall thickening and prominent submucosa .[27] ## X-ray An x-ray may be helpful in the diagnosis of Typhlitis but nonspecific. Findings on an x-ray suggestive of Neutropenic enterocolitis include inflated cecum with dilated small bowel loops, can detect free air.[28] ## CT Scan - A computed tomography (CT) scan of the abdomen may be helpful in the diagnosis of Neutropenic enterocolitis. Findings on CT scan suggestive of Neutropenic enterocolitis include Intestinal wall thickening, mesenteric stranding, intestinal dilatation, pneumatosis, distention and circumferential thickening of the cecal wall.[29] - - - - # Treatment ## Medical Therapy - The mainstay of treatment for Neutropenic enterocolitis consists of both supportive therapy and antimicrobials[30] - Supportive therapy for Neutropenic colitis include bowel rest with nasogastric suction, intravenous fluids, and, if necessary, parenteral nutrition. - Empiric therapy for Neutropenic colitis depends on antimicrobial exposure, bacteremia and local resistance pattern. - Pipericillin-tazobactum, carbapenam, or an antipseudomonal cephalosporin is recommended among patients who develop neutropenic colitis and vancomycin is considered in case of mucositis is suspected, which is against gram positive bacteria.[31][32] ## Surgery - All individuals with Neutropenic enterocolitis should seek surgical advice as soon as possible.[33] - Surgery is usually reserved for patients with either bowel perforation, pneumoperitoneum, or persistent gastrointestinal bleeding. ## Primary Prevention Effective measures for the primary prevention of Neutropenic enterocolitis include early detection and treatment can help to avoid problems and improve outcomes in patients who have undergone intensive chemotherapy or a stem cell transplant.Treatment with G-CSF not only speeds recovery from neutropenia episodes that occur during chemotherapy, but it also reduces the risk of consequences including mucositis.[34] ## Secondary Prevention Effective measures for the secondary prevention include early surgical evaluation in the management of this condition, as it can be life-saving for some patients who present with a complicated Neutropenic enterocolitis[35]	https://www.wikidoc.org/index.php/Neutropenic_colitis
4e66febf5c1e2736845ec8b69299b950e492f195	wikidoc	New pages	New pages # Overview WikiDoc being a large online textbook of medicine with several dedicated contributors like students, physicians and researchers, the "New Pages" project is intended to guide all the registered contributors working both onsite and remotely in creating their new pages in an easy way that would preserve the consistency and structure of the pages. Creating a new page is the fundamental step that editor’s should be aware while beginning their topics. # Statement of Need To create a new page there is a need of user-friendly guidelines that are specific for different projects. All these guidelines should be made accessible to the editors under a single assemblage. # How Can WikiDoc Meet These Unmet Needs WikiDoc chief editor along with other editors and scholars have been working under the project name “New Pages” for framing standard guidelines that are specific for their respective topics and projects like new diseases, board review, crowdiagnosis, critical pathways, guidelines, microchapters, prevalence, resident survival guide, WikiDoc in other languages and Wikipatient. We constantly work together to update and improve the guidelines, making it an user efficient tool. # How Can You Help WikiDoc Meet These Needs WikiDoc seeks medical students, interns, residents, attending physicians, hospitalists, specialist doctors, researchers, nurses, physician assistants, nurse practitioners getting on board with different WikiDoc projects to actively contribute to the "New Pages" project so that the quality of the pages will keep flourishing.	New pages Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mugilan Poongkunran M.B.B.S [2]; Vendhan Ramanujam M.B.B.S [3] # Overview WikiDoc being a large online textbook of medicine with several dedicated contributors like students, physicians and researchers, the "New Pages" project is intended to guide all the registered contributors working both onsite and remotely in creating their new pages in an easy way that would preserve the consistency and structure of the pages. Creating a new page is the fundamental step that editor’s should be aware while beginning their topics. # Statement of Need To create a new page there is a need of user-friendly guidelines that are specific for different projects. All these guidelines should be made accessible to the editors under a single assemblage. # How Can WikiDoc Meet These Unmet Needs WikiDoc chief editor along with other editors and scholars have been working under the project name “New Pages” for framing standard guidelines that are specific for their respective topics and projects like new diseases, board review, crowdiagnosis, critical pathways, guidelines, microchapters, prevalence, resident survival guide, WikiDoc in other languages and Wikipatient. We constantly work together to update and improve the guidelines, making it an user efficient tool. # How Can You Help WikiDoc Meet These Needs WikiDoc seeks medical students, interns, residents, attending physicians, hospitalists, specialist doctors, researchers, nurses, physician assistants, nurse practitioners getting on board with different WikiDoc projects to actively contribute to the "New Pages" project so that the quality of the pages will keep flourishing. Template:WikiDoc Sources	https://www.wikidoc.org/index.php/New_pages
9d18841bc8bf5d4a270de7228f951023021da2ad	wikidoc	Sorafenib	Sorafenib - Dosage: 200 mg q12h, taken 1 hour before or 2 hours after a meal. Treatment should continue until the patient is no longer clinically benefiting from therapy or until unacceptable toxicity occurs. Temporary interruption of Sorafenib is recommended in patients undergoing major surgical procedures. Temporary interruption or permanent discontinuation of Sorafenib may be required for the following: Cardiac ischemia or infarction Hemorrhage requiring medical intervention Severe or persistent hypertension despite adequate anti-hypertensive therapy Gastrointestinal perforation QTc prolongation Severe drug-induced liver injury - Temporary interruption or permanent discontinuation of Sorafenib may be required for the following: Cardiac ischemia or infarction Hemorrhage requiring medical intervention Severe or persistent hypertension despite adequate anti-hypertensive therapy Gastrointestinal perforation QTc prolongation Severe drug-induced liver injury - Cardiac ischemia or infarction - Hemorrhage requiring medical intervention - Severe or persistent hypertension despite adequate anti-hypertensive therapy - Gastrointestinal perforation - QTc prolongation - Severe drug-induced liver injury When dose reduction is necessary, the Sorafenib dose may be reduced to 400 mg once daily. If additional dose reduction is required, Sorafenib may be reduced to a single 400 mg dose every other day. If dermatological toxicity presented, the following scheme should be followed: Following improvement of Grade 2 or 3 dermatologic toxicity to Grade 0–1 after at least 28 days of treatment on a reduced dose of Sorafenib, the dose of Sorafenib may be increased one dose level from the reduced dose. Approximately 50% of patients requiring a dose reduction for dermatologic toxicity are expected to meet these criteria for resumption of the higher dose and roughly 50% of patients resuming the previous dose are expected to tolerate the higher dose (that is, maintain the higher dose level without recurrent Grade 2 or higher dermatologic toxicity) - Sorafenib in combination with carboplatin and paclitaxel is contraindicated in patients with squamous cell lung cancer. - In the HCC study, the incidence of cardiac ischemia/infarction was 2.7% in Sorafenib-treated patients compared with 1.3% in the placebo-treated group, in RCC Study 1, the incidence of cardiac ischemia/infarction was higher in the Sorafenib-treated group (2.9%) compared with the placebo-treated group (0.4%), and in the DTC study, the incidence of cardiac ischemia/infarction was 1.9% in the Sorafenib-treated group compared with 0% in the placebo-treated group. Patients with unstable coronary artery disease or recent myocardial infarction were excluded from this study. Temporary or permanent discontinuation of Sorafenib should be considered in patients who develop cardiac ischemia and/or infarction. - An increased risk of bleeding may occur following Sorafenib administration. In the HCC study, an excess of bleeding regardless of causality was not apparent and the rate of bleeding from esophageal varices was 2.4% in Sorafenib-treated patients and 4% in placebo-treated patients. Bleeding with a fatal outcome from any site was reported in 2.4% of Sorafenib-treated patients and 4% in placebo-treated patients. In RCC Study 1, bleeding regardless of causality was reported in 15.3% of patients in the Sorafenib-treated group and 8.2% of patients in the placebo-treated group. The incidence of CTCAE Grade 3 and 4 bleeding was 2% and 0%, respectively, in Sorafenib-treated patients, and 1.3% and 0.2%, respectively, in placebo-treated patients. There was one fatal hemorrhage in each treatment group in RCC Study 1. In the DTC study, bleeding was reported in 17.4% of Sorafenib-treated patients and 9.6% of placebo-treated patients; however the incidence of CTCAE Grade 3 bleeding was 1% in Sorafenib-treated patients and 1.4% in placebo-treated patients. There was no Grade 4 bleeding reported and there was one fatal hemorrhage in a placebo-treated patient. If any bleeding necessitates medical intervention, permanent discontinuation of Sorafenib should be considered. Due to the potential risk of bleeding, tracheal, bronchial, and esophageal infiltration should be treated with local therapy prior to administering Sorafenib in patients with DTC. - Monitor blood pressure weekly during the first 6 weeks of Sorafenib. Thereafter, monitor blood pressure and treat hypertension, if required, in accordance with standard medical practice. In the HCC study, hypertension was reported in approximately 9.4% of Sorafenib-treated patients and 4.3% of patients in the placebo-treated group. In RCC Study 1, hypertension was reported in approximately 16.9% of Sorafenib-treated patients and 1.8% of patients in the placebo-treated group. In the DTC study, hypertension was reported in 40.6% of Sorafenib-treated patients and 12.4% of placebo-treated patients. Hypertension was usually mild to moderate, occurred early in the course of treatment, and was managed with standard antihypertensive therapy. In cases of severe or persistent hypertension despite institution of antihypertensive therapy, consider temporary or permanent discontinuation of Sorafenib. Permanent discontinuation due to hypertension occurred in 1 of 297 Sorafenib-treated patients in the HCC study, 1 of 451 Sorafenib-treated patients in RCC Study 1, and 1 of 207 Sorafenib-treated patients in the DTC study. - Hand-foot skin reaction and rash represent the most common adverse reactions attributed to Sorafenib. Rash and hand-foot skin reaction are usually CTCAE Grade 1 and 2 and generally appear during the first six weeks of treatment with Sorafenib. Management of dermatologic toxicities may include topical therapies for symptomatic relief, temporary treatment interruption and/or dose modification of Sorafenib, or in severe or persistent cases, permanent discontinuation of Sorafenib. Permanent discontinuation of therapy due to hand-foot skin reaction occurred in 4 (1.3%) of 297 Sorafenib-treated patients with HCC, 3 (0.7%) of 451 Sorafenib-treated patients with RCC, and 11 (5.3%) of 207 Sorafenib-treated patients with DTC. - There have been reports of severe dermatologic toxicities, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). These cases may be life-threatening. Discontinue Sorafenib if SJS or TEN are suspected. - Gastrointestinal perforation is an uncommon adverse reaction and has been reported in less than 1% of patients taking Sorafenib. In some cases this was not associated with apparent intra-abdominal tumor. In the event of a gastrointestinal perforation, discontinue Sorafenib. - Infrequent bleeding or elevations in the International Normalized Ratio (INR) have been reported in some patients taking warfarin while on Sorafenib. Monitor patients taking concomitant warfarin regularly for changes in prothrombin time (PT), INR or clinical bleeding episodes. - No formal studies of the effect of Sorafenib on wound healing have been conducted. Temporary interruption of Sorafenib is recommended in patients undergoing major surgical procedures. There is limited clinical experience regarding the timing of reinitiation of Sorafenib following major surgical intervention. Therefore, the decision to resume Sorafenib following a major surgical intervention should be based on clinical judgment of adequate wound healing. - In a subset analysis of two randomized controlled trials in chemo-naive patients with Stage IIIB-IV non-small cell lung cancer, patients with squamous cell carcinoma experienced higher mortality with the addition of Sorafenib compared to those treated with carboplatin/paclitaxel alone (HR 1.81, 95% CI 1.19–2.74) and gemcitabine/cisplatin alone (HR 1.22, 95% CI 0.82-1.80). The use of Sorafenib in combination with carboplatin/paclitaxel is contraindicated in patients with squamous cell lung cancer. Sorafenib in combination with gemcitabine/cisplatin is not recommended in patients with squamous cell lung cancer. The safety and effectiveness of Sorafenib has not been established in patients with non-small cell lung cancer. - Sorafenib can prolong the QT/QTc interval. QT/QTc interval prolongation increases the risk for ventricular arrhythmias. Avoid Sorafenib in patients with congenital long QT syndrome. Monitor electrolytes and electrocardiograms in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics. Correct electrolyte abnormalities (magnesium, potassium, calcium). Interrupt Sorafenib if QTc interval is greater than 500 milliseconds or for an increase from baseline of 60 milliseconds or greater. - Sorafenib-induced hepatitis is characterized by a hepatocellular pattern of liver damage with significant increases of transaminases which may result in hepatic failure and death. Increases in bilirubin and INR may also occur. The incidence of severe drug-induced liver injury, defined as elevated transaminase levels above 20 times the upper limit of normal or transaminase elevations with significant clinical sequelae (for example, elevated INR, ascites, fatal, or transplantation), was two of 3,357 patients (0.06%) in a global monotherapy database. Monitor liver function tests regularly. In case of significantly increased transaminases without alternative explanation, such as viral hepatitis or progressing underlying malignancy, discontinue Sorafenib. - Based on its mechanism of action and findings in animals, Sorafenib may cause fetal harm when administered to a pregnant woman. Sorafenib caused embryo-fetal toxicities in animals at maternal exposures that were significantly lower than the human exposures at the recommended dose of 400 mg twice daily. Advise women of childbearing potential to avoid becoming pregnant while on Sorafenib because of the potential hazard to the fetus. - Sorafenib impairs exogenous thyroid suppression. In the DTC study, 99% of patients had a baseline thyroid stimulating hormone (TSH) level less than 0.5 mU/L. Elevation of TSH level above 0.5 mU/L was observed in 41% of Sorafenib-treated patients as compared with 16% of placebo-treated patients. For patients with impaired TSH suppression while receiving Sorafenib, the median maximal TSH was 1.6 mU/L and 25% had TSH levels greater than 4.4 mU/L. Monitor TSH levels monthly and adjust thyroid replacement medication as needed in patients with DTC. Adverse Reactions Reported in at Least 10% of Patients and at a Higher Rate in Sorafenib Arm than the Placebo Arm – HCC Study: - Fatigue - Weight loss - Rash/Desquamation - Pruritus - Hand-Foot skin reaction - Dry skin - Alopecia - Diarrhea - Anorexia - Nausea - Vomiting - Constipation - Liver dysfunction - Abdominal pain Hypertension was reported in 9% of patients treated with Sorafenib and 4% of those treated with placebo. CTCAE Grade 3 hypertension was reported in 4% of Sorafenib-treated patients and 1% of placebo-treated patients. No patients were reported with CTCAE Grade 4 reactions in either treatment group. Hemorrhage/bleeding was reported in 18% of those receiving Sorafenib and 20% of placebo-treated patients. The rates of CTCAE Grade 3 and 4 bleeding were also higher in the placebo-treated group (CTCAE Grade 3 – 3% Sorafenib and 5% placebo and CTCAE Grade 4 – 2% Sorafenib and 4% placebo). Bleeding from esophageal varices was reported in 2.4% in Sorafenib-treated patients and 4% of placebo-treated patients. Renal failure was reported in <1% of patients treated with Sorafenib and 3% of placebo-treated patients. The rate of adverse reactions (including those associated with progressive disease) resulting in permanent discontinuation was similar in both the Sorafenib and placebo-treated groups (32% of Sorafenib-treated patients and 35% of placebo-treated patients). The following laboratory abnormalities were observed in patients with HCC: - Hypophosphatemia was a common laboratory finding, observed in 35% of Sorafenib-treated patients compared to 11% of placebo-treated patients; CTCAE Grade 3 hypophosphatemia (1–2 mg/dL) occurred in 11% of Sorafenib-treated patients and 2% of patients in the placebo-treated group; there was 1 case of CTCAE Grade 4 hypophosphatemia (<1 mg/dL) reported in the placebo-treated group. The etiology of hypophosphatemia associated with Sorafenib is not known. - Elevated lipase was observed in 40% of patients treated with Sorafenib compared to 37% of patients in the placebo-treated group. CTCAE Grade 3 or 4 lipase elevations occurred in 9% of patients in each group. Elevated amylase was observed in 34% of patients treated with Sorafenib compared to 29% of patients in the placebo-treated group. CTCAE Grade 3 or 4 amylase elevations were reported in 2% of patients in each group. Many of the lipase and amylase elevations were transient, and in the majority of cases Sorafenib treatment was not interrupted. Clinical pancreatitis was reported in 1 of 297 Sorafenib-treated patients (CTCAE Grade 2). - Elevations in liver function tests were comparable between the 2 arms of the study. Hypoalbuminemia was observed in 59% of Sorafenib-treated patients and 47% of placebo-treated patients; no CTCAE Grade 3 or 4 hypoalbuminemia was observed in either group. - INR elevations were observed in 42% of Sorafenib-treated patients and 34% of placebo-treated patients; CTCAE Grade 3 INR elevations were reported in 4% of Sorafenib-treated patients and 2% of placebo-treated patients; there was no CTCAE Grade 4 INR elevation in either group. - Lymphopenia was observed in 47% of Sorafenib-treated patients and 42% of placebo-treated patients. - Thrombocytopenia was observed in 46% of Sorafenib-treated patients and 41% of placebo-treated patients; CTCAE Grade 3 or 4 thrombocytopenia was reported in 4% of Sorafenib-treated patients and less than 1% of placebo-treated patients. - Hypocalcemia was reported in 27% of Sorafenib-treated patients and 15% of placebo-treated patients. CTCAE Grade 3 hypocalcemia (6–7 mg /dL) occurred in 2% of Sorafenib-treated patients and 1% of placebo-treated patients. CTCAE Grade 4 hypocalcemia (<6 mg/dL) occurred in 0.4% of Sorafenib-treated patients and in no placebo-treated patients. - Hypokalemia was reported in 9.5% of Sorafenib- treated patients compared to 5.9% of placebo-treated patients. Most reports of hypokalemia were low grade (CTCAE Grade 1). CTCAE Grade 3 hypokalemia occurred in 0.4% of Sorafenib-treated patients and 0.7% of placebo-treated patients. There were no reports of Grade 4 hypokalemia. # Adverse Reactions in RCC Study 1 Adverse Reactions Reported in at Least 10% of Patients and at a Higher Rate in Sorafenib Arm than the Placebo Arm – RCC Study 1: - Hypertension - Fatigue - Weight loss - Rash/Desquamation - Hand-foot skin reaction - Alopecia - Pruritus - Dry skin - Diarrhea - Nausea - Anorexia - Vomiting - Constipation - Hemorrhage - All sites - Sensory neuropathy - Abdominal Pain - Joint Pain - Headache - Dyspnea The following laboratory abnormalities were observed in patients with RCC in Study 1: - Hypophosphatemia was a common laboratory finding, observed in 45% of Sorafenib-treated patients compared to 11% of placebo-treated patients. CTCAE Grade 3 hypophosphatemia (1–2 mg/dL) occurred in 13% of Sorafenib-treated patients and 3% of patients in the placebo-treated group. There were no cases of CTCAE Grade 4 hypophosphatemia (<1 mg/dL) reported in either Sorafenib or placebo-treated patients. The etiology of hypophosphatemia associated with Sorafenib is not known. - Elevated lipase was observed in 41% of patients treated with Sorafenib compared to 30% of patients in the placebo-treated group. CTCAE Grade 3 or 4 lipase elevations occurred in 12% of patients in the Sorafenib-treated group compared to 7% of patients in the placebo-treated group. Elevated amylase was observed in 30% of patients treated with Sorafenib compared to 23% of patients in the placebo-treated group. CTCAE Grade 3 or 4 amylase elevations were reported in 1% of patients in the Sorafenib-treated group compared to 3% of patients in the placebo-treated group. Many of the Sorafenib and amylase elevations were transient, and in the majority of cases Sorafenib treatment was not interrupted. Clinical pancreatitis was reported in 3 of 451 Sorafenib-treated patients (one CTCAE Grade 2 and two Grade 4) and 1 of 451 patients (CTCAE Grade 2) in the placebo-treated group. - Lymphopenia was observed in 23% of Sorafenib-treated patients and 13% of placebo-treated patients. CTCAE Grade 3 or 4 lymphopenia was reported in 13% of Sorafenib-treated patients and 7% of placebo-treated patients. Neutropenia was observed in 18% of Sorafenib-treated patients and 10% of placebo-treated patients. CTCAE Grade 3 or 4 neutropenia was reported in 5% of Sorafenib-treated patients and 2% of placebo-treated patients. - Anemia was observed in 44% of Sorafenib-treated patients and 49% of placebo-treated patients. CTCAE Grade 3 or 4 anemia was reported in 2% of Sorafenib-treated patients and 4% of placebo-treated patients. - Thrombocytopenia was observed in 12% of Sorafenib-treated patients and 5% of placebo-treated patients. CTCAE Grade 3 or 4 thrombocytopenia was reported in 1% of Sorafenib-treated patients and in no placebo-treated patients. - Hypocalcemia was reported in 12% of Sorafenib-treated patients and 8% of placebo-treated patients. CTCAE Grade 3 hypocalcemia (6–7 mg/dL) occurred in 1% of Sorafenib-treated patients and 0.2% of placebo-treated patients, and CTCAE Grade 4 hypocalcemia (<6 mg/dL) occurred in 1% of Sorafenib-treated patients and 0.5% of placebo-treated patients. - Hypokalemia was reported in 5.4% of Sorafenib-treated patients compared to 0.7% of placebo-treated patients. Most reports of hypokalemia were low grade (CTCAE Grade 1). CTCAE Grade 3 hypokalemia occurred in 1.1% of Sorafenib-treated patients and 0.2% of placebo-treated patients. There were no reports of Grade 4 hypokalemia. # Adverse Reactions in DTC Study Per-Patient Incidence of Selected Adverse Reactions Occurring at a Higher Incidence in Sorafenib-Treated Patients : - Diarrhea - Nausea - Abdominal pain - Constipation - Stomatitis - Vomiting - Oral pain - Fatigue - Asthenia - Pyrexia - Weight loss - Decreased appetite - Pain in extremities - Muscle spasms - Squamous cell carcinoma of skin - Headache - Dysgeusia - Epistaxis - Dysphonia - PPES - Alopecia - Rash - Pruritus - Dry skin - Erythema - Hyperkeratosis - Hypertension - Elevated TSH levels are discussed elsewhere in the labeling. The relative increase for the following laboratory abnormalities observed in Sorafenib-treated DTC patients as compared to placebo-treated patients is similar to that observed in the RCC and HCC studies: lipase, amylase, hypokalemia, hypophosphatemia, neutropenia, lymphopenia, anemia, and thrombocytopenia. - Serum ALT and AST elevations were observed in 59% and 54% of the Sorafenib-treated patients as compared to 24% and 15% of placebo-treated patients, respectively. High grade (≥ 3) ALT and AST elevations were observed in 4% and 2%, respectively, in the Sorafenib-treated patients as compared to none of the placebo-treated patients. - Hypocalcemia was more frequent and more severe in patients with DTC, especially those with a history of hypoparathyroidism, compared to patients with RCC or HCC. Hypocalcemia was observed in 36% of DTC patients receiving Sorafenib (with 10% ≥ Grade 3) as compared with 11% of placebo-treated patients (3% ≥ Grade 3). In the DTC study, serum calcium levels were monitored monthly. # Additional Data from Multiple Clinical Trials The following additional drug-related adverse reactions and laboratory abnormalities were reported from clinical trials of Sorafenib (very common 10% or greater, common 1 to less than 10%, uncommon 0.1% to less than 1%, rare less than 0.1 %): - Cardiovascular Common: congestive heart failure, myocardial ischemia and/or infarction Uncommon: hypertensive crisis Rare: QT prolongation - Common: congestive heart failure, myocardial ischemia and/or infarction - Uncommon: hypertensive crisis - Rare: QT prolongation - Dermatologic Very common: erythema Common: exfoliative dermatitis, acne, flushing, folliculitis, hyperkeratosis Uncommon: eczema, erythema and multiform. - Very common: erythema - Common: exfoliative dermatitis, acne, flushing, folliculitis, hyperkeratosis - Uncommon: eczema, erythema and multiform. - Digestive Very common: increased lipase, increased amylase Common: mucositis, stomatitis (including dry mouth and glossodynia), dyspepsia, dysphagia, gastrointestinal reflux Uncommon: pancreatitis, gastritis, gastrointestinal perforations, cholecystitis, cholangitis Note that elevations in lipase are very common (41%, see below); a diagnosis of pancreatitis should not be made solely on the basis of abnormal laboratory values - Very common: increased lipase, increased amylase - Common: mucositis, stomatitis (including dry mouth and glossodynia), dyspepsia, dysphagia, gastrointestinal reflux - Uncommon: pancreatitis, gastritis, gastrointestinal perforations, cholecystitis, cholangitis Note that elevations in lipase are very common (41%, see below); a diagnosis of pancreatitis should not be made solely on the basis of abnormal laboratory values - Note that elevations in lipase are very common (41%, see below); a diagnosis of pancreatitis should not be made solely on the basis of abnormal laboratory values - General Disorders Very common: infection, hemorrhage (including gastrointestinal and respiratory tract and uncommon cases of cerebral hemorrhage), asthenia, pain (including mouth, bone, and tumor pain), pyrexia, decreased appetite Common: influenza-like illness. - Very common: infection, hemorrhage (including gastrointestinal and respiratory tract and uncommon cases of cerebral hemorrhage), asthenia, pain (including mouth, bone, and tumor pain), pyrexia, decreased appetite - Common: influenza-like illness. - Hematologic Very common: leukopenia, lymphopenia Common: anemia, neutropenia, thrombocytopenia Uncommon: INR abnormal - Very common: leukopenia, lymphopenia - Common: anemia, neutropenia, thrombocytopenia - Uncommon: INR abnormal - Hepatobiliary disorders: Rare: drug-induced hepatitis (including hepatic failure and death) - Hypersensitivity Uncommon: hypersensitivity reactions (including skin reactions and urticaria), anaphylactic reaction - Uncommon: hypersensitivity reactions (including skin reactions and urticaria), anaphylactic reaction - Metabolic and Nutritional Very common: hypophosphatemia Common: transient increases in transaminases, hypocalcemia, hypokalemia, hyponatremia, hypothyroidism Uncommon: dehydration, transient increases in alkaline phosphatase, increased bilirubin (including jaundice), hyperthyroidism - Very common: hypophosphatemia - Common: transient increases in transaminases, hypocalcemia, hypokalemia, hyponatremia, hypothyroidism - Uncommon: dehydration, transient increases in alkaline phosphatase, increased bilirubin (including jaundice), hyperthyroidism - Musculoskeletal Very common: arthralgia Common: myalgia, muscle spasms - Very common: arthralgia - Common: myalgia, muscle spasms - Nervous System and Psychiatric Common: depression, dysgeusia Uncommon: tinnitus, reversible posterior leukoencephalopathy - Common: depression, dysgeusia - Uncommon: tinnitus, reversible posterior leukoencephalopathy - Renal and Genitourinary Common: renal failure, proteinuria Rare: nephrotic syndrome - Common: renal failure, proteinuria - Rare: nephrotic syndrome - Reproductive Common: erectile dysfunction Uncommon: gynecomastia - Common: erectile dysfunction - Uncommon: gynecomastia - Respiratory Common: rhinorrhea Uncommon: interstitial lung disease-like events (includes reports of pneumonitis, radiation pneumonitis, acute respiratory distress, interstitial pneumonia, pulmonitis and lung inflammation) - Common: rhinorrhea - Uncommon: interstitial lung disease-like events (includes reports of pneumonitis, radiation pneumonitis, acute respiratory distress, interstitial pneumonia, pulmonitis and lung inflammation) In addition, the following medically significant adverse reactions were uncommon during clinical trials of Sorafenib: transient ischemic attack, arrhythmia, and thromboembolism. For these adverse reactions, the causal relationship of Sorafenib has not been established. - Dermatologic: Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN) - Hypersensitivity: Angioedema - Musculoskeletal: Rhabdomyolysis, osteonecrosis of the jaw - Respiratory: Interstitial lung disease-like events (which may have a life-threatening or fatal outcome) - Rifampin, a strong CYP3A4 inducer, administered at a dose of 600 mg once daily for 5 days with a single oral dose of Sorafenib 400 mg in healthy volunteers resulted in a 37% decrease in the mean AUC of sorafenib. Avoid concomitant use of strong CYP3A4 inducers (such as, carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampin, rifabutin, St. John’s wort), when possible, because these drugs can decrease the systemic exposure to sorafenib. - Ketoconazole, a strong inhibitor of CYP3A4 and P-glycoprotein, administered at a dose of 400 mg once daily for 7 days did not alter the mean AUC of a single oral dose of Sorafenib 50 mg in healthy volunteers. - Sorafenib 400 mg twice daily for 28 days did not increase the systemic exposure of concomitantly administered midazolam (CYP3A4 substrate), dextromethorphan (CYP2D6 substrate), and omeprazole (CYP2C19 substrate) - Neomycin administered as an oral dose of 1 g three times daily for 5 days decreased the mean AUC of sorafenib by 54% in healthy volunteers administered a single oral dose of Sorafenib 400 mg. The effects of other antibiotics on the pharmacokinetics of sorafenib have not been studied. - The aqueous solubility of sorafenib is pH dependent, with higher pH resulting in lower solubility. However, omeprazole, a proton pump inhibitor, administered at a dose of 40 mg once daily for 5 days, did not result in a clinically meaningful change in sorafenib single dose exposure. No dose adjustment for Sorafenib is necessary. - When administered to rats and rabbits during the period of organogenesis, sorafenib was teratogenic and induced embryo-fetal toxicity (including increased post-implantation loss, resorptions, skeletal retardations, and retarded fetal weight). The effects occurred at doses considerably below the recommended human dose of 400 mg twice daily (approximately 500 mg/m2/day on a body surface area basis). Adverse intrauterine development effects were seen at doses ≥0.2 mg/kg/day (1.2 mg/m2/day) in rats and 0.3 mg/kg/day (3.6 mg/m2/day) in rabbits. These doses result in exposures (AUC) approximately 0.008 times the AUC seen in patients at the recommended human dose. A NOAEL (no observed adverse effect level) was not defined for either species, since lower doses were not tested. - Following administration of radiolabeled sorafenib to lactating Wistar rats, approximately 27% of the radioactivity was secreted into the milk. The milk to plasma AUC ratio was approximately 5:1. - Repeat dosing of sorafenib to young and growing dogs resulted in irregular thickening of the femoral growth plate at daily sorafenib doses ≥ 600 mg/m2 (approximately 0.3 times the AUC at the recommended human dose), hypocellularity of the bone marrow adjoining the growth plate at 200 mg/m2/day (approximately 0.1 times the AUC at the recommended human dose), and alterations of the dentin composition at 600 mg/m2/day. Similar effects were not observed in adult dogs when dosed for 4 weeks or less. - After administration of Sorafenib tablets, the mean relative bioavailability was 38–49% when compared to an oral solution. Following oral administration, sorafenib reached peak plasma levels in approximately 3 hours. With a moderate-fat meal (30% fat; 700 calories), bioavailability was similar to that in the fasted state. With a high-fat meal (50% fat; 900 calories), bioavailability was reduced by 29% compared to that in the fasted state. It is recommended that Sorafenib be administered without food. Mean Cmax and AUC increased less than proportionally beyond oral doses of 400 mg administered twice daily. In vitro binding of sorafenib to human plasma proteins was 99.5%. - Sorafenib undergoes oxidative metabolism by hepatic CYP3A4, as well as glucuronidation by UGT1A9. Inducers of CYP3A4 activity can decrease the systemic exposure of sorafenib. Sorafenib accounted for approximately 70–85% of the circulating analytes in plasma at steady-state. Eight metabolites of sorafenib have been identified, of which 5 have been detected in plasma. The main circulating metabolite of sorafenib, the pyridine N-oxide that comprises approximately 9–16% of circulating analytes at steady-state, showed in vitro potency similar to that of sorafenib. Following oral administration of a 100 mg dose of a solution formulation of sorafenib, 96% of the dose was recovered within 14 days, with 77% of the dose excreted in feces and 19% of the dose excreted in urine as glucuronidated metabolites. Unchanged sorafenib, accounting for 51% of the dose, was found in feces but not in urine. - A study of the pharmacokinetics of sorafenib indicated that the mean AUC of sorafenib in Asians (N=78) was 30% lower than in Caucasians (N=40). Gender and age do not have a clinically meaningful effect on the pharmacokinetics of sorafenib. - Mild (CLcr 50-80 mL/min), moderate (CLcr 30 - <50 mL/min), and severe (CLcr <30 mL/min) renal impairment do not affect the pharmacokinetics of sorafenib. No dose adjustment is necessary. - Mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment do not affect the pharmacokinetics of sorafenib. No dose adjustment is necessary. Studies in human liver microsomes demonstrated that sorafenib competitively inhibited CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. However, Sorafenib 400 mg twice daily for 28 days with substrates of CYP3A4, CYP2D6 and CYP2C19 did not increase the systemic exposure of these substrates. Studies with cultured human hepatocytes demonstrated that sorafenib did not increase CYP1A2 and CYP3A4 activities, suggesting that sorafenib is unlikely to induce CYP1A2 or CYP3A4 in humans. Sorafenib inhibits glucuronidation by UGT1A1 and UGT1A9 in vitro. Sorafenib could increase the systemic exposure of concomitantly administered drugs that are UGT1A1 or UGT1A9 substrates. Sorafenib inhibited P-glycoprotein in vitro. Sorafenib could increase the concentrations of concomitantly administered drugs that are P-glycoprotein substrates. - Carcinogenicity studies have not been performed with sorafenib. Sorafenib was clastogenic when tested in an in vitro mammalian cell assay (Chinese hamster ovary) in the presence of metabolic activation. Sorafenib was not mutagenic in the in vitro Ames bacterial cell assay or clastogenic in an in vivo mouse micronucleus assay. One intermediate in the manufacturing process, which is also present in the final drug substance (<0.15%), was positive for mutagenesis in an in vitro bacterial cell assay (Ames test) when tested independently. - No specific studies with sorafenib have been conducted in animals to evaluate the effect on fertility. However, results from the repeat-dose toxicity studies suggest there is a potential for sorafenib to impair reproductive function and fertility. Multiple adverse effects were observed in male and female reproductive organs, with the rat being more susceptible than mice or dogs. Typical changes in rats consisted of testicular atrophy or degeneration, degeneration of epididymis, prostate, and seminal vesicles, central necrosis of the corpora lutea and arrested follicular development. Sorafenib-related effects on the reproductive organs of rats were manifested at daily oral doses ≥ 5 mg/kg (30 mg/m2). This dose results in an exposure (AUC) that is approximately 0.5 times the AUC in patients at the recommended human dose. Dogs showed tubular degeneration in the testes at 30 mg/kg/day (600 mg/m2/day). This dose results in an exposure that is approximately 0.3 times the AUC at the recommended human dose. Oligospermia was observed in dogs at 60 mg/kg/day (1200 mg/m2/day) of sorafenib. Adequate contraception should be used during therapy and for at least 2 weeks after completing therapy. - The HCC Study was a Phase 3, international, multicenter, randomized, double blind, placebo-controlled trial in patients with unresectable hepatocellular carcinoma. Overall survival was the primary endpoint. A total of 602 patients were randomized; 299 to Sorafenib 400 mg twice daily and 303 to matching placebo. Demographics and baseline disease characteristics were similar between the Sorafenib and placebo-treated groups with regard to age, gender, race, performance status, etiology (including hepatitis B, hepatitis C and alcoholic liver disease), TNM stage (stage I: <1% vs. <1%; stage II: 10.4% vs. 8.3%; stage III: 37.8% vs. 43.6%; stage IV: 50.8% vs. 46.9%), absence of both macroscopic vascular invasion and extrahepatic tumor spread (30.1% vs. 30.0%), and Barcelona Clinic Liver Cancer stage (stage B: 18.1% vs. 16.8%; stage C: 81.6% vs. 83.2%; stage D: <1% vs. 0%). Liver impairment by Child-Pugh score was comparable between the Sorafenib and placebo-treated groups (Class A: 95% vs. 98%; B: 5% vs. 2%). Only one patient with Child-Pugh class C was entered. Prior treatments included surgical resection procedures (19.1% vs. 20.5%), locoregional therapies (including radiofrequency ablation, percutaneous ethanol injection and transarterial chemoembolization; 38.8% vs. 40.6%), radiotherapy (4.3% vs. 5.0%) and systemic therapy (3.0% vs. 5.0%). - The trial was stopped for efficacy following a pre-specified second interim analysis for survival showing a statistically significant advantage for Sorafenib over placebo for overall survival (HR: 0.69, p= 0.00058) (see Table 4 and Figure 1). This advantage was consistent across all subsets analyzed. Final analysis of time to tumor progression (TTP) based on data from an earlier time point (by independent radiologic review) also was significantly longer in the Sorafenib arm (HR: 0.58, p=0.000007). - The safety and efficacy of Sorafenib in the treatment of advanced renal cell carcinoma (RCC) were studied in the following two randomized controlled clinical trials. RCC Study 1 was a Phase 3, international, multicenter, randomized, double blind, placebo-controlled trial in patients with advanced renal cell carcinoma who had received one prior systemic therapy. Primary study endpoints included overall survival and progression-free survival (PFS). Tumor response rate was a secondary endpoint. The PFS analysis included 769 patients stratified by MSKCC (Memorial Sloan Kettering Cancer Center) prognostic risk category (low or intermediate) and country and randomized to Sorafenib 400 mg twice daily (N=384) or to placebo (N=385). Table 8 summarizes the demographic and disease characteristics of the study population analyzed. Baseline demographics and disease characteristics were well balanced for both treatment groups. The median time from initial diagnosis of RCC to randomization was 1.6 and 1.9 years for the Sorafenib and placebo-treated groups, respectively. - The safety and effectiveness of Sorafenib was established in a multicenter, randomized (1:1), double-blind, placebo-controlled trial conducted in 417 patients with locally recurrent or metastatic, progressive differentiated thyroid carcinoma (DTC) refractory to radioactive iodine] (RAI) treatment]. Randomization was stratified by age (< 60 years versus ≥ 60 years) and geographical region (North America, Europe, and Asia). - All patients were required to have actively progressing disease defined as progression within 14 months of enrollment. RAI-refractory disease was defined based on four criteria that were not mutually exclusive. All RAI treatments and diagnostic scans were to be performed under conditions of a low iodine diet and adequate TSH stimulation. Following are the RAI-refractory criteria and the proportion of patients in the study that met each one: a target lesion with no iodine uptake on RAI scan (68%); tumors with iodine uptake and progression after RAI treatment within 16 months of enrollment (12%); tumors with iodine uptake and multiple RAI treatments with the last treatment greater than 16 months prior to enrollment, and disease progression after each of two RAI treatments administered within 16 months of each other (7%); cumulative RAI dose ≥ 600 mCi administered (34%). The major efficacy outcome measure was progression-free survival (PFS) as determined by a blinded, independent radiological review using a modified Response Evaluation Criteria in Solid Tumors v. 1.0 (RECIST). RECIST was modified by inclusion of clinical progression of bone lesions based on the need for external beam radiation (4.4% of progression events). Additional efficacy outcomes measures included overall survival (OS), tumor response rate, and duration of response. - Patients were randomized to receive Sorafenib 400 mg twice daily (n=207) or placebo (n=210). Of the 417 patients randomized, 48% were male, the median age was 63 years, 61% were 60 years or older, 60% were white, 62% had an ECOG performance status of 0, and 99% had undergone thyroidectomy. The histological diagnoses were papillary carcinoma in 57%, follicular carcinoma (including Hürthle cell) in 25%, and poorly differentiated carcinoma in 10%, and other in 8% of the study population. Metastases were present in 96% of the patients: lungs in 86%, lymph nodes in 51%, and bone in 27%. The median cumulative RAI activity administered prior to study entry was 400 mCi. A statistically significant prolongation in PFS was demonstrated among Sorafenib-treated patients compared to those receiving placebo. Following investigator-determined disease progression, 157 (75%) patients randomized to placebo crossed over to open-label Sorafenib, and 61 (30%) patients randomized to Sorafenib received open-label Sorafenib There was no statistically significant difference in overall survival between the two treatment arms (see Table 9 and Figure 3). Bottles of 120 tablets NDC 50419-488-58	Sorafenib - Dosage: 200 mg q12h, taken 1 hour before or 2 hours after a meal. Treatment should continue until the patient is no longer clinically benefiting from therapy or until unacceptable toxicity occurs. Temporary interruption of Sorafenib is recommended in patients undergoing major surgical procedures. Temporary interruption or permanent discontinuation of Sorafenib may be required for the following: Cardiac ischemia or infarction Hemorrhage requiring medical intervention Severe or persistent hypertension despite adequate anti-hypertensive therapy Gastrointestinal perforation QTc prolongation Severe drug-induced liver injury - Temporary interruption or permanent discontinuation of Sorafenib may be required for the following: Cardiac ischemia or infarction Hemorrhage requiring medical intervention Severe or persistent hypertension despite adequate anti-hypertensive therapy Gastrointestinal perforation QTc prolongation Severe drug-induced liver injury - Cardiac ischemia or infarction - Hemorrhage requiring medical intervention - Severe or persistent hypertension despite adequate anti-hypertensive therapy - Gastrointestinal perforation - QTc prolongation - Severe drug-induced liver injury When dose reduction is necessary, the Sorafenib dose may be reduced to 400 mg once daily. If additional dose reduction is required, Sorafenib may be reduced to a single 400 mg dose every other day. If dermatological toxicity presented, the following scheme should be followed: Following improvement of Grade 2 or 3 dermatologic toxicity to Grade 0–1 after at least 28 days of treatment on a reduced dose of Sorafenib, the dose of Sorafenib may be increased one dose level from the reduced dose. Approximately 50% of patients requiring a dose reduction for dermatologic toxicity are expected to meet these criteria for resumption of the higher dose and roughly 50% of patients resuming the previous dose are expected to tolerate the higher dose (that is, maintain the higher dose level without recurrent Grade 2 or higher dermatologic toxicity) - Sorafenib in combination with carboplatin and paclitaxel is contraindicated in patients with squamous cell lung cancer. - In the HCC study, the incidence of cardiac ischemia/infarction was 2.7% in Sorafenib-treated patients compared with 1.3% in the placebo-treated group, in RCC Study 1, the incidence of cardiac ischemia/infarction was higher in the Sorafenib-treated group (2.9%) compared with the placebo-treated group (0.4%), and in the DTC study, the incidence of cardiac ischemia/infarction was 1.9% in the Sorafenib-treated group compared with 0% in the placebo-treated group. Patients with unstable coronary artery disease or recent myocardial infarction were excluded from this study. Temporary or permanent discontinuation of Sorafenib should be considered in patients who develop cardiac ischemia and/or infarction. - An increased risk of bleeding may occur following Sorafenib administration. In the HCC study, an excess of bleeding regardless of causality was not apparent and the rate of bleeding from esophageal varices was 2.4% in Sorafenib-treated patients and 4% in placebo-treated patients. Bleeding with a fatal outcome from any site was reported in 2.4% of Sorafenib-treated patients and 4% in placebo-treated patients. In RCC Study 1, bleeding regardless of causality was reported in 15.3% of patients in the Sorafenib-treated group and 8.2% of patients in the placebo-treated group. The incidence of CTCAE Grade 3 and 4 bleeding was 2% and 0%, respectively, in Sorafenib-treated patients, and 1.3% and 0.2%, respectively, in placebo-treated patients. There was one fatal hemorrhage in each treatment group in RCC Study 1. In the DTC study, bleeding was reported in 17.4% of Sorafenib-treated patients and 9.6% of placebo-treated patients; however the incidence of CTCAE Grade 3 bleeding was 1% in Sorafenib-treated patients and 1.4% in placebo-treated patients. There was no Grade 4 bleeding reported and there was one fatal hemorrhage in a placebo-treated patient. If any bleeding necessitates medical intervention, permanent discontinuation of Sorafenib should be considered. Due to the potential risk of bleeding, tracheal, bronchial, and esophageal infiltration should be treated with local therapy prior to administering Sorafenib in patients with DTC. - Monitor blood pressure weekly during the first 6 weeks of Sorafenib. Thereafter, monitor blood pressure and treat hypertension, if required, in accordance with standard medical practice. In the HCC study, hypertension was reported in approximately 9.4% of Sorafenib-treated patients and 4.3% of patients in the placebo-treated group. In RCC Study 1, hypertension was reported in approximately 16.9% of Sorafenib-treated patients and 1.8% of patients in the placebo-treated group. In the DTC study, hypertension was reported in 40.6% of Sorafenib-treated patients and 12.4% of placebo-treated patients. Hypertension was usually mild to moderate, occurred early in the course of treatment, and was managed with standard antihypertensive therapy. In cases of severe or persistent hypertension despite institution of antihypertensive therapy, consider temporary or permanent discontinuation of Sorafenib. Permanent discontinuation due to hypertension occurred in 1 of 297 Sorafenib-treated patients in the HCC study, 1 of 451 Sorafenib-treated patients in RCC Study 1, and 1 of 207 Sorafenib-treated patients in the DTC study. - Hand-foot skin reaction and rash represent the most common adverse reactions attributed to Sorafenib. Rash and hand-foot skin reaction are usually CTCAE Grade 1 and 2 and generally appear during the first six weeks of treatment with Sorafenib. Management of dermatologic toxicities may include topical therapies for symptomatic relief, temporary treatment interruption and/or dose modification of Sorafenib, or in severe or persistent cases, permanent discontinuation of Sorafenib. Permanent discontinuation of therapy due to hand-foot skin reaction occurred in 4 (1.3%) of 297 Sorafenib-treated patients with HCC, 3 (0.7%) of 451 Sorafenib-treated patients with RCC, and 11 (5.3%) of 207 Sorafenib-treated patients with DTC. - There have been reports of severe dermatologic toxicities, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). These cases may be life-threatening. Discontinue Sorafenib if SJS or TEN are suspected. - Gastrointestinal perforation is an uncommon adverse reaction and has been reported in less than 1% of patients taking Sorafenib. In some cases this was not associated with apparent intra-abdominal tumor. In the event of a gastrointestinal perforation, discontinue Sorafenib. - Infrequent bleeding or elevations in the International Normalized Ratio (INR) have been reported in some patients taking warfarin while on Sorafenib. Monitor patients taking concomitant warfarin regularly for changes in prothrombin time (PT), INR or clinical bleeding episodes. - No formal studies of the effect of Sorafenib on wound healing have been conducted. Temporary interruption of Sorafenib is recommended in patients undergoing major surgical procedures. There is limited clinical experience regarding the timing of reinitiation of Sorafenib following major surgical intervention. Therefore, the decision to resume Sorafenib following a major surgical intervention should be based on clinical judgment of adequate wound healing. - In a subset analysis of two randomized controlled trials in chemo-naive patients with Stage IIIB-IV non-small cell lung cancer, patients with squamous cell carcinoma experienced higher mortality with the addition of Sorafenib compared to those treated with carboplatin/paclitaxel alone (HR 1.81, 95% CI 1.19–2.74) and gemcitabine/cisplatin alone (HR 1.22, 95% CI 0.82-1.80). The use of Sorafenib in combination with carboplatin/paclitaxel is contraindicated in patients with squamous cell lung cancer. Sorafenib in combination with gemcitabine/cisplatin is not recommended in patients with squamous cell lung cancer. The safety and effectiveness of Sorafenib has not been established in patients with non-small cell lung cancer. - Sorafenib can prolong the QT/QTc interval. QT/QTc interval prolongation increases the risk for ventricular arrhythmias. Avoid Sorafenib in patients with congenital long QT syndrome. Monitor electrolytes and electrocardiograms in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics. Correct electrolyte abnormalities (magnesium, potassium, calcium). Interrupt Sorafenib if QTc interval is greater than 500 milliseconds or for an increase from baseline of 60 milliseconds or greater. - Sorafenib-induced hepatitis is characterized by a hepatocellular pattern of liver damage with significant increases of transaminases which may result in hepatic failure and death. Increases in bilirubin and INR may also occur. The incidence of severe drug-induced liver injury, defined as elevated transaminase levels above 20 times the upper limit of normal or transaminase elevations with significant clinical sequelae (for example, elevated INR, ascites, fatal, or transplantation), was two of 3,357 patients (0.06%) in a global monotherapy database. Monitor liver function tests regularly. In case of significantly increased transaminases without alternative explanation, such as viral hepatitis or progressing underlying malignancy, discontinue Sorafenib. - Based on its mechanism of action and findings in animals, Sorafenib may cause fetal harm when administered to a pregnant woman. Sorafenib caused embryo-fetal toxicities in animals at maternal exposures that were significantly lower than the human exposures at the recommended dose of 400 mg twice daily. Advise women of childbearing potential to avoid becoming pregnant while on Sorafenib because of the potential hazard to the fetus. - Sorafenib impairs exogenous thyroid suppression. In the DTC study, 99% of patients had a baseline thyroid stimulating hormone (TSH) level less than 0.5 mU/L. Elevation of TSH level above 0.5 mU/L was observed in 41% of Sorafenib-treated patients as compared with 16% of placebo-treated patients. For patients with impaired TSH suppression while receiving Sorafenib, the median maximal TSH was 1.6 mU/L and 25% had TSH levels greater than 4.4 mU/L. Monitor TSH levels monthly and adjust thyroid replacement medication as needed in patients with DTC. Adverse Reactions Reported in at Least 10% of Patients and at a Higher Rate in Sorafenib Arm than the Placebo Arm – HCC Study: - Fatigue - Weight loss - Rash/Desquamation - Pruritus - Hand-Foot skin reaction - Dry skin - Alopecia - Diarrhea - Anorexia - Nausea - Vomiting - Constipation - Liver dysfunction - Abdominal pain Hypertension was reported in 9% of patients treated with Sorafenib and 4% of those treated with placebo. CTCAE Grade 3 hypertension was reported in 4% of Sorafenib-treated patients and 1% of placebo-treated patients. No patients were reported with CTCAE Grade 4 reactions in either treatment group. Hemorrhage/bleeding was reported in 18% of those receiving Sorafenib and 20% of placebo-treated patients. The rates of CTCAE Grade 3 and 4 bleeding were also higher in the placebo-treated group (CTCAE Grade 3 – 3% Sorafenib and 5% placebo and CTCAE Grade 4 – 2% Sorafenib and 4% placebo). Bleeding from esophageal varices was reported in 2.4% in Sorafenib-treated patients and 4% of placebo-treated patients. Renal failure was reported in <1% of patients treated with Sorafenib and 3% of placebo-treated patients. The rate of adverse reactions (including those associated with progressive disease) resulting in permanent discontinuation was similar in both the Sorafenib and placebo-treated groups (32% of Sorafenib-treated patients and 35% of placebo-treated patients). The following laboratory abnormalities were observed in patients with HCC: - Hypophosphatemia was a common laboratory finding, observed in 35% of Sorafenib-treated patients compared to 11% of placebo-treated patients; CTCAE Grade 3 hypophosphatemia (1–2 mg/dL) occurred in 11% of Sorafenib-treated patients and 2% of patients in the placebo-treated group; there was 1 case of CTCAE Grade 4 hypophosphatemia (<1 mg/dL) reported in the placebo-treated group. The etiology of hypophosphatemia associated with Sorafenib is not known. - Elevated lipase was observed in 40% of patients treated with Sorafenib compared to 37% of patients in the placebo-treated group. CTCAE Grade 3 or 4 lipase elevations occurred in 9% of patients in each group. Elevated amylase was observed in 34% of patients treated with Sorafenib compared to 29% of patients in the placebo-treated group. CTCAE Grade 3 or 4 amylase elevations were reported in 2% of patients in each group. Many of the lipase and amylase elevations were transient, and in the majority of cases Sorafenib treatment was not interrupted. Clinical pancreatitis was reported in 1 of 297 Sorafenib-treated patients (CTCAE Grade 2). - Elevations in liver function tests were comparable between the 2 arms of the study. Hypoalbuminemia was observed in 59% of Sorafenib-treated patients and 47% of placebo-treated patients; no CTCAE Grade 3 or 4 hypoalbuminemia was observed in either group. - INR elevations were observed in 42% of Sorafenib-treated patients and 34% of placebo-treated patients; CTCAE Grade 3 INR elevations were reported in 4% of Sorafenib-treated patients and 2% of placebo-treated patients; there was no CTCAE Grade 4 INR elevation in either group. - Lymphopenia was observed in 47% of Sorafenib-treated patients and 42% of placebo-treated patients. - Thrombocytopenia was observed in 46% of Sorafenib-treated patients and 41% of placebo-treated patients; CTCAE Grade 3 or 4 thrombocytopenia was reported in 4% of Sorafenib-treated patients and less than 1% of placebo-treated patients. - Hypocalcemia was reported in 27% of Sorafenib-treated patients and 15% of placebo-treated patients. CTCAE Grade 3 hypocalcemia (6–7 mg /dL) occurred in 2% of Sorafenib-treated patients and 1% of placebo-treated patients. CTCAE Grade 4 hypocalcemia (<6 mg/dL) occurred in 0.4% of Sorafenib-treated patients and in no placebo-treated patients. - Hypokalemia was reported in 9.5% of Sorafenib- treated patients compared to 5.9% of placebo-treated patients. Most reports of hypokalemia were low grade (CTCAE Grade 1). CTCAE Grade 3 hypokalemia occurred in 0.4% of Sorafenib-treated patients and 0.7% of placebo-treated patients. There were no reports of Grade 4 hypokalemia. ### Adverse Reactions in RCC Study 1 Adverse Reactions Reported in at Least 10% of Patients and at a Higher Rate in Sorafenib Arm than the Placebo Arm – RCC Study 1: - Hypertension - Fatigue - Weight loss - Rash/Desquamation - Hand-foot skin reaction - Alopecia - Pruritus - Dry skin - Diarrhea - Nausea - Anorexia - Vomiting - Constipation - Hemorrhage - All sites - Sensory neuropathy - Abdominal Pain - Joint Pain - Headache - Dyspnea The following laboratory abnormalities were observed in patients with RCC in Study 1: - Hypophosphatemia was a common laboratory finding, observed in 45% of Sorafenib-treated patients compared to 11% of placebo-treated patients. CTCAE Grade 3 hypophosphatemia (1–2 mg/dL) occurred in 13% of Sorafenib-treated patients and 3% of patients in the placebo-treated group. There were no cases of CTCAE Grade 4 hypophosphatemia (<1 mg/dL) reported in either Sorafenib or placebo-treated patients. The etiology of hypophosphatemia associated with Sorafenib is not known. - Elevated lipase was observed in 41% of patients treated with Sorafenib compared to 30% of patients in the placebo-treated group. CTCAE Grade 3 or 4 lipase elevations occurred in 12% of patients in the Sorafenib-treated group compared to 7% of patients in the placebo-treated group. Elevated amylase was observed in 30% of patients treated with Sorafenib compared to 23% of patients in the placebo-treated group. CTCAE Grade 3 or 4 amylase elevations were reported in 1% of patients in the Sorafenib-treated group compared to 3% of patients in the placebo-treated group. Many of the Sorafenib and amylase elevations were transient, and in the majority of cases Sorafenib treatment was not interrupted. Clinical pancreatitis was reported in 3 of 451 Sorafenib-treated patients (one CTCAE Grade 2 and two Grade 4) and 1 of 451 patients (CTCAE Grade 2) in the placebo-treated group. - Lymphopenia was observed in 23% of Sorafenib-treated patients and 13% of placebo-treated patients. CTCAE Grade 3 or 4 lymphopenia was reported in 13% of Sorafenib-treated patients and 7% of placebo-treated patients. Neutropenia was observed in 18% of Sorafenib-treated patients and 10% of placebo-treated patients. CTCAE Grade 3 or 4 neutropenia was reported in 5% of Sorafenib-treated patients and 2% of placebo-treated patients. - Anemia was observed in 44% of Sorafenib-treated patients and 49% of placebo-treated patients. CTCAE Grade 3 or 4 anemia was reported in 2% of Sorafenib-treated patients and 4% of placebo-treated patients. - Thrombocytopenia was observed in 12% of Sorafenib-treated patients and 5% of placebo-treated patients. CTCAE Grade 3 or 4 thrombocytopenia was reported in 1% of Sorafenib-treated patients and in no placebo-treated patients. - Hypocalcemia was reported in 12% of Sorafenib-treated patients and 8% of placebo-treated patients. CTCAE Grade 3 hypocalcemia (6–7 mg/dL) occurred in 1% of Sorafenib-treated patients and 0.2% of placebo-treated patients, and CTCAE Grade 4 hypocalcemia (<6 mg/dL) occurred in 1% of Sorafenib-treated patients and 0.5% of placebo-treated patients. - Hypokalemia was reported in 5.4% of Sorafenib-treated patients compared to 0.7% of placebo-treated patients. Most reports of hypokalemia were low grade (CTCAE Grade 1). CTCAE Grade 3 hypokalemia occurred in 1.1% of Sorafenib-treated patients and 0.2% of placebo-treated patients. There were no reports of Grade 4 hypokalemia. ### Adverse Reactions in DTC Study Per-Patient Incidence of Selected Adverse Reactions Occurring at a Higher Incidence in Sorafenib-Treated Patients [Between Arm Difference of ≥ 5% (All Grades)1 or ≥ 2% (Grades 3 and 4)]: - Diarrhea - Nausea - Abdominal pain - Constipation - Stomatitis - Vomiting - Oral pain - Fatigue - Asthenia - Pyrexia - Weight loss - Decreased appetite - Pain in extremities - Muscle spasms - Squamous cell carcinoma of skin - Headache - Dysgeusia - Epistaxis - Dysphonia - PPES - Alopecia - Rash - Pruritus - Dry skin - Erythema - Hyperkeratosis - Hypertension - Elevated TSH levels are discussed elsewhere in the labeling. The relative increase for the following laboratory abnormalities observed in Sorafenib-treated DTC patients as compared to placebo-treated patients is similar to that observed in the RCC and HCC studies: lipase, amylase, hypokalemia, hypophosphatemia, neutropenia, lymphopenia, anemia, and thrombocytopenia. - Serum ALT and AST elevations were observed in 59% and 54% of the Sorafenib-treated patients as compared to 24% and 15% of placebo-treated patients, respectively. High grade (≥ 3) ALT and AST elevations were observed in 4% and 2%, respectively, in the Sorafenib-treated patients as compared to none of the placebo-treated patients. - Hypocalcemia was more frequent and more severe in patients with DTC, especially those with a history of hypoparathyroidism, compared to patients with RCC or HCC. Hypocalcemia was observed in 36% of DTC patients receiving Sorafenib (with 10% ≥ Grade 3) as compared with 11% of placebo-treated patients (3% ≥ Grade 3). In the DTC study, serum calcium levels were monitored monthly. ### Additional Data from Multiple Clinical Trials The following additional drug-related adverse reactions and laboratory abnormalities were reported from clinical trials of Sorafenib (very common 10% or greater, common 1 to less than 10%, uncommon 0.1% to less than 1%, rare less than 0.1 %): - Cardiovascular Common: congestive heart failure, myocardial ischemia and/or infarction Uncommon: hypertensive crisis Rare: QT prolongation - Common: congestive heart failure, myocardial ischemia and/or infarction - Uncommon: hypertensive crisis - Rare: QT prolongation - Dermatologic Very common: erythema Common: exfoliative dermatitis, acne, flushing, folliculitis, hyperkeratosis Uncommon: eczema, erythema and multiform. - Very common: erythema - Common: exfoliative dermatitis, acne, flushing, folliculitis, hyperkeratosis - Uncommon: eczema, erythema and multiform. - Digestive Very common: increased lipase, increased amylase Common: mucositis, stomatitis (including dry mouth and glossodynia), dyspepsia, dysphagia, gastrointestinal reflux Uncommon: pancreatitis, gastritis, gastrointestinal perforations, cholecystitis, cholangitis Note that elevations in lipase are very common (41%, see below); a diagnosis of pancreatitis should not be made solely on the basis of abnormal laboratory values - Very common: increased lipase, increased amylase - Common: mucositis, stomatitis (including dry mouth and glossodynia), dyspepsia, dysphagia, gastrointestinal reflux - Uncommon: pancreatitis, gastritis, gastrointestinal perforations, cholecystitis, cholangitis Note that elevations in lipase are very common (41%, see below); a diagnosis of pancreatitis should not be made solely on the basis of abnormal laboratory values - Note that elevations in lipase are very common (41%, see below); a diagnosis of pancreatitis should not be made solely on the basis of abnormal laboratory values - General Disorders Very common: infection, hemorrhage (including gastrointestinal and respiratory tract and uncommon cases of cerebral hemorrhage), asthenia, pain (including mouth, bone, and tumor pain), pyrexia, decreased appetite Common: influenza-like illness. - Very common: infection, hemorrhage (including gastrointestinal and respiratory tract and uncommon cases of cerebral hemorrhage), asthenia, pain (including mouth, bone, and tumor pain), pyrexia, decreased appetite - Common: influenza-like illness. - Hematologic Very common: leukopenia, lymphopenia Common: anemia, neutropenia, thrombocytopenia Uncommon: INR abnormal - Very common: leukopenia, lymphopenia - Common: anemia, neutropenia, thrombocytopenia - Uncommon: INR abnormal - Hepatobiliary disorders: Rare: drug-induced hepatitis (including hepatic failure and death) - Hypersensitivity Uncommon: hypersensitivity reactions (including skin reactions and urticaria), anaphylactic reaction - Uncommon: hypersensitivity reactions (including skin reactions and urticaria), anaphylactic reaction - Metabolic and Nutritional Very common: hypophosphatemia Common: transient increases in transaminases, hypocalcemia, hypokalemia, hyponatremia, hypothyroidism Uncommon: dehydration, transient increases in alkaline phosphatase, increased bilirubin (including jaundice), hyperthyroidism - Very common: hypophosphatemia - Common: transient increases in transaminases, hypocalcemia, hypokalemia, hyponatremia, hypothyroidism - Uncommon: dehydration, transient increases in alkaline phosphatase, increased bilirubin (including jaundice), hyperthyroidism - Musculoskeletal Very common: arthralgia Common: myalgia, muscle spasms - Very common: arthralgia - Common: myalgia, muscle spasms - Nervous System and Psychiatric Common: depression, dysgeusia Uncommon: tinnitus, reversible posterior leukoencephalopathy - Common: depression, dysgeusia - Uncommon: tinnitus, reversible posterior leukoencephalopathy - Renal and Genitourinary Common: renal failure, proteinuria Rare: nephrotic syndrome - Common: renal failure, proteinuria - Rare: nephrotic syndrome - Reproductive Common: erectile dysfunction Uncommon: gynecomastia - Common: erectile dysfunction - Uncommon: gynecomastia - Respiratory Common: rhinorrhea Uncommon: interstitial lung disease-like events (includes reports of pneumonitis, radiation pneumonitis, acute respiratory distress, interstitial pneumonia, pulmonitis and lung inflammation) - Common: rhinorrhea - Uncommon: interstitial lung disease-like events (includes reports of pneumonitis, radiation pneumonitis, acute respiratory distress, interstitial pneumonia, pulmonitis and lung inflammation) In addition, the following medically significant adverse reactions were uncommon during clinical trials of Sorafenib: transient ischemic attack, arrhythmia, and thromboembolism. For these adverse reactions, the causal relationship of Sorafenib has not been established. - Dermatologic: Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN) - Hypersensitivity: Angioedema - Musculoskeletal: Rhabdomyolysis, osteonecrosis of the jaw - Respiratory: Interstitial lung disease-like events (which may have a life-threatening or fatal outcome) - Rifampin, a strong CYP3A4 inducer, administered at a dose of 600 mg once daily for 5 days with a single oral dose of Sorafenib 400 mg in healthy volunteers resulted in a 37% decrease in the mean AUC of sorafenib. Avoid concomitant use of strong CYP3A4 inducers (such as, carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampin, rifabutin, St. John’s wort), when possible, because these drugs can decrease the systemic exposure to sorafenib. - Ketoconazole, a strong inhibitor of CYP3A4 and P-glycoprotein, administered at a dose of 400 mg once daily for 7 days did not alter the mean AUC of a single oral dose of Sorafenib 50 mg in healthy volunteers. - Sorafenib 400 mg twice daily for 28 days did not increase the systemic exposure of concomitantly administered midazolam (CYP3A4 substrate), dextromethorphan (CYP2D6 substrate), and omeprazole (CYP2C19 substrate) - Neomycin administered as an oral dose of 1 g three times daily for 5 days decreased the mean AUC of sorafenib by 54% in healthy volunteers administered a single oral dose of Sorafenib 400 mg. The effects of other antibiotics on the pharmacokinetics of sorafenib have not been studied. - The aqueous solubility of sorafenib is pH dependent, with higher pH resulting in lower solubility. However, omeprazole, a proton pump inhibitor, administered at a dose of 40 mg once daily for 5 days, did not result in a clinically meaningful change in sorafenib single dose exposure. No dose adjustment for Sorafenib is necessary. - When administered to rats and rabbits during the period of organogenesis, sorafenib was teratogenic and induced embryo-fetal toxicity (including increased post-implantation loss, resorptions, skeletal retardations, and retarded fetal weight). The effects occurred at doses considerably below the recommended human dose of 400 mg twice daily (approximately 500 mg/m2/day on a body surface area basis). Adverse intrauterine development effects were seen at doses ≥0.2 mg/kg/day (1.2 mg/m2/day) in rats and 0.3 mg/kg/day (3.6 mg/m2/day) in rabbits. These doses result in exposures (AUC) approximately 0.008 times the AUC seen in patients at the recommended human dose. A NOAEL (no observed adverse effect level) was not defined for either species, since lower doses were not tested. - Following administration of radiolabeled sorafenib to lactating Wistar rats, approximately 27% of the radioactivity was secreted into the milk. The milk to plasma AUC ratio was approximately 5:1. - Repeat dosing of sorafenib to young and growing dogs resulted in irregular thickening of the femoral growth plate at daily sorafenib doses ≥ 600 mg/m2 (approximately 0.3 times the AUC at the recommended human dose), hypocellularity of the bone marrow adjoining the growth plate at 200 mg/m2/day (approximately 0.1 times the AUC at the recommended human dose), and alterations of the dentin composition at 600 mg/m2/day. Similar effects were not observed in adult dogs when dosed for 4 weeks or less. - After administration of Sorafenib tablets, the mean relative bioavailability was 38–49% when compared to an oral solution. Following oral administration, sorafenib reached peak plasma levels in approximately 3 hours. With a moderate-fat meal (30% fat; 700 calories), bioavailability was similar to that in the fasted state. With a high-fat meal (50% fat; 900 calories), bioavailability was reduced by 29% compared to that in the fasted state. It is recommended that Sorafenib be administered without food. Mean Cmax and AUC increased less than proportionally beyond oral doses of 400 mg administered twice daily. In vitro binding of sorafenib to human plasma proteins was 99.5%. - Sorafenib undergoes oxidative metabolism by hepatic CYP3A4, as well as glucuronidation by UGT1A9. Inducers of CYP3A4 activity can decrease the systemic exposure of sorafenib. Sorafenib accounted for approximately 70–85% of the circulating analytes in plasma at steady-state. Eight metabolites of sorafenib have been identified, of which 5 have been detected in plasma. The main circulating metabolite of sorafenib, the pyridine N-oxide that comprises approximately 9–16% of circulating analytes at steady-state, showed in vitro potency similar to that of sorafenib. Following oral administration of a 100 mg dose of a solution formulation of sorafenib, 96% of the dose was recovered within 14 days, with 77% of the dose excreted in feces and 19% of the dose excreted in urine as glucuronidated metabolites. Unchanged sorafenib, accounting for 51% of the dose, was found in feces but not in urine. - A study of the pharmacokinetics of sorafenib indicated that the mean AUC of sorafenib in Asians (N=78) was 30% lower than in Caucasians (N=40). Gender and age do not have a clinically meaningful effect on the pharmacokinetics of sorafenib. - Mild (CLcr 50-80 mL/min), moderate (CLcr 30 - <50 mL/min), and severe (CLcr <30 mL/min) renal impairment do not affect the pharmacokinetics of sorafenib. No dose adjustment is necessary. - Mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment do not affect the pharmacokinetics of sorafenib. No dose adjustment is necessary. Studies in human liver microsomes demonstrated that sorafenib competitively inhibited CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. However, Sorafenib 400 mg twice daily for 28 days with substrates of CYP3A4, CYP2D6 and CYP2C19 did not increase the systemic exposure of these substrates. Studies with cultured human hepatocytes demonstrated that sorafenib did not increase CYP1A2 and CYP3A4 activities, suggesting that sorafenib is unlikely to induce CYP1A2 or CYP3A4 in humans. Sorafenib inhibits glucuronidation by UGT1A1 and UGT1A9 in vitro. Sorafenib could increase the systemic exposure of concomitantly administered drugs that are UGT1A1 or UGT1A9 substrates. Sorafenib inhibited P-glycoprotein in vitro. Sorafenib could increase the concentrations of concomitantly administered drugs that are P-glycoprotein substrates. - Carcinogenicity studies have not been performed with sorafenib. Sorafenib was clastogenic when tested in an in vitro mammalian cell assay (Chinese hamster ovary) in the presence of metabolic activation. Sorafenib was not mutagenic in the in vitro Ames bacterial cell assay or clastogenic in an in vivo mouse micronucleus assay. One intermediate in the manufacturing process, which is also present in the final drug substance (<0.15%), was positive for mutagenesis in an in vitro bacterial cell assay (Ames test) when tested independently. - No specific studies with sorafenib have been conducted in animals to evaluate the effect on fertility. However, results from the repeat-dose toxicity studies suggest there is a potential for sorafenib to impair reproductive function and fertility. Multiple adverse effects were observed in male and female reproductive organs, with the rat being more susceptible than mice or dogs. Typical changes in rats consisted of testicular atrophy or degeneration, degeneration of epididymis, prostate, and seminal vesicles, central necrosis of the corpora lutea and arrested follicular development. Sorafenib-related effects on the reproductive organs of rats were manifested at daily oral doses ≥ 5 mg/kg (30 mg/m2). This dose results in an exposure (AUC) that is approximately 0.5 times the AUC in patients at the recommended human dose. Dogs showed tubular degeneration in the testes at 30 mg/kg/day (600 mg/m2/day). This dose results in an exposure that is approximately 0.3 times the AUC at the recommended human dose. Oligospermia was observed in dogs at 60 mg/kg/day (1200 mg/m2/day) of sorafenib. Adequate contraception should be used during therapy and for at least 2 weeks after completing therapy. - The HCC Study was a Phase 3, international, multicenter, randomized, double blind, placebo-controlled trial in patients with unresectable hepatocellular carcinoma. Overall survival was the primary endpoint. A total of 602 patients were randomized; 299 to Sorafenib 400 mg twice daily and 303 to matching placebo. Demographics and baseline disease characteristics were similar between the Sorafenib and placebo-treated groups with regard to age, gender, race, performance status, etiology (including hepatitis B, hepatitis C and alcoholic liver disease), TNM stage (stage I: <1% vs. <1%; stage II: 10.4% vs. 8.3%; stage III: 37.8% vs. 43.6%; stage IV: 50.8% vs. 46.9%), absence of both macroscopic vascular invasion and extrahepatic tumor spread (30.1% vs. 30.0%), and Barcelona Clinic Liver Cancer stage (stage B: 18.1% vs. 16.8%; stage C: 81.6% vs. 83.2%; stage D: <1% vs. 0%). Liver impairment by Child-Pugh score was comparable between the Sorafenib and placebo-treated groups (Class A: 95% vs. 98%; B: 5% vs. 2%). Only one patient with Child-Pugh class C was entered. Prior treatments included surgical resection procedures (19.1% vs. 20.5%), locoregional therapies (including radiofrequency ablation, percutaneous ethanol injection and transarterial chemoembolization; 38.8% vs. 40.6%), radiotherapy (4.3% vs. 5.0%) and systemic therapy (3.0% vs. 5.0%). - The trial was stopped for efficacy following a pre-specified second interim analysis for survival showing a statistically significant advantage for Sorafenib over placebo for overall survival (HR: 0.69, p= 0.00058) (see Table 4 and Figure 1). This advantage was consistent across all subsets analyzed. Final analysis of time to tumor progression (TTP) based on data from an earlier time point (by independent radiologic review) also was significantly longer in the Sorafenib arm (HR: 0.58, p=0.000007). - The safety and efficacy of Sorafenib in the treatment of advanced renal cell carcinoma (RCC) were studied in the following two randomized controlled clinical trials. RCC Study 1 was a Phase 3, international, multicenter, randomized, double blind, placebo-controlled trial in patients with advanced renal cell carcinoma who had received one prior systemic therapy. Primary study endpoints included overall survival and progression-free survival (PFS). Tumor response rate was a secondary endpoint. The PFS analysis included 769 patients stratified by MSKCC (Memorial Sloan Kettering Cancer Center) prognostic risk category (low or intermediate) and country and randomized to Sorafenib 400 mg twice daily (N=384) or to placebo (N=385). Table 8 summarizes the demographic and disease characteristics of the study population analyzed. Baseline demographics and disease characteristics were well balanced for both treatment groups. The median time from initial diagnosis of RCC to randomization was 1.6 and 1.9 years for the Sorafenib and placebo-treated groups, respectively. - The safety and effectiveness of Sorafenib was established in a multicenter, randomized (1:1), double-blind, placebo-controlled trial conducted in 417 patients with locally recurrent or metastatic, progressive differentiated thyroid carcinoma (DTC) refractory to radioactive iodine] (RAI) treatment]. Randomization was stratified by age (< 60 years versus ≥ 60 years) and geographical region (North America, Europe, and Asia). - All patients were required to have actively progressing disease defined as progression within 14 months of enrollment. RAI-refractory disease was defined based on four criteria that were not mutually exclusive. All RAI treatments and diagnostic scans were to be performed under conditions of a low iodine diet and adequate TSH stimulation. Following are the RAI-refractory criteria and the proportion of patients in the study that met each one: a target lesion with no iodine uptake on RAI scan (68%); tumors with iodine uptake and progression after RAI treatment within 16 months of enrollment (12%); tumors with iodine uptake and multiple RAI treatments with the last treatment greater than 16 months prior to enrollment, and disease progression after each of two RAI treatments administered within 16 months of each other (7%); cumulative RAI dose ≥ 600 mCi administered (34%). The major efficacy outcome measure was progression-free survival (PFS) as determined by a blinded, independent radiological review using a modified Response Evaluation Criteria in Solid Tumors v. 1.0 (RECIST). RECIST was modified by inclusion of clinical progression of bone lesions based on the need for external beam radiation (4.4% of progression events). Additional efficacy outcomes measures included overall survival (OS), tumor response rate, and duration of response. - Patients were randomized to receive Sorafenib 400 mg twice daily (n=207) or placebo (n=210). Of the 417 patients randomized, 48% were male, the median age was 63 years, 61% were 60 years or older, 60% were white, 62% had an ECOG performance status of 0, and 99% had undergone thyroidectomy. The histological diagnoses were papillary carcinoma in 57%, follicular carcinoma (including Hürthle cell) in 25%, and poorly differentiated carcinoma in 10%, and other in 8% of the study population. Metastases were present in 96% of the patients: lungs in 86%, lymph nodes in 51%, and bone in 27%. The median cumulative RAI activity administered prior to study entry was 400 mCi. A statistically significant prolongation in PFS was demonstrated among Sorafenib-treated patients compared to those receiving placebo. Following investigator-determined disease progression, 157 (75%) patients randomized to placebo crossed over to open-label Sorafenib, and 61 (30%) patients randomized to Sorafenib received open-label Sorafenib There was no statistically significant difference in overall survival between the two treatment arms (see Table 9 and Figure 3). Bottles of 120 tablets NDC 50419-488-58 Template:WH Template:WikiDoc Sources	https://www.wikidoc.org/index.php/NexAVAR
6b1885d2ebc014cf738512e6da1e397ee794b6e2	wikidoc	Nicastrin	Nicastrin Nicastrin, also known as NCSTN, is a protein that in humans is encoded by the NCSTN gene. # Function Nicastrin (abbreviated NCT) is a protein that is part of the gamma secretase protein complex, which is one of the proteases involved in processing amyloid precursor protein (APP) to the short Alzheimer's disease-associated peptide amyloid beta. The other proteins in the complex are PSEN1 (presenilin-1), which is the catalytically active component of the complex, APH-1 (anterior pharynx-defective 1), and PEN-2 (presenilin enhancer 2). Nicastrin itself is not catalytically active, but instead promotes the maturation and proper trafficking of the other proteins in the complex, all of which undergo significant post-translational modification before becoming active in the cell. Nicastrin has also been identified as a regulator of neprilysin, an enzyme involved in the degradation of amyloid beta fragment. # History The protein was named after the Italian village Nicastro, reflecting the fact that Alzheimer's disease was described in 1963 after studying descendants of an extended family originating in the village of Nicastro that had Familial Alzheimer's Disease (FAD). # Interactions Nicastrin has been shown to interact with PSEN1 and PSEN2.	Nicastrin Nicastrin, also known as NCSTN, is a protein that in humans is encoded by the NCSTN gene.[1][2][3] # Function Nicastrin (abbreviated NCT) is a protein that is part of the gamma secretase protein complex, which is one of the proteases involved in processing amyloid precursor protein (APP) to the short Alzheimer's disease-associated peptide amyloid beta. The other proteins in the complex are PSEN1 (presenilin-1), which is the catalytically active component of the complex, APH-1 (anterior pharynx-defective 1), and PEN-2 (presenilin enhancer 2).[4] Nicastrin itself is not catalytically active, but instead promotes the maturation and proper trafficking of the other proteins in the complex, all of which undergo significant post-translational modification before becoming active in the cell.[5] Nicastrin has also been identified as a regulator of neprilysin, an enzyme involved in the degradation of amyloid beta fragment.[6] # History The protein was named after the Italian village Nicastro, reflecting the fact that Alzheimer's disease was described in 1963 after studying descendants of an extended family originating in the village of Nicastro that had Familial Alzheimer's Disease (FAD).[7] # Interactions Nicastrin has been shown to interact with PSEN1[8][9][10][11][12] and PSEN2.[8][12]	https://www.wikidoc.org/index.php/Nicastrin
241b22d0b38d7d8e06f4a756a37c64247cbf119c	wikidoc	Nicorette	Nicorette Nicorette is a branded over-the-counter palliative treatment which is used to ameliorate the withdrawal effects involved in quitting smoking. It was part of Pfizer Consumer Healthcare Products Company, which was sold to Johnson & Johnson in 2006. Originally available as a patch for topical application, it was later made available as a nicotine gum (composed of nicotine polacrilex) lozenge, inhaler, and nasal spray. All these products contain nicotine as the active ingredient and work by delivering this into the bloodstream. These treatments are commonly referred to as nicotine replacement therapies. Alternative brand names include Prostep, Habitrol, Nicotrol, Nicoderm, and Commit. Commit lozenges are an oral palliative aid in the cessation of smoking. Formats of both 4 mg (for those who smoke their first daily cigarette within 30 minutes of waking) and 2 mg (for those who wait more than 30 minutes before the first daily dose of nicotine), are available. The lozenges, which are of a minty flavour, are meant to be taken orally at least nine times a day during the first two weeks after a nicotine user is willing to quit using tobacco products. Nicorette inhalers are widely available over the counter. In the United States they are branded as Nictrol Inhalers and are only available on prescription. It is encouraged that you should stop using Nicorette after 12 weeks. This product can become addictive just like smoking if abused. An internet search can find many overseas or Canadian retailers shipping to the USA for half price. # Gum Flavors - Original - Mint - Fruit Chill - Fresh Mint	Nicorette Nicorette is a branded over-the-counter palliative treatment which is used to ameliorate the withdrawal effects involved in quitting smoking. It was part of Pfizer Consumer Healthcare Products Company, which was sold to Johnson & Johnson in 2006. Originally available as a patch for topical application, it was later made available as a nicotine gum (composed of nicotine polacrilex) lozenge, inhaler, and nasal spray. All these products contain nicotine as the active ingredient and work by delivering this into the bloodstream. These treatments are commonly referred to as nicotine replacement therapies. Alternative brand names include Prostep, Habitrol, Nicotrol, Nicoderm, and Commit. Commit lozenges are an oral palliative aid in the cessation of smoking. Formats of both 4 mg (for those who smoke their first daily cigarette within 30 minutes of waking) and 2 mg (for those who wait more than 30 minutes before the first daily dose of nicotine), are available. The lozenges, which are of a minty flavour, are meant to be taken orally at least nine times a day during the first two weeks after a nicotine user is willing to quit using tobacco products. Nicorette inhalers are widely available over the counter. In the United States they are branded as Nictrol Inhalers and are only available on prescription. It is encouraged that you should stop using Nicorette after 12 weeks. This product can become addictive just like smoking if abused. An internet search can find many overseas or Canadian retailers shipping to the USA for half price. # Gum Flavors - Original - Mint - Fruit Chill - Fresh Mint # External links - Nicorette Homepage - Nicoderm website Template:Treatment-stub sv:Nicorette Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Nicorette
7f59a15a2b67308f34fc9f442af51f41398852a4	wikidoc	Nicotiana	Nicotiana Nicotiana refers to a genus of short-leafed plants of the nightshade family indigenous to North and South America. The leaves of various Nicotiana sp., also commonly referred to as tobacco plants, are cultivated and grown to produce tobacco. The plants contain high quantities of nicotine and as such are commonly used as entheogens and used for pleasure. The leaves processed into forms where they can be smoked, chewed, and sniffed. Of all Nicotiana species, N. tabacum is the most widely cultivated and used worldwide for production of tobacco leaf for cigarettes. Many plants including tobacco and eggplant contain nicotine, a powerful neurotoxin that is particularly harmful to insects. However, tobacco contains a higher concentration of nicotine. # Cultivation ## Sowing Nicotiana seeds are scattered onto the surface of the soil, as their germination is activated by light. In colonial Virginia, seedbeds were fertilized with wood ash or animal manure (frequently powdered horse manure). Seedbeds were then covered with branches to protect the young plants from frost damage. These plants were left to grow until around April. In the nineteenth century, young plants came under increasing attack from the flea beetle (Epitrix cucumeris or Epitrix pubescens), causing destruction of half the United States tobacco crop in 1876. In the years afterward, many experiments were attempted and discussed to control the flea beetle. By 1880 it was discovered that replacing the branches with a frame covered by thin fabric would effectively protect plants from the beetle. This practice spread until it became ubiquitous in the 1890s. Today, in the United States, unlike other countries, Nicotiana is often fertilized with the mineral apatite in order to partially starve the plant for nitrogen, which changes the taste of the tobacco. ## Transplanting After the plants have reached a certain height, they are transplanted into fields. This was originally done by making a relatively large hole in the tilled earth with a tobacco peg, then placing the small plant in the hole. Various mechanical tobacco planters were invented throughout the late 19th and early 20th century to automate this process, making a hole, fertilizing it, and guiding a plant into the hole with one motion. # Species Nicotiana acuminata Nicotiana alata Nicotiana attenuata Nicotiana benthamiana Nicotiana clevelandii Nicotiana × digluta Nicotiana excelsior Nicotiana forgetiana Nicotiana glauca Nicotiana glutinosa Nicotiana langsdorffii Nicotiana longiflora Nicotiana obtusifolia (synonym: Nicotiana trigonophylla) Nicotiana paniculata Nicotiana plumbagifolia Nicotiana quadrivalvis Nicotiana repanda Nicotiana rustica Nicotiana suaveolens Nicotiana sylvestris Nicotiana tabacum (a cultivated hybrid, not a species) Nicotiana tomentosa ITIS 30562 as of August 26, 2005 # Gallery - Nicotiana glauca Nicotiana glauca - Nicotiana rustica Nicotiana rustica - Flower of Nicotiana tabacum	Nicotiana Nicotiana refers to a genus of short-leafed plants of the nightshade family indigenous to North and South America. The leaves of various Nicotiana sp., also commonly referred to as tobacco plants, are cultivated and grown to produce tobacco. The plants contain high quantities of nicotine and as such are commonly used as entheogens and used for pleasure. The leaves processed into forms where they can be smoked, chewed, and sniffed. Of all Nicotiana species, N. tabacum is the most widely cultivated and used worldwide for production of tobacco leaf for cigarettes. Many plants including tobacco and eggplant contain nicotine, a powerful neurotoxin that is particularly harmful to insects. However, tobacco contains a higher concentration of nicotine. # Cultivation ## Sowing Nicotiana seeds are scattered onto the surface of the soil, as their germination is activated by light. In colonial Virginia, seedbeds were fertilized with wood ash or animal manure (frequently powdered horse manure). Seedbeds were then covered with branches to protect the young plants from frost damage. These plants were left to grow until around April. In the nineteenth century, young plants came under increasing attack from the flea beetle (Epitrix cucumeris or Epitrix pubescens), causing destruction of half the United States tobacco crop in 1876. In the years afterward, many experiments were attempted and discussed to control the flea beetle. By 1880 it was discovered that replacing the branches with a frame covered by thin fabric would effectively protect plants from the beetle. This practice spread until it became ubiquitous in the 1890s. Today, in the United States, unlike other countries, Nicotiana is often fertilized with the mineral apatite in order to partially starve the plant for nitrogen, which changes the taste of the tobacco. ## Transplanting After the plants have reached a certain height, they are transplanted into fields. This was originally done by making a relatively large hole in the tilled earth with a tobacco peg, then placing the small plant in the hole. Various mechanical tobacco planters were invented throughout the late 19th and early 20th century to automate this process, making a hole, fertilizing it, and guiding a plant into the hole with one motion. # Species Nicotiana acuminata Nicotiana alata Nicotiana attenuata Nicotiana benthamiana Nicotiana clevelandii Nicotiana × digluta Nicotiana excelsior Nicotiana forgetiana Nicotiana glauca Nicotiana glutinosa Nicotiana langsdorffii Nicotiana longiflora Nicotiana obtusifolia (synonym: Nicotiana trigonophylla[1]) Nicotiana paniculata Nicotiana plumbagifolia Nicotiana quadrivalvis Nicotiana repanda Nicotiana rustica Nicotiana suaveolens Nicotiana sylvestris Nicotiana tabacum (a cultivated hybrid, not a species) Nicotiana tomentosa ITIS 30562 as of August 26, 2005 # Gallery - Nicotiana glauca Nicotiana glauca - Nicotiana rustica Nicotiana rustica - Flower of Nicotiana tabacum	https://www.wikidoc.org/index.php/Nicotiana
07ff3f198cbe1afbf08613e052a3c33f9ecb8dd9	wikidoc	Nifuratel	Nifuratel # Overview Nifuratel (brand name Macmiror, or—in combination with nystatin—Macmiror Complex) is a drug used in gynecology. It is a local antiprotozoal and antifungal agent that may also be given orally. Nifuratel is not approved for use in the United States. Nifuratel appears to have a broad antibacterial spectrum of action and is effective against Chlamydia trachomatis and Mycoplasma spp. as well as fungal infections from Candida spp. Taken orally, or as a vaginal pessary, it is used in the treatment of a wide range of infections of the genito-urinary tract, especially if there is no accurate diagnosis available. For example it may be used in the treatment of women exhibiting vaginal discharge where there is uncertainty as to whether the cause is Trichomonas vaginalis or Candida strains such as Candida albicans. Side effects appear to be minimal or non-existent and it has a safe toxicological profile.	Nifuratel Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Nifuratel (brand name Macmiror, or—in combination with nystatin—Macmiror Complex) is a drug used in gynecology. It is a local antiprotozoal and antifungal agent that may also be given orally. Nifuratel is not approved for use in the United States. Nifuratel appears to have a broad antibacterial spectrum of action and is effective against Chlamydia trachomatis and Mycoplasma spp. as well as fungal infections from Candida spp.[1] Taken orally, or as a vaginal pessary, it is used in the treatment of a wide range of infections of the genito-urinary tract, especially if there is no accurate diagnosis available. For example it may be used in the treatment of women exhibiting vaginal discharge where there is uncertainty as to whether the cause is Trichomonas vaginalis or Candida strains such as Candida albicans. Side effects appear to be minimal or non-existent and it has a safe toxicological profile.[2]	https://www.wikidoc.org/index.php/Nifuratel
75ebcb995d8a31099eb4afa93f12e2aecd587fa9	wikidoc	Nigericin	Nigericin Nigericin is an antibiotic derived from Streptomyces hygroscopicus. Commercially it is obtained as a byproduct, or contaminant, at the fermentation of Geldanamycin. It is also called Polyetherin A, Azalomycin M, Helixin C, Antibiotic K178, Antibiotic X-464. Nigericin acts as an H+, K+, Pb++ ionophore. It most commonly is an antiporter of H+ and K+. In the past Nigericin was used as an antibiotic active against gram positive bacteria. It inhibits the Golgi functions. Nigericin exhibits anti-HIV activity. # Properties - CAS number: 28643-80-3 - Merck index: 12, 6633 - Molecular weight: 747 - Formula C40H67O11Na The properties are copied from a manufacturer's Nigericin product page] # External references	Nigericin Nigericin is an antibiotic derived from Streptomyces hygroscopicus. Commercially it is obtained as a byproduct, or contaminant, at the fermentation of Geldanamycin. It is also called Polyetherin A, Azalomycin M, Helixin C, Antibiotic K178, Antibiotic X-464. Nigericin acts as an H+, K+, Pb++ ionophore. It most commonly is an antiporter of H+ and K+. In the past Nigericin was used as an antibiotic active against gram positive bacteria. It inhibits the Golgi functions. Nigericin exhibits anti-HIV activity. # Properties - CAS number: 28643-80-3 - Merck index: 12, 6633 - Molecular weight: 747 - Formula C40H67O11Na The properties are copied from a manufacturer's Nigericin product page] # External references Template:WH Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Nigericin
c12b067cbcb9e078e0dae950e46b5fe82c56f2d7	wikidoc	Nightmare	Nightmare # Overview A nightmare is a dream which causes a strong unpleasant emotional response from the sleeper, typically fear or horror, or the sensations of pain, falling, drowning or death. Such dreams can be related to physical causes such as a high fever, or psychological ones such as psychological trauma or stress in the sleeper's life, or can have no apparent cause. If a person has experienced a psychologically traumatic situation in life—for example, a person who may have been captured and tortured—the experience may come back to haunt them in their nightmares. Sleepers may waken in a state of distress and be unable to get back to sleep for some time. Occasional nightmares are commonplace, but recurrent nightmares can interfere with sleep and may cause people to seek medical help. A recently proposed treatment consists of imagery rehearsal. This approach appears to reduce the effects of nightmares and other symptoms in acute stress disorder and post-traumatic stress disorder. Practitioners of lucid dreaming claim that it can help conquer nightmares of this type, rather than of the traditional type (see below). # Historic use of term Nightmare was the original term for the state later known as waking dream (cf. Mary Shelley and Frankenstein's Genesis), and more currently as sleep paralysis, associated with rapid eye movement (REM) sleep. The original definition was codified by Dr Johnson in his A Dictionary of the English Language and was thus understood, among others by Erasmus Darwin and Henry Fuseli, to include a "morbid oppression during sleep, resembling the pressure of weight upon the breast." Such nightmares were widely considered to be the work of demons and more specifically incubi, which were thought to sit on the chests of sleepers. In Old English the name for these beings was mare or mære (from a proto-Germanic *marōn, related to Old High German and Old Norse mara), hence comes the mare part in nightmare. Folk belief in Newfoundland, South Carolina and Georgia describe the negative figure of the Hag who leaves her physical body at night, and sits on the chest of her victim. The victim usually wakes with a feeling of terror, has difficulty breathing because of a perceived heavy invisible weight on his or her chest, and is unable to move i.e., experiences sleep paralysis. This nightmare experience is described as being "hag-ridden" in the Gullah lore. The "Old Hag" was a nightmare spirit in British and also Anglophone North American folklore. Various forms of magic and spiritual possession were also advanced as causes. In nineteenth century Europe, the vagaries of diet were thought to be responsible. For example, in Charles Dickens's A Christmas Carol, Ebenezer Scrooge attributes the ghost he sees to "... an undigested bit of beef, a blot of mustard, a crumb of cheese, a fragment of an underdone potato..." In a similar vein, the Household Cyclopedia (1881) offers the following advice about nightmares:	Nightmare For patient information click here Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview A nightmare is a dream which causes a strong unpleasant emotional response from the sleeper, typically fear or horror, or the sensations of pain, falling, drowning or death. Such dreams can be related to physical causes such as a high fever, or psychological ones such as psychological trauma or stress in the sleeper's life, or can have no apparent cause. If a person has experienced a psychologically traumatic situation in life—for example, a person who may have been captured and tortured—the experience may come back to haunt them in their nightmares. Sleepers may waken in a state of distress and be unable to get back to sleep for some time. Occasional nightmares are commonplace, but recurrent nightmares can interfere with sleep and may cause people to seek medical help. A recently proposed treatment consists of imagery rehearsal.[1] This approach appears to reduce the effects of nightmares and other symptoms in acute stress disorder and post-traumatic stress disorder.[2] Practitioners of lucid dreaming claim that it can help conquer nightmares of this type,[3] rather than of the traditional type (see below). # Historic use of term Nightmare was the original term for the state later known as waking dream (cf. Mary Shelley and Frankenstein's Genesis), and more currently as sleep paralysis, associated with rapid eye movement (REM) sleep. The original definition was codified by Dr Johnson in his A Dictionary of the English Language and was thus understood, among others by Erasmus Darwin and Henry Fuseli,[4] to include a "morbid oppression during sleep, resembling the pressure of weight upon the breast." Such nightmares were widely considered to be the work of demons and more specifically incubi, which were thought to sit on the chests of sleepers. In Old English the name for these beings was mare or mære (from a proto-Germanic *marōn, related to Old High German and Old Norse mara), hence comes the mare part in nightmare. Folk belief in Newfoundland, South Carolina and Georgia describe the negative figure of the Hag who leaves her physical body at night, and sits on the chest of her victim. The victim usually wakes with a feeling of terror, has difficulty breathing because of a perceived heavy invisible weight on his or her chest, and is unable to move i.e., experiences sleep paralysis. This nightmare experience is described as being "hag-ridden" in the Gullah lore. The "Old Hag" was a nightmare spirit in British and also Anglophone North American folklore. Various forms of magic and spiritual possession were also advanced as causes. In nineteenth century Europe, the vagaries of diet were thought to be responsible. For example, in Charles Dickens's A Christmas Carol, Ebenezer Scrooge attributes the ghost he sees to "... an undigested bit of beef, a blot of mustard, a crumb of cheese, a fragment of an underdone potato..." In a similar vein, the Household Cyclopedia (1881) offers the following advice about nightmares:	https://www.wikidoc.org/index.php/Nightmare
1dd43acf930ad5f6fbbbb44b491a31ca9642a7f5	wikidoc	Nilotinib	Nilotinib # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Nilotinib is a kinase inhibitor that is FDA approved for the treatment of newly diagnosed adult patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase and chronic phase (CP) and accelerated phase (AP) Ph+ CML in adult patients resistant to or intolerant to prior therapy that included imatinib. There is a Black Box Warning for this drug as shown here. Common adverse reactions include nausea, rash, headache, fatigue, pruritus, vomiting, diarrhea, cough, constipation, arthralgia, nasopharyngitis, pyrexia, and night sweats. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - The recommended dose of Tasigna is 300 mg orally twice daily. - The recommended dose of Tasigna (nilotinib) is 400 mg orally twice daily. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Nilotinib in adult patients. ### Non–Guideline-Supported Use - Nilotinib dose, ranging from 50 to 1200 mg orally once daily and 400 to 600 mg twice daily. - Nilotinib 400 mg twice daily. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Nilotinib in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Nilotinib in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Nilotinib in pediatric patients. # Contraindications - Do not use in patients with hypokalemia, hypomagnesemia, or long QT syndrome. # Warnings ### Precautions - Myelosuppression - Treatment with Tasigna can cause Grade 3/4 thrombocytopenia, neutropenia and anemia. Perform complete blood counts every 2 weeks for the first 2 months and then monthly thereafter, or as clinically indicated. Myelosuppression was generally reversible and usually managed by withholding Tasigna temporarily or dose reduction. - QT Prolongation - Tasigna has been shown to prolong cardiac ventricular repolarization as measured by the QT interval on the surface ECG in a concentration-dependent manner. Prolongation of the QT interval can result in a type of ventricular tachycardia called torsade de pointes, which may result in syncope, seizure, and/or death. ECGs should be performed at baseline, 7 days after initiation of Tasigna, and periodically as clinically indicated and following dose adjustments. - Tasigna should not be used in patients who have hypokalemia, hypomagnesemia or long QT syndrome. Before initiating Tasigna and periodically, test electrolyte, calcium and magnesium blood levels. Hypokalemia or hypomagnesemia must be corrected prior to initiating Tasigna and these electrolytes should be monitored periodically during therapy. - Significant prolongation of the QT interval may occur when Tasigna is inappropriately taken with food and/or strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT. Therefore, coadministration with food must be avoided and concomitant use with strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT should be avoided. The presence of hypokalemia and hypomagnesemia may further prolong the QT interval. - Sudden Deaths - Sudden deaths have been reported in 0.3% of patients with CML treated with nilotinib in clinical studies of 5,661 patients. The relative early occurrence of some of these deaths relative to the initiation of nilotinib suggests the possibility that ventricular repolarization abnormalities may have contributed to their occurrence. - Cardiac and Vascular Events - Cardiovascular events, including arterial vascular occlusive events, were reported in a randomized, clinical trial in newly diagnosed CML patients and observed in the post-marketing reports of patients receiving nilotinib therapy. With a median time on therapy of 48 months in the clinical trial, cases of cardiovascular events included ischemic heart disease-related events (5.0% and 5.8% in the nilotinib 300 mg and 400 mg bid arms respectively, and 1.8% in the imatinib arm), peripheral arterial occlusive disease (1.8% and 2.2% in the nilotinib 300 mg and 400 mg bid arms respectively, and 0% in the imatinib arm), and ischemic cerebrovascular events (1.1% and 1.8% in the nilotinib 300 mg and 400 mg bid arms respectively, and 0.7% in the imatinib arm). If acute signs or symptoms of cardiovascular events occur, advise patients to seek immediate medical attention. The cardiovascular status of patients should be evaluated and cardiovascular risk factors should be monitored and actively managed during Tasigna therapy according to standard guidelines. - Pancreatitis and Elevated Serum Lipase - can cause increases in serum lipase. Patients with a previous history of pancreatitis may be at greater risk of elevated serum lipase. If lipase elevations are accompanied by abdominal symptoms, interrupt dosing and consider appropriate diagnostics to exclude pancreatitis. Test serum lipase levels monthly or as clinically indicated. - Hepatotoxicity - Tasigna may result in hepatotoxicity as measured by elevations in bilirubin, AST/ALT, and alkaline phosphatase. Monitor hepatic function tests monthly or as clinically indicated. - Electrolyte Abnormalities - The use of Tasigna can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia. Electrolyte abnormalities must be corrected prior to initiating Tasigna and these electrolytes should be monitored periodically during therapy. - Drug Interactions - Avoid administration of Tasigna with agents that may increase nilotinib exposure (e.g., strong CYP3A4 inhibitors) or anti-arrhythmic drugs (including, but not limited to amiodarone, disopyramide, procainamide, quinidine and sotalol) and other drugs that may prolong QT interval (including, but not limited to chloroquine, clarithromycin, haloperidol, methadone, moxifloxacin and pimozide). Should treatment with any of these agents be required, interrupt therapy with Tasigna. If interruption of treatment with Tasigna is not possible, patients who require treatment with a drug that prolongs QT or strongly inhibits CYP3A4 should be closely monitored for prolongation of the QT interval. - Food Effects - The bioavailability of nilotinib is increased with food, thus Tasigna must not be taken with food. No food should be consumed for at least 2 hours before and for at least 1 hour after the dose is taken. Also avoid grapefruit products and other foods that are known to inhibit CYP3A4. - Hepatic Impairment - Nilotinib exposure is increased in patients with impaired hepatic function. Use a lower starting dose for patients with mild to severe hepatic impairment (at baseline) and monitor the QT interval frequently. - Tumor Lysis Syndrome - Tumor lysis syndrome cases have been reported in Tasigna treated patients with resistant or intolerant CML. Malignant disease progression, high WBC counts and/or dehydration were present in the majority of these cases. Due to potential for tumor lysis syndrome, maintain adequate hydration and correct uric acid levels prior to initiating therapy with Tasigna. - Total Gastrectomy - Since the exposure of nilotinib is reduced in patients with total gastrectomy, perform more frequent monitoring of these patients. Consider dose increase or alternative therapy in patients with total gastrectomy. - Lactose - Since the capsules contain lactose, Tasigna is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency with a severe degree of intolerance to lactose-containing products, or of glucose-galactose malabsorption. - Monitoring Laboratory Tests - Complete blood counts should be performed every 2 weeks for the first 2 months and then monthly thereafter. Chemistry panels, including electrolytes, calcium, magnesium, lipid profile, and glucose should be checked prior to therapy and periodically. ECGs should be obtained at baseline, 7 days after initiation and periodically thereafter, as well as following dose adjustments. Laboratory monitoring for patients receiving Tasigna may need to be performed more or less frequently at the physician’s discretion. - Embryo-Fetal Toxicity - There are no adequate and well controlled studies of Tasigna in pregnant women. However, Tasigna may cause fetal harm when administered to a pregnant woman. Nilotinib caused embryo-fetal toxicities in animals at maternal exposures that were lower than the expected human exposure at the recommended doses of nilotinib. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of child-bearing potential should avoid becoming pregnant while taking Tasigna. # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. - The data below reflect exposure to Tasigna from a randomized trial in patients with newly diagnosed Ph+ CML in chronic phase treated at the recommended dose of 300 mg twice daily (n=279). The median time on treatment in the nilotinib 300 mg twice daily group was 48 months (range 0.1 to 59 months). The median actual dose intensity was 594 mg/day in the nilotinib 300 mg twice daily group. - The most common (>10%) non-hematologic adverse drug reactions were rash, pruritus, headache, nausea, fatigue, alopecia and myalgia. Upper abdominal pain, constipation, diarrhea, dry skin, muscle spasms, arthralgia, abdominal pain, peripheral edema, vomiting, and asthenia were observed less commonly (≤10% and >5%) and have been of mild to moderate severity, manageable and generally did not require dose reduction. Pleural and pericardial effusions, occurred in 1% and <;&lt1% of patients, respectively. Gastrointestinal hemorrhage was reported in 3% of patients. - Increase in QTcF >60 msec from baseline was observed in 1 patient (0.4%) in the 300 mg twice daily treatment group. No patient had an absolute QTcF of >500 msec while on study drug. - The most common hematologic adverse drug reactions (all grades) were myelosuppression including: thrombocytopenia (18%), neutropenia (15%) and anemia (7%). See Table 7 for Grade 3/4 laboratory abnormalities. - Discontinuation due to adverse reactions, regardless of relationship to study drug, was observed in 10% of patients. - In the single open-label multicenter clinical trial, a total of 458 patients with Ph+ CML-CP and CML-AP resistant to or intolerant to at least one prior therapy including imatinib were treated (CML-CP=321; CML-AP=137) at the recommended dose of 400 mg twice daily. - The median duration of exposure in days for CML-CP and CML-AP patients is 561 (range 1 to 1096) and 264 (range 2 to 1160), respectively. The median dose intensity for patients with CML-CP and CML-AP is 789 mg/day (range 151 to 1110) and 780 mg/day (range 150 to 1149), respectively and corresponded to the planned 400 mg twice daily dosing. - The median cumulative duration in days of dose interruptions for the CML-CP patients was 20 (range 1 to 345), and the median duration in days of dose interruptions for the CML-AP patients was 23 (range 1 to 234). - In patients with CML-CP, the most commonly reported non-hematologic adverse drug reactions (≥10%) were rash, pruritus, nausea, fatigue, headache, constipation, diarrhea, vomiting and myalgia. The common serious drug-related adverse reactions (≥1% and <10%) were thrombocytopenia, neutropenia and anemia. - In patients with CML-AP, the most commonly reported non-hematologic adverse drug reactions (≥10%) were rash, pruritus and fatigue. The common serious adverse drug reactions (≥1% and <;&lt10%) were thrombocytopenia, neutropenia, febrile neutropenia, pneumonia, leukopenia, intracranial hemorrhage, elevated lipase and pyrexia. - Sudden deaths and QT prolongation were reported. The maximum mean QTcF change from baseline at steady-state was 10 msec. Increase in QTcF >60 msec from baseline was observed in 4.1% of the patients and QTcF of >500 msec was observed in 4 patients (<1%). - Discontinuation due to adverse drug reactions was observed in 16% of CML-CP and 10% of CML-AP patients. - Tables 5 and 6 show the percentage of patients experiencing non-hematologic adverse reactions (excluding laboratory abnormalities) regardless of relationship to study drug. Adverse reactions reported in greater than 10% of patients who received at least 1 dose of Tasigna are listed. - The following adverse drug reactions were reported in patients in the Tasigna clinical studies at the recommended doses. These adverse drug reactions are ranked under a heading of frequency, the most frequent first using the following convention: common (≥1% and <10%), uncommon (≥0.1% and <1%), and unknown frequency (single events). For laboratory abnormalities, very common events (≥10%), which were not included in Tables 5 and 6, are also reported. These adverse reactions are included based on clinical relevance and ranked in order of decreasing seriousness within each category, obtained from 2 clinical studies: - Newly diagnosed Ph+ CML-CP 48 month analysis and, - Resistant or intolerant Ph+ CML-CP and CMP-AP 24 months’ analysis. Common: folliculitis, upper respiratory tract infection (including pharyngitis, nasopharyngitis, rhinitis). Uncommon: pneumonia, bronchitis, urinary tract infection, candidiasis (including oral candidiasis), gastroenteritis. Unknown frequency: sepsis, subcutaneous abscess, anal abscess, furuncle, tinea pedis. Common: skin papilloma. Unknown frequency: oral papilloma, paraproteinemia. Common: eosinophilia, febrile neutropenia, pancytopenia, lymphopenia. Unknown frequency: thrombocythemia, leukocytosis. Unknown frequency: hypersensitivity. Uncommon: hyperthyroidism, hypothyroidism. Unknown frequency: hyperparathyroidism secondary, thyroiditis. Very Common: hypophosphatemia. Common: electrolyte imbalance (including hypomagnesemia, hyperkalemia, hypokalemia, hyponatremia, hypocalcemia, hypercalcemia, hyperphosphatemia), diabetes mellitus, hyperglycemia, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia. Uncommon: gout, dehydration, increased appetite. Unknown frequency: hyperuricemia, hypoglycemia. Common: depression, insomnia, anxiety. Unknown frequency: disorientation, confusional state, amnesia, dysphoria. Common: dizziness, peripheral neuropathy, hypoesthesia, paresthesia. Uncommon: intracranial hemorrhage, migraine, loss of consciousness (including syncope), tremor, disturbance in attention, hyperesthesia. Unknown frequency: transient ischemic attack, brain edema, optic neuritis, lethargy, dysesthesia, restless legs syndrome. Common: eye hemorrhage, periorbital edema, eye pruritus, conjunctivitis, dry eye (including xerophthalmia). Uncommon: vision impairment, vision blurred, visual acuity reduced, photopsia, hyperemia (scleral, conjunctival, ocular), eye irritation, conjunctival hemorrhage. Unknown frequency: papilloedema, diplopia, photophobia, eye swelling, blepharitis, eye pain, chorioretinopathy, conjunctivitis allergic, ocular surface disease. Common: vertigo. Unknown frequency: hearing impaired, ear pain, tinnitus. Common: angina pectoris, arrhythmia (including atrioventricular block, cardiac flutter, extrasystoles, atrial fibrillation, tachycardia, bradycardia), palpitations, electrocardiogram QT prolonged. Uncommon: cardiac failure, pericardial effusion, coronary artery disease, cyanosis, cardiac murmur. Unknown frequency: myocardial infarction, ventricular dysfunction, pericarditis, ejection fraction decrease. Common: hypertension, flushing. Uncommon: hypertensive crisis, peripheral arterial occlusive disease, intermittent claudication, arterial stenosis limb, hematoma, arteriosclerosis. Unknown frequency: shock hemorrhagic, hypotension, thrombosis. Common: dyspnea, dyspnea exertional, epistaxis, cough, dysphonia. Uncommon: pulmonary edema, pleural effusion, interstitial lung disease, pleuritic pain, pleurisy, pharyngolaryngeal pain, throat irritation. Unknown frequency: pulmonary hypertension, wheezing, oropharyngeal pain. Common: pancreatitis, abdominal discomfort, abdominal distension, dyspepsia, dysgeusia, flatulence. Uncommon: gastrointestinal hemorrhage, melena, mouth ulceration, gastroesophageal reflux, stomatitis, esophageal pain, dry mouth, gastritis, sensitivity of teeth. Unknown frequency: gastrointestinal ulcer perforation, retroperitoneal hemorrhage, hematemesis, gastric ulcer, esophagitis ulcerative, subileus, enterocolitis, hemorrhoids, hiatus hernia, rectal hemorrhage, gingivitis. Very Common: hyperbilirubinemia. Common: hepatic function abnormal. Uncommon: hepatotoxicity, toxic hepatitis, jaundice. Unknown frequency: cholestasis, hepatomegaly. Common: night sweats, eczema, urticaria, erythema, hyperhidrosis, contusion, acne, dermatitis (including allergic, exfoliative and acneiform), dry skin. Uncommon: exfoliative rash, drug eruption, pain of skin, ecchymosis, swelling of face. Unknown frequency: psoriasis, erythema multiforme, erythema nodosum, skin ulcer, palmar-plantar erythrodysesthesia syndrome, petechiae, photosensitivity, blister, dermal cyst, sebaceous hyperplasia, skin atrophy, skin discoloration, skin exfoliation, skin hyperpigmentation, skin hypertrophy, hyperkeratosis. Common: bone pain, musculoskeletal chest pain, musculoskeletal pain, back pain, neck pain, flank pain. Uncommon: musculoskeletal stiffness, muscular weakness, joint swelling. Unknown frequency: arthritis. Common: pollakiuria. Uncommon: dysuria, micturition urgency, nocturia. Unknown frequency: renal failure, hematuria, urinary incontinence, chromaturia. Uncommon: breast pain, gynecomastia, erectile dysfunction. Unknown frequency: breast induration, menorrhagia, nipple swelling. Common: pyrexia, chest pain (including non-cardiac chest pain), pain, chest discomfort, malaise. Uncommon: face edema, gravitational edema, influenza-like illness, chills, feeling body temperature change (including feeling hot, feeling cold). Unknown frequency: localized edema. Very Common: alanine aminotransferase increased, aspartate aminotransferase increased, lipase increased. Common: hemoglobin decreased, blood amylase increased, gamma-glutamyltransferase increased, blood creatinine phosphokinase increased, blood alkaline phosphatase increased, weight decreased, weight increased, lipoprotein increased (including very low density and high density). Uncommon: blood lactate dehydrogenase increased, blood urea increased, globulins decreased. Unknown frequency: troponin increased, blood bilirubin unconjugated increased, insulin C-peptide decreased, blood parathyroid hormone increased. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Nilotinib in the drug label. # Drug Interactions - Effects of Nilotinib on Drug Metabolizing Enzymes and Drug Transport Systems - Nilotinib is a competitive inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6 and UGT1A1 in vitro, potentially increasing the concentrations of drugs eliminated by these enzymes. In vitro studies also suggest that nilotinib may induce CYP2B6, CYP2C8 and CYP2C9, and decrease the concentrations of drugs which are eliminated by these enzymes. - In patients with CML, multiple doses of Tasigna increased the systemic exposure of oral midazolam (a substrate of CYP3A4) 2.6-fold. Tasigna is a moderate CYP3A4 inhibitor. As a result, the systemic exposure of drugs metabolized by CYP3A4 (e.g., certain HMG-CoA reductase inhibitors) may be increased when co-administered with Tasigna. Dose adjustment may be necessary for drugs that are CYP3A4 substrates, especially those that have narrow therapeutic indices (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, sirolimus and tacrolimus) when co-administered with Tasigna. - Single-dose administration of Tasigna to healthy subjects did not change the pharmacokinetics and pharmacodynamics of warfarin (a CYP2C9 substrate). The ability of multiple doses of Tasigna to induce metabolism of drugs other than midazolam has not been determined in vivo. Monitor patients closely when co-administering Tasigna with drugs that have a narrow therapeutic index and are substrates for CYP2B6, CYP2C8, or CYP2C9 enzymes. - Nilotinib inhibits human P-glycoprotein (P-gp). If Tasigna is administered with drugs that are substrates of P-gp, increased concentrations of the substrate drug are likely, and caution should be exercised. - Drugs that Inhibit or Induce Cytochrome P450 3A4 Enzymes - Nilotinib undergoes metabolism by CYP3A4, and concomitant administration of strong inhibitors or inducers of CYP3A4 can increase or decrease nilotinib concentrations significantly. The administration of Tasigna with agents that are strong CYP3A4 inhibitors should be avoided. Concomitant use of Tasigna with medicinal products and herbal preparations that are potent inducers of CYP3A4 is likely to reduce exposure to nilotinib to a clinically relevant extent. Therefore, in patients receiving Tasigna, concomitant use of alternative therapeutic agents with less potential for CYP3A4 induction should be selected. - Ketoconazole: In healthy subjects receiving ketoconazole, a CYP3A4 inhibitor, at 400 mg once daily for 6 days, systemic exposure (AUC) to nilotinib was increased approximately 3-fold. - Rifampicin: In healthy subjects receiving the CYP3A4 inducer, rifampicin, at 600 mg daily for 12 days, systemic exposure (AUC) to nilotinib was decreased approximately 80%. - Drugs that Affect Gastric pH - Nilotinib has pH-dependent solubility, with decreased solubility at higher pH. Drugs such as proton pump inhibitors that inhibit gastric acid secretion to elevate the gastric pH may decrease the solubility of nilotinib and reduce its bioavailability. In healthy subjects, coadministration of a single 400 mg dose of Tasigna with multiple doses of esomeprazole (a proton pump inhibitor) at 40 mg daily decreased the nilotinib AUC by 34%. Increasing the dose of Tasigna when coadministered with such agents is not likely to compensate for the loss of exposure. Since proton pump inhibitors affect pH of the upper GI tract for an extended period, separation of doses may not eliminate the interaction. The concomitant use of proton pump inhibitors with Tasigna is not recommended. - In healthy subjects, no significant change in nilotinib pharmacokinetics was observed when a single 400 mg dose of Tasigna was administered 10 hours after and 2 hours before famotidine (an H2 blocker). Therefore, when the concurrent use of a H2 blocker is necessary, it may be administered approximately 10 hours before and approximately 2 hours after the dose of Tasigna. - Administration of an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) to healthy subjects, 2 hours before or 2 hours after a single 400 mg dose of Tasigna did not alter nilotinib pharmacokinetics. Therefore, if necessary, an antacid may be administered approximately 2 hours before or approximately 2 hours after the dose of Tasigna. - Drugs that Inhibit Drug Transport Systems - Nilotinib is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1). If Tasigna is administered with drugs that inhibit P-gp, increased concentrations of nilotinib are likely, and caution should be exercised. - Drugs that May Prolong the QT Interval - The administration of Tasigna with agents that may prolong the QT interval such as anti-arrhythmic medicines should be avoided. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category D - Risk Summary - Based on its mechanism of action and findings in animals, Tasigna may cause fetal harm when administered to a pregnant woman. Women should be advised to avoid becoming pregnant while on Tasigna. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. - Animal Data - Nilotinib was studied for effects on embryo-fetal development in pregnant rats and rabbits given oral doses of 10, 30, 100 mg/kg/day, and 30, 100, 300 mg/kg/day, respectively, during organogenesis. In rats, nilotinib at doses of 100 mg/kg/day (approximately 5.7 times the AUC in patients at the dose of 400 mg twice daily) was associated with maternal toxicity (decreased gestation weight, gravid uterine weight, net weight gain, and food consumption). Nilotinib at doses ≥30 mg/kg/day (approximately 2 times the AUC in patients at the dose of 400 mg twice daily) resulted in embryo-fetal toxicity as shown by increased resorption and post-implantation loss, and at 100 mg/kg/day, a decrease in viable fetuses. In rabbits, maternal toxicity at 300 mg/kg/day (approximately one-half the human exposure based on AUC) was associated with mortality, abortion, decreased gestation weights and decreased food consumption. Embryonic toxicity (increased resorption) and minor skeletal anomalies were observed at a dose of 300 mg/kg/day. Nilotinib is not considered teratogenic. - When pregnant rats were dosed with nilotinib during organogenesis and through lactation, the adverse effects included a longer gestational period, lower pup body weights until weaning and decreased fertility indices in the pups when they reached maturity, all at a maternal dose of 360 mg/m2 (approximately 0.7 times the clinical dose of 400 mg twice daily based on body surface area). At doses up to 120 mg/m2 (approximately 0.25 times the clinical dose of 400 mg twice daily based on body surface area) no adverse effects were seen in the maternal animals or the pups. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nilotinib in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Nilotinib during labor and delivery. ### Nursing Mothers - It is not known whether nilotinib is excreted in human milk. One study in lactating rats demonstrates that nilotinib is excreted into milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Tasigna, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use - The safety and effectiveness of Tasigna in pediatric patients have not been established. ### Geriatic Use - In the clinical trials of Tasigna (patients with newly diagnosed Ph+ CML-CP and resistant or intolerant Ph+ CML-CP and CML-AP), approximately 12% and 30% of patients were 65 years or over respectively. - Patients with newly diagnosed Ph+ CML-CP: There was no difference in major molecular response between patients aged <65 years and those ≥65 years. - Patients with resistant or intolerant CML-CP: There was no difference in major cytogenetic response rate between patients aged <65 years and those ≥65 years. - Patients with resistant or intolerant CML-AP: The hematologic response rate was 44% in patients <65 years of age and 29% in patients ≥65 years. - No major differences for safety were observed in patients ≥65 years of age as compared to patients <;&lt65 years. ### Gender There is no FDA guidance on the use of Nilotinib with respect to specific gender populations. ### Race There is no FDA guidance on the use of Nilotinib with respect to specific racial populations. ### Renal Impairment - Clinical studies have not been performed in patients with impaired renal function. Clinical studies have excluded patients with serum creatinine concentration >1.5 times the upper limit of the normal range. - Since nilotinib and its metabolites are not renally excreted, a decrease in total body clearance is not anticipated in patients with renal impairment. ### Hepatic Impairment - Nilotinib exposure is increased in patients with impaired hepatic function. In a study of subjects with mild to severe hepatic impairment following a single dose administration of 200 mg of Tasigna, the mean AUC values were increased on average of 35%, 35%, and 56% in subjects with mild (Child-Pugh class A, score 5 to 6), moderate (Child-Pugh class B, score 7 to 9) and severe hepatic impairment (Child-Pugh class C, score 10 to 15), respectively, compared to a control group of subjects with normal hepatic function. Table 8 summarizes the Child-Pugh Liver Function Classification applied in this study. A lower starting dose is recommended in patients with hepatic impairment and the QT interval should be monitored closely in these patients. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Nilotinib in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Nilotinib in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Nilotinib in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Nilotinib in the drug label. # Overdosage ## Acute Overdose - Overdose with nilotinib has been reported, where an unspecified number of Tasigna capsules were ingested in combination with alcohol and other drugs. Events included neutropenia, vomiting, and drowsiness. In the event of overdose, the patient should be observed and appropriate supportive treatment given. ## Chronic Overdose There is limited information regarding Chronic Overdose of Nilotinib in the drug label. # Pharmacology ## Mechanism of Action - Nilotinib is an inhibitor of the BCR-ABL kinase. Nilotinib binds to and stabilizes the inactive conformation of the kinase domain of ABL protein. In vitro, nilotinib inhibited BCR-ABL mediated proliferation of murine leukemic cell lines and human cell lines derived from patients with Ph+ CML. Under the conditions of the assays, nilotinib was able to overcome imatinib resistance resulting from BCR-ABL kinase mutations, in 32 out of 33 mutations tested. In vivo, nilotinib reduced the tumor size in a murine BCR-ABL xenograft model. Nilotinib inhibited the autophosphorylation of the following kinases at IC50 values as indicated: BCR-ABL (20 to 60 nM), PDGFR (69 nM), c-KIT (210 nM), CSF-1R (125 to 250 nM), and DDR1 (3.7 nM). ## Structure - Tasigna (nilotinib) belongs to a pharmacologic class of drugs known as kinase inhibitors. - Nilotinib drug substance, a monohydrate monohydrochloride, is a white to slightly yellowish to slightly greenish yellow powder with the anhydrous molecular formula and weight, respectively, of C28H22F3N7OHCl - H2O and 584. The solubility of nilotinib in aqueous solutions decreases with increasing pH. Nilotinib is not optically active. The pKa1 was determined to be 2.1; pKa2 was estimated to be 5.4. - The chemical name of nilotinib is 4-methyl-N--3-amino]-benzamide, monohydrochloride, monohydrate. Its structure is shown below: - Tasigna (nilotinib) capsules, for oral use, contain 150 mg or 200 mg nilotinib base, anhydrous (as hydrochloride, monohydrate) with the following inactive ingredients: colloidal silicon dioxide, crospovidone, lactose monohydrate, magnesium stearate and poloxamer 188. The capsules contain gelatin, iron oxide (red), iron oxide (yellow), iron oxide (black), and titanium dioxide. ## Pharmacodynamics - asigna can increase bilirubin levels. A pharmacogenetic analysis of 97 patients evaluated the polymorphisms of UGT1A1 and its potential association with hyperbilirubinemia during Tasigna treatment. In this study, the (TA)7/(TA)7 genotype was associated with a statistically significant increase in the risk of hyperbilirubinemia relative to the (TA)6/(TA)6 and (TA)6/(TA)7 genotypes. However, the largest increases in bilirubin were observed in the (TA)7/(TA)7 genotype (UGT1A1*28) patients. - QT/QTc Prolongation - In a placebo-controlled study in healthy volunteers designed to assess the effects of Tasigna on the QT interval, administration of Tasigna was associated with concentration-dependent QT prolongation; the maximum mean placebo-adjusted QTcF change from baseline was 18 msec (1-sided 95% Upper CI: 26 msec). A positive control was not included in the QT study of healthy volunteers. Peak plasma concentrations in the QT study were 26% lower than those observed in patients enrolled in the single-arm study. ## Pharmacokinetics - Absorption and Distribution - The absolute bioavailability of nilotinib has not been determined. As compared to an oral drink solution (pH of 1.2 to 1.3), relative bioavailability of nilotinib capsule is approximately 50%. Peak concentrations of nilotinib are reached 3 hours after oral administration. - Steady-state nilotinib exposure was dose-dependent with less than dose-proportional increases in systemic exposure at dose levels higher than 400 mg given as once daily dosing. Daily serum exposure to nilotinib following 400 mg twice daily dosing at steady state was 35% higher than with 800 mg once daily dosing. Steady state exposure (AUC) of nilotinib with 400 mg twice daily dosing was 13% higher than with 300 mg twice daily dosing. The average steady state nilotinib trough and peak concentrations did not change over 12 months. There was no relevant increase in exposure to nilotinib when the dose was increased from 400 mg twice daily to 600 mg twice daily. - The bioavailability of nilotinib was increased when given with a meal. Compared to the fasted state, the systemic exposure (AUC) increased by 82% when the dose was given 30 minutes after a high fat meal. - Single dose administration of two 200 mg nilotinib capsules each dispersed in 1 teaspoon of applesauce and administered within 15 minutes was shown to be bioequivalent to a single dose administration of two 200 mg intact capsules. The blood-to-serum ratio of nilotinib is 0.68. Serum protein binding is approximately 98% on the basis of in vitro experiments. - Median steady-state trough concentration of nilotinib was decreased by 53% in patients with total gastrectomy compared to patients who had not undergone surgeries . - Pharmacokinetics, Metabolism and Excretion - The apparent elimination half-life estimated from the multiple dose pharmacokinetic studies with daily dosing was approximately 17 hours. Inter-patient variability in nilotinib AUC was 32% to 64%. Steady state conditions were achieved by Day 8. An increase in serum exposure to nilotinib between the first dose and steady state was approximately 2-fold for daily dosing and 3.8-fold for twice-daily dosing. - Main metabolic pathways identified in healthy subjects are oxidation and hydroxylation. Nilotinib is the main circulating component in the serum. None of the metabolites contribute significantly to the pharmacological activity of nilotinib. - After a single dose of radiolabeled nilotinib in healthy subjects, more than 90% of the administered dose was eliminated within 7 days: mainly in feces (93% of the dose). Parent drug accounted for 69% of the dose. - Age, body weight, gender, or ethnic origin did not significantly affect the pharmacokinetics of nilotinib. - Drug-Drug Interactions - In a Phase 1 trial of nilotinib 400 mg twice daily in combination with imatinib 400 mg daily or 400 mg twice daily, the AUC increased 30% to 50% for nilotinib and approximately 20% for imatinib. ## Nonclinical Toxicology - A 2-year carcinogenicity study was conducted orally in rats at nilotinib doses of 5, 15, and 40 mg/kg/day. Exposures in animals at the highest dose tested were approximately 2 to 3 fold the human exposure (based on AUC) at the nilotinib dose of 400 mg twice daily. The study was negative for carcinogenic findings. - Nilotinib was not mutagenic in a bacterial mutagenesis (Ames) assay, was not clastogenic in a chromosome aberration assay in human lymphocytes, did not induce DNA damage (comet assay) in L5178Y mouse lymphoma cells, nor was it clastogenic in an in vivo rat bone marrow micronucleus assay with two oral treatments at doses up to 2000 mg/kg/dose. - There were no effects on male or female rat and female rabbit mating or fertility at doses up to 180 mg/kg in rats (approximately 4 to 7 fold for males and females, respectively, the AUC in patients at the dose of 400 mg twice daily) or 300 mg/kg in rabbits (approximately one-half the AUC in patients at the dose of 400 mg twice daily). The effect of Tasigna on human fertility is unknown. In a study where male and female rats were treated with nilotinib at oral doses of 20 to 180 mg/kg/day (approximately 1 to 6.6 fold the AUC in patients at the dose of 400 mg twice daily) during the pre-mating and mating periods and then mated, and dosing of pregnant rats continued through gestation Day 6, nilotinib increased post-implantation loss and early resorption, and decreased the number of viable fetuses and litter size at all doses tested. # Clinical Studies - An open-label, multicenter, randomized trial was conducted to determine the efficacy of Tasigna versus imatinib tablets in adult patients with cytogenetically confirmed newly diagnosed Ph+ CML-CP. Patients were within 6 months of diagnosis and were previously untreated for CML-CP, except for hydroxyurea and/or anagrelide. Efficacy was based on a total of 846 patients: 283 patients in the imatinib 400 mg once daily group, 282 patients in the nilotinib 300 mg twice daily group, 281 patients in the nilotinib 400 mg twice daily group. - Median age was 46 years in the imatinib group and 47 years in both nilotinib groups, with 12%, 13%, and 10% of patients ≥65 years of age in imatinib 400 mg once daily, nilotinib 300 mg twice daily and nilotinib 400 mg twice daily treatment groups, respectively. There were slightly more male than female patients in all groups (56%, 56%, and 62% in imatinib 400 mg once daily, nilotinib 300 mg twice daily and nilotinib 400 mg twice daily treatment groups, respectively). More than 60% of all patients were Caucasian, and 25% were Asian. - The primary data analysis was performed when all 846 patients completed 12 months of treatment (or discontinued earlier). Subsequent analyses were done when patients completed 24, 36, and 48 months of treatment (or discontinued earlier). The median time on treatment was approximately 48 months in all three treatment groups. This study is on-going and further data will be required to determine long-term outcome. - The primary efficacy endpoint was major molecular response (MMR) at 12 months after the start of study medication. MMR was defined as ≤0.1% BCR-ABL/ABL % by international scale measured by RQ-PCR, which corresponds to a ≥3 log reduction of BCR-ABL transcript from standardized baseline. Efficacy endpoints are summarized in Table 9 below. - Three patients in the nilotinib arm progressed to either accelerated phase (including clonal evolution) or blast crisis (2 within the first 6 months of treatment and 1 within 36 to 48 months while 17 patients on the imatinib arm progressed to either accelerated phase (including clonal evolution) or blast crisis (8 patients within first 6 months, 4 within 6 to 12 months, 4 within 12 to 18 months and 1 within 18 to 24 months). - A single-arm, open-label, multicenter study was conducted to evaluate the efficacy and safety of Tasigna (400 mg twice daily) in patients with imatinib-resistant or -intolerant CML with separate cohorts for chronic and accelerated phase disease. The definition of imatinib resistance included failure to achieve a complete hematologic response (by 3 months), cytogenetic response (by 6 months) or major cytogenetic response (by 12 months) or progression of disease after a previous cytogenetic or hematologic response. Imatinib intolerance was defined as discontinuation of treatment due to toxicity and lack of a major cytogenetic response at time of study entry. At the time of data cut-off, 321 patients with CML-CP and 137 patients with CML-AP with a minimum follow-up of 24 months were enrolled. In this study, about 50% of CML-CP and CML-AP patients were males, over 90% (CML-CP) and 80% (CML-AP) were Caucasian, and approximately 30% were age 65 years or older. - Overall, 73% of patients were imatinib resistant while 27% were imatinib intolerant. The median time of prior imatinib treatment was approximately 32 (CML-CP) and 28 (CML-AP) months. Prior therapy included hydroxyurea in 85% of patients, interferon in 56% and stem cell or bone marrow transplant in 8%. The median highest prior imatinib dose was 600 mg/day for patients with CML-CP and CML-AP, and the highest prior imatinib dose was ≥600 mg/day in 74% of all patients with 40% of patients receiving imatinib doses ≥800 mg/day. - Median duration of nilotinib treatment was 18.4 months in patients with CML-CP and 8.7 months in patients with CML-AP. - The efficacy endpoint in CML-CP was unconfirmed major cytogenetic response (MCyR) which included complete and partial cytogenetic responses. - The efficacy endpoint in CML-AP was confirmed hematologic response (HR), defined as either a complete hematologic response (CHR) or no evidence of leukemia (NEL). The rates of response for CML-CP and CML-AP patients are reported in Table 10. - Median durations of response had not been reached at the time of data analysis. - The MCyR rate in 321 CML-CP patients was 51%. The median time to MCyR among responders was 2.8 months (range 1 to 28 months). The median duration of MCyR cannot be estimated. The median duration of exposure on this single arm-trial was 18.4 months. Among the CML-CP patients who achieved MCyR, 62% of them had MCyR lasting more than 18 months. The CCyR rate was 37%. - The overall confirmed hematologic response rate in 137 patients with CML-AP was 39%. The median time to first hematologic response among responders was 1 month (range 1 to 14 months). Among the CML-AP patients who achieved HR, 44% of them had a response lasting for more than 18 months. - After imatinib failure, 24 different BCR-ABL mutations were noted in 42% of chronic phase and 54% of accelerated phase CML patients who were evaluated for mutations. # How Supplied - Tasigna (nilotinib) 150 mg capsules are red opaque hard gelatin capsules, size 1 with black axial imprint “NVR/BCR”. Tasigna (nilotinib) 200 mg capsules are light yellow opaque hard gelatin capsules, size 0 with the red axial imprint “NVR/TKI.” Tasigna capsules are supplied in blister packs. - 150 mg - Carton of 4 blister packs of (4x28) ………………………….…….NDC 0078-0592-87 - Blisters of 28 capsules……………………………………….…….NDC 0078-0592-51 - 200 mg - Carton of 4 blister packs of (4x28) ………………………….…….NDC 0078-0526-87 - Blisters of 28 capsules……………………………………….…….NDC 0078-0526-51 - Tasigna (nilotinib) capsules should be stored at 25°C (77°F); excursions permitted between 15° to 30°C (59° to 86°F). ## Storage There is limited information regarding Nilotinib Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Cardiac and Vascular Events - Advise patients that cardiovascular events (including ischemic heart disease, peripheral arterial occlusive disease, and ischemic cerebrovascular events) have been reported. Advise patients to seek immediate medical attention with any symptoms suggestive of a cardiovascular event. Cardiovascular status of patients should be evaluated and cardiovascular risk factors should be monitored and managed during Tasigna therapy according to standard guidelines. - Taking Tasigna - Advise patients to take Tasigna doses twice daily approximately 12 hours apart. The capsules should be swallowed whole with water. - Advise patients to take Tasigna on an empty stomach. No food should be consumed for at least 2 hours before the dose is taken and for at least 1 hour after the dose is taken. Patients should not consume grapefruit products and other foods that are known to inhibit CYP3A4 at any time during Tasigna treatment. - If the patient missed a dose of Tasigna, the patient should take the next scheduled dose at its regular time. The patient should not take two doses at the same time. - Should patients be unable to swallow capsules, the contents of each capsule may be dispersed in one teaspoon of applesauce and the mixture swallowed immediately (within 15 minutes). - Drug Interactions - Tasigna and certain other medicines, including over the counter medications or herbal supplements (such as St. John’s Wort), can interact with each other. - Pregnancy - Advise patients that the use of Tasigna during pregnancy may cause harm to the fetus and that Tasigna should not be taken during pregnancy unless necessary. Women of childbearing potential should use highly effective contraceptives while taking Tasigna. Sexually active female patients taking Tasigna should use adequate contraception. - Compliance - Advise patients of the following: Continue taking Tasigna every day for as long as their doctor tells them. This is a long-term treatment. Do not change dose or stop taking Tasigna without first consulting their doctor. If a dose is missed, take the next dose as scheduled. Do not take a double dose to make up for the missed capsules. - Continue taking Tasigna every day for as long as their doctor tells them. - This is a long-term treatment. - Do not change dose or stop taking Tasigna without first consulting their doctor. - If a dose is missed, take the next dose as scheduled. Do not take a double dose to make up for the missed capsules. # Precautions with Alcohol - Alcohol-Nilotinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - TASIGNA® # Look-Alike Drug Names There is limited information regarding Nilotinib Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Nilotinib Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Nilotinib is a kinase inhibitor that is FDA approved for the treatment of newly diagnosed adult patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase and chronic phase (CP) and accelerated phase (AP) Ph+ CML in adult patients resistant to or intolerant to prior therapy that included imatinib. There is a Black Box Warning for this drug as shown here. Common adverse reactions include nausea, rash, headache, fatigue, pruritus, vomiting, diarrhea, cough, constipation, arthralgia, nasopharyngitis, pyrexia, and night sweats. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - The recommended dose of Tasigna is 300 mg orally twice daily. - The recommended dose of Tasigna (nilotinib) is 400 mg orally twice daily. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Nilotinib in adult patients. ### Non–Guideline-Supported Use - Nilotinib dose, ranging from 50 to 1200 mg orally once daily and 400 to 600 mg twice daily.[1] - Nilotinib 400 mg twice daily.[2] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Nilotinib in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Nilotinib in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Nilotinib in pediatric patients. # Contraindications - Do not use in patients with hypokalemia, hypomagnesemia, or long QT syndrome. # Warnings ### Precautions - Myelosuppression - Treatment with Tasigna can cause Grade 3/4 thrombocytopenia, neutropenia and anemia. Perform complete blood counts every 2 weeks for the first 2 months and then monthly thereafter, or as clinically indicated. Myelosuppression was generally reversible and usually managed by withholding Tasigna temporarily or dose reduction. - QT Prolongation - Tasigna has been shown to prolong cardiac ventricular repolarization as measured by the QT interval on the surface ECG in a concentration-dependent manner. Prolongation of the QT interval can result in a type of ventricular tachycardia called torsade de pointes, which may result in syncope, seizure, and/or death. ECGs should be performed at baseline, 7 days after initiation of Tasigna, and periodically as clinically indicated and following dose adjustments. - Tasigna should not be used in patients who have hypokalemia, hypomagnesemia or long QT syndrome. Before initiating Tasigna and periodically, test electrolyte, calcium and magnesium blood levels. Hypokalemia or hypomagnesemia must be corrected prior to initiating Tasigna and these electrolytes should be monitored periodically during therapy. - Significant prolongation of the QT interval may occur when Tasigna is inappropriately taken with food and/or strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT. Therefore, coadministration with food must be avoided and concomitant use with strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT should be avoided. The presence of hypokalemia and hypomagnesemia may further prolong the QT interval. - Sudden Deaths - Sudden deaths have been reported in 0.3% of patients with CML treated with nilotinib in clinical studies of 5,661 patients. The relative early occurrence of some of these deaths relative to the initiation of nilotinib suggests the possibility that ventricular repolarization abnormalities may have contributed to their occurrence. - Cardiac and Vascular Events - Cardiovascular events, including arterial vascular occlusive events, were reported in a randomized, clinical trial in newly diagnosed CML patients and observed in the post-marketing reports of patients receiving nilotinib therapy. With a median time on therapy of 48 months in the clinical trial, cases of cardiovascular events included ischemic heart disease-related events (5.0% and 5.8% in the nilotinib 300 mg and 400 mg bid arms respectively, and 1.8% in the imatinib arm), peripheral arterial occlusive disease (1.8% and 2.2% in the nilotinib 300 mg and 400 mg bid arms respectively, and 0% in the imatinib arm), and ischemic cerebrovascular events (1.1% and 1.8% in the nilotinib 300 mg and 400 mg bid arms respectively, and 0.7% in the imatinib arm). If acute signs or symptoms of cardiovascular events occur, advise patients to seek immediate medical attention. The cardiovascular status of patients should be evaluated and cardiovascular risk factors should be monitored and actively managed during Tasigna therapy according to standard guidelines. - Pancreatitis and Elevated Serum Lipase - can cause increases in serum lipase. Patients with a previous history of pancreatitis may be at greater risk of elevated serum lipase. If lipase elevations are accompanied by abdominal symptoms, interrupt dosing and consider appropriate diagnostics to exclude pancreatitis. Test serum lipase levels monthly or as clinically indicated. - Hepatotoxicity - Tasigna may result in hepatotoxicity as measured by elevations in bilirubin, AST/ALT, and alkaline phosphatase. Monitor hepatic function tests monthly or as clinically indicated. - Electrolyte Abnormalities - The use of Tasigna can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia. Electrolyte abnormalities must be corrected prior to initiating Tasigna and these electrolytes should be monitored periodically during therapy. - Drug Interactions - Avoid administration of Tasigna with agents that may increase nilotinib exposure (e.g., strong CYP3A4 inhibitors) or anti-arrhythmic drugs (including, but not limited to amiodarone, disopyramide, procainamide, quinidine and sotalol) and other drugs that may prolong QT interval (including, but not limited to chloroquine, clarithromycin, haloperidol, methadone, moxifloxacin and pimozide). Should treatment with any of these agents be required, interrupt therapy with Tasigna. If interruption of treatment with Tasigna is not possible, patients who require treatment with a drug that prolongs QT or strongly inhibits CYP3A4 should be closely monitored for prolongation of the QT interval. - Food Effects - The bioavailability of nilotinib is increased with food, thus Tasigna must not be taken with food. No food should be consumed for at least 2 hours before and for at least 1 hour after the dose is taken. Also avoid grapefruit products and other foods that are known to inhibit CYP3A4. - Hepatic Impairment - Nilotinib exposure is increased in patients with impaired hepatic function. Use a lower starting dose for patients with mild to severe hepatic impairment (at baseline) and monitor the QT interval frequently. - Tumor Lysis Syndrome - Tumor lysis syndrome cases have been reported in Tasigna treated patients with resistant or intolerant CML. Malignant disease progression, high WBC counts and/or dehydration were present in the majority of these cases. Due to potential for tumor lysis syndrome, maintain adequate hydration and correct uric acid levels prior to initiating therapy with Tasigna. - Total Gastrectomy - Since the exposure of nilotinib is reduced in patients with total gastrectomy, perform more frequent monitoring of these patients. Consider dose increase or alternative therapy in patients with total gastrectomy. - Lactose - Since the capsules contain lactose, Tasigna is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency with a severe degree of intolerance to lactose-containing products, or of glucose-galactose malabsorption. - Monitoring Laboratory Tests - Complete blood counts should be performed every 2 weeks for the first 2 months and then monthly thereafter. Chemistry panels, including electrolytes, calcium, magnesium, lipid profile, and glucose should be checked prior to therapy and periodically. ECGs should be obtained at baseline, 7 days after initiation and periodically thereafter, as well as following dose adjustments. Laboratory monitoring for patients receiving Tasigna may need to be performed more or less frequently at the physician’s discretion. - Embryo-Fetal Toxicity - There are no adequate and well controlled studies of Tasigna in pregnant women. However, Tasigna may cause fetal harm when administered to a pregnant woman. Nilotinib caused embryo-fetal toxicities in animals at maternal exposures that were lower than the expected human exposure at the recommended doses of nilotinib. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of child-bearing potential should avoid becoming pregnant while taking Tasigna. # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. - The data below reflect exposure to Tasigna from a randomized trial in patients with newly diagnosed Ph+ CML in chronic phase treated at the recommended dose of 300 mg twice daily (n=279). The median time on treatment in the nilotinib 300 mg twice daily group was 48 months (range 0.1 to 59 months). The median actual dose intensity was 594 mg/day in the nilotinib 300 mg twice daily group. - The most common (>10%) non-hematologic adverse drug reactions were rash, pruritus, headache, nausea, fatigue, alopecia and myalgia. Upper abdominal pain, constipation, diarrhea, dry skin, muscle spasms, arthralgia, abdominal pain, peripheral edema, vomiting, and asthenia were observed less commonly (≤10% and >5%) and have been of mild to moderate severity, manageable and generally did not require dose reduction. Pleural and pericardial effusions, occurred in 1% and <;&lt1% of patients, respectively. Gastrointestinal hemorrhage was reported in 3% of patients. - Increase in QTcF >60 msec from baseline was observed in 1 patient (0.4%) in the 300 mg twice daily treatment group. No patient had an absolute QTcF of >500 msec while on study drug. - The most common hematologic adverse drug reactions (all grades) were myelosuppression including: thrombocytopenia (18%), neutropenia (15%) and anemia (7%). See Table 7 for Grade 3/4 laboratory abnormalities. - Discontinuation due to adverse reactions, regardless of relationship to study drug, was observed in 10% of patients. - In the single open-label multicenter clinical trial, a total of 458 patients with Ph+ CML-CP and CML-AP resistant to or intolerant to at least one prior therapy including imatinib were treated (CML-CP=321; CML-AP=137) at the recommended dose of 400 mg twice daily. - The median duration of exposure in days for CML-CP and CML-AP patients is 561 (range 1 to 1096) and 264 (range 2 to 1160), respectively. The median dose intensity for patients with CML-CP and CML-AP is 789 mg/day (range 151 to 1110) and 780 mg/day (range 150 to 1149), respectively and corresponded to the planned 400 mg twice daily dosing. - The median cumulative duration in days of dose interruptions for the CML-CP patients was 20 (range 1 to 345), and the median duration in days of dose interruptions for the CML-AP patients was 23 (range 1 to 234). - In patients with CML-CP, the most commonly reported non-hematologic adverse drug reactions (≥10%) were rash, pruritus, nausea, fatigue, headache, constipation, diarrhea, vomiting and myalgia. The common serious drug-related adverse reactions (≥1% and <10%) were thrombocytopenia, neutropenia and anemia. - In patients with CML-AP, the most commonly reported non-hematologic adverse drug reactions (≥10%) were rash, pruritus and fatigue. The common serious adverse drug reactions (≥1% and <;&lt10%) were thrombocytopenia, neutropenia, febrile neutropenia, pneumonia, leukopenia, intracranial hemorrhage, elevated lipase and pyrexia. - Sudden deaths and QT prolongation were reported. The maximum mean QTcF change from baseline at steady-state was 10 msec. Increase in QTcF >60 msec from baseline was observed in 4.1% of the patients and QTcF of >500 msec was observed in 4 patients (<1%). - Discontinuation due to adverse drug reactions was observed in 16% of CML-CP and 10% of CML-AP patients. - Tables 5 and 6 show the percentage of patients experiencing non-hematologic adverse reactions (excluding laboratory abnormalities) regardless of relationship to study drug. Adverse reactions reported in greater than 10% of patients who received at least 1 dose of Tasigna are listed. - The following adverse drug reactions were reported in patients in the Tasigna clinical studies at the recommended doses. These adverse drug reactions are ranked under a heading of frequency, the most frequent first using the following convention: common (≥1% and <10%), uncommon (≥0.1% and <1%), and unknown frequency (single events). For laboratory abnormalities, very common events (≥10%), which were not included in Tables 5 and 6, are also reported. These adverse reactions are included based on clinical relevance and ranked in order of decreasing seriousness within each category, obtained from 2 clinical studies: - Newly diagnosed Ph+ CML-CP 48 month analysis and, - Resistant or intolerant Ph+ CML-CP and CMP-AP 24 months’ analysis. Common: folliculitis, upper respiratory tract infection (including pharyngitis, nasopharyngitis, rhinitis). Uncommon: pneumonia, bronchitis, urinary tract infection, candidiasis (including oral candidiasis), gastroenteritis. Unknown frequency: sepsis, subcutaneous abscess, anal abscess, furuncle, tinea pedis. Common: skin papilloma. Unknown frequency: oral papilloma, paraproteinemia. Common: eosinophilia, febrile neutropenia, pancytopenia, lymphopenia. Unknown frequency: thrombocythemia, leukocytosis. Unknown frequency: hypersensitivity. Uncommon: hyperthyroidism, hypothyroidism. Unknown frequency: hyperparathyroidism secondary, thyroiditis. Very Common: hypophosphatemia. Common: electrolyte imbalance (including hypomagnesemia, hyperkalemia, hypokalemia, hyponatremia, hypocalcemia, hypercalcemia, hyperphosphatemia), diabetes mellitus, hyperglycemia, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia. Uncommon: gout, dehydration, increased appetite. Unknown frequency: hyperuricemia, hypoglycemia. Common: depression, insomnia, anxiety. Unknown frequency: disorientation, confusional state, amnesia, dysphoria. Common: dizziness, peripheral neuropathy, hypoesthesia, paresthesia. Uncommon: intracranial hemorrhage, migraine, loss of consciousness (including syncope), tremor, disturbance in attention, hyperesthesia. Unknown frequency: transient ischemic attack, brain edema, optic neuritis, lethargy, dysesthesia, restless legs syndrome. Common: eye hemorrhage, periorbital edema, eye pruritus, conjunctivitis, dry eye (including xerophthalmia). Uncommon: vision impairment, vision blurred, visual acuity reduced, photopsia, hyperemia (scleral, conjunctival, ocular), eye irritation, conjunctival hemorrhage. Unknown frequency: papilloedema, diplopia, photophobia, eye swelling, blepharitis, eye pain, chorioretinopathy, conjunctivitis allergic, ocular surface disease. Common: vertigo. Unknown frequency: hearing impaired, ear pain, tinnitus. Common: angina pectoris, arrhythmia (including atrioventricular block, cardiac flutter, extrasystoles, atrial fibrillation, tachycardia, bradycardia), palpitations, electrocardiogram QT prolonged. Uncommon: cardiac failure, pericardial effusion, coronary artery disease, cyanosis, cardiac murmur. Unknown frequency: myocardial infarction, ventricular dysfunction, pericarditis, ejection fraction decrease. Common: hypertension, flushing. Uncommon: hypertensive crisis, peripheral arterial occlusive disease, intermittent claudication, arterial stenosis limb, hematoma, arteriosclerosis. Unknown frequency: shock hemorrhagic, hypotension, thrombosis. Common: dyspnea, dyspnea exertional, epistaxis, cough, dysphonia. Uncommon: pulmonary edema, pleural effusion, interstitial lung disease, pleuritic pain, pleurisy, pharyngolaryngeal pain, throat irritation. Unknown frequency: pulmonary hypertension, wheezing, oropharyngeal pain. Common: pancreatitis, abdominal discomfort, abdominal distension, dyspepsia, dysgeusia, flatulence. Uncommon: gastrointestinal hemorrhage, melena, mouth ulceration, gastroesophageal reflux, stomatitis, esophageal pain, dry mouth, gastritis, sensitivity of teeth. Unknown frequency: gastrointestinal ulcer perforation, retroperitoneal hemorrhage, hematemesis, gastric ulcer, esophagitis ulcerative, subileus, enterocolitis, hemorrhoids, hiatus hernia, rectal hemorrhage, gingivitis. Very Common: hyperbilirubinemia. Common: hepatic function abnormal. Uncommon: hepatotoxicity, toxic hepatitis, jaundice. Unknown frequency: cholestasis, hepatomegaly. Common: night sweats, eczema, urticaria, erythema, hyperhidrosis, contusion, acne, dermatitis (including allergic, exfoliative and acneiform), dry skin. Uncommon: exfoliative rash, drug eruption, pain of skin, ecchymosis, swelling of face. Unknown frequency: psoriasis, erythema multiforme, erythema nodosum, skin ulcer, palmar-plantar erythrodysesthesia syndrome, petechiae, photosensitivity, blister, dermal cyst, sebaceous hyperplasia, skin atrophy, skin discoloration, skin exfoliation, skin hyperpigmentation, skin hypertrophy, hyperkeratosis. Common: bone pain, musculoskeletal chest pain, musculoskeletal pain, back pain, neck pain, flank pain. Uncommon: musculoskeletal stiffness, muscular weakness, joint swelling. Unknown frequency: arthritis. Common: pollakiuria. Uncommon: dysuria, micturition urgency, nocturia. Unknown frequency: renal failure, hematuria, urinary incontinence, chromaturia. Uncommon: breast pain, gynecomastia, erectile dysfunction. Unknown frequency: breast induration, menorrhagia, nipple swelling. Common: pyrexia, chest pain (including non-cardiac chest pain), pain, chest discomfort, malaise. Uncommon: face edema, gravitational edema, influenza-like illness, chills, feeling body temperature change (including feeling hot, feeling cold). Unknown frequency: localized edema. Very Common: alanine aminotransferase increased, aspartate aminotransferase increased, lipase increased. Common: hemoglobin decreased, blood amylase increased, gamma-glutamyltransferase increased, blood creatinine phosphokinase increased, blood alkaline phosphatase increased, weight decreased, weight increased, lipoprotein increased (including very low density and high density). Uncommon: blood lactate dehydrogenase increased, blood urea increased, globulins decreased. Unknown frequency: troponin increased, blood bilirubin unconjugated increased, insulin C-peptide decreased, blood parathyroid hormone increased. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Nilotinib in the drug label. # Drug Interactions - Effects of Nilotinib on Drug Metabolizing Enzymes and Drug Transport Systems - Nilotinib is a competitive inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6 and UGT1A1 in vitro, potentially increasing the concentrations of drugs eliminated by these enzymes. In vitro studies also suggest that nilotinib may induce CYP2B6, CYP2C8 and CYP2C9, and decrease the concentrations of drugs which are eliminated by these enzymes. - In patients with CML, multiple doses of Tasigna increased the systemic exposure of oral midazolam (a substrate of CYP3A4) 2.6-fold. Tasigna is a moderate CYP3A4 inhibitor. As a result, the systemic exposure of drugs metabolized by CYP3A4 (e.g., certain HMG-CoA reductase inhibitors) may be increased when co-administered with Tasigna. Dose adjustment may be necessary for drugs that are CYP3A4 substrates, especially those that have narrow therapeutic indices (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, sirolimus and tacrolimus) when co-administered with Tasigna. - Single-dose administration of Tasigna to healthy subjects did not change the pharmacokinetics and pharmacodynamics of warfarin (a CYP2C9 substrate). The ability of multiple doses of Tasigna to induce metabolism of drugs other than midazolam has not been determined in vivo. Monitor patients closely when co-administering Tasigna with drugs that have a narrow therapeutic index and are substrates for CYP2B6, CYP2C8, or CYP2C9 enzymes. - Nilotinib inhibits human P-glycoprotein (P-gp). If Tasigna is administered with drugs that are substrates of P-gp, increased concentrations of the substrate drug are likely, and caution should be exercised. - Drugs that Inhibit or Induce Cytochrome P450 3A4 Enzymes - Nilotinib undergoes metabolism by CYP3A4, and concomitant administration of strong inhibitors or inducers of CYP3A4 can increase or decrease nilotinib concentrations significantly. The administration of Tasigna with agents that are strong CYP3A4 inhibitors should be avoided. Concomitant use of Tasigna with medicinal products and herbal preparations that are potent inducers of CYP3A4 is likely to reduce exposure to nilotinib to a clinically relevant extent. Therefore, in patients receiving Tasigna, concomitant use of alternative therapeutic agents with less potential for CYP3A4 induction should be selected. - Ketoconazole: In healthy subjects receiving ketoconazole, a CYP3A4 inhibitor, at 400 mg once daily for 6 days, systemic exposure (AUC) to nilotinib was increased approximately 3-fold. - Rifampicin: In healthy subjects receiving the CYP3A4 inducer, rifampicin, at 600 mg daily for 12 days, systemic exposure (AUC) to nilotinib was decreased approximately 80%. - Drugs that Affect Gastric pH - Nilotinib has pH-dependent solubility, with decreased solubility at higher pH. Drugs such as proton pump inhibitors that inhibit gastric acid secretion to elevate the gastric pH may decrease the solubility of nilotinib and reduce its bioavailability. In healthy subjects, coadministration of a single 400 mg dose of Tasigna with multiple doses of esomeprazole (a proton pump inhibitor) at 40 mg daily decreased the nilotinib AUC by 34%. Increasing the dose of Tasigna when coadministered with such agents is not likely to compensate for the loss of exposure. Since proton pump inhibitors affect pH of the upper GI tract for an extended period, separation of doses may not eliminate the interaction. The concomitant use of proton pump inhibitors with Tasigna is not recommended. - In healthy subjects, no significant change in nilotinib pharmacokinetics was observed when a single 400 mg dose of Tasigna was administered 10 hours after and 2 hours before famotidine (an H2 blocker). Therefore, when the concurrent use of a H2 blocker is necessary, it may be administered approximately 10 hours before and approximately 2 hours after the dose of Tasigna. - Administration of an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) to healthy subjects, 2 hours before or 2 hours after a single 400 mg dose of Tasigna did not alter nilotinib pharmacokinetics. Therefore, if necessary, an antacid may be administered approximately 2 hours before or approximately 2 hours after the dose of Tasigna. - Drugs that Inhibit Drug Transport Systems - Nilotinib is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1). If Tasigna is administered with drugs that inhibit P-gp, increased concentrations of nilotinib are likely, and caution should be exercised. - Drugs that May Prolong the QT Interval - The administration of Tasigna with agents that may prolong the QT interval such as anti-arrhythmic medicines should be avoided. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category D - Risk Summary - Based on its mechanism of action and findings in animals, Tasigna may cause fetal harm when administered to a pregnant woman. Women should be advised to avoid becoming pregnant while on Tasigna. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. - Animal Data - Nilotinib was studied for effects on embryo-fetal development in pregnant rats and rabbits given oral doses of 10, 30, 100 mg/kg/day, and 30, 100, 300 mg/kg/day, respectively, during organogenesis. In rats, nilotinib at doses of 100 mg/kg/day (approximately 5.7 times the AUC in patients at the dose of 400 mg twice daily) was associated with maternal toxicity (decreased gestation weight, gravid uterine weight, net weight gain, and food consumption). Nilotinib at doses ≥30 mg/kg/day (approximately 2 times the AUC in patients at the dose of 400 mg twice daily) resulted in embryo-fetal toxicity as shown by increased resorption and post-implantation loss, and at 100 mg/kg/day, a decrease in viable fetuses. In rabbits, maternal toxicity at 300 mg/kg/day (approximately one-half the human exposure based on AUC) was associated with mortality, abortion, decreased gestation weights and decreased food consumption. Embryonic toxicity (increased resorption) and minor skeletal anomalies were observed at a dose of 300 mg/kg/day. Nilotinib is not considered teratogenic. - When pregnant rats were dosed with nilotinib during organogenesis and through lactation, the adverse effects included a longer gestational period, lower pup body weights until weaning and decreased fertility indices in the pups when they reached maturity, all at a maternal dose of 360 mg/m2 (approximately 0.7 times the clinical dose of 400 mg twice daily based on body surface area). At doses up to 120 mg/m2 (approximately 0.25 times the clinical dose of 400 mg twice daily based on body surface area) no adverse effects were seen in the maternal animals or the pups. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nilotinib in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Nilotinib during labor and delivery. ### Nursing Mothers - It is not known whether nilotinib is excreted in human milk. One study in lactating rats demonstrates that nilotinib is excreted into milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Tasigna, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use - The safety and effectiveness of Tasigna in pediatric patients have not been established. ### Geriatic Use - In the clinical trials of Tasigna (patients with newly diagnosed Ph+ CML-CP and resistant or intolerant Ph+ CML-CP and CML-AP), approximately 12% and 30% of patients were 65 years or over respectively. - Patients with newly diagnosed Ph+ CML-CP: There was no difference in major molecular response between patients aged <65 years and those ≥65 years. - Patients with resistant or intolerant CML-CP: There was no difference in major cytogenetic response rate between patients aged <65 years and those ≥65 years. - Patients with resistant or intolerant CML-AP: The hematologic response rate was 44% in patients <65 years of age and 29% in patients ≥65 years. - No major differences for safety were observed in patients ≥65 years of age as compared to patients <;&lt65 years. ### Gender There is no FDA guidance on the use of Nilotinib with respect to specific gender populations. ### Race There is no FDA guidance on the use of Nilotinib with respect to specific racial populations. ### Renal Impairment - Clinical studies have not been performed in patients with impaired renal function. Clinical studies have excluded patients with serum creatinine concentration >1.5 times the upper limit of the normal range. - Since nilotinib and its metabolites are not renally excreted, a decrease in total body clearance is not anticipated in patients with renal impairment. ### Hepatic Impairment - Nilotinib exposure is increased in patients with impaired hepatic function. In a study of subjects with mild to severe hepatic impairment following a single dose administration of 200 mg of Tasigna, the mean AUC values were increased on average of 35%, 35%, and 56% in subjects with mild (Child-Pugh class A, score 5 to 6), moderate (Child-Pugh class B, score 7 to 9) and severe hepatic impairment (Child-Pugh class C, score 10 to 15), respectively, compared to a control group of subjects with normal hepatic function. Table 8 summarizes the Child-Pugh Liver Function Classification applied in this study. A lower starting dose is recommended in patients with hepatic impairment and the QT interval should be monitored closely in these patients. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Nilotinib in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Nilotinib in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Nilotinib in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Nilotinib in the drug label. # Overdosage ## Acute Overdose - Overdose with nilotinib has been reported, where an unspecified number of Tasigna capsules were ingested in combination with alcohol and other drugs. Events included neutropenia, vomiting, and drowsiness. In the event of overdose, the patient should be observed and appropriate supportive treatment given. ## Chronic Overdose There is limited information regarding Chronic Overdose of Nilotinib in the drug label. # Pharmacology ## Mechanism of Action - Nilotinib is an inhibitor of the BCR-ABL kinase. Nilotinib binds to and stabilizes the inactive conformation of the kinase domain of ABL protein. In vitro, nilotinib inhibited BCR-ABL mediated proliferation of murine leukemic cell lines and human cell lines derived from patients with Ph+ CML. Under the conditions of the assays, nilotinib was able to overcome imatinib resistance resulting from BCR-ABL kinase mutations, in 32 out of 33 mutations tested. In vivo, nilotinib reduced the tumor size in a murine BCR-ABL xenograft model. Nilotinib inhibited the autophosphorylation of the following kinases at IC50 values as indicated: BCR-ABL (20 to 60 nM), PDGFR (69 nM), c-KIT (210 nM), CSF-1R (125 to 250 nM), and DDR1 (3.7 nM). ## Structure - Tasigna (nilotinib) belongs to a pharmacologic class of drugs known as kinase inhibitors. - Nilotinib drug substance, a monohydrate monohydrochloride, is a white to slightly yellowish to slightly greenish yellow powder with the anhydrous molecular formula and weight, respectively, of C28H22F3N7O•HCl • H2O and 584. The solubility of nilotinib in aqueous solutions decreases with increasing pH. Nilotinib is not optically active. The pKa1 was determined to be 2.1; pKa2 was estimated to be 5.4. - The chemical name of nilotinib is 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide, monohydrochloride, monohydrate. Its structure is shown below: - Tasigna (nilotinib) capsules, for oral use, contain 150 mg or 200 mg nilotinib base, anhydrous (as hydrochloride, monohydrate) with the following inactive ingredients: colloidal silicon dioxide, crospovidone, lactose monohydrate, magnesium stearate and poloxamer 188. The capsules contain gelatin, iron oxide (red), iron oxide (yellow), iron oxide (black), and titanium dioxide. ## Pharmacodynamics - asigna can increase bilirubin levels. A pharmacogenetic analysis of 97 patients evaluated the polymorphisms of UGT1A1 and its potential association with hyperbilirubinemia during Tasigna treatment. In this study, the (TA)7/(TA)7 genotype was associated with a statistically significant increase in the risk of hyperbilirubinemia relative to the (TA)6/(TA)6 and (TA)6/(TA)7 genotypes. However, the largest increases in bilirubin were observed in the (TA)7/(TA)7 genotype (UGT1A1*28) patients. - QT/QTc Prolongation - In a placebo-controlled study in healthy volunteers designed to assess the effects of Tasigna on the QT interval, administration of Tasigna was associated with concentration-dependent QT prolongation; the maximum mean placebo-adjusted QTcF change from baseline was 18 msec (1-sided 95% Upper CI: 26 msec). A positive control was not included in the QT study of healthy volunteers. Peak plasma concentrations in the QT study were 26% lower than those observed in patients enrolled in the single-arm study. ## Pharmacokinetics - Absorption and Distribution - The absolute bioavailability of nilotinib has not been determined. As compared to an oral drink solution (pH of 1.2 to 1.3), relative bioavailability of nilotinib capsule is approximately 50%. Peak concentrations of nilotinib are reached 3 hours after oral administration. - Steady-state nilotinib exposure was dose-dependent with less than dose-proportional increases in systemic exposure at dose levels higher than 400 mg given as once daily dosing. Daily serum exposure to nilotinib following 400 mg twice daily dosing at steady state was 35% higher than with 800 mg once daily dosing. Steady state exposure (AUC) of nilotinib with 400 mg twice daily dosing was 13% higher than with 300 mg twice daily dosing. The average steady state nilotinib trough and peak concentrations did not change over 12 months. There was no relevant increase in exposure to nilotinib when the dose was increased from 400 mg twice daily to 600 mg twice daily. - The bioavailability of nilotinib was increased when given with a meal. Compared to the fasted state, the systemic exposure (AUC) increased by 82% when the dose was given 30 minutes after a high fat meal. - Single dose administration of two 200 mg nilotinib capsules each dispersed in 1 teaspoon of applesauce and administered within 15 minutes was shown to be bioequivalent to a single dose administration of two 200 mg intact capsules. The blood-to-serum ratio of nilotinib is 0.68. Serum protein binding is approximately 98% on the basis of in vitro experiments. - Median steady-state trough concentration of nilotinib was decreased by 53% in patients with total gastrectomy compared to patients who had not undergone surgeries [see Warnings and Precautions (5.12)]. - Pharmacokinetics, Metabolism and Excretion - The apparent elimination half-life estimated from the multiple dose pharmacokinetic studies with daily dosing was approximately 17 hours. Inter-patient variability in nilotinib AUC was 32% to 64%. Steady state conditions were achieved by Day 8. An increase in serum exposure to nilotinib between the first dose and steady state was approximately 2-fold for daily dosing and 3.8-fold for twice-daily dosing. - Main metabolic pathways identified in healthy subjects are oxidation and hydroxylation. Nilotinib is the main circulating component in the serum. None of the metabolites contribute significantly to the pharmacological activity of nilotinib. - After a single dose of radiolabeled nilotinib in healthy subjects, more than 90% of the administered dose was eliminated within 7 days: mainly in feces (93% of the dose). Parent drug accounted for 69% of the dose. - Age, body weight, gender, or ethnic origin did not significantly affect the pharmacokinetics of nilotinib. - Drug-Drug Interactions - In a Phase 1 trial of nilotinib 400 mg twice daily in combination with imatinib 400 mg daily or 400 mg twice daily, the AUC increased 30% to 50% for nilotinib and approximately 20% for imatinib. ## Nonclinical Toxicology - A 2-year carcinogenicity study was conducted orally in rats at nilotinib doses of 5, 15, and 40 mg/kg/day. Exposures in animals at the highest dose tested were approximately 2 to 3 fold the human exposure (based on AUC) at the nilotinib dose of 400 mg twice daily. The study was negative for carcinogenic findings. - Nilotinib was not mutagenic in a bacterial mutagenesis (Ames) assay, was not clastogenic in a chromosome aberration assay in human lymphocytes, did not induce DNA damage (comet assay) in L5178Y mouse lymphoma cells, nor was it clastogenic in an in vivo rat bone marrow micronucleus assay with two oral treatments at doses up to 2000 mg/kg/dose. - There were no effects on male or female rat and female rabbit mating or fertility at doses up to 180 mg/kg in rats (approximately 4 to 7 fold for males and females, respectively, the AUC in patients at the dose of 400 mg twice daily) or 300 mg/kg in rabbits (approximately one-half the AUC in patients at the dose of 400 mg twice daily). The effect of Tasigna on human fertility is unknown. In a study where male and female rats were treated with nilotinib at oral doses of 20 to 180 mg/kg/day (approximately 1 to 6.6 fold the AUC in patients at the dose of 400 mg twice daily) during the pre-mating and mating periods and then mated, and dosing of pregnant rats continued through gestation Day 6, nilotinib increased post-implantation loss and early resorption, and decreased the number of viable fetuses and litter size at all doses tested. # Clinical Studies - An open-label, multicenter, randomized trial was conducted to determine the efficacy of Tasigna versus imatinib tablets in adult patients with cytogenetically confirmed newly diagnosed Ph+ CML-CP. Patients were within 6 months of diagnosis and were previously untreated for CML-CP, except for hydroxyurea and/or anagrelide. Efficacy was based on a total of 846 patients: 283 patients in the imatinib 400 mg once daily group, 282 patients in the nilotinib 300 mg twice daily group, 281 patients in the nilotinib 400 mg twice daily group. - Median age was 46 years in the imatinib group and 47 years in both nilotinib groups, with 12%, 13%, and 10% of patients ≥65 years of age in imatinib 400 mg once daily, nilotinib 300 mg twice daily and nilotinib 400 mg twice daily treatment groups, respectively. There were slightly more male than female patients in all groups (56%, 56%, and 62% in imatinib 400 mg once daily, nilotinib 300 mg twice daily and nilotinib 400 mg twice daily treatment groups, respectively). More than 60% of all patients were Caucasian, and 25% were Asian. - The primary data analysis was performed when all 846 patients completed 12 months of treatment (or discontinued earlier). Subsequent analyses were done when patients completed 24, 36, and 48 months of treatment (or discontinued earlier). The median time on treatment was approximately 48 months in all three treatment groups. This study is on-going and further data will be required to determine long-term outcome. - The primary efficacy endpoint was major molecular response (MMR) at 12 months after the start of study medication. MMR was defined as ≤0.1% BCR-ABL/ABL % by international scale measured by RQ-PCR, which corresponds to a ≥3 log reduction of BCR-ABL transcript from standardized baseline. Efficacy endpoints are summarized in Table 9 below. - Three patients in the nilotinib arm progressed to either accelerated phase (including clonal evolution) or blast crisis (2 within the first 6 months of treatment and 1 within 36 to 48 months while 17 patients on the imatinib arm progressed to either accelerated phase (including clonal evolution) or blast crisis (8 patients within first 6 months, 4 within 6 to 12 months, 4 within 12 to 18 months and 1 within 18 to 24 months). - A single-arm, open-label, multicenter study was conducted to evaluate the efficacy and safety of Tasigna (400 mg twice daily) in patients with imatinib-resistant or -intolerant CML with separate cohorts for chronic and accelerated phase disease. The definition of imatinib resistance included failure to achieve a complete hematologic response (by 3 months), cytogenetic response (by 6 months) or major cytogenetic response (by 12 months) or progression of disease after a previous cytogenetic or hematologic response. Imatinib intolerance was defined as discontinuation of treatment due to toxicity and lack of a major cytogenetic response at time of study entry. At the time of data cut-off, 321 patients with CML-CP and 137 patients with CML-AP with a minimum follow-up of 24 months were enrolled. In this study, about 50% of CML-CP and CML-AP patients were males, over 90% (CML-CP) and 80% (CML-AP) were Caucasian, and approximately 30% were age 65 years or older. - Overall, 73% of patients were imatinib resistant while 27% were imatinib intolerant. The median time of prior imatinib treatment was approximately 32 (CML-CP) and 28 (CML-AP) months. Prior therapy included hydroxyurea in 85% of patients, interferon in 56% and stem cell or bone marrow transplant in 8%. The median highest prior imatinib dose was 600 mg/day for patients with CML-CP and CML-AP, and the highest prior imatinib dose was ≥600 mg/day in 74% of all patients with 40% of patients receiving imatinib doses ≥800 mg/day. - Median duration of nilotinib treatment was 18.4 months in patients with CML-CP and 8.7 months in patients with CML-AP. - The efficacy endpoint in CML-CP was unconfirmed major cytogenetic response (MCyR) which included complete and partial cytogenetic responses. - The efficacy endpoint in CML-AP was confirmed hematologic response (HR), defined as either a complete hematologic response (CHR) or no evidence of leukemia (NEL). The rates of response for CML-CP and CML-AP patients are reported in Table 10. - Median durations of response had not been reached at the time of data analysis. - The MCyR rate in 321 CML-CP patients was 51%. The median time to MCyR among responders was 2.8 months (range 1 to 28 months). The median duration of MCyR cannot be estimated. The median duration of exposure on this single arm-trial was 18.4 months. Among the CML-CP patients who achieved MCyR, 62% of them had MCyR lasting more than 18 months. The CCyR rate was 37%. - The overall confirmed hematologic response rate in 137 patients with CML-AP was 39%. The median time to first hematologic response among responders was 1 month (range 1 to 14 months). Among the CML-AP patients who achieved HR, 44% of them had a response lasting for more than 18 months. - After imatinib failure, 24 different BCR-ABL mutations were noted in 42% of chronic phase and 54% of accelerated phase CML patients who were evaluated for mutations. # How Supplied - Tasigna (nilotinib) 150 mg capsules are red opaque hard gelatin capsules, size 1 with black axial imprint “NVR/BCR”. Tasigna (nilotinib) 200 mg capsules are light yellow opaque hard gelatin capsules, size 0 with the red axial imprint “NVR/TKI.” Tasigna capsules are supplied in blister packs. - 150 mg - Carton of 4 blister packs of (4x28) ………………………….…….NDC 0078-0592-87 - Blisters of 28 capsules……………………………………….…….NDC 0078-0592-51 - 200 mg - Carton of 4 blister packs of (4x28) ………………………….…….NDC 0078-0526-87 - Blisters of 28 capsules……………………………………….…….NDC 0078-0526-51 - Tasigna (nilotinib) capsules should be stored at 25°C (77°F); excursions permitted between 15° to 30°C (59° to 86°F). ## Storage There is limited information regarding Nilotinib Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Cardiac and Vascular Events - Advise patients that cardiovascular events (including ischemic heart disease, peripheral arterial occlusive disease, and ischemic cerebrovascular events) have been reported. Advise patients to seek immediate medical attention with any symptoms suggestive of a cardiovascular event. Cardiovascular status of patients should be evaluated and cardiovascular risk factors should be monitored and managed during Tasigna therapy according to standard guidelines. - Taking Tasigna - Advise patients to take Tasigna doses twice daily approximately 12 hours apart. The capsules should be swallowed whole with water. - Advise patients to take Tasigna on an empty stomach. No food should be consumed for at least 2 hours before the dose is taken and for at least 1 hour after the dose is taken. Patients should not consume grapefruit products and other foods that are known to inhibit CYP3A4 at any time during Tasigna treatment. - If the patient missed a dose of Tasigna, the patient should take the next scheduled dose at its regular time. The patient should not take two doses at the same time. - Should patients be unable to swallow capsules, the contents of each capsule may be dispersed in one teaspoon of applesauce and the mixture swallowed immediately (within 15 minutes). - Drug Interactions - Tasigna and certain other medicines, including over the counter medications or herbal supplements (such as St. John’s Wort), can interact with each other. - Pregnancy - Advise patients that the use of Tasigna during pregnancy may cause harm to the fetus and that Tasigna should not be taken during pregnancy unless necessary. Women of childbearing potential should use highly effective contraceptives while taking Tasigna. Sexually active female patients taking Tasigna should use adequate contraception. - Compliance - Advise patients of the following: Continue taking Tasigna every day for as long as their doctor tells them. This is a long-term treatment. Do not change dose or stop taking Tasigna without first consulting their doctor. If a dose is missed, take the next dose as scheduled. Do not take a double dose to make up for the missed capsules. - Continue taking Tasigna every day for as long as their doctor tells them. - This is a long-term treatment. - Do not change dose or stop taking Tasigna without first consulting their doctor. - If a dose is missed, take the next dose as scheduled. Do not take a double dose to make up for the missed capsules. # Precautions with Alcohol - Alcohol-Nilotinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - TASIGNA®[4] # Look-Alike Drug Names There is limited information regarding Nilotinib Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Nilotinib
ec2e5a0b3e1e801b4dff1963b898a66ce2ee94f4	wikidoc	Niraparib	Niraparib # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Niraparib is a poly(ADP-ribose) polymerase (PARP) inhibitor that is FDA approved for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. Common adverse reactions include thrombocytopenia, anemia, neutropenia, leukopenia, palpitations, nausea, constipation, vomiting, abdominal pain/distention, mucositis/stomatitis, diarrhea, dyspepsia, dry mouth, fatigue/asthenia, decreased appetite, urinary tract infection, AST/ALT elevation, myalgia, back pain, arthralgia, headache, dizziness, dysgeusia, insomnia, anxiety, nasopharyngitis, dyspnea, cough, rash, and hypertension. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Niraparib is indicated for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. - The recommended dose of niraparib as monotherapy is 300 mg (three 100 mg capsules) taken orally once daily. - Instruct patients to take their dose of niraparib at approximately the same time each day. Each capsule should be swallowed whole. Niraparib may be taken with or without food. Bedtime administration may be a potential method for managing nausea. - Patients should start treatment with ZEJULA no later than 8 weeks after their most recent platinum-containing regimen. - Niraparib treatment should be continued until disease progression or unacceptable toxicity. - In the case of a missed dose of niraparib, instruct patients to take their next dose at its regularly scheduled time. If a patient vomits or misses a dose of niraparib, an additional dose should not be taken. - To manage adverse reactions, consider interruption of treatment, dose reduction, or dose discontinuation. The recommended dose modifications for adverse reactions are listed in Tables 1, 2 and 3. - 100 mg capsule having a white body with "100 mg" printed in black ink, and a purple cap with "Niraparib" printed in white ink. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding niraparib Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding niraparib Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Niraparib FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding niraparib Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding niraparib Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications - None. # Warnings - Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML), including cases with fatal outcome, have been reported in patients who received niraparib. In Trial 1 (NOVA), MDS/AML occurred in 5 out of 367 (1.4%) of patients who received niraparib and in 2 out of 179 (1.1%) patients who received placebo. Overall, MDS/AML has been reported in 7 out of 751 (0.9%) patients treated with niraparib in clinical studies. - The duration of niraparib treatment in patients prior to developing MDS/AML varied from <1 month to 2 years. All patients had received previous chemotherapy with platinum and some had also received other DNA damaging agents and radiotherapy. Discontinue niraparib if MDS/AML is confirmed. - Hematologic adverse reactions (thrombocytopenia, anemia and neutropenia) have been reported in patients treated with niraparib. Grade ≥3 thrombocytopenia, anemia and neutropenia were reported, respectively, in 29%, 25%, and 20% of patients receiving niraparib. Discontinuation due to thrombocytopenia, anemia, and neutropenia occurred, respectively, in 3%, 1%, and 2% of patients. - Do not start niraparib until patients have recovered from hematological toxicity caused by previous chemotherapy (≤ Grade 1). Monitor complete blood counts weekly for the first month, monthly for the next 11 months of treatment, and periodically after this time. If hematological toxicities do not resolve within 28 days following interruption, discontinue niraparib, and refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. - Hypertension and hypertensive crisis have been reported in patients treated with niraparib. Grade 3-4 hypertension occurred in 9% of niraparib treated patients compared to 2% of placebo treated patients in Trial 1. Discontinuation due to hypertension occurred in <1% of patients. - Monitor blood pressure and heart rate monthly for the first year and periodically thereafter during treatment with niraparib. Closely monitor patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. Medically manage hypertension with antihypertensive medications and adjustment of the niraparib dose, if necessary. - Based on its mechanism of action, niraparib can cause fetal harm when administered to a pregnant woman. Niraparib has the potential to cause teratogenicity and/or embryo-fetal death since niraparib is genotoxic and targets actively dividing cells in animals and patients (e.g., bone marrow). Due to the potential risk to a fetus based on its mechanism of action, animal developmental and reproductive toxicology studies were not conducted with niraparib. - Apprise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months after the last dose of niraparib. # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. - The safety of niraparib monotherapy 300 mg once daily has been studied in 367 patients with platinum-sensitive recurrent ovarian, fallopian tube, and primary peritoneal cancer in Trial 1 (NOVA). Adverse reactions in Trial 1 led to dose reduction or interruption in 69% of patients, most frequently from thrombocytopenia (41%) and anemia (20%). The permanent discontinuation rate due to adverse reactions in Trial 1 was 15%. The median exposure to niraparib in these patients was 250 days. - Table 4 and Table 5 summarize the common adverse reactions and abnormal laboratory findings, respectively, observed in patients treated with niraparib. - The following adverse reactions and laboratory abnormalities have been identified in ≥1 to <10% of the 367 patients receiving niraparib in the NOVA trial and not included in the table: tachycardia, peripheral edema, hypokalemia, bronchitis, conjunctivitis, gamma-glutamyl transferase increased, blood creatinine increased, blood alkaline phosphatase increased, weight decreased, depression, epistaxis. ## Postmarketing Experience There is limited information regarding Niraparib Postmarketing Experience in the drug label. # Drug Interactions There is limited information regarding Niraparib Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Based on its mechanism of action, niraparib can cause fetal harm when administered to pregnant women. There are no data regarding the use of niraparib in pregnant women to inform the drug-associated risk. Niraparib has the potential to cause teratogenicity and/or embryo-fetal death since niraparib is genotoxic and targets actively dividing cells in animals and patients (e.g., bone marrow). Due to the potential risk to a fetus based on its mechanism of action, animal developmental and reproductive toxicology studies were not conducted with niraparib. Apprise pregnant women of the potential risk to a fetus. - The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Niraparib in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Niraparib during labor and delivery. ### Nursing Mothers - No data are available regarding the presence of niraparib or its metabolites in human milk, or on its effects on the breastfed infant or milk production. Because of the potential for serious adverse reactions in breastfed infants from niraparib, advise a lactating woman not to breastfeed during treatment with niraparib and for 1 month after receiving the final dose. ### Pediatric Use - Safety and effectiveness of niraparib have not been established in pediatric patients. ### Geriatic Use - In Trial 1 (NOVA), 35% of patients were aged ≥65 years and 8% were aged ≥75 years. No overall differences in safety and effectiveness of niraparib were observed between these patients and younger patients but greater sensitivity of some older individuals cannot be ruled out. ### Gender There is no FDA guidance on the use of Niraparib with respect to specific gender populations. ### Race There is no FDA guidance on the use of Niraparib with respect to specific racial populations. ### Renal Impairment - No dose adjustment is necessary for patients with mild (CLcr:60 to 89 mL/min) to moderate (CLcr:30 to 59 mL/min) renal impairment. The degree of renal impairment was determined by creatinine clearance as estimated by the Cockcroft-Gault equation. The safety of niraparib in patients with severe renal impairment or end stage renal disease undergoing hemodialysis is unknown. ### Hepatic Impairment - No dose adjustment is needed in patients with mild hepatic impairment according to the National Cancer Institute – Organ Dysfunction Working Group (NCI-ODWG) criteria. The safety of niraparib in patients with moderate to severe hepatic impairment is unknown. ### Females of Reproductive Potential and Males - Niraparib can cause fetal harm when administered to a pregnant woman. - A pregnancy test is recommended for females of reproductive potential prior to initiating niraparib treatment. Females - Niraparib can cause fetal harm when administered to a pregnant woman. - Advise females of reproductive potential to use effective contraception treatment with niraparib and for at least for 6 months following the last dose. Males - Based on animal studies, niraparib may impair fertility in males of reproductive potential. ### Immunocompromised Patients There is no FDA guidance one the use of Niraparib in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring - Evidence of disease response or stabilization is indicative of efficacy. - Pregnancy test: Prior to therapy initiation. - CBC: Weekly for the first month, monthly for the next 11 months, and periodically thereafter for clinically significant changes; if hematologic toxicity occurs, monitor weekly; include a differential. - Blood pressure and heart rate: Monthly for the first year and periodically thereafter, especially in patients with cardiovascular disorders (eg, coronary insufficiency, cardiac arrhythmias, hypertension). # IV Compatibility There is limited information regarding the compatibility of Niraparib and IV administrations. # Overdosage - There is no specific treatment in the event of niraparib overdose, and symptoms of overdose are not established. In the event of an overdose, healthcare practitioners should follow general supportive measures and should treat symptomatically. # Pharmacology ## Mechanism of Action - Niraparib is an inhibitor of poly(ADP-ribose) polymerase (PARP) enzymes, PARP-1 and PARP-2, which play a role in DNA repair. In vitro studies have shown that niraparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes resulting in DNA damage, apoptosis and cell death. Increased niraparib-induced cytotoxicity was observed in tumor cell lines with or without deficiencies in BRCA1/2. Niraparib decreased tumor growth in mouse xenograft models of human cancer cell lines with deficiencies in BRCA1/2 and in human patient-derived xenograft tumor models with homologous recombination deficiency that had either mutated or wild type BRCA1/2. ## Structure ## Pharmacodynamics - The pharmacodynamic response of niraparib has not been characterized. - Niraparib has the potential to cause effects on pulse rate and blood pressure in patients receiving the recommended dose, which may be related to pharmacological inhibition of the dopamine transporter (DAT), norepinephrine transporter (NET) and serotonin transporter (SERT). - In the NOVA study, mean pulse rate and blood pressure increased over baseline in the niraparib arm relative to the placebo arm at all on-study assessments. Mean greatest increases from baseline in pulse rate on treatment were 24.1 and 15.8 beats/min in the niraparib and placebo arms, respectively. Mean greatest increases from baseline in systolic blood pressure on treatment were 24.5 and 18.3 mmHg in the niraparib and placebo arms, respectively. Mean greatest increases from baseline in diastolic blood pressure on treatment were 16.5 and 11.6 mmHg in the niraparib and placebo arms, respectively. - The potential for QTc prolongation with niraparib was evaluated in a randomized, placebo-controlled trial in cancer patients (367 patients on niraparib and 179 patients on placebo). No large changes in the mean QTc interval (>20 ms) were detected in the trial following the treatment of niraparib 300 mg once daily. ## Pharmacokinetics - Following a single-dose administration of 300 mg niraparib, the mean (±SD) peak plasma concentration (Cmax) was 804 (± 403) ng/mL. The systemic exposures (Cmax and AUC) of niraparib increased in a dose proportional manner with daily doses ranging from 30 mg (0.1 times the approved recommended dosage) to 400 mg (1.3 times the approved recommended dosage). The accumulation ratio of niraparib exposure following 21 days of repeated daily doses was approximately 2 fold for doses ranging from 30 mg to 400 mg. - The absolute bioavailability of niraparib is approximately 73%. Following oral administration of niraparib, peak plasma concentration, Cmax, is reached within 3 hours. - Concomitant administration of a high fat meal (800-1,000 calories with approximately 50% of total caloric content of the meal from fat) did not significantly affect the pharmacokinetics of niraparib. - Niraparib is 83.0% bound to human plasma proteins. The average (±SD) apparent volume of distribution (Vd/F) was 1220 (±1114) L. In a population pharmacokinetic analysis, the Vd/F of niraparib was 1074 L in cancer patients. - Following multiple daily doses of 300 mg niraparib, the mean half-life (t1/2) is 36 hours. In a population pharmacokinetic analysis, the apparent total clearance (CL/F) of niraparib was 16.2 L/h in cancer patients. Metabolism - Niraparib is metabolized primarily by carboxylesterases (CEs) to form a major inactive metabolite, which subsequently undergoes glucuronidation. Excretion - Following administration of a single oral 300 mg dose of radio-labeled niraparib, the average percent recovery of the administered dose over 21 days was 47.5% (range 33.4% to 60.2%) in urine, and 38.8% (range 28.3% to 47.0%) in feces. In pooled samples collected over 6 days, unchanged niraparib accounted for 11% and 19% of the administered dose recovered in urine and feces, respectively. - Age (18 to 65 years old), race/ethnicity, and mild to moderate renal impairment had no clinically significant effect on the pharmacokinetics of niraparib. - The effect of severe renal impairment or end-stage renal disease undergoing hemodialysis on the pharmacokinetics of niraparib is unknown. - The effect of moderate or severe hepatic impairment on the pharmacokinetics of niraparib is unknown. - No formal drug interaction studies have been performed with niraparib. - In Vitro Studies - Inhibition of CYPs: Neither niraparib nor the major primary metabolite M1 is an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. - Induction of CYPs: Neither niraparib nor M1 is a CYP3A4 inducer. Niraparib weakly induces CYP1A2 in vitro. - Substrate of CYPs: Niraparib is a substrate of carboxylesterases (CEs) and UDP-glucuronosyltransferases (UGTs) in vivo. - Inhibition of transporter systems: Niraparib is a weak inhibitor of BCRP, but does not inhibit P-gp or BSEP. The M1 metabolite is not an inhibitor of P-gp, BCRP, or BSEP. Neither niraparib nor M1 is an inhibitor of organic anion transport polypeptide 1B1 (OATP1B1), 1B3 (OATP1B3), or organic cation transporter 1 (OCT1), organic anion transporter 1 (OAT1), 3 (OAT3), or organic cation transporter 2 (OCT2). - Substrate of transporter systems: Niraparib is a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). Niraparib is not a substrate of bile salt export pump (BSEP). The M1 metabolite is not a substrate of P-gp, BCRP, or BSEP. Neither niraparib nor M1 is a substrate of organic anion transport polypeptide 1B1 (OATP1B1), 1B3 (OATP1B3), or organic cation transporter 1 (OCT1), organic anion transporter 1 (OAT1), 3 (OAT3), or organic cation transporter 2 (OCT2). ## Nonclinical Toxicology - Carcinogenicity studies have not been conducted with niraparib. - Niraparib was clastogenic in an in vitro mammalian chromosomal aberration assay and in an in vivo rat bone marrow micronucleus assay. This clastogenicity is consistent with genomic instability resulting from the primary pharmacology of niraparib and indicates potential for genotoxicity in humans. Niraparib was not mutagenic in a bacterial reverse mutation assay (Ames) test. - Fertility studies in animals have not been conducted with niraparib. In repeat-dose oral toxicity studies, niraparib was administered daily for up to 3 months duration in rats and dogs. Reduced sperm, spermatids and germ cells in epididymides and testes were observed at doses ≥10 mg/kg and ≥1.5 mg/kg in rats and dogs, respectively. These dose levels resulted in systemic exposures approximately 0.3 and 0.012 times, respectively, the human exposure (AUC0-24hr) at the recommended dose of 300 mg daily. There was a trend toward reversibility of these findings 4 weeks after dosing was stopped. - In vitro, niraparib bound to the dopamine transporter (DAT), norepinephrine transporter (NET) and serotonin transporter (SERT) and inhibited uptake of norepinephrine and dopamine in cells with IC50 values that were lower than the Cmin at steady-state in patients receiving the recommended dose. Niraparib has the potential to cause effects in patients related to inhibition of these transporters (e.g., cardiovascular or CNS). - Intravenous administration of niraparib to vagotomized dogs over 30 minutes at 1, 3 and 10 mg/kg resulted in an increased range of arterial pressures of 13-20, 18-27 and 19-25% and increased range of heart rates of 2-11, 4-17 and 12-21% above pre-dose levels, respectively. The unbound plasma concentrations of niraparib in dogs at these dose levels were approximately 0.7, 2 and 8 times the unbound Cmax at steady-state in patients receiving the recommended dose. - In addition, niraparib crossed the blood-brain barrier in rats and monkeys following oral administration. The cerebrospinal fluid (CSF):plasma Cmax ratios of niraparib administered at 10 mg/kg orally to two Rhesus monkeys were 0.10 and 0.52. # Clinical Studies - Trial 1 (NOVA) was a double-blind, placebo-controlled trial in which patients (n=553) with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer were randomized 2:1 to niraparib 300 mg orally daily or matched placebo within 8 weeks of the last therapy. All patients had received at least two prior platinum-containing regimens and were in response (complete or partial) to their most recent platinum-based regimen. - Randomization was stratified by time to progression after the penultimate platinum therapy (6 to <12 months and ≥12 months); use of bevacizumab in conjunction with the penultimate or last platinum regimen (yes/no); and best response during the most recent platinum regimen (complete response and partial response). Eligible patients were assigned to one of two cohorts based on the results of the BRACAnalysis CDx. Patients with deleterious or suspected deleterious germline BRCA mutations (gBRCAm) were assigned to the germline BRCA mutated (gBRCAmut) cohort (n=203), and those without germline BRCA mutations were assigned to the non-gBRCAmut cohort (n=350). - The major efficacy outcome measure, PFS (progression-free survival), was determined primarily by central independent assessment per RECIST (Response Evaluation Criteria in Solid Tumors, version 1.1). In some cases, criteria other than RECIST, such as clinical signs and symptoms and increasing CA-125, were also applied. - The median age of patients ranged from 57-64 years among patients treated with niraparib and 58-67 years among patients treated with placebo. Eighty-six percent of all patients were white. Sixty-seven percent of patients receiving niraparib and 69% of patients receiving placebo had an ECOG of 0 at study baseline. Approximately 40% of patients were enrolled in the U.S. or Canada and 51% of all patients were in complete response to most recent platinum-based regimen, with 39% on both arms with an interval of 6-12 months since the penultimate platinum regimen. Twenty-six percent of those treated with niraparib and 31% treated with placebo had received prior bevacizumab therapy. Approximately 40% of patients had 3 or more lines of treatment. - The trial demonstrated a statistically significant improvement in PFS for patients randomized to niraparib as compared with placebo in the gBRCAmut cohort and the non-gBRCAmut cohort (Table 6, and Figures 1 and 2). - At the time of the PFS analysis, limited overall survival data were available with 17% deaths across the two cohorts. # How Supplied - Niraparib is available as capsules having a white body printed with "100 mg" in black ink, and a purple cap printed with "Niraparib" in white ink. - Each capsule contains 100 mg of niraparib free base. ## Storage - Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C to 30°C (59°F to 86°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise the patient to read the FDA-approved patient labeling. - Advise patients to contact their healthcare provider if they experience weakness, feeling tired, fever, weight loss, frequent infections, bruising, bleeding easily, breathlessness, blood in urine or stool, and/or laboratory findings of low blood cell counts, or a need for blood transfusions. This may be a sign of hematological toxicity or myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) which has been reported in patients treated with niraparib. - Advise patients that periodic monitoring of their blood counts is required. Advise patients to contact their healthcare provider for new onset of bleeding, fever, or symptoms of infection. - Advise patients to undergo monthly blood pressure and heart rate monitoring for the first year of treatment and then periodically thereafter and to contact their healthcare provider if blood pressure is elevated. - Inform patients on how to take niraparib. Niraparib should be taken once daily. Instruct patients that if they miss a dose of niraparib, not to take an extra dose to make up for the one that they missed. They should take their next dose at the regularly scheduled time. Each capsule should be swallowed whole. Niraparib may be taken with or without food. Bedtime administration may be a potential method for managing nausea. - Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the risk to a fetus and potential loss of the pregnancy. - Advise females of reproductive potential to use effective contraception during treatment with niraparib and for at least 6 months after receiving the last dose. - Advise patients not to breastfeed while taking niraparib and for 1 month after the last dose. # Precautions with Alcohol Alcohol-Niraparib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names - Zejula # Look-Alike Drug Names There is limited information regarding Niraparib Look-Alike Drug Names in the drug label. # Drug Shortage Status Drug Shortage # Price	Niraparib Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sonya Gelfand # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Niraparib is a poly(ADP-ribose) polymerase (PARP) inhibitor that is FDA approved for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. Common adverse reactions include thrombocytopenia, anemia, neutropenia, leukopenia, palpitations, nausea, constipation, vomiting, abdominal pain/distention, mucositis/stomatitis, diarrhea, dyspepsia, dry mouth, fatigue/asthenia, decreased appetite, urinary tract infection, AST/ALT elevation, myalgia, back pain, arthralgia, headache, dizziness, dysgeusia, insomnia, anxiety, nasopharyngitis, dyspnea, cough, rash, and hypertension. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Niraparib is indicated for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. - The recommended dose of niraparib as monotherapy is 300 mg (three 100 mg capsules) taken orally once daily. - Instruct patients to take their dose of niraparib at approximately the same time each day. Each capsule should be swallowed whole. Niraparib may be taken with or without food. Bedtime administration may be a potential method for managing nausea. - Patients should start treatment with ZEJULA no later than 8 weeks after their most recent platinum-containing regimen. - Niraparib treatment should be continued until disease progression or unacceptable toxicity. - In the case of a missed dose of niraparib, instruct patients to take their next dose at its regularly scheduled time. If a patient vomits or misses a dose of niraparib, an additional dose should not be taken. - To manage adverse reactions, consider interruption of treatment, dose reduction, or dose discontinuation. The recommended dose modifications for adverse reactions are listed in Tables 1, 2 and 3. - 100 mg capsule having a white body with "100 mg" printed in black ink, and a purple cap with "Niraparib" printed in white ink. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding niraparib Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding niraparib Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Niraparib FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding niraparib Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding niraparib Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications - None. # Warnings - Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML), including cases with fatal outcome, have been reported in patients who received niraparib. In Trial 1 (NOVA), MDS/AML occurred in 5 out of 367 (1.4%) of patients who received niraparib and in 2 out of 179 (1.1%) patients who received placebo. Overall, MDS/AML has been reported in 7 out of 751 (0.9%) patients treated with niraparib in clinical studies. - The duration of niraparib treatment in patients prior to developing MDS/AML varied from <1 month to 2 years. All patients had received previous chemotherapy with platinum and some had also received other DNA damaging agents and radiotherapy. Discontinue niraparib if MDS/AML is confirmed. - Hematologic adverse reactions (thrombocytopenia, anemia and neutropenia) have been reported in patients treated with niraparib. Grade ≥3 thrombocytopenia, anemia and neutropenia were reported, respectively, in 29%, 25%, and 20% of patients receiving niraparib. Discontinuation due to thrombocytopenia, anemia, and neutropenia occurred, respectively, in 3%, 1%, and 2% of patients. - Do not start niraparib until patients have recovered from hematological toxicity caused by previous chemotherapy (≤ Grade 1). Monitor complete blood counts weekly for the first month, monthly for the next 11 months of treatment, and periodically after this time. If hematological toxicities do not resolve within 28 days following interruption, discontinue niraparib, and refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. - Hypertension and hypertensive crisis have been reported in patients treated with niraparib. Grade 3-4 hypertension occurred in 9% of niraparib treated patients compared to 2% of placebo treated patients in Trial 1. Discontinuation due to hypertension occurred in <1% of patients. - Monitor blood pressure and heart rate monthly for the first year and periodically thereafter during treatment with niraparib. Closely monitor patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. Medically manage hypertension with antihypertensive medications and adjustment of the niraparib dose, if necessary. - Based on its mechanism of action, niraparib can cause fetal harm when administered to a pregnant woman. Niraparib has the potential to cause teratogenicity and/or embryo-fetal death since niraparib is genotoxic and targets actively dividing cells in animals and patients (e.g., bone marrow). Due to the potential risk to a fetus based on its mechanism of action, animal developmental and reproductive toxicology studies were not conducted with niraparib. - Apprise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months after the last dose of niraparib. # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. - The safety of niraparib monotherapy 300 mg once daily has been studied in 367 patients with platinum-sensitive recurrent ovarian, fallopian tube, and primary peritoneal cancer in Trial 1 (NOVA). Adverse reactions in Trial 1 led to dose reduction or interruption in 69% of patients, most frequently from thrombocytopenia (41%) and anemia (20%). The permanent discontinuation rate due to adverse reactions in Trial 1 was 15%. The median exposure to niraparib in these patients was 250 days. - Table 4 and Table 5 summarize the common adverse reactions and abnormal laboratory findings, respectively, observed in patients treated with niraparib. - The following adverse reactions and laboratory abnormalities have been identified in ≥1 to <10% of the 367 patients receiving niraparib in the NOVA trial and not included in the table: tachycardia, peripheral edema, hypokalemia, bronchitis, conjunctivitis, gamma-glutamyl transferase increased, blood creatinine increased, blood alkaline phosphatase increased, weight decreased, depression, epistaxis. ## Postmarketing Experience There is limited information regarding Niraparib Postmarketing Experience in the drug label. # Drug Interactions There is limited information regarding Niraparib Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Based on its mechanism of action, niraparib can cause fetal harm when administered to pregnant women. There are no data regarding the use of niraparib in pregnant women to inform the drug-associated risk. Niraparib has the potential to cause teratogenicity and/or embryo-fetal death since niraparib is genotoxic and targets actively dividing cells in animals and patients (e.g., bone marrow). Due to the potential risk to a fetus based on its mechanism of action, animal developmental and reproductive toxicology studies were not conducted with niraparib. Apprise pregnant women of the potential risk to a fetus. - The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Niraparib in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Niraparib during labor and delivery. ### Nursing Mothers - No data are available regarding the presence of niraparib or its metabolites in human milk, or on its effects on the breastfed infant or milk production. Because of the potential for serious adverse reactions in breastfed infants from niraparib, advise a lactating woman not to breastfeed during treatment with niraparib and for 1 month after receiving the final dose. ### Pediatric Use - Safety and effectiveness of niraparib have not been established in pediatric patients. ### Geriatic Use - In Trial 1 (NOVA), 35% of patients were aged ≥65 years and 8% were aged ≥75 years. No overall differences in safety and effectiveness of niraparib were observed between these patients and younger patients but greater sensitivity of some older individuals cannot be ruled out. ### Gender There is no FDA guidance on the use of Niraparib with respect to specific gender populations. ### Race There is no FDA guidance on the use of Niraparib with respect to specific racial populations. ### Renal Impairment - No dose adjustment is necessary for patients with mild (CLcr:60 to 89 mL/min) to moderate (CLcr:30 to 59 mL/min) renal impairment. The degree of renal impairment was determined by creatinine clearance as estimated by the Cockcroft-Gault equation. The safety of niraparib in patients with severe renal impairment or end stage renal disease undergoing hemodialysis is unknown. ### Hepatic Impairment - No dose adjustment is needed in patients with mild hepatic impairment according to the National Cancer Institute – Organ Dysfunction Working Group (NCI-ODWG) criteria. The safety of niraparib in patients with moderate to severe hepatic impairment is unknown. ### Females of Reproductive Potential and Males - Niraparib can cause fetal harm when administered to a pregnant woman. - A pregnancy test is recommended for females of reproductive potential prior to initiating niraparib treatment. Females - Niraparib can cause fetal harm when administered to a pregnant woman. - Advise females of reproductive potential to use effective contraception treatment with niraparib and for at least for 6 months following the last dose. Males - Based on animal studies, niraparib may impair fertility in males of reproductive potential. ### Immunocompromised Patients There is no FDA guidance one the use of Niraparib in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring - Evidence of disease response or stabilization is indicative of efficacy. - Pregnancy test: Prior to therapy initiation. - CBC: Weekly for the first month, monthly for the next 11 months, and periodically thereafter for clinically significant changes; if hematologic toxicity occurs, monitor weekly; include a differential. - Blood pressure and heart rate: Monthly for the first year and periodically thereafter, especially in patients with cardiovascular disorders (eg, coronary insufficiency, cardiac arrhythmias, hypertension). # IV Compatibility There is limited information regarding the compatibility of Niraparib and IV administrations. # Overdosage - There is no specific treatment in the event of niraparib overdose, and symptoms of overdose are not established. In the event of an overdose, healthcare practitioners should follow general supportive measures and should treat symptomatically. # Pharmacology ## Mechanism of Action - Niraparib is an inhibitor of poly(ADP-ribose) polymerase (PARP) enzymes, PARP-1 and PARP-2, which play a role in DNA repair. In vitro studies have shown that niraparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes resulting in DNA damage, apoptosis and cell death. Increased niraparib-induced cytotoxicity was observed in tumor cell lines with or without deficiencies in BRCA1/2. Niraparib decreased tumor growth in mouse xenograft models of human cancer cell lines with deficiencies in BRCA1/2 and in human patient-derived xenograft tumor models with homologous recombination deficiency that had either mutated or wild type BRCA1/2. ## Structure ## Pharmacodynamics - The pharmacodynamic response of niraparib has not been characterized. - Niraparib has the potential to cause effects on pulse rate and blood pressure in patients receiving the recommended dose, which may be related to pharmacological inhibition of the dopamine transporter (DAT), norepinephrine transporter (NET) and serotonin transporter (SERT). - In the NOVA study, mean pulse rate and blood pressure increased over baseline in the niraparib arm relative to the placebo arm at all on-study assessments. Mean greatest increases from baseline in pulse rate on treatment were 24.1 and 15.8 beats/min in the niraparib and placebo arms, respectively. Mean greatest increases from baseline in systolic blood pressure on treatment were 24.5 and 18.3 mmHg in the niraparib and placebo arms, respectively. Mean greatest increases from baseline in diastolic blood pressure on treatment were 16.5 and 11.6 mmHg in the niraparib and placebo arms, respectively. - The potential for QTc prolongation with niraparib was evaluated in a randomized, placebo-controlled trial in cancer patients (367 patients on niraparib and 179 patients on placebo). No large changes in the mean QTc interval (>20 ms) were detected in the trial following the treatment of niraparib 300 mg once daily. ## Pharmacokinetics - Following a single-dose administration of 300 mg niraparib, the mean (±SD) peak plasma concentration (Cmax) was 804 (± 403) ng/mL. The systemic exposures (Cmax and AUC) of niraparib increased in a dose proportional manner with daily doses ranging from 30 mg (0.1 times the approved recommended dosage) to 400 mg (1.3 times the approved recommended dosage). The accumulation ratio of niraparib exposure following 21 days of repeated daily doses was approximately 2 fold for doses ranging from 30 mg to 400 mg. - The absolute bioavailability of niraparib is approximately 73%. Following oral administration of niraparib, peak plasma concentration, Cmax, is reached within 3 hours. - Concomitant administration of a high fat meal (800-1,000 calories with approximately 50% of total caloric content of the meal from fat) did not significantly affect the pharmacokinetics of niraparib. - Niraparib is 83.0% bound to human plasma proteins. The average (±SD) apparent volume of distribution (Vd/F) was 1220 (±1114) L. In a population pharmacokinetic analysis, the Vd/F of niraparib was 1074 L in cancer patients. - Following multiple daily doses of 300 mg niraparib, the mean half-life (t1/2) is 36 hours. In a population pharmacokinetic analysis, the apparent total clearance (CL/F) of niraparib was 16.2 L/h in cancer patients. Metabolism - Niraparib is metabolized primarily by carboxylesterases (CEs) to form a major inactive metabolite, which subsequently undergoes glucuronidation. Excretion - Following administration of a single oral 300 mg dose of radio-labeled niraparib, the average percent recovery of the administered dose over 21 days was 47.5% (range 33.4% to 60.2%) in urine, and 38.8% (range 28.3% to 47.0%) in feces. In pooled samples collected over 6 days, unchanged niraparib accounted for 11% and 19% of the administered dose recovered in urine and feces, respectively. - Age (18 to 65 years old), race/ethnicity, and mild to moderate renal impairment had no clinically significant effect on the pharmacokinetics of niraparib. - The effect of severe renal impairment or end-stage renal disease undergoing hemodialysis on the pharmacokinetics of niraparib is unknown. - The effect of moderate or severe hepatic impairment on the pharmacokinetics of niraparib is unknown. - No formal drug interaction studies have been performed with niraparib. - In Vitro Studies - Inhibition of CYPs: Neither niraparib nor the major primary metabolite M1 is an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. - Induction of CYPs: Neither niraparib nor M1 is a CYP3A4 inducer. Niraparib weakly induces CYP1A2 in vitro. - Substrate of CYPs: Niraparib is a substrate of carboxylesterases (CEs) and UDP-glucuronosyltransferases (UGTs) in vivo. - Inhibition of transporter systems: Niraparib is a weak inhibitor of BCRP, but does not inhibit P-gp or BSEP. The M1 metabolite is not an inhibitor of P-gp, BCRP, or BSEP. Neither niraparib nor M1 is an inhibitor of organic anion transport polypeptide 1B1 (OATP1B1), 1B3 (OATP1B3), or organic cation transporter 1 (OCT1), organic anion transporter 1 (OAT1), 3 (OAT3), or organic cation transporter 2 (OCT2). - Substrate of transporter systems: Niraparib is a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). Niraparib is not a substrate of bile salt export pump (BSEP). The M1 metabolite is not a substrate of P-gp, BCRP, or BSEP. Neither niraparib nor M1 is a substrate of organic anion transport polypeptide 1B1 (OATP1B1), 1B3 (OATP1B3), or organic cation transporter 1 (OCT1), organic anion transporter 1 (OAT1), 3 (OAT3), or organic cation transporter 2 (OCT2). ## Nonclinical Toxicology - Carcinogenicity studies have not been conducted with niraparib. - Niraparib was clastogenic in an in vitro mammalian chromosomal aberration assay and in an in vivo rat bone marrow micronucleus assay. This clastogenicity is consistent with genomic instability resulting from the primary pharmacology of niraparib and indicates potential for genotoxicity in humans. Niraparib was not mutagenic in a bacterial reverse mutation assay (Ames) test. - Fertility studies in animals have not been conducted with niraparib. In repeat-dose oral toxicity studies, niraparib was administered daily for up to 3 months duration in rats and dogs. Reduced sperm, spermatids and germ cells in epididymides and testes were observed at doses ≥10 mg/kg and ≥1.5 mg/kg in rats and dogs, respectively. These dose levels resulted in systemic exposures approximately 0.3 and 0.012 times, respectively, the human exposure (AUC0-24hr) at the recommended dose of 300 mg daily. There was a trend toward reversibility of these findings 4 weeks after dosing was stopped. - In vitro, niraparib bound to the dopamine transporter (DAT), norepinephrine transporter (NET) and serotonin transporter (SERT) and inhibited uptake of norepinephrine and dopamine in cells with IC50 values that were lower than the Cmin at steady-state in patients receiving the recommended dose. Niraparib has the potential to cause effects in patients related to inhibition of these transporters (e.g., cardiovascular or CNS). - Intravenous administration of niraparib to vagotomized dogs over 30 minutes at 1, 3 and 10 mg/kg resulted in an increased range of arterial pressures of 13-20, 18-27 and 19-25% and increased range of heart rates of 2-11, 4-17 and 12-21% above pre-dose levels, respectively. The unbound plasma concentrations of niraparib in dogs at these dose levels were approximately 0.7, 2 and 8 times the unbound Cmax at steady-state in patients receiving the recommended dose. - In addition, niraparib crossed the blood-brain barrier in rats and monkeys following oral administration. The cerebrospinal fluid (CSF):plasma Cmax ratios of niraparib administered at 10 mg/kg orally to two Rhesus monkeys were 0.10 and 0.52. # Clinical Studies - Trial 1 (NOVA) was a double-blind, placebo-controlled trial in which patients (n=553) with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer were randomized 2:1 to niraparib 300 mg orally daily or matched placebo within 8 weeks of the last therapy. All patients had received at least two prior platinum-containing regimens and were in response (complete or partial) to their most recent platinum-based regimen. - Randomization was stratified by time to progression after the penultimate platinum therapy (6 to <12 months and ≥12 months); use of bevacizumab in conjunction with the penultimate or last platinum regimen (yes/no); and best response during the most recent platinum regimen (complete response and partial response). Eligible patients were assigned to one of two cohorts based on the results of the BRACAnalysis CDx. Patients with deleterious or suspected deleterious germline BRCA mutations (gBRCAm) were assigned to the germline BRCA mutated (gBRCAmut) cohort (n=203), and those without germline BRCA mutations were assigned to the non-gBRCAmut cohort (n=350). - The major efficacy outcome measure, PFS (progression-free survival), was determined primarily by central independent assessment per RECIST (Response Evaluation Criteria in Solid Tumors, version 1.1). In some cases, criteria other than RECIST, such as clinical signs and symptoms and increasing CA-125, were also applied. - The median age of patients ranged from 57-64 years among patients treated with niraparib and 58-67 years among patients treated with placebo. Eighty-six percent of all patients were white. Sixty-seven percent of patients receiving niraparib and 69% of patients receiving placebo had an ECOG of 0 at study baseline. Approximately 40% of patients were enrolled in the U.S. or Canada and 51% of all patients were in complete response to most recent platinum-based regimen, with 39% on both arms with an interval of 6-12 months since the penultimate platinum regimen. Twenty-six percent of those treated with niraparib and 31% treated with placebo had received prior bevacizumab therapy. Approximately 40% of patients had 3 or more lines of treatment. - The trial demonstrated a statistically significant improvement in PFS for patients randomized to niraparib as compared with placebo in the gBRCAmut cohort and the non-gBRCAmut cohort (Table 6, and Figures 1 and 2). - At the time of the PFS analysis, limited overall survival data were available with 17% deaths across the two cohorts. # How Supplied - Niraparib is available as capsules having a white body printed with "100 mg" in black ink, and a purple cap printed with "Niraparib" in white ink. - Each capsule contains 100 mg of niraparib free base. ## Storage - Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C to 30°C (59°F to 86°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise the patient to read the FDA-approved patient labeling. - Advise patients to contact their healthcare provider if they experience weakness, feeling tired, fever, weight loss, frequent infections, bruising, bleeding easily, breathlessness, blood in urine or stool, and/or laboratory findings of low blood cell counts, or a need for blood transfusions. This may be a sign of hematological toxicity or myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) which has been reported in patients treated with niraparib. - Advise patients that periodic monitoring of their blood counts is required. Advise patients to contact their healthcare provider for new onset of bleeding, fever, or symptoms of infection. - Advise patients to undergo monthly blood pressure and heart rate monitoring for the first year of treatment and then periodically thereafter and to contact their healthcare provider if blood pressure is elevated. - Inform patients on how to take niraparib. Niraparib should be taken once daily. Instruct patients that if they miss a dose of niraparib, not to take an extra dose to make up for the one that they missed. They should take their next dose at the regularly scheduled time. Each capsule should be swallowed whole. Niraparib may be taken with or without food. Bedtime administration may be a potential method for managing nausea. - Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the risk to a fetus and potential loss of the pregnancy. - Advise females of reproductive potential to use effective contraception during treatment with niraparib and for at least 6 months after receiving the last dose. - Advise patients not to breastfeed while taking niraparib and for 1 month after the last dose. # Precautions with Alcohol Alcohol-Niraparib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names - Zejula # Look-Alike Drug Names There is limited information regarding Niraparib Look-Alike Drug Names in the drug label. # Drug Shortage Status Drug Shortage # Price	https://www.wikidoc.org/index.php/Niraparib
2289786372286c65a6939d412345465b3feb6d27	wikidoc	Nitrilase	Nitrilase Nitrilase enzymes (nitrile aminohydrolase; EC 3.5.5.1) catalyse the hydrolysis of nitriles to carboxylic acids and ammonia, without the formation of "free" amide intermediates. Nitrilases are involved in natural product biosynthesis and post translational modifications in plants, animals, fungi and certain prokaryotes. Nitrilases can also be used as catalysts in preparative organic chemistry. Among others, nitrilases have been used for the resolution of racemic mixtures. Nitrilase should not be confused with nitrile hydratase (nitrile hydro-lyase; EC 4.2.1.84) which hydrolyses nitriles to amides. Nitrile hydratases are almost invariably co-expressed with an amidase, which converts the amide to the carboxylic acid. Consequently, it can sometimes be difficult to distinguish nitrilase activity from nitrile hydratase plus amidase activity. # Mechanism Nitrilase was first discovered in the early 1960s for its ability to catalyze the hydration of a nitrile to a carboxylic acid. Although it was known at the time that nitrilase could operate with wide substrate specificity in producing the corresponding acid, later studies reported the first NHase (nitrile hydratase) activity exhibited by nitrilase. That is, amide compounds could also be formed via nitrile hydrolysis. Further research has revealed several conditions that promote amide formation, which are outlined below. - Early release of the enzyme-bound substrate after the first water hydrolysis followed by delayed addition of the second water - Low temperature and increased pH conditions. For bioconversions by nitrilase for most bacteria and fungi, the optimal pH range is between 7.0-8.0 and the optimal temperature range is between 30-50℃. - Electron withdrawing groups at the ⍺-position Below is a list of steps involved in transforming a generic nitrile compound with nitrilase: - The electrophilic carbon of the nitrile is subject to nucleophilic attack by one of the two SH groups on nitrilase. - The thioimidate formed is subsequently hydrolyzed to the acylenzyme and ammonia is created as a byproduct. - The acylenzyme can undergo one of two pathways depending on the conditions highlighted above: Further hydrolyzation of the acylenzyme with water produces the carboxylic acid and the regenerated enzyme. The acylenzyme is hydrolyzed by ammonia, displacing the enzyme and forming the amide product. - Further hydrolyzation of the acylenzyme with water produces the carboxylic acid and the regenerated enzyme. - The acylenzyme is hydrolyzed by ammonia, displacing the enzyme and forming the amide product. # Structure Most nitrilases are made up of a single polypeptide ranging from 32-45 kDa, and its structure is an ⍺-β-β-⍺ fold. The favored form of the enzyme is a large aggregate consisting of 6-26 subunits. Nitrilase exploits the lys-cys-glu catalytic triad which is essential for its active site function and enhancing its performance. The structure of a thermoactive nitrilase from P. abyssi consists of a 2-fold symmetric dimer in which each subunit contains 262 residues. Similar to other nitrilases in the nitrilase family, each subunit has an ⍺-β-β-⍺ sandwich fold; when the two subunits come together and interact, the protein forms a ‘super-sandwich’ (⍺-β-β-⍺-⍺-β-β-⍺) structure. In order to dimerize, the C-terminals of each subunit extend out from the core and interact with each other, and this is largely made possible by the salt bridges formed between arginine and glutamate residues. Although the exact binding mechanism to the nitrile substrate still remains unknown, by drawing comparisons between the sequence and structure with other nitrilases, the catalytic triad was determined to consist of Glu 42, Lys 113, and Cys 146. With the aid of protein modeling programs, Glu 42 was observed to be the catalytic base in activating the nucleophile (Cys 146) based on the relatively short distance between the O in Glu and S in Cys. Likewise, Lys 113 was inferred to be the catalytic acid responsible for proton transfer to the substrate. # Biological Function Nitrilases have critical roles in plant-microbe interactions for defense, detoxification, nitrogen utilization, and plant hormone synthesis. In plants, there are two distinguishable groups in regard to substrate specificity: those with high hydrolytic activity towards arylacetonitriles and those with high activity towards β-cyano-L-alanine. N121, 2, and 3 of the A. thaliana species are examples of the first group of plant nitrilases (arylacetonitrilases) which hydrolyze the nitriles produced during the synthesis or degradation of cyanogenic glycosides and glucosinolates. The arylcetonitrile substrates for these particular enzymes consist of phenylpropionitrile and other products that result from glucosinolate metabolism. N1T4 however, belongs to the second group of plant nitrilases and is critical for cyanide detoxification in plants. Moreover, microbes could also potentially utilize nitrilase for detoxifying and assimilating nitriles and cyanide that exist in the plant environment. An example of this is the β-cyano-L-alanine nitrilase by the plant bacterium P. fluorescens SBW25. Although it is unknown whether this plant bacterium encounters toxic levels of β-cyano-ʟ-alanine in natural settings, nitrilase activity has been observed in cyanogenic plants; thus, it seems that the nitrilase serves as a predominant mechanism for detoxifying cyanide instead of β-cyano-ʟ-alanine. Other bacterial applications of nitrilases produced by plant-associated microorganisms include the degradation of plant nitriles for a carbon and nitrogen source. P. fluorescens EBC191 hydrolyzes many arylacetonitriles, namely mandelonitrile, which serves as a defense against herbivores. # Further reading - Winkler M, Glieder A, Klempier N (March 2006). "Enzyme stabilizer DTT catalyzes nitrilase analogue hydrolysis of nitriles". Chemical Communications (12): 1298–300. doi:10.1039/B516937B. PMID 16538253..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}	Nitrilase Nitrilase enzymes (nitrile aminohydrolase; EC 3.5.5.1) catalyse the hydrolysis of nitriles to carboxylic acids and ammonia, without the formation of "free" amide intermediates.[1] Nitrilases are involved in natural product biosynthesis and post translational modifications in plants, animals, fungi and certain prokaryotes. Nitrilases can also be used as catalysts in preparative organic chemistry. Among others, nitrilases have been used for the resolution of racemic mixtures. Nitrilase should not be confused with nitrile hydratase (nitrile hydro-lyase; EC 4.2.1.84) which hydrolyses nitriles to amides. Nitrile hydratases are almost invariably co-expressed with an amidase, which converts the amide to the carboxylic acid. Consequently, it can sometimes be difficult to distinguish nitrilase activity from nitrile hydratase plus amidase activity. # Mechanism Nitrilase was first discovered in the early 1960s for its ability to catalyze the hydration of a nitrile to a carboxylic acid.[2] Although it was known at the time that nitrilase could operate with wide substrate specificity in producing the corresponding acid, later studies reported the first NHase (nitrile hydratase) activity exhibited by nitrilase.[3][4] That is, amide compounds could also be formed via nitrile hydrolysis. Further research has revealed several conditions that promote amide formation, which are outlined below.[4] - Early release of the enzyme-bound substrate after the first water hydrolysis followed by delayed addition of the second water - Low temperature and increased pH conditions. For bioconversions by nitrilase for most bacteria and fungi, the optimal pH range is between 7.0-8.0 and the optimal temperature range is between 30-50℃. - Electron withdrawing groups at the ⍺-position Below is a list of steps involved in transforming a generic nitrile compound with nitrilase:[4] - The electrophilic carbon of the nitrile is subject to nucleophilic attack by one of the two SH groups on nitrilase. - The thioimidate formed is subsequently hydrolyzed to the acylenzyme and ammonia is created as a byproduct. - The acylenzyme can undergo one of two pathways depending on the conditions highlighted above: Further hydrolyzation of the acylenzyme with water produces the carboxylic acid and the regenerated enzyme. The acylenzyme is hydrolyzed by ammonia, displacing the enzyme and forming the amide product. - Further hydrolyzation of the acylenzyme with water produces the carboxylic acid and the regenerated enzyme. - The acylenzyme is hydrolyzed by ammonia, displacing the enzyme and forming the amide product. # Structure Most nitrilases are made up of a single polypeptide ranging from 32-45 kDa,[7] and its structure is an ⍺-β-β-⍺ fold.[4] The favored form of the enzyme is a large aggregate consisting of 6-26 subunits.[7] Nitrilase exploits the lys-cys-glu catalytic triad which is essential for its active site function and enhancing its performance.[4][7] The structure of a thermoactive nitrilase from P. abyssi consists of a 2-fold symmetric dimer in which each subunit contains 262 residues.[8][9] Similar to other nitrilases in the nitrilase family, each subunit has an ⍺-β-β-⍺ sandwich fold; when the two subunits come together and interact, the protein forms a ‘super-sandwich’ (⍺-β-β-⍺-⍺-β-β-⍺) structure.[1] In order to dimerize, the C-terminals of each subunit extend out from the core and interact with each other, and this is largely made possible by the salt bridges formed between arginine and glutamate residues.[1] Although the exact binding mechanism to the nitrile substrate still remains unknown, by drawing comparisons between the sequence and structure with other nitrilases, the catalytic triad was determined to consist of Glu 42, Lys 113, and Cys 146.[1][4][7] With the aid of protein modeling programs, Glu 42 was observed to be the catalytic base in activating the nucleophile (Cys 146) based on the relatively short distance between the O in Glu and S in Cys. Likewise, Lys 113 was inferred to be the catalytic acid responsible for proton transfer to the substrate.[8][10] # Biological Function Nitrilases have critical roles in plant-microbe interactions for defense, detoxification, nitrogen utilization, and plant hormone synthesis.[11] In plants, there are two distinguishable groups in regard to substrate specificity: those with high hydrolytic activity towards arylacetonitriles and those with high activity towards β-cyano-L-alanine. N121, 2, and 3 of the A. thaliana species are examples of the first group of plant nitrilases (arylacetonitrilases) which hydrolyze the nitriles produced during the synthesis or degradation of cyanogenic glycosides and glucosinolates. The arylcetonitrile substrates for these particular enzymes consist of phenylpropionitrile and other products that result from glucosinolate metabolism.[11][12] N1T4 however, belongs to the second group of plant nitrilases and is critical for cyanide detoxification in plants.[3][11][13] Moreover, microbes could also potentially utilize nitrilase for detoxifying and assimilating nitriles and cyanide that exist in the plant environment.[11] An example of this is the β-cyano-L-alanine nitrilase by the plant bacterium P. fluorescens SBW25.[14] Although it is unknown whether this plant bacterium encounters toxic levels of β-cyano-ʟ-alanine in natural settings, nitrilase activity has been observed in cyanogenic plants; thus, it seems that the nitrilase serves as a predominant mechanism for detoxifying cyanide instead of β-cyano-ʟ-alanine.[11][14] Other bacterial applications of nitrilases produced by plant-associated microorganisms include the degradation of plant nitriles for a carbon and nitrogen source. P. fluorescens EBC191 hydrolyzes many arylacetonitriles, namely mandelonitrile, which serves as a defense against herbivores.[11][15][16] # Further reading - Winkler M, Glieder A, Klempier N (March 2006). "Enzyme stabilizer DTT catalyzes nitrilase analogue hydrolysis of nitriles". Chemical Communications (12): 1298–300. doi:10.1039/B516937B. 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63b18fcbc25a2036aeb646cdd350bb0e6050a3e9	wikidoc	Nivolumab	Nivolumab # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Nivolumab is an monoclonal antibody that is FDA approved for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V400 mutation positive, a BRAF inhibitor. Common adverse reactions include pruritus, rash , hyperkalemia , hyponatremia alkaline phosphatase raised , ALT/SGPT level raised , AST/SGOT level raised , Serum bilirubin raised ,Serum creatinine raised ,Cough , Upper respiratory infection. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Nivolumab ® is indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V400 mutation positive, a BRAF inhibitor . - This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. - The recommended dose of Nivolumab is 3 mg/kg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. - There are no recommended dose modifications for hypothyroidism or hyperthyroidism. - Withhold Nivolumab for any of the following: - Grade 2 pneumonitis - Grade 2 or 3 colitis - Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than 3 and up to 5 times upper limit of normal (ULN) or total bilirubin greater than 1.5 and up to 3 times ULN - Creatinine greater than 1.5 and up to 6 times ULN or greater than 1.5 times baseline - Any other severe or Grade 3 treatment-related adverse reactions - Resume Nivolumab in patients whose adverse reactions recover to Grade 0-1. - Permanently discontinue Nivolumab for any of the following: - Any life-threatening or Grade 4 adverse reaction - Grade 3 or 4 pneumonitis - Grade 4 colitis - AST or ALT greater than 5 times ULN or total bilirubin greater than 3 times ULN - Creatinine greater than 6 times ULN - Any severe or Grade 3 treatment-related adverse reaction that recurs - Inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks - Persistent Grade 2 or 3 treatment-related adverse reactions that do not recover to Grade 0-1 within 12 weeks after last dose of Nivolumab - Visually inspect drug product solution for particulate matter and discoloration prior to administration. Nivolumab is a clear to opalescent, colorless to pale-yellow solution. Discard the vial if the solution is cloudy, is discolored, or contains extraneous particulate matter other than a few translucent-to-white, proteinaceous particles. Do not shake the vial. - Withdraw the required volume of Nivolumab and transfer into an intravenous container. - Dilute Nivolumab with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP, to prepare an infusion with a final concentration ranging from 1 mg/mL to 10 mg/mL. - Mix diluted solution by gentle inversion. Do not shake. - Discard partially used vials or empty vials of Nivolumab . - The product does not contain a preservative. - After preparation, store the Nivolumab infusion either: - at room temperature for no more than 4 hours from the time of preparation. This includes room temperature storage of the infusion in the IV container and time for administration of the infusion or - under refrigeration at 2°C to 8°C (36°F-46°F) for no more than 24 hours from the time of infusion preparation. - Do not freeze. - Administer the infusion over 60 minutes through an intravenous line containing a sterile, non-pyrogenic, low protein binding in-line filter (pore size of 0.2 micrometer to 1.2 micrometer). - Do not coadminister other drugs through the same intravenous line. - Flush the intravenous line at end of infusion. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Nivolumab in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Nivolumab in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - The safety and effectiveness of Nivolumab have not been established in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - The safety and effectiveness of Nivolumab have not been established in pediatric patients. ### Non–Guideline-Supported Use - The safety and effectiveness of Nivolumab have not been established in pediatric patients. # Contraindications - None. # Warnings - Severe pneumonitis or interstitial lung disease, including fatal cases, occurred with Nivolumab treatment. Across the clinical trial experience in 574 patients with solid tumors, fatal immune-mediated pneumonitis occurred in 0.9% (5/574) of patients receiving Nivolumab . No cases of fatal pneumonitis occurred in Trial 1; all five fatal cases occurred in a dose-finding study with Nivolumab doses of 1 mg/kg (two patients), 3 mg/kg (two patients), and 10 mg/kg (one patient). - In Trial 1, pneumonitis, including interstitial lung disease, occurred in 3.4% (9/268) of patients receiving Nivolumab and none of the 102 patients receiving chemotherapy. Immune-mediated pneumonitis, defined as requiring use of corticosteroids and no clear alternate etiology, occurred in 2.2% (6/268) of patients receiving Nivolumab : one with Grade 3 and five with Grade 2 pneumonitis. The median time to onset for the six cases was 2.2 months (range: 25 days-3.5 months). In two patients, pneumonitis was diagnosed after discontinuation of Nivolumab for other reasons, and Grade 2 pneumonitis led to interruption or permanent discontinuation of Nivolumab in the remaining four patients. All six patients received high-dose corticosteroids (at least 40 mg prednisone equivalents per day); immune-mediated pneumonitis improved to Grade 0 or 1 with corticosteroids in all six patients. There were two patients with Grade 2 pneumonitis that completely resolved (defined as improved to Grade 0 with completion of corticosteroids) and Nivolumab was restarted without recurrence of pneumonitis. - Monitor patients for signs and symptoms of pneumonitis. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for Grade 2 or greater pneumonitis, followed by corticosteroid taper. Permanently discontinue Nivolumab for severe (Grade 3) or life-threatening (Grade 4) pneumonitis and withhold Nivolumab until resolution for moderate (Grade 2) pneumonitis. - In Trial 1, diarrhea or colitis occurred in 21% (57/268) of patients receiving Nivolumab and 18% (18/102) of patients receiving chemotherapy. immune-mediated colitis, defined as requiring use of corticosteroids with no clear alternate etiology, occurred in 2.2% (6/268) of patients receiving Nivolumab : five patients with Grade 3 and one patient with Grade 2 colitis. The median time to onset of immune-mediated colitis from initiation of Nivolumab was 2.5 months (range: 1-6 months). In three patients, colitis was diagnosed after discontinuation of Nivolumab for other reasons, and Grade 2 or 3 colitis led to interruption or permanent discontinuation of Nivolumab in the remaining three patients. Five of these six patients received high-dose corticosteroids (at least 40 mg prednisone equivalents) for a median duration of 1.4 months (range: 3 days-2.4 months) preceding corticosteroid taper. The sixth patient continued on low-dose corticosteroids started for another immune-mediated adverse reaction. Immune-mediated colitis improved to Grade 0 with corticosteroids in five patients, including one patient with Grade 3 colitis retreated after complete resolution (defined as improved to Grade 0 with completion of corticosteroids) without additional events of colitis. Grade 2 colitis was ongoing in one patient. - Monitor patients for immune-mediated colitis. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper for severe (Grade 3) or life-threatening (Grade 4) colitis. Administer corticosteroids at a dose of 0.5 to 1 mg/kg/day prednisone equivalents followed by corticosteroid taper for moderate (Grade 2) colitis of more than 5 days duration; if worsening or no improvement occurs despite initiation of corticosteroids, increase dose to 1 to 2 mg/kg/day prednisone equivalents. Withhold Nivolumab for Grade 2 or 3 immune-mediated colitis. Permanently discontinue Nivolumab for Grade 4 colitis or for recurrent colitis upon restarting Nivolumab . - In Trial 1, there was an increased incidence of liver test abnormalities in the Nivolumab -treated group as compared to the chemotherapy-treated group, with increases in AST (28% vs. 12%), alkaline phosphatase (22% vs. 13%), ALT (16% vs. 5%), and total bilirubin (9% vs. 0). Immune-mediated hepatitis, defined as requirement for corticosteroids and no clear alternate etiology, occurred in 1.1% (3/268) of patients receiving Nivolumab : two patients with Grade 3 and one patient with Grade 2 hepatitis. The time to onset was 97, 113, and 86 days after initiation of Nivolumab . In one patient, hepatitis was diagnosed after discontinuation of Nivolumab for other reasons. In two patients, Nivolumab was withheld. All three patients received high-dose corticosteroids (at least 40 mg prednisone equivalents). Liver tests improved to Grade 1 within 4-15 days of initiation of corticosteroids. Immune-mediated hepatitis resolved and did not recur with continuation of corticosteroids in two patients; the third patient died of disease progression with persistent hepatitis. The two patients with Grade 3 hepatitis that resolved restarted Nivolumab and, in one patient, Grade 3 immune-mediated hepatitis recurred resulting in permanent discontinuation of Nivolumab . - Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for Grade 2 or greater transaminase elevations, with or without concomitant elevation in total bilirubin. Withhold Nivolumab for moderate (Grade 2) and permanently discontinue Nivolumab for severe (Grade 3) or life-threatening (Grade 4) immune-mediated hepatitis. - In Trial 1, there was an increased incidence of elevated creatinine in the Nivolumab -treated group as compared to the chemotherapy-treated group (13% vs. 9%). Grade 2 or 3 immune-mediated nephritis or renal dysfunction (defined as ≥ Grade 2 increased creatinine, requirement for corticosteroids, and no clear alternate etiology) occurred in 0.7% (2/268) of patients at 3.5 and 6 months after Nivolumab initiation, respectively. Nivolumab was permanently discontinued in both patients; both received high-dose corticosteroids (at least 40 mg prednisone equivalents). Immune-mediated nephritis resolved and did not recur with continuation of corticosteroids in one patient. Renal dysfunction was ongoing in one patient. - Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper for life-threatening (Grade 4) serum creatinine elevation and permanently discontinue Nivolumab . For severe (Grade 3) or moderate (Grade 2) serum creatinine elevation, withhold Nivolumab and administer corticosteroids at a dose of 0.5 to 1 mg/kg/day prednisone equivalents followed by corticosteroid taper; if worsening or no improvement occurs, increase dose of corticosteroids to 1 to 2 mg/kg/day prednisone equivalents and permanently discontinue Nivolumab . - In Trial 1, where patients were evaluated at baseline and during the trial for thyroid function, Grade 1 or 2 hypothyroidism occurred in 8% (21/268) of patients receiving Nivolumab and none of the 102 patients receiving chemotherapy. The median time to onset was 2.5 months (range: 24 days-11.7 months). Seventeen of the 21 patients with hypothyroidism received levothyroxine. Fifteen of 17 patients received subsequent Nivolumab dosing while continuing to receive levothyroxine. - Grade 1 or 2 hyperthyroidism occurred in 3% (8/268) of patients receiving Nivolumab and 1% (1/102) of patients receiving chemotherapy. The median time to onset in Nivolumab -treated patients was 1.6 months (range: 0-3.3 months). Four of five patients with Grade 1 hyperthyroidism and two of three patients with Grade 2 hyperthyroidism had documented resolution of hyperthyroidism; all three patients received medical management for Grade 2 hyperthyroidism. - Monitor thyroid function prior to and periodically during treatment. Administer hormone replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. There are no recommended dose adjustments of Nivolumab for hypothyroidism or hyperthyroidism. - Other clinically significant immune-mediated adverse reactions can occur. Immune-mediated adverse reactions may occur after discontinuation of Nivolumab therapy. - The following clinically significant, immune-mediated adverse reactions occurred in less than 1% of Nivolumab -treated patients in Trial 1: pancreatitis, uveitis, demyelination, autoimmune neuropathy, adrenal insufficiency, and facial and abducens nerve paresis. - Across clinical trials of Nivolumab administered at doses of 3 mg/kg and 10 mg/kg the following additional clinically significant, immune-mediated adverse reactions were identified: hypophysitis, diabetic ketoacidosis, hypopituitarism, Guillain-Barré syndrome, and myasthenic syndrome. - For any suspected immune-mediated adverse reactions, exclude other causes. Based on the severity of the adverse reaction, withhold Nivolumab , administer high-dose corticosteroids, and if appropriate, initiate hormone-replacement therapy. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider restarting Nivolumab after completion of corticosteroid taper based on the severity of the event - Based on its mechanism of action and data from animal studies, Nivolumab can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant death. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Nivolumab and for at least 5 months after the last dose of Nivolumab # Adverse Reactions ## Clinical Trials Experience - The following adverse reactions are discussed in greater detail in other sections of the labeling. - Immune-Mediated Pneumonitis - Immune-Mediated Colitis - Immune-Mediated Hepatitis - Immune-Mediated Nephritis and Renal Dysfunction - Immune-Mediated Hypothyroidism and Hyperthyroidism - Other Immune-Mediated Adverse Reactions - Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. - The data described in the WARNINGS section and below reflect exposure to Nivolumab in Trial 1, a randomized, open-label trial in which 370 patients with unresectable or metastatic melanoma received Nivolumab 3 mg/kg every 2 weeks (n=268) or investigator’s choice of chemotherapy (n=102), either dacarbazine 1000 mg/m2 every 3 weeks or the combination of carboplatin AUC 6 every 3 weeks plus paclitaxel 175 mg/m2 every 3 weeks. The median duration of exposure was 5.3 months (range: 1 day-13.8+ months) with a median of eight doses (range: 1 to 31) in Nivolumab -treated patients and was 2 months (range: 1 day-9.6+ months) in chemotherapy treated patients. In this ongoing trial, 24% of patients received Nivolumab for greater than 6 months and 3% of patients received Nivolumab for greater than 1 year. - Clinically significant adverse reactions were also evaluated in 574 patients with solid tumors enrolled in two clinical trials receiving Nivolumab at doses of 0.1 to 10 mg/kg every 2 weeks, supplemented by immune-mediated adverse reaction reports across ongoing clinical trials. - In Trial 1, patients had documented disease progression following treatment with ipilimumab and, if BRAF V400 mutation positive, a BRAF inhibitor. The trial excluded patients with autoimmune disease, prior ipilimumab-related Grade 4 adverse reactions (except for endocrinopathies) or Grade 3 ipilimumab-related adverse reactions that had not resolved or were inadequately controlled within 12 weeks of the initiating event, patients with a condition requiring chronic systemic treatment with corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications, a positive test for hepatitis B or C, and a history of HIV. - The study population characteristics in the Nivolumab group and the chemotherapy group were similar: 66% male, median age 59.5 years, 98% white, baseline ECOG performance status 0 (59%) or 1 (41%), 74% with M1c stage disease, 73% with cutaneous melanoma, 11% with mucosal melanoma, 73% received two or more prior therapies for advanced or metastatic disease, and 18% had brain metastasis. There were more patients in the Nivolumab group with elevated LDH at baseline (51% vs. 38%). - Nivolumab was discontinued for adverse reactions in 9% of patients. Twenty-six percent of patients receiving Nivolumab had a drug delay for an adverse reaction. Serious adverse reactions occurred in 41% of patients receiving Nivolumab . Grade 3 and 4 adverse reactions occurred in 42% of patients receiving Nivolumab . The most frequent Grade 3 and 4 adverse reactions reported in 2% to less than 5% of patients receiving Nivolumab were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. - Table 1 summarizes the adverse reactions that occurred in at least 10% of Nivolumab -treated patients. The most common adverse reaction (reported in at least 20% of patients) was rash. - As with all therapeutic proteins, there is a potential for immunogenicity. - Of 281 patients who were treated with Nivolumab 3 mg/kg every 2 weeks and evaluable for the presence of anti-product antibodies, 24 patients (8.5%) tested positive for treatment-emergent anti-product antibodies by an electrochemiluminescent (ECL) assay. Neutralizing antibodies were detected in two patients (0.7%). There was no evidence of altered pharmacokinetic profile or toxicity profile with anti-product binding antibody development based on the population pharmacokinetic and exposure-response analyses. - The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to Nivolumab with the incidences of antibodies to other products may be misleading. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Nivolumab in the drug label. # Drug Interactions - No formal pharmacokinetic drug-drug interaction studies have been conducted with Nivolumab . # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Based on its mechanism of action and data from animal studies, Nivolumab can cause fetal harm when administered to a pregnant woman . In animal reproduction studies, administration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant death . Human IgG4 is known to cross the placental barrier and nivolumab is an immunoglobulin G4 (IgG4); therefore, nivolumab has the potential to be transmitted from the mother to the developing fetus. The effects of Nivolumab are likely to be greater during the second and third trimesters of pregnancy. There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus. - The background risk of major birth defects and miscarriage for the indicated population is unknown; however, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies. - A central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the fetus. Blockade of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the fetus and to increase fetal loss. The effects of nivolumab on prenatal and postnatal development were evaluated in monkeys that received nivolumab twice weekly from the onset of organogenesis through delivery, at exposure levels of between 9 and 42 times higher than those observed at the clinical dose of 3 mg/kg of nivolumab (based on AUC). Nivolumab administration resulted in a non-dose-related increase in spontaneous abortion and increased neonatal death. Based on its mechanism of action, fetal exposure to nivolumab may increase the risk of developing immune-mediated disorders or altering the normal immune response and immune-mediated disorders have been reported in PD-1 knockout mice. In surviving infants (18 of 32 compared to 11 of 16 vehicle-exposed infants) of cynomolgus monkeys treated with nivolumab, there were no apparent malformations and no effects on neurobehavioral, immunological, or clinical pathology parameters throughout the 6-month postnatal period. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nivolumab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Nivolumab during labor and delivery. ### Nursing Mothers - It is not known whether Nivolumab is present in human milk. Because many drugs, including antibodies are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Nivolumab , advise women to discontinue breastfeeding during treatment with Nivolumab . ### Pediatric Use - The safety and effectiveness of Nivolumab have not been established in pediatric patients. ### Geriatic Use - Clinical studies of Nivolumab did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. Of the 272 patients randomized to Nivolumab in Trial 1, 35% of patients were 65 years or older and 15% were 75 years or older. ### Gender There is no FDA guidance on the use of Nivolumab with respect to specific gender populations. ### Race There is no FDA guidance on the use of Nivolumab with respect to specific racial populations. ### Renal Impairment - Based on a population pharmacokinetic analysis, no dose adjustment is recommended in patients with renal impairment ### Hepatic Impairment - Based on a population pharmacokinetic analysis, no dose adjustment is recommended for patients with mild hepatic impairment. Nivolumab has not been studied in patients with moderate or severe hepatic impairment ### Females of Reproductive Potential and Males - Based on its mechanism of action, Nivolumab can cause fetal harm when administered to a pregnant woman . Advise females of reproductive potential to use effective contraception during treatment with Nivolumab and for at least 5 months following the last dose of Nivolumab . ### Immunocompromised Patients There is no FDA guidance one the use of Nivolumab in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring There is limited information regarding Monitoring of Nivolumab in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Nivolumab in the drug label. # Overdosage - There is no information on overdosage with Nivolumab . # Pharmacology ## Mechanism of Action - Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T-cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors. Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth. ## Structure - Nivolumab is a human monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. Nivolumab is an IgG4 kappa immunoglobulin that has a calculated molecular mass of 146 kDa. - Nivolumab is a sterile, preservative-free, non-pyrogenic, clear to opalescent, colorless to pale-yellow liquid that may contain light (few) particles. Nivolumab injection for intravenous infusion is supplied in single-use vials. Each mL of Nivolumab solution contains nivolumab 10 mg, mannitol (30 mg), pentetic acid (0.008 mg), polysorbate 80 (0.2 mg), sodium chloride (2.92 mg), sodium citrate dihydrate (5.88 mg), and Water for Injection, USP. May contain hydrochloric acid and/or sodium hydroxide to adjust pH to 6. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Nivolumab in the drug label. ## Pharmacokinetics - The pharmacokinetics (PK) of nivolumab was studied in patients over a dose range of 0.1 to 20 mg/kg administered as a single dose or as multiple doses of Nivolumab every 2 or 3 weeks. Based on a population pharmacokinetic (PK) analysis using data from 909 patients, the geometric mean (% coefficient of variation ) clearance (CL) is 9.5 mL/h (49.7%), geometric mean volume of distribution at steady state (Vss) is 8.0 L (30.4%), and geometric mean elimination half-life (t1/2) is 26.7 days (101%). Steady-state concentrations of nivolumab were reached by 12 weeks when administered at 3 mg/kg every 2 weeks, and systemic accumulation was approximately 3-fold. The exposure to nivolumab increased dose proportionally over the dose range of 0.1 to 10 mg/kg administered every 2 weeks. - Specific Populations: Based on a population PK analysis using data from 909 patients, the clearance of nivolumab increased with increasing body weight supporting a weight-based dose. The population PK analysis suggested that the following factors had no clinically important effect on the clearance of nivolumab: age (29 to 87 years), gender, race, baseline LDH, PD-L1 expression, tumor type, tumor size, renal impairment, and mild hepatic impairment. - Renal Impairment: The effect of renal impairment on the clearance of nivolumab was evaluated by a population PK analysis in patients with mild (eGFR 60 to 89 mL/min/1.73 m2; n=313), moderate (eGFR 30 to 59 mL/min/1.73 m2; n=140), or severe (eGFR 15 to 29 mL/min/1.73 m2; n=3) renal impairment. No clinically important differences in the clearance of nivolumab were found between patients with renal impairment and patients with normal renal function . - Hepatic Impairment: The effect of hepatic impairment on the clearance of nivolumab was evaluated by population PK analyses in patients with mild hepatic impairment (total bilirubin less than or equal to the upper limit of normal and AST greater than ULN or TB less than 1 to 1.5 times ULN and any AST; n=92). No clinically important differences in the clearance of nivolumab were found between patients with mild hepatic impairment and patients with normal hepatic function. Nivolumab has not been studied in patients with moderate (TB greater than 1.5 to 3 times ULN and any AST) or severe hepatic impairment (TB greater than 3 times ULN and any AST) ## Nonclinical Toxicology - No studies have been performed to assess the potential of nivolumab for carcinogenicity or genotoxicity. Fertility studies have not been performed with nivolumab. In 1-month and 3-month repeat-dose toxicology studies in monkeys, there were no notable effects in the male and female reproductive organs; however, most animals in these studies were not sexually mature. - In animal models, inhibition of PD-1 signaling increased the severity of some infections and enhanced inflammatory responses. M.tuberculosis-infected PD-1 knockout mice exhibit markedly decreased survival compared with wild-type controls, which correlated with increased bacterial proliferation and inflammatory responses in these animals. PD-1 knockout mice have also shown decreased survival following infection with lymphocytic choriomeningitis virus. # Clinical Studies - Trial 1 was a multicenter, open-label trial that randomized (2:1) patients with unresectable or metastatic melanoma to receive either Nivolumab administered intravenously at 3 mg/kg every 2 weeks or investigator’s choice of chemotherapy, either single-agent dacarbazine 1000 mg/m2 every 3 weeks or the combination of carboplatin AUC 6 every 3 weeks plus paclitaxel 175 mg/m2 every 3 weeks. Patients were required to have progression of disease on or following ipilimumab treatment and, if BRAF V400 mutation positive, a BRAF inhibitor. The trial excluded patients with autoimmune disease, medical conditions requiring systemic immunosuppression, ocular melanoma, active brain metastasis, or a history of Grade 4 ipilimumab-related adverse reactions (except for endocrinopathies) or Grade 3 ipilimumab-related adverse reactions that had not resolved or were inadequately controlled within 12 weeks of the initiating event. Tumor assessments were conducted 9 weeks after randomization then every 6 weeks for the first year, and every 12 weeks thereafter. - Efficacy was evaluated in a single-arm, non-comparative, planned interim analysis of the first 120 patients who received Nivolumab in Trial 1 and in whom the minimum duration of follow up was 6 months. The major efficacy outcome measures in this population were confirmed objective response rate (ORR) as measured by blinded independent central review using Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and duration of response. - Among the 120 patients treated with Nivolumab , the median age was 58 years (range: 25-88), 65% of patients were male, 98% were white, and the ECOG PS was 0 (58%) or 1 (42%). Disease characteristics were M1c disease (76%), BRAF V400 mutation positive (22%), elevated LDH (56%), history of brain metastases (18%), and two or more prior systemic therapies for metastatic disease (68%). - The ORR was 32% (95% confidence interval: 23, 41), consisting of 4 complete responses and 34 partial responses in Nivolumab -treated patients. Of 38 patients with responses, 33 patients (87%) had ongoing responses with durations ranging from 2.6+ to 10+ months, which included 13 patients with ongoing responses of 6 months or longer. - There were objective responses in patients with and without BRAF V400 mutation positive-melanoma. # How Supplied - Nivolumab ® (nivolumab) is available as follows: ## Storage - Store Nivolumab under refrigeration at 2°C to 8°C (36°F-46°F). Protect Nivolumab from light by storing in the original package until time of use. Do not freeze or shake. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise the patient to read the FDA-approved patient labeling (MEDICATION GUIDE). - Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and interruption or discontinuation of Nivolumab , including: - Pneumonitis: Advise patients to contact their healthcare provider immediately for any new or worsening cough, chest pain, or shortness of breath . - Colitis: Advise patients to contact their healthcare provider immediately for diarrhea or severe abdominal pain . - Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, pain on the right side of abdomen, lethargy, or easy bruising or bleeding - Nephritis and Renal Dysfunction: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis including decreased urine output, blood in urine, swelling in ankles(Pedal edema), loss of appetite, and any other symptoms of renal dysfunction . - Hypothyroidism and Hyperthyroidism: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypothyroidism and hyperthyroidism . - Advise patients of the importance of keeping scheduled appointments for blood work or other laboratory tests . - Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy . - Advise females of reproductive potential to use effective contraception during treatment with Nivolumab and for at least 5 months following the last dose of Nivolumab . - Advise women not to breastfeed while taking Nivolumab # Precautions with Alcohol - Alcohol-Nivolumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Opdivo® # Look-Alike Drug Names There is limited information regarding Nivolumab Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Nivolumab Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, M.B.B.S. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Nivolumab is an monoclonal antibody that is FDA approved for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V400 mutation positive, a BRAF inhibitor. Common adverse reactions include pruritus, rash , hyperkalemia , hyponatremia alkaline phosphatase raised , ALT/SGPT level raised , AST/SGOT level raised , Serum bilirubin raised ,Serum creatinine raised ,Cough , Upper respiratory infection. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Nivolumab ® is indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V400 mutation positive, a BRAF inhibitor . - This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. - The recommended dose of Nivolumab is 3 mg/kg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. - There are no recommended dose modifications for hypothyroidism or hyperthyroidism. - Withhold Nivolumab for any of the following: - Grade 2 pneumonitis - Grade 2 or 3 colitis - Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than 3 and up to 5 times upper limit of normal (ULN) or total bilirubin greater than 1.5 and up to 3 times ULN - Creatinine greater than 1.5 and up to 6 times ULN or greater than 1.5 times baseline - Any other severe or Grade 3 treatment-related adverse reactions - Resume Nivolumab in patients whose adverse reactions recover to Grade 0-1. - Permanently discontinue Nivolumab for any of the following: - Any life-threatening or Grade 4 adverse reaction - Grade 3 or 4 pneumonitis - Grade 4 colitis - AST or ALT greater than 5 times ULN or total bilirubin greater than 3 times ULN - Creatinine greater than 6 times ULN - Any severe or Grade 3 treatment-related adverse reaction that recurs - Inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks - Persistent Grade 2 or 3 treatment-related adverse reactions that do not recover to Grade 0-1 within 12 weeks after last dose of Nivolumab - Visually inspect drug product solution for particulate matter and discoloration prior to administration. Nivolumab is a clear to opalescent, colorless to pale-yellow solution. Discard the vial if the solution is cloudy, is discolored, or contains extraneous particulate matter other than a few translucent-to-white, proteinaceous particles. Do not shake the vial. - Withdraw the required volume of Nivolumab and transfer into an intravenous container. - Dilute Nivolumab with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP, to prepare an infusion with a final concentration ranging from 1 mg/mL to 10 mg/mL. - Mix diluted solution by gentle inversion. Do not shake. - Discard partially used vials or empty vials of Nivolumab . - The product does not contain a preservative. - After preparation, store the Nivolumab infusion either: - at room temperature for no more than 4 hours from the time of preparation. This includes room temperature storage of the infusion in the IV container and time for administration of the infusion or - under refrigeration at 2°C to 8°C (36°F-46°F) for no more than 24 hours from the time of infusion preparation. - Do not freeze. - Administer the infusion over 60 minutes through an intravenous line containing a sterile, non-pyrogenic, low protein binding in-line filter (pore size of 0.2 micrometer to 1.2 micrometer). - Do not coadminister other drugs through the same intravenous line. - Flush the intravenous line at end of infusion. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Nivolumab in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Nivolumab in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - The safety and effectiveness of Nivolumab have not been established in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - The safety and effectiveness of Nivolumab have not been established in pediatric patients. ### Non–Guideline-Supported Use - The safety and effectiveness of Nivolumab have not been established in pediatric patients. # Contraindications - None. # Warnings - Severe pneumonitis or interstitial lung disease, including fatal cases, occurred with Nivolumab treatment. Across the clinical trial experience in 574 patients with solid tumors, fatal immune-mediated pneumonitis occurred in 0.9% (5/574) of patients receiving Nivolumab . No cases of fatal pneumonitis occurred in Trial 1; all five fatal cases occurred in a dose-finding study with Nivolumab doses of 1 mg/kg (two patients), 3 mg/kg (two patients), and 10 mg/kg (one patient). - In Trial 1, pneumonitis, including interstitial lung disease, occurred in 3.4% (9/268) of patients receiving Nivolumab and none of the 102 patients receiving chemotherapy. Immune-mediated pneumonitis, defined as requiring use of corticosteroids and no clear alternate etiology, occurred in 2.2% (6/268) of patients receiving Nivolumab : one with Grade 3 and five with Grade 2 pneumonitis. The median time to onset for the six cases was 2.2 months (range: 25 days-3.5 months). In two patients, pneumonitis was diagnosed after discontinuation of Nivolumab for other reasons, and Grade 2 pneumonitis led to interruption or permanent discontinuation of Nivolumab in the remaining four patients. All six patients received high-dose corticosteroids (at least 40 mg prednisone equivalents per day); immune-mediated pneumonitis improved to Grade 0 or 1 with corticosteroids in all six patients. There were two patients with Grade 2 pneumonitis that completely resolved (defined as improved to Grade 0 with completion of corticosteroids) and Nivolumab was restarted without recurrence of pneumonitis. - Monitor patients for signs and symptoms of pneumonitis. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for Grade 2 or greater pneumonitis, followed by corticosteroid taper. Permanently discontinue Nivolumab for severe (Grade 3) or life-threatening (Grade 4) pneumonitis and withhold Nivolumab until resolution for moderate (Grade 2) pneumonitis. - In Trial 1, diarrhea or colitis occurred in 21% (57/268) of patients receiving Nivolumab and 18% (18/102) of patients receiving chemotherapy. immune-mediated colitis, defined as requiring use of corticosteroids with no clear alternate etiology, occurred in 2.2% (6/268) of patients receiving Nivolumab : five patients with Grade 3 and one patient with Grade 2 colitis. The median time to onset of immune-mediated colitis from initiation of Nivolumab was 2.5 months (range: 1-6 months). In three patients, colitis was diagnosed after discontinuation of Nivolumab for other reasons, and Grade 2 or 3 colitis led to interruption or permanent discontinuation of Nivolumab in the remaining three patients. Five of these six patients received high-dose corticosteroids (at least 40 mg prednisone equivalents) for a median duration of 1.4 months (range: 3 days-2.4 months) preceding corticosteroid taper. The sixth patient continued on low-dose corticosteroids started for another immune-mediated adverse reaction. Immune-mediated colitis improved to Grade 0 with corticosteroids in five patients, including one patient with Grade 3 colitis retreated after complete resolution (defined as improved to Grade 0 with completion of corticosteroids) without additional events of colitis. Grade 2 colitis was ongoing in one patient. - Monitor patients for immune-mediated colitis. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper for severe (Grade 3) or life-threatening (Grade 4) colitis. Administer corticosteroids at a dose of 0.5 to 1 mg/kg/day prednisone equivalents followed by corticosteroid taper for moderate (Grade 2) colitis of more than 5 days duration; if worsening or no improvement occurs despite initiation of corticosteroids, increase dose to 1 to 2 mg/kg/day prednisone equivalents. Withhold Nivolumab for Grade 2 or 3 immune-mediated colitis. Permanently discontinue Nivolumab for Grade 4 colitis or for recurrent colitis upon restarting Nivolumab . - In Trial 1, there was an increased incidence of liver test abnormalities in the Nivolumab -treated group as compared to the chemotherapy-treated group, with increases in AST (28% vs. 12%), alkaline phosphatase (22% vs. 13%), ALT (16% vs. 5%), and total bilirubin (9% vs. 0). Immune-mediated hepatitis, defined as requirement for corticosteroids and no clear alternate etiology, occurred in 1.1% (3/268) of patients receiving Nivolumab : two patients with Grade 3 and one patient with Grade 2 hepatitis. The time to onset was 97, 113, and 86 days after initiation of Nivolumab . In one patient, hepatitis was diagnosed after discontinuation of Nivolumab for other reasons. In two patients, Nivolumab was withheld. All three patients received high-dose corticosteroids (at least 40 mg prednisone equivalents). Liver tests improved to Grade 1 within 4-15 days of initiation of corticosteroids. Immune-mediated hepatitis resolved and did not recur with continuation of corticosteroids in two patients; the third patient died of disease progression with persistent hepatitis. The two patients with Grade 3 hepatitis that resolved restarted Nivolumab and, in one patient, Grade 3 immune-mediated hepatitis recurred resulting in permanent discontinuation of Nivolumab . - Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for Grade 2 or greater transaminase elevations, with or without concomitant elevation in total bilirubin. Withhold Nivolumab for moderate (Grade 2) and permanently discontinue Nivolumab for severe (Grade 3) or life-threatening (Grade 4) immune-mediated hepatitis. - In Trial 1, there was an increased incidence of elevated creatinine in the Nivolumab -treated group as compared to the chemotherapy-treated group (13% vs. 9%). Grade 2 or 3 immune-mediated nephritis or renal dysfunction (defined as ≥ Grade 2 increased creatinine, requirement for corticosteroids, and no clear alternate etiology) occurred in 0.7% (2/268) of patients at 3.5 and 6 months after Nivolumab initiation, respectively. Nivolumab was permanently discontinued in both patients; both received high-dose corticosteroids (at least 40 mg prednisone equivalents). Immune-mediated nephritis resolved and did not recur with continuation of corticosteroids in one patient. Renal dysfunction was ongoing in one patient. - Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper for life-threatening (Grade 4) serum creatinine elevation and permanently discontinue Nivolumab . For severe (Grade 3) or moderate (Grade 2) serum creatinine elevation, withhold Nivolumab and administer corticosteroids at a dose of 0.5 to 1 mg/kg/day prednisone equivalents followed by corticosteroid taper; if worsening or no improvement occurs, increase dose of corticosteroids to 1 to 2 mg/kg/day prednisone equivalents and permanently discontinue Nivolumab . - In Trial 1, where patients were evaluated at baseline and during the trial for thyroid function, Grade 1 or 2 hypothyroidism occurred in 8% (21/268) of patients receiving Nivolumab and none of the 102 patients receiving chemotherapy. The median time to onset was 2.5 months (range: 24 days-11.7 months). Seventeen of the 21 patients with hypothyroidism received levothyroxine. Fifteen of 17 patients received subsequent Nivolumab dosing while continuing to receive levothyroxine. - Grade 1 or 2 hyperthyroidism occurred in 3% (8/268) of patients receiving Nivolumab and 1% (1/102) of patients receiving chemotherapy. The median time to onset in Nivolumab -treated patients was 1.6 months (range: 0-3.3 months). Four of five patients with Grade 1 hyperthyroidism and two of three patients with Grade 2 hyperthyroidism had documented resolution of hyperthyroidism; all three patients received medical management for Grade 2 hyperthyroidism. - Monitor thyroid function prior to and periodically during treatment. Administer hormone replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. There are no recommended dose adjustments of Nivolumab for hypothyroidism or hyperthyroidism. - Other clinically significant immune-mediated adverse reactions can occur. Immune-mediated adverse reactions may occur after discontinuation of Nivolumab therapy. - The following clinically significant, immune-mediated adverse reactions occurred in less than 1% of Nivolumab -treated patients in Trial 1: pancreatitis, uveitis, demyelination, autoimmune neuropathy, adrenal insufficiency, and facial and abducens nerve paresis. - Across clinical trials of Nivolumab administered at doses of 3 mg/kg and 10 mg/kg the following additional clinically significant, immune-mediated adverse reactions were identified: hypophysitis, diabetic ketoacidosis, hypopituitarism, Guillain-Barré syndrome, and myasthenic syndrome. - For any suspected immune-mediated adverse reactions, exclude other causes. Based on the severity of the adverse reaction, withhold Nivolumab , administer high-dose corticosteroids, and if appropriate, initiate hormone-replacement therapy. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider restarting Nivolumab after completion of corticosteroid taper based on the severity of the event - Based on its mechanism of action and data from animal studies, Nivolumab can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant death. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Nivolumab and for at least 5 months after the last dose of Nivolumab # Adverse Reactions ## Clinical Trials Experience - The following adverse reactions are discussed in greater detail in other sections of the labeling. - Immune-Mediated Pneumonitis - Immune-Mediated Colitis - Immune-Mediated Hepatitis - Immune-Mediated Nephritis and Renal Dysfunction - Immune-Mediated Hypothyroidism and Hyperthyroidism - Other Immune-Mediated Adverse Reactions - Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. - The data described in the WARNINGS section and below reflect exposure to Nivolumab in Trial 1, a randomized, open-label trial in which 370 patients with unresectable or metastatic melanoma received Nivolumab 3 mg/kg every 2 weeks (n=268) or investigator’s choice of chemotherapy (n=102), either dacarbazine 1000 mg/m2 every 3 weeks or the combination of carboplatin AUC 6 every 3 weeks plus paclitaxel 175 mg/m2 every 3 weeks. The median duration of exposure was 5.3 months (range: 1 day-13.8+ months) with a median of eight doses (range: 1 to 31) in Nivolumab -treated patients and was 2 months (range: 1 day-9.6+ months) in chemotherapy treated patients. In this ongoing trial, 24% of patients received Nivolumab for greater than 6 months and 3% of patients received Nivolumab for greater than 1 year. - Clinically significant adverse reactions were also evaluated in 574 patients with solid tumors enrolled in two clinical trials receiving Nivolumab at doses of 0.1 to 10 mg/kg every 2 weeks, supplemented by immune-mediated adverse reaction reports across ongoing clinical trials. - In Trial 1, patients had documented disease progression following treatment with ipilimumab and, if BRAF V400 mutation positive, a BRAF inhibitor. The trial excluded patients with autoimmune disease, prior ipilimumab-related Grade 4 adverse reactions (except for endocrinopathies) or Grade 3 ipilimumab-related adverse reactions that had not resolved or were inadequately controlled within 12 weeks of the initiating event, patients with a condition requiring chronic systemic treatment with corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications, a positive test for hepatitis B or C, and a history of HIV. - The study population characteristics in the Nivolumab group and the chemotherapy group were similar: 66% male, median age 59.5 years, 98% white, baseline ECOG performance status 0 (59%) or 1 (41%), 74% with M1c stage disease, 73% with cutaneous melanoma, 11% with mucosal melanoma, 73% received two or more prior therapies for advanced or metastatic disease, and 18% had brain metastasis. There were more patients in the Nivolumab group with elevated LDH at baseline (51% vs. 38%). - Nivolumab was discontinued for adverse reactions in 9% of patients. Twenty-six percent of patients receiving Nivolumab had a drug delay for an adverse reaction. Serious adverse reactions occurred in 41% of patients receiving Nivolumab . Grade 3 and 4 adverse reactions occurred in 42% of patients receiving Nivolumab . The most frequent Grade 3 and 4 adverse reactions reported in 2% to less than 5% of patients receiving Nivolumab were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. - Table 1 summarizes the adverse reactions that occurred in at least 10% of Nivolumab -treated patients. The most common adverse reaction (reported in at least 20% of patients) was rash. - As with all therapeutic proteins, there is a potential for immunogenicity. - Of 281 patients who were treated with Nivolumab 3 mg/kg every 2 weeks and evaluable for the presence of anti-product antibodies, 24 patients (8.5%) tested positive for treatment-emergent anti-product antibodies by an electrochemiluminescent (ECL) assay. Neutralizing antibodies were detected in two patients (0.7%). There was no evidence of altered pharmacokinetic profile or toxicity profile with anti-product binding antibody development based on the population pharmacokinetic and exposure-response analyses. - The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to Nivolumab with the incidences of antibodies to other products may be misleading. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Nivolumab in the drug label. # Drug Interactions - No formal pharmacokinetic drug-drug interaction studies have been conducted with Nivolumab . # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Based on its mechanism of action and data from animal studies, Nivolumab can cause fetal harm when administered to a pregnant woman . In animal reproduction studies, administration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant death [see DATA]. Human IgG4 is known to cross the placental barrier and nivolumab is an immunoglobulin G4 (IgG4); therefore, nivolumab has the potential to be transmitted from the mother to the developing fetus. The effects of Nivolumab are likely to be greater during the second and third trimesters of pregnancy. There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus. - The background risk of major birth defects and miscarriage for the indicated population is unknown; however, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies. - A central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the fetus. Blockade of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the fetus and to increase fetal loss. The effects of nivolumab on prenatal and postnatal development were evaluated in monkeys that received nivolumab twice weekly from the onset of organogenesis through delivery, at exposure levels of between 9 and 42 times higher than those observed at the clinical dose of 3 mg/kg of nivolumab (based on AUC). Nivolumab administration resulted in a non-dose-related increase in spontaneous abortion and increased neonatal death. Based on its mechanism of action, fetal exposure to nivolumab may increase the risk of developing immune-mediated disorders or altering the normal immune response and immune-mediated disorders have been reported in PD-1 knockout mice. In surviving infants (18 of 32 compared to 11 of 16 vehicle-exposed infants) of cynomolgus monkeys treated with nivolumab, there were no apparent malformations and no effects on neurobehavioral, immunological, or clinical pathology parameters throughout the 6-month postnatal period. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nivolumab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Nivolumab during labor and delivery. ### Nursing Mothers - It is not known whether Nivolumab is present in human milk. Because many drugs, including antibodies are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Nivolumab , advise women to discontinue breastfeeding during treatment with Nivolumab . ### Pediatric Use - The safety and effectiveness of Nivolumab have not been established in pediatric patients. ### Geriatic Use - Clinical studies of Nivolumab did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. Of the 272 patients randomized to Nivolumab in Trial 1, 35% of patients were 65 years or older and 15% were 75 years or older. ### Gender There is no FDA guidance on the use of Nivolumab with respect to specific gender populations. ### Race There is no FDA guidance on the use of Nivolumab with respect to specific racial populations. ### Renal Impairment - Based on a population pharmacokinetic analysis, no dose adjustment is recommended in patients with renal impairment ### Hepatic Impairment - Based on a population pharmacokinetic analysis, no dose adjustment is recommended for patients with mild hepatic impairment. Nivolumab has not been studied in patients with moderate or severe hepatic impairment ### Females of Reproductive Potential and Males - Based on its mechanism of action, Nivolumab can cause fetal harm when administered to a pregnant woman . Advise females of reproductive potential to use effective contraception during treatment with Nivolumab and for at least 5 months following the last dose of Nivolumab . ### Immunocompromised Patients There is no FDA guidance one the use of Nivolumab in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring There is limited information regarding Monitoring of Nivolumab in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Nivolumab in the drug label. # Overdosage - There is no information on overdosage with Nivolumab . # Pharmacology ## Mechanism of Action - Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T-cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors. Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth. ## Structure - Nivolumab is a human monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. Nivolumab is an IgG4 kappa immunoglobulin that has a calculated molecular mass of 146 kDa. - Nivolumab is a sterile, preservative-free, non-pyrogenic, clear to opalescent, colorless to pale-yellow liquid that may contain light (few) particles. Nivolumab injection for intravenous infusion is supplied in single-use vials. Each mL of Nivolumab solution contains nivolumab 10 mg, mannitol (30 mg), pentetic acid (0.008 mg), polysorbate 80 (0.2 mg), sodium chloride (2.92 mg), sodium citrate dihydrate (5.88 mg), and Water for Injection, USP. May contain hydrochloric acid and/or sodium hydroxide to adjust pH to 6. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Nivolumab in the drug label. ## Pharmacokinetics - The pharmacokinetics (PK) of nivolumab was studied in patients over a dose range of 0.1 to 20 mg/kg administered as a single dose or as multiple doses of Nivolumab every 2 or 3 weeks. Based on a population pharmacokinetic (PK) analysis using data from 909 patients, the geometric mean (% coefficient of variation [CV%]) clearance (CL) is 9.5 mL/h (49.7%), geometric mean volume of distribution at steady state (Vss) is 8.0 L (30.4%), and geometric mean elimination half-life (t1/2) is 26.7 days (101%). Steady-state concentrations of nivolumab were reached by 12 weeks when administered at 3 mg/kg every 2 weeks, and systemic accumulation was approximately 3-fold. The exposure to nivolumab increased dose proportionally over the dose range of 0.1 to 10 mg/kg administered every 2 weeks. - Specific Populations: Based on a population PK analysis using data from 909 patients, the clearance of nivolumab increased with increasing body weight supporting a weight-based dose. The population PK analysis suggested that the following factors had no clinically important effect on the clearance of nivolumab: age (29 to 87 years), gender, race, baseline LDH, PD-L1 expression, tumor type, tumor size, renal impairment, and mild hepatic impairment. - Renal Impairment: The effect of renal impairment on the clearance of nivolumab was evaluated by a population PK analysis in patients with mild (eGFR 60 to 89 mL/min/1.73 m2; n=313), moderate (eGFR 30 to 59 mL/min/1.73 m2; n=140), or severe (eGFR 15 to 29 mL/min/1.73 m2; n=3) renal impairment. No clinically important differences in the clearance of nivolumab were found between patients with renal impairment and patients with normal renal function . - Hepatic Impairment: The effect of hepatic impairment on the clearance of nivolumab was evaluated by population PK analyses in patients with mild hepatic impairment (total bilirubin [TB] less than or equal to the upper limit of normal [ULN] and AST greater than ULN or TB less than 1 to 1.5 times ULN and any AST; n=92). No clinically important differences in the clearance of nivolumab were found between patients with mild hepatic impairment and patients with normal hepatic function. Nivolumab has not been studied in patients with moderate (TB greater than 1.5 to 3 times ULN and any AST) or severe hepatic impairment (TB greater than 3 times ULN and any AST) ## Nonclinical Toxicology - No studies have been performed to assess the potential of nivolumab for carcinogenicity or genotoxicity. Fertility studies have not been performed with nivolumab. In 1-month and 3-month repeat-dose toxicology studies in monkeys, there were no notable effects in the male and female reproductive organs; however, most animals in these studies were not sexually mature. - In animal models, inhibition of PD-1 signaling increased the severity of some infections and enhanced inflammatory responses. M.tuberculosis-infected PD-1 knockout mice exhibit markedly decreased survival compared with wild-type controls, which correlated with increased bacterial proliferation and inflammatory responses in these animals. PD-1 knockout mice have also shown decreased survival following infection with lymphocytic choriomeningitis virus. # Clinical Studies - Trial 1 was a multicenter, open-label trial that randomized (2:1) patients with unresectable or metastatic melanoma to receive either Nivolumab administered intravenously at 3 mg/kg every 2 weeks or investigator’s choice of chemotherapy, either single-agent dacarbazine 1000 mg/m2 every 3 weeks or the combination of carboplatin AUC 6 every 3 weeks plus paclitaxel 175 mg/m2 every 3 weeks. Patients were required to have progression of disease on or following ipilimumab treatment and, if BRAF V400 mutation positive, a BRAF inhibitor. The trial excluded patients with autoimmune disease, medical conditions requiring systemic immunosuppression, ocular melanoma, active brain metastasis, or a history of Grade 4 ipilimumab-related adverse reactions (except for endocrinopathies) or Grade 3 ipilimumab-related adverse reactions that had not resolved or were inadequately controlled within 12 weeks of the initiating event. Tumor assessments were conducted 9 weeks after randomization then every 6 weeks for the first year, and every 12 weeks thereafter. - Efficacy was evaluated in a single-arm, non-comparative, planned interim analysis of the first 120 patients who received Nivolumab in Trial 1 and in whom the minimum duration of follow up was 6 months. The major efficacy outcome measures in this population were confirmed objective response rate (ORR) as measured by blinded independent central review using Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and duration of response. - Among the 120 patients treated with Nivolumab , the median age was 58 years (range: 25-88), 65% of patients were male, 98% were white, and the ECOG PS was 0 (58%) or 1 (42%). Disease characteristics were M1c disease (76%), BRAF V400 mutation positive (22%), elevated LDH (56%), history of brain metastases (18%), and two or more prior systemic therapies for metastatic disease (68%). - The ORR was 32% (95% confidence interval: 23, 41), consisting of 4 complete responses and 34 partial responses in Nivolumab -treated patients. Of 38 patients with responses, 33 patients (87%) had ongoing responses with durations ranging from 2.6+ to 10+ months, which included 13 patients with ongoing responses of 6 months or longer. - There were objective responses in patients with and without BRAF V400 mutation positive-melanoma. # How Supplied - Nivolumab ® (nivolumab) is available as follows: ## Storage - Store Nivolumab under refrigeration at 2°C to 8°C (36°F-46°F). Protect Nivolumab from light by storing in the original package until time of use. Do not freeze or shake. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise the patient to read the FDA-approved patient labeling (MEDICATION GUIDE). - Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and interruption or discontinuation of Nivolumab , including: - Pneumonitis: Advise patients to contact their healthcare provider immediately for any new or worsening cough, chest pain, or shortness of breath . - Colitis: Advise patients to contact their healthcare provider immediately for diarrhea or severe abdominal pain . - Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, pain on the right side of abdomen, lethargy, or easy bruising or bleeding - Nephritis and Renal Dysfunction: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis including decreased urine output, blood in urine, swelling in ankles(Pedal edema), loss of appetite, and any other symptoms of renal dysfunction . - Hypothyroidism and Hyperthyroidism: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypothyroidism and hyperthyroidism . - Advise patients of the importance of keeping scheduled appointments for blood work or other laboratory tests . - Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy . - Advise females of reproductive potential to use effective contraception during treatment with Nivolumab and for at least 5 months following the last dose of Nivolumab . - Advise women not to breastfeed while taking Nivolumab # Precautions with Alcohol - Alcohol-Nivolumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Opdivo® # Look-Alike Drug Names There is limited information regarding Nivolumab Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Nivolumab
d15101fe7e705e6f0d8e7cd1d59e6cbf62fd1341	wikidoc	Nocturnin	Nocturnin Nocturnin is a human hydrolase enzyme that is involved in metabolism and its expression is controlled by the rhythmic circadian clock. It is encoded by the NOCT gene located on chromosome 4. Nocturnin contains a c-terminal structural domain of the Endonuclease/Exonuclease/phosphatase family. The Drosophila melanogaster ortholog of Nocturnin is Curled. Knockouts of Curled lead to the curled wing phenotype in fruit flies. The curled wing phenotype was first discovered by Thomas Hunt Morgan in 1915. In mice the Nocturnin ortholog is responsible for controlling diet and weight-gain, knockout mice do not gain weight when placed on a high-fat diet, when compared to normal mice containing Nocturnin. In mice it has also been shown that Nocturnin is rhythmically expressed even when mice are placed in complete darkness, demonstrating that Nocturnin expression is driven by our body's internal clock. # Enzymatic activity Nocturnin was previously thought to deadenylate mRNAs of metabolic genes, but two studies in 2018 demonstrated that Nocturnin does not directly posses ribonuclease activity. # Structure Nocturnin contains a c-terminal structural domain of the Endonuclease/Exonuclease/phosphatase family. Its fold is similar to that of DNase I, AP endonuclease, INPP5B, Sphingomyelin phosphodiesterase, TDP2, PDE12, and CNOT6L. Five conserved catalytic residues help coordinate a Magnesium atom, which participates in the putative hydrolase reaction of Nocturnin.	Nocturnin Nocturnin is a human hydrolase enzyme that is involved in metabolism and its expression is controlled by the rhythmic circadian clock. It is encoded by the NOCT gene located on chromosome 4. Nocturnin contains a c-terminal structural domain of the Endonuclease/Exonuclease/phosphatase family. The Drosophila melanogaster ortholog of Nocturnin is Curled. Knockouts of Curled lead to the curled wing phenotype in fruit flies. The curled wing phenotype was first discovered by Thomas Hunt Morgan in 1915.[1] In mice the Nocturnin ortholog is responsible for controlling diet and weight-gain, knockout mice do not gain weight when placed on a high-fat diet, when compared to normal mice containing Nocturnin.[2] In mice it has also been shown that Nocturnin is rhythmically expressed even when mice are placed in complete darkness, demonstrating that Nocturnin expression is driven by our body's internal clock.[3] # Enzymatic activity Nocturnin was previously thought to deadenylate mRNAs of metabolic genes,[4] but two studies in 2018 demonstrated that Nocturnin does not directly posses ribonuclease activity.[5][6] # Structure Nocturnin contains a c-terminal structural domain of the Endonuclease/Exonuclease/phosphatase family. Its fold is similar to that of DNase I, AP endonuclease, INPP5B, Sphingomyelin phosphodiesterase, TDP2, PDE12, and CNOT6L. Five conserved catalytic residues help coordinate a Magnesium atom, which participates in the putative hydrolase reaction of Nocturnin.	https://www.wikidoc.org/index.php/Nocturnin
bf38c488644eb8ac1679c5b1d77dc7311a0e76b5	wikidoc	Nonochton	Nonochton Nonochton is the Classical Nahuatl name for a plant whose identity is uncertain. Suggested plants include Portulaca, Pereskiopsis, and Lycianthes moziniana, a plant now called tlanochtle in the local variety of modern Nahuatl spoken by highland farmers that cultivate it for its fruit. In Aztec medicine, nonochton was used as an ingredient in a remedy for pain at the heart: For him whose heart pains him or burns, take the plant nonochton that grows near an ants’ nest, gold, electrum, teo-xihuitl, chichiltic tapachtli and tetlahuitl, with the burned heart of a deer, and grind them up together in water; let him drink the liquor.	Nonochton Nonochton is the Classical Nahuatl name for a plant whose identity is uncertain. Suggested plants include Portulaca, Pereskiopsis,[1] and Lycianthes moziniana, a plant now called tlanochtle in the local variety of modern Nahuatl spoken by highland farmers that cultivate it for its fruit.[2] In Aztec medicine, nonochton was used as an ingredient in a remedy for pain at the heart: For him whose heart pains him or burns, take the plant nonochton that grows near an ants’ nest, gold, electrum, teo-xihuitl, chichiltic tapachtli and tetlahuitl, with the burned heart of a deer, and grind them up together in water; let him drink the liquor.	https://www.wikidoc.org/index.php/Nonochton
9a7888063b2b5671105cf6f50262f0c85170fe0c	wikidoc	Nootropic	Nootropic # Overview Nootropic, popularly referred to as "smart drugs", "smart nutrients", "cognitive enhancers" and "brain enhancers", is a class of drugs that improve impaired human cognitive abilities (the functions and capacities of the brain). This article covers all substances, including drugs, nutrients, and herbs, that have purported cognitive enhancing effects. The word nootropic was coined in 1964 by the Romanian Dr. Corneliu E. Giurgea, derived from the Greek words noos, or "mind," and tropein meaning "to bend/turn". Typically, nootropics are alleged to work by altering the availability of the brain's supply of neurochemicals (neurotransmitters, enzymes, and hormones), by improving the brain's oxygen supply, or by stimulating nerve growth. However the efficacy of alleged nootropic substances in most cases has not been conclusively determined. This is complicated by the difficulty of defining and quantifying cognition and intelligence. # Availability Nootropic drugs are generally only available by prescription or through personal importation. The other nootropic substances listed below are either nutritional supplements or plant components (herbs, roots, beans, bark, etc.), and are generally available over the counter at health food and grocery stores, and are used as nutritional supplements. The drugs are used to treat people with cognitive learning difficulties, neural degradation (Alzheimer's disease or Parkinson's disease), and for cases of oxygen deficit to prevent hypoxia. These drugs have a variety of human enhancement applications as well and are marketed heavily on the World Wide Web. Nevertheless, intense marketing may not correlate with efficacy; while scientific studies support some of the claimed benefits, it is worth noting that many of the claims attributed to most nootropics have not been formally tested. # Therapy or enhancement Some argue that nootropics may theoretically be used for human enhancement, boosting mental function in otherwise normal healthy people. However, there is much controversy over the legitimacy (efficacy) and ethics of such applications. This may contribute to the lack of research on such effects. # Examples The term "drug" here is used as a legal designation, and does not indicate greater efficacy. With nootropics, the effects, effectiveness, and potency differ from substance to substance and from individual to individual. See the substance descriptions below for more detail. ## Replenishing and increasing neurotransmitters As the brain ages, its ability to produce and maintain youthful levels of neurotransmitters declines. There are various reasons for such an insufficiency. For instance, there might be a lack of enzymes involved in the neurotransmitter synthesis. Nevertheless, in many cases, providing the brain with ample raw materials necessary to make neurotransmitters can restore them to more youthful levels and thus help maintain cognitive function at vigorous youthful levels. Furthermore, there are declines in immune and endocrine functioning. Certain nootropics enhance immune and endocrine functioning. ### Cholinergics Cholinergics are substances that affect the neurotransmitter acetylcholine or the components of the nervous system that use acetylcholine. Acetylcholine facilitates memory, concentration, focus, and high-order thought processes (abstract thought, calculation, innovation, etc.). Increasing the availability of this neurotransmitter in the brain may improve these functions and increase the duration in which they may be engaged without slowing down or stopping. Oversupplying the brain with acetylcholine may have the opposite effect, temporarily reducing rather than improving mental performance. Cholinergic nootropics include acetylcholine precursors and coors, and acetylcholinesterase inhibitors: Piracetam (Nootropil) - Prescription drug (in Europe). The original (first), and most commonly taken nootropic drug. It is a cholinergic agent, synergistic with DMAE, Centrophenoxine, choline, and Hydergine. Increases brain cell metabolism and energy levels, and speeds up interhemispheric flow of information (left-right brain hemisphere communication). Increases alertness, improves concentration, and enhances memory. Protects neurons from hypoxia, and stimulates growth of acetylcholine receptors. May also cause nerves to regenerate. Piracetam markedly decreases the formation of neuronal lipofuscin. It improves posture in elderly people. It is not regulated in the US. It is a pyrrolidone derivative. Aniracetam is a pyrrolidone derivative drug, analogous of piracetam, and considered more potent. Like piracetam, aniracetam protects against some memory impairing chemicals, such as diethyldithiocarbamate and clonidine. Also like piracetam, aniracetam may enhance memory in aging adults by increasing levels of brain biogenic monoamines, which are beneficial to learning and memory. Both racetams have possible therapeutic use in treating fetal alcohol syndrome. Aniracetam increases vigilance. Aniracetam has shown to positively potentiate AMPA receptors. Oxiracetam is a drug of the racetam family. It is similar to, but far stronger than piracetam and aniracetam. Several animal studies suggest that the substance is safe even when high doses are consumed for a long period of time. However the mechanism of action of oxiracetam is still a matter of research. - Acetyl-L-carnitine (ALCAR) - Amino acid. Precursor of acetylcholine (donating the acetyl portion to the acetylcholine molecule). It is synergistic with lipoic acid. - Choline - precursor to acetylcholine (an essential component of the acetylcholine molecule). Alpha-GPC (L-alpha glycerylphosphorylcholine, Choline alfoscerate) - most effective choline precursor, readily crosses the blood-brain barrier. CDP-Choline (Cytidine Diphosphate Choline) - choline precursor, tends to be less expensive and similar in effect to Alpha GPC. Choline bitartrate - precursor of acetylcholine, anti-depressant. Choline citrate - precursor of the neurotransmitter acetylcholine, anti-depressant. Citicoline The choline compounds PC and citicoline are thought to promote synthesis and transmission of neurotransmitters important to memory. - Alpha-GPC (L-alpha glycerylphosphorylcholine, Choline alfoscerate) - most effective choline precursor, readily crosses the blood-brain barrier. - CDP-Choline (Cytidine Diphosphate Choline) - choline precursor, tends to be less expensive and similar in effect to Alpha GPC. - Choline bitartrate - precursor of acetylcholine, anti-depressant. - Choline citrate - precursor of the neurotransmitter acetylcholine, anti-depressant. - Citicoline The choline compounds PC and citicoline are thought to promote synthesis and transmission of neurotransmitters important to memory. - DMAE - approved treatment for ADD/ADHD, precursor of acetylcholine, cholinergic agent, removes lipofuscin from the brain, anti-depressant. - Galantamine - acetylcholinesterase inhibitor made from chemical synthesis or extract from plants such as Red Spider Lily (Lycoris radiata). - Huperzine A - potent acetylcholinesterase inhibitor derived from Chinese club-moss. - Ispronicline - recently developed selective α4β2 partial agonist - Lecithin - contains phosphatidylcholine, precursor of acetylcholine. - Other pyrrolidone derivatives: Etiracetam - It increases vigilance. Nefiracetam - Drug. Analog of piracetam, and facilitates hippocampal neurotransmission. Oxiracetam - Drug. Analog of piracetam, and 2 to 4 times stronger. Improves memory, concentration, and vigilance. When fed to pregnant rats, the offspring of those rats were more intelligent than the offspring of rats fed a saline solution placebo. Pramiracetam - Drug. Analog of piracetam. In animal studies, nootropics such as piracetam, oxiracetam and aniracetam are known to facilitate the formation of long term memory traces and to restore object recognition in aging rats. There is evidence that the beneficial effect of racetams may result from an interaction with the central glutamatergic receptor function. - Etiracetam - It increases vigilance. - Nefiracetam - Drug. Analog of piracetam, and facilitates hippocampal neurotransmission. - Oxiracetam - Drug. Analog of piracetam, and 2 to 4 times stronger. Improves memory, concentration, and vigilance. When fed to pregnant rats, the offspring of those rats were more intelligent than the offspring of rats fed a saline solution placebo. - Pramiracetam - Drug. Analog of piracetam. - In animal studies, nootropics such as piracetam, oxiracetam and aniracetam are known to facilitate the formation of long term memory traces and to restore object recognition in aging rats. There is evidence that the beneficial effect of racetams may result from an interaction with the central glutamatergic receptor function. - Vitamin B5 - cofactor in the conversion of choline into acetylcholine, cholinergic agent, increases stamina (including mental stamina). Excess acetylcholine is considered by many to be potentially harmful; see cholinesterase inhibitor. ### Dopaminergics Dopaminergics are substances that affect the neurotransmitter dopamine or the components of the nervous system that use dopamine. Dopamine is produced in the synthesis of all catecholamine neurotransmitters, and is the rate limiting step for this synthesis. Dopaminergic nootropics include dopamine precursors and cofactors, and dopamine reuptake inhibitors: - Mucuna pruriens - Seed powder contains high concentrations of levodopa (L-dopa), a direct precursor of the neurotransmitter dopamine. - Lazabemide is a MAO-B inhibitor and has potent membrane lipid antioxidant activity. The antioxidant effects of lazabemide are attributed to its chemical structure and direct physicochemical interactions with the membrane lipid bilayer. It is a potent antioxidant, even more powerful than selegiline (deprenyl) or vitamin E, and is used to treat Alzheimer’s disease. - L-dopa - Prescription drug and dietary supplement. Precursor to the neurotransmitter dopamine, anti-depressant. - Phenylalanine (requires Vitamin B6 and Vitamin C) - Essential amino acid. Precursor to dopamine, anti-depressant, sleep reducer. - Theanine - Found in tea. Increases serotonin and dopamine levels in the brain. Increases alpha-wave based alert relaxation. - Tyrosine (requires Vitamin B6 and Vitamin C) - Amino acid. Precursor to dopamine, anti-depressant, sleep reducer. - Vitamin C - improves cardiovascular elasticity and integrity, membrane stabilizer and major anti-oxidant (protects brain cells and prevents brain cell death), cofactor in the production of the neurotransmitters dopamine and serotonin. - Vitamin B6 - co-factor used by the body to produce dopamine. - Yohimbe - Bark. Boosts dopamine levels, though how it does this is not yet understood. Aphrodisiac. Yohimbe poses some health risks through its side-effects: it is a neuro-paralytic which slows down breathing and induces acidosis, some symptoms of which are malaise, nausea, and vomiting. Contraindicated for users of megadoses of acidic vitamins or nutrients. - Deprenyl - (selegiline) L-Deprenyl is an irreversible MAO-B inhibitor, an enzyme that breaks down dopamine. Thus, it is used to treat Parkinson's disease, and to delay the progression of Alzheimer's disease. It protects against the genotoxin AraC, provides neuroprotection against growth factor withdrawal in PC12 cells, protects against oxidative stress in mesencephalatic neurons, and delays neuronal cell death in the hippocampus after global ischemia. - Tolcapone - Inhibits COMT (an enzyme that breaks down the neurotransmitters dopamine, epinephrine, and norepinephrine) and increases performance in tasks depending on working memory in individuals with the val/val and val/met genotype of the val158Met polymorphism of the catechol-O-methyltransferase gene, while decreasing it in presence of the met/met version. Tolcapone presents the risk of deadly side effects. ### Serotonergics Serotonergics are substances that affect the neurotransmitter serotonin or the components of the nervous system that use serotonin. Serotonergic nootropics include serotonin precursors and cofactors, and serotonin reuptake inhibitors: - Griffonia simplicifolia a natural source of 5-HTP (an alternative in countries where 5-HTP not legal, freely available.) - Tryptophan (requires Vitamin B6 and Vitamin C) - Essential amino acid. Precursor to serotonin, found in high concentration in bananas and meats, also in milk, promotes relaxed poise and sound sleep. 5-HTP is a form of Tryptophan. - 5HT2A agonists such as LSD and 2C-T-7 have been shown to produce nootropic effects when used at a dose much lower than a hallucinogenic dose. (e.g. 10 μg for LSD and 1 mg 2C-T-7, 1/25 of a normal recreational dose ) - SSRIs - Class of antidepressants that increase active serotonin levels, ie, in the synaptic junction, by inhibiting its reuptake. Have also been shown to promote Neurogenesis in the hippocampus. ## Anti-depression, adaptogenic (antistress), and mood stabilization Stress, Depression, and depressed mood negatively affect cognitive performance. It is reasoned that counteracting and preventing depression and stress may be an effective nootropic strategy. Below are a list of substances purported to function as nootropics, and claimed effects: - Ashwagandha (Withania somnifera) - Root. Also known as Indian ginseng. Adaptogen used as a tonic to normalize body processes and reduce stress and anxiety. - Inositol - Is a B-vitamin like substance with anti-anxiety effects. It is believed to produce its anti-anxiety effects by improving the binding of gabaergics to GABAA receptors. Inositol is a sugar, and is therefore an alternative energy source for brain and muscle tissues. It produces a sugar high without a sugar low, making it especially suited for sweetening tea (instead of sugar). It is also a membrane stabilizer which can strengthen (and therefore help protect) neurons. - Kava-kava - The roots of the Kava-Kava plant contain Kavalactones which have GABAergic properties and are used to combat anxiety. - Lemon Balm (Melissa officinalis) - Herb. Anti-depressant. - Passion Flower is used to treat depression. It is commonly combined with St. John’s Wort and Valerian, which work synergistically to reestablish the patients emotional balance without causing tachyphylaxia, hangovers, or addiction. - Rhodiola Rosea - Herb. Adaptogen; elevates mood, alleviates depression. Promotes mental energy and stamina, reduces fatigue. - St John's Wort - Herb. The active components: hypericin and hyperforin, are clinically indicated to be effective in cases of mild to moderate depression, on par with synthetic drugs. However, St John's Wort is not suitable for the treatment of severe depression or suicidal tendencies. Side effects include gastrointestinal complaints and allergic reactions such as pruritus and phototoxicity. - Ginseng, Siberian (Eleutherococcus senticosus) - Root. Anti-anxiety adaptogen that normalizes physical stress and mental consequences. - Selegiline (Deprenyl) - Along with Piracetam and Meclofenoxate, Deprenyl decreases the amount of lipofuscin pigment and ceroid pigment accumulations in the brain by improving cellular recycling activities. Therefore, these nootropics may slow age-related diseases in the brain. Selegiline, an MAO-B inhibitor, is used as an antioxidant for the treatment of Alzheimer’s disease. - Sutherlandia frutescens - Herb. Adaptogen, blood detoxifier. - Tea - Herb. Contains theophylline and theanine. Increases alpha-wave based alert relaxation (relieves stress). - Theanine - Amino acid. Found in tea. Increases serotonin and dopamine levels in the brain. Increases alpha-wave based alert relaxation. Also stimulates the GABAergic system. - Tianeptine - Anxiolytic anti-depressant. It enhances working and reference memory in rats. - Vasopressin - Drug. Memory hormone produced by the pituitary gland which improves both memory encoding and recall. Rapidly counters chronic apathy syndrome and drug-induced vasopressin depletion. - Nicotinic acid (vitamin B3) - Essential nutrient. Mild enhancer of concentration and memory. Vasodilator - Mood stabilizer, with a powerful anti-anxiety effect — perhaps the best and most immediate stress reliever available (note that other forms of vitamin B do not have this effect). Side effects: gastric upset (which is easily prevented and relieved with antacids), reduced blood pressure and flushing of the skin (caused by vasodilation), and itchy sensation in the skin caused by histamine release. - Vitis vinifera (Grape Seed) Grape seed has antistress (adaptogenic) activity, protects against memory loss induced by scopolamine, is an antioxidant, has nootropic activities, and supports the traditional claims for the use of grape fruits and seeds in stress induced disorders. ## Brain function and improved oxygen supply - Acetyl-L-carnitine (ALCAR) - Amino acid. Transports fatty acids through cellular membranes and cytosol into cells' mitochondria, where the fats undergo oxidation to produce ATP, the universal energy molecule. Synergistic with lipoic acid. - Chromium- stabilises blood sugar levels promoting concentration. - Coenzyme q-10 syn. Ubiquinone - increases oxygen transport through the mitochondria of the cells. - Creatine - increases brain energy levels via ATP production. - Inositol - B vitamin which synergizes with other nootropics - Lipoic acid - synergistic with Acetyl-L-carnitine. - Piracetam - improves alertness, blood flow, oxygen supply, and stroke recovery. - Pyritinol (Enerbol) - Drug. Enhances oxygen and glucose uptake in the brain, and allows glucose to pass more easily through the blood-brain barrier. It is also a powerful anti-oxidant which scavenges hydroxyl radicals created in the very processes it is involved in. - Vinpocetine - Vinpocetine increases blood circulation and metabolism in the brain. Animal studies have shown that vinpocetine can reduce the loss of neurons due to decreased blood flow. - Prazosin - Alpha-blocking blood pressure medication also prescribed as an anti-PTSD medication, appears to block the increase of steroid hormones known as glucocorticoids, Oregon Health & Science University and Portland Veterans Affairs Medical Center researchers have found. Elevated levels of glucocorticoids are associated with atrophy in nerve branches where impulses are transmitted, and even nerve cell death, in the hippocampus. ## Mental agility, concentration, stamina, and focus - Adrafinil (Olmifon) - Drug. - Caffeine - Drug. improves concentration, idea production, but hinders memory encoding. Also produces the jitters. Caffeine is the most widely used psychoactive substance in the world, and may be susceptible to strong levels of tolerance. - Coffee - Bean. Contains caffeine; brewed coffee is high in antioxidants. - Nicergoline - Drug. Nicergoline is an ergoloid mesylate derivative used to treat senile dementia. It has also been found to increase mental agility and enhance clarity and perception. It increases vigilance. Increases arterial flow and use of oxygen and glucose in the brain. - Nicotine - stimulus barrier (aids in concentration). Stimulus barrier rebound effect (an unpleasant side effect). - Cocaine - Drug. - Methylphenidate (Ritalin) - Drug - Dextroamphetamine - (Adderall, Dexedrine) - Drug. - Modafinil - (Provigil) - Drug. - Piracetam - improves alertness, socialization, and co-operation in the brain impaired from age, dementia, and reduced blood flow. - Phenibut - - Theophylline - - Amphetamine - aids in concentration, focus and stamina. Prescribed for ADD/ADHD - Carphedon (Phenotropil) - ## Purported memory enhancement and learning improvement All of the "nergics" listed above are purported to improve memory (encoding and recall), as do all nootropics which improve general brain performance in categories such as the brain energy and oxygen supply, and nerve growth stimulation and protection. Other agents purported to have these specific benefits are mentioned in their own sections. Other nootropics with specific effects on memory encoding and recall include: - Bacopa monniera (Brahmi) - Herb. Elevates curiosity, enhances memory and concentration. Brahmi also protects against amnesia inducing chemicals such as scopolamine or loss of memory due to electro convulsive shocks. It is a traditional ayurvedic medicine. - Piracetam - improves memory. Used to treat Alzheimer's, dementia, dyslexia and Down's syndrome - Rosemary - Herb. Rosemary has a very old, albeit unverified, reputation for improving memory. - Vasopressin - Hormone, prescription drug. - Dextroamphetamine- Adderall, Dexedrine. - Nicotine - Improves working memory and learning ## Nerve growth stimulation and brain cell protection - Acetyl-L-carnitine (ALCAR) - Amino acid. Inhibits lipofuscin formation. - Bacopa monnieri (Brahmi) - Herb. Improves protein synthesis in brain cell repair and new dendritic growth. - Selegiline (Deprenyl) - Drug. Brain cell protectant, delays senescence of brain cells, proven to increase maximum life span in laboratory rats. - Ergoloid mesylates (Hydergine) - Drug. Mimics nerve growth factor (NGF), and is a powerful anti-oxidant capable of delaying brain death in cases of heart failure and stroke by several minutes with regular use. It increases vigilance. - Idebenone - stimulates nerve growth, and has same effects as Coenzyme q-10. - Inositol - Membrane stabilizer. Strengthens neurons, making them less susceptible to damage. - Pyritinol (Enerbol) - Drug. Powerful anti-oxidant which scavenges hydroxyl radicals. - Rasagiline (Azilect) - Drug. Treats Parkinson’s disease either as monotherapy (by itself) or in addition to levodopa therapy. Promotes increased and sustained levels of dopamine by selectively inhibiting an enzyme, monoamine oxidase-B. - Vitamin C - Membrane stabilizer, involved in collagen synthesis. Vitamin C is also a co-factor in the brain's production of dopamine. ## Recreational drugs with purported nootropic effects - Amphetamine-type stimulants (such as Adderall, Dexedrine, Desoxyn, etc.) are Schedule II controlled substances in the United States, and Class B drugs in the United Kingdom, with comparable legal controls in effect in most countries throughout the world. They are prescribed for attention-deficit disorders, narcolepsy, and certain cases of obesity; and are issued to counteract fatigue and to enhance performance for pilots in the armed forces of the United States of America. These also heighten alertness, mental focus, vigilance, stamina, and sex drive. They tend to be habit-forming, and exhibit side effects with prolonged or heavy use. Personal importation of amphetamine-class drugs is prohibited in many countries, and their use for recreation or for performance enhancement without a medical prescription is likewise illegal in most countries. - LSD - Schedule I / Class A drug. At higher doses, the impact of the senses on one's mind are expanded to such an overwhelming degree that what is being sensed seems qualitatively different. Many psychedelic drugs are known to produce this overwhelming effect on the mind. Aldous Huxley called this state of mind "Mind at Large". Activity in the Raphe Nuclei and Locus ceruleus increases dramatically following administration of LSD to produce extremely heightened creativity in many users. This effect on the creative process is a phenomenon that may be due to ascending traffic in the reticular activation system, which can result in stimulus overload. The longest single research project with LSD, at Spring Grove Hospital, Maryland, showed an average 10% increase in linear IQ alone. Also produces hallucinogenic and entheogenic effects at doses as low as 30–40 μg (micrograms), with the likelihood of having a bad trip increasing as dose is increased if these effects are undesired. May also cause cognitive shifts, synesthesia, and flashbacks. The drug sometimes spurs long-term or even permanent changes in a user's personality and life perspective. (For more details, see Albert Hofmann: LSD - My Problem Child.) - 4-methylaminorex - Pemoline (Cylert) - Psilocybin and Psilocin - MDPV - Mescaline ## Dietary Nootropics Some regular food items are rich sources of substances with alleged nootropic benefits: - Nuts, in particular walnuts, are rich sources of alpha-linolenic acid (ALA), a type of omega-3 fatty acid. A mixture of walnuts served with dried fruit pieces is known in some regions as student food (orig. German: Studentenfutter) and is popularly recommended as a snack for students. - Oily fish, such as salmon or fresh tuna (not tuna canned in oil) are also good sources of omega-3 fatty acids such as eicosapentaenoic acid and docosahexaenoic acid, whose lack in diet has been associated with increased risk of mental illnesses such as depression, anxiety, aggressive behavior, schizophrenia, or hyper-activity in children (see omega-3 fatty acids article) ## Other nootropics - Adafenoxate - Has an anti-anxiety effect for rats and possibly the same for humans. - Moderate use of alcohol - Moderate drinking has been associated with better cognitive ability than both abstention and heavy drinking. - Butea frondosa - "The plant Butea frondosa has been indicated in the Indian system of medicine as a plant augmenting memory and as a rejuvenator. ... B. frondosa possesses anti-stress and weak nootropic activity." - BMY 21502 - Injured animals treated with BMY-21502 at one week post-injury showed significant improvement in post-injury learning ability compared to injured animals treated with vehicle. Paradoxically, in uninjured control animals BMY-21502 treatment appeared to worsen learning scores. The results of this study indicate that BMY-21502 may be useful for attenuating the dysfunction in learning ability that occurs following traumatic brain injury. - Cabergoline (Dostinex) - A lysergic acid amide derivative, is a potent dopamine receptor agonist on D2 receptors. Maybe carcinogenic. - Celastrus paniculatus - Oil made from the seeds of this shrub are used in Ayurvedice medicine to increase memory and facilitate learning. It allegedly induces a feeling of well-being and has reported aphrodisiac effects. - Cerebrolysin - A neuroprotective nootropic agent, might affect Alzheimer's disease pathology. Currently in clinical trials - Clausenamide - Facilitated learning and memory acquisition in step down and step through tests and increased thickness of cerebral cortex and synapse density significantly in the dentate cells over pyramidel cells in hippocampal region in mice. - Coluracetam - It may also have potential use in prevention and treatment of ischemic retinopathy and retinal and optic nerve injury - Desmopressin (DDAVP) - Analog of vasopressin, a neuropeptide responsible for memory. - DHEA - Hormone created by the adrenal glands; Precursor to Estrogen and Testosterone - Dostinex - (see Cabergoline above) - Fasoracetam - A nootropic drug of the racetam family. - Essential Fatty Acids- Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are the best known. EPA in particular, has an anti-depressant function and is positively indicated in trials with autism and learning difficulties - Fipexide (Vigilor) - It protects against some memory impairing chemicals, such as diethyldithiocarbamate and clonidine. - Gerovital H3 - Romanian anti-aging formula containing procaine hydrochloride, but which breaks down into PABA and DMAE. - Ginkgo biloba - Ginkgo (Ginkgo biloba), a root, is used to treat a variety of problems, including chronic cerebrovascular insufficiency, tinnitus, vertigo and peripheral arterial disease. Patients with dementia treated with ginkgo showed significant improvement of symptoms like memory loss, concentration difficulties, fatigue, anxiety and depressive mood. However, because Ginkgo is a vasodilator, it ought not be taken with Aspirin, for doing so could increase the risk of bleeding. Ginkgo is widely used in Europe to treat subjective tinnitus, however, there is as yet no hard evidence supporting this assertion. Ginkgolides are extracts from the leaves of the tree. They produce a beneficial effect for Alzheimer’s disease, and for amyloid-B, the toxic prion protein, which suggests they could be relevant to treating those diseases. - Gotu Kola - Herb and root. - Meclofenoxate - Has an anti-anxiety effect for rats and possibly the same for humans. Like Fipexide, it protects against some memory impairing chemicals, such as diethyldithiocarbamate and clonidine. Like many racetams, it may treat fetal alcohol syndrome. - Milacemide - A glycine prodrug which is both an inhibitor and a substrate for monoamine oxidase-type B (MAO-B) and also an inhibitor of MAO-type A (MAO-A). - Nimodipine - A dihydropyridine calcium channel blocker originally developed for the treatment of high blood pressure. - Ondansetron (Zofran) - A serotonin 5-HT3 receptor antagonist used mainly as an antiemetic to treat nausea and vomiting following chemotherapy. - Phenytoin (Dilantin) - A neuroleptic and anti-siezure medication advocated by Jack Dreyfus for a variety of psychological conditions. - Phosphatidylserine- In animals, PS has been shown to attenuate many neuronal effects of aging, and to restore normal memory on a variety of tasks. - Picamilon or Pikamilone - Compound of Niacin and GABA. It can pass the blood-brain barrier and increase amount of GABA in the brain. - Pregnenolone - Hormone; Precursor to DHEA; - Pyroglutamate - An amino acid shown to improve learning. - Royal Jelly - Produced by bees for the Queen. Can cause fatal allergic reactions in rare cases - Sapunifiram - Semax - A neuropeptide (stimulator of the nervous system) developed from a short fragment of ACTH, Pro8-Gly9-Pro10 ACTH(4-10). Claims of significant increase in salvation of neurons are made - Somatotropin - Growth hormone, a polypeptide containing 191 amino acids, produced by the anterior pituitary, the front section of the pituitary gland. It acts by stimulating the release of another hormone called somatomedin by the liver, thereby causing growth. - Sulbutiamine (Arcalion) - Drug - derivative of thiamine (vitamin B1) that can cross the blood-brain barrier and work as anti-fatigue and cognitive support agent. - Sunifiram - Turmeric - has possible benefits in Alzheimer's disease, cancer and liver disorders. Turmeric, under the name Avea, is becoming popular to treat depression. - Unifiram - Xanthinol Nicotinate (Complamin) - A drug that has been shown to stimulate memory and concentration, by improving blood flow to the brain.	Nootropic # Overview Nootropic, popularly referred to as "smart drugs", "smart nutrients", "cognitive enhancers" and "brain enhancers", is a class of drugs that improve impaired human cognitive abilities (the functions and capacities of the brain).[1] This article covers all substances, including drugs, nutrients, and herbs, that have purported cognitive enhancing effects. The word nootropic was coined in 1964 by the Romanian Dr. Corneliu E. Giurgea, derived from the Greek words noos, or "mind," and tropein meaning "to bend/turn". Typically, nootropics are alleged to work by altering the availability of the brain's supply of neurochemicals (neurotransmitters, enzymes, and hormones), by improving the brain's oxygen supply, or by stimulating nerve growth. However the efficacy of alleged nootropic substances in most cases has not been conclusively determined. This is complicated by the difficulty of defining and quantifying cognition and intelligence. # Availability Nootropic drugs are generally only available by prescription or through personal importation. The other nootropic substances listed below are either nutritional supplements or plant components (herbs, roots, beans, bark, etc.), and are generally available over the counter at health food and grocery stores, and are used as nutritional supplements. The drugs are used to treat people with cognitive learning difficulties, neural degradation (Alzheimer's disease or Parkinson's disease), and for cases of oxygen deficit to prevent hypoxia. These drugs have a variety of human enhancement applications as well and are marketed heavily on the World Wide Web. Nevertheless, intense marketing may not correlate with efficacy; while scientific studies support some of the claimed benefits, it is worth noting that many of the claims attributed to most nootropics have not been formally tested. # Therapy or enhancement Some argue that nootropics may theoretically be used for human enhancement, boosting mental function in otherwise normal healthy people. However, there is much controversy over the legitimacy (efficacy) and ethics of such applications. This may contribute to the lack of research on such effects. # Examples The term "drug" here is used as a legal designation, and does not indicate greater efficacy. With nootropics, the effects, effectiveness, and potency differ from substance to substance and from individual to individual. See the substance descriptions below for more detail. ## Replenishing and increasing neurotransmitters As the brain ages, its ability to produce and maintain youthful levels of neurotransmitters declines.[2] There are various reasons for such an insufficiency. For instance, there might be a lack of enzymes involved in the neurotransmitter synthesis. Nevertheless, in many cases, providing the brain with ample raw materials necessary to make neurotransmitters can restore them to more youthful levels and thus help maintain cognitive function at vigorous youthful levels. Furthermore, there are declines in immune and endocrine functioning. [3] Certain nootropics enhance immune and endocrine functioning. ### Cholinergics Cholinergics are substances that affect the neurotransmitter acetylcholine or the components of the nervous system that use acetylcholine. Acetylcholine facilitates memory, concentration, focus, and high-order thought processes (abstract thought, calculation, innovation, etc.). Increasing the availability of this neurotransmitter in the brain may improve these functions and increase the duration in which they may be engaged without slowing down or stopping. Oversupplying the brain with acetylcholine may have the opposite effect, temporarily reducing rather than improving mental performance. Cholinergic nootropics include acetylcholine precursors and coors, and acetylcholinesterase inhibitors: Piracetam (Nootropil) - Prescription drug (in Europe). The original (first),[4] and most commonly taken[5][4] nootropic drug. It is a cholinergic agent, synergistic with DMAE, Centrophenoxine, choline, and Hydergine. Increases brain cell metabolism and energy levels,[6][4] and speeds up interhemispheric flow of information (left-right brain hemisphere communication).[7] Increases alertness,[8] improves concentration, and enhances memory. Protects neurons from hypoxia,[4] and stimulates growth of acetylcholine receptors. May also cause nerves to regenerate. Piracetam markedly decreases the formation of neuronal lipofuscin.[9] It improves posture in elderly people.[10] It is not regulated in the US. It is a pyrrolidone derivative. Aniracetam is a pyrrolidone derivative drug, analogous of piracetam, and considered more potent. Like piracetam, aniracetam protects against some memory impairing chemicals, such as diethyldithiocarbamate and clonidine.[11] Also like piracetam, aniracetam may enhance memory in aging adults by increasing levels of brain biogenic monoamines, which are beneficial to learning and memory.[2] Both racetams have possible therapeutic use in treating fetal alcohol syndrome.[12] Aniracetam increases vigilance[8]. Aniracetam has shown to positively potentiate AMPA receptors. Oxiracetam is a drug of the racetam family. It is similar to, but far stronger than piracetam and aniracetam.[citation needed] Several animal studies suggest that the substance is safe even when high doses are consumed for a long period of time. However the mechanism of action of oxiracetam is still a matter of research. - Acetyl-L-carnitine (ALCAR) - Amino acid. Precursor of acetylcholine (donating the acetyl portion to the acetylcholine molecule). It is synergistic with lipoic acid.[13] - Choline - precursor to acetylcholine (an essential component of the acetylcholine molecule). Alpha-GPC (L-alpha glycerylphosphorylcholine, Choline alfoscerate) - most effective choline precursor, readily crosses the blood-brain barrier. CDP-Choline (Cytidine Diphosphate Choline) - choline precursor, tends to be less expensive and similar in effect to Alpha GPC. Choline bitartrate - precursor of acetylcholine, anti-depressant. Choline citrate - precursor of the neurotransmitter acetylcholine, anti-depressant. Citicoline The choline compounds PC and citicoline are thought to promote synthesis and transmission of neurotransmitters important to memory.[4] - Alpha-GPC (L-alpha glycerylphosphorylcholine, Choline alfoscerate) - most effective choline precursor, readily crosses the blood-brain barrier. - CDP-Choline (Cytidine Diphosphate Choline) - choline precursor, tends to be less expensive and similar in effect to Alpha GPC. - Choline bitartrate - precursor of acetylcholine, anti-depressant. - Choline citrate - precursor of the neurotransmitter acetylcholine, anti-depressant. - Citicoline The choline compounds PC and citicoline are thought to promote synthesis and transmission of neurotransmitters important to memory.[4] - DMAE - approved treatment for ADD/ADHD, precursor of acetylcholine, cholinergic agent, removes lipofuscin from the brain, anti-depressant. - Galantamine - acetylcholinesterase inhibitor made from chemical synthesis or extract from plants such as Red Spider Lily (Lycoris radiata). - Huperzine A - potent acetylcholinesterase inhibitor derived from Chinese club-moss. - Ispronicline - recently developed selective α4β2 partial agonist - Lecithin - contains phosphatidylcholine, precursor of acetylcholine. - Other pyrrolidone derivatives: Etiracetam - It increases vigilance.[8] Nefiracetam - Drug. Analog of piracetam, and facilitates hippocampal neurotransmission.[14] Oxiracetam - Drug. Analog of piracetam, and 2 to 4 times stronger. Improves memory, concentration, and vigilance. When fed to pregnant rats, the offspring of those rats were more intelligent than the offspring of rats fed a saline solution placebo. Pramiracetam - Drug. Analog of piracetam. In animal studies, nootropics such as piracetam, oxiracetam and aniracetam are known to facilitate the formation of long term memory traces and to restore object recognition in aging rats. [15] There is evidence that the beneficial effect of racetams may result from an interaction with the central glutamatergic receptor function. [15] - Etiracetam - It increases vigilance.[8] - Nefiracetam - Drug. Analog of piracetam, and facilitates hippocampal neurotransmission.[14] - Oxiracetam - Drug. Analog of piracetam, and 2 to 4 times stronger. Improves memory, concentration, and vigilance. When fed to pregnant rats, the offspring of those rats were more intelligent than the offspring of rats fed a saline solution placebo. - Pramiracetam - Drug. Analog of piracetam. - In animal studies, nootropics such as piracetam, oxiracetam and aniracetam are known to facilitate the formation of long term memory traces and to restore object recognition in aging rats. [15] There is evidence that the beneficial effect of racetams may result from an interaction with the central glutamatergic receptor function. [15] - Vitamin B5 - cofactor in the conversion of choline into acetylcholine, cholinergic agent, increases stamina (including mental stamina). Excess acetylcholine is considered by many to be potentially harmful; see cholinesterase inhibitor. ### Dopaminergics Dopaminergics are substances that affect the neurotransmitter dopamine or the components of the nervous system that use dopamine. Dopamine is produced in the synthesis of all catecholamine neurotransmitters, and is the rate limiting step for this synthesis. Dopaminergic nootropics include dopamine precursors and cofactors, and dopamine reuptake inhibitors: - Mucuna pruriens - Seed powder contains high concentrations of levodopa (L-dopa),[16] a direct precursor of the neurotransmitter dopamine. - Lazabemide is a MAO-B inhibitor and has potent membrane lipid antioxidant activity. The antioxidant effects of lazabemide are attributed to its chemical structure and direct physicochemical interactions with the membrane lipid bilayer. It is a potent antioxidant, even more powerful than selegiline (deprenyl) or vitamin E, and is used to treat Alzheimer’s disease.[17] - L-dopa - Prescription drug and dietary supplement. Precursor to the neurotransmitter dopamine, anti-depressant. - Phenylalanine (requires Vitamin B6 and Vitamin C) - Essential amino acid. Precursor to dopamine, anti-depressant, sleep reducer. - Theanine - Found in tea. Increases serotonin and dopamine levels in the brain. Increases alpha-wave based alert relaxation. - Tyrosine (requires Vitamin B6 and Vitamin C) - Amino acid. Precursor to dopamine, anti-depressant, sleep reducer. - Vitamin C - improves cardiovascular elasticity and integrity, membrane stabilizer and major anti-oxidant (protects brain cells and prevents brain cell death), cofactor in the production of the neurotransmitters dopamine and serotonin. - Vitamin B6 - co-factor used by the body to produce dopamine. - Yohimbe - Bark. Boosts dopamine levels, though how it does this is not yet understood. Aphrodisiac. Yohimbe poses some health risks through its side-effects: it is a neuro-paralytic which slows down breathing and induces acidosis, some symptoms of which are malaise, nausea, and vomiting. Contraindicated for users of megadoses of acidic vitamins or nutrients. - Deprenyl - (selegiline) L-Deprenyl is an irreversible MAO-B inhibitor, an enzyme that breaks down dopamine. Thus, it is used to treat Parkinson's disease, and to delay the progression of Alzheimer's disease. It protects against the genotoxin AraC, provides neuroprotection against growth factor withdrawal in PC12 cells, protects against oxidative stress in mesencephalatic neurons, and delays neuronal cell death in the hippocampus after global ischemia.[18] - Tolcapone - Inhibits COMT (an enzyme that breaks down the neurotransmitters dopamine, epinephrine, and norepinephrine) and increases performance in tasks depending on working memory in individuals with the val/val and val/met genotype of the val158Met polymorphism of the catechol-O-methyltransferase gene, while decreasing it in presence of the met/met version. Tolcapone presents the risk of deadly side effects. ### Serotonergics Serotonergics are substances that affect the neurotransmitter serotonin or the components of the nervous system that use serotonin. Serotonergic nootropics include serotonin precursors and cofactors, and serotonin reuptake inhibitors: - Griffonia simplicifolia a natural source of 5-HTP (an alternative in countries where 5-HTP not legal, freely available.) - Tryptophan (requires Vitamin B6 and Vitamin C) - Essential amino acid. Precursor to serotonin, found in high concentration in bananas and meats, also in milk, promotes relaxed poise and sound sleep. 5-HTP is a form of Tryptophan. - 5HT2A agonists such as LSD and 2C-T-7 have been shown to produce nootropic effects when used at a dose much lower than a hallucinogenic dose. (e.g. 10 μg for LSD and 1 mg 2C-T-7, 1/25 of a normal recreational dose ) - SSRIs - Class of antidepressants that increase active serotonin levels, ie, in the synaptic junction, by inhibiting its reuptake. Have also been shown to promote Neurogenesis in the hippocampus. ## Anti-depression, adaptogenic (antistress), and mood stabilization Stress, Depression, and depressed mood negatively affect cognitive performance. It is reasoned that counteracting and preventing depression and stress may be an effective nootropic strategy. Below are a list of substances purported to function as nootropics, and claimed effects: - Ashwagandha (Withania somnifera) - Root. Also known as Indian ginseng. Adaptogen used as a tonic to normalize body processes and reduce stress and anxiety. - Inositol - Is a B-vitamin like substance with anti-anxiety effects. It is believed to produce its anti-anxiety effects by improving the binding of gabaergics to GABAA receptors. Inositol is a sugar, and is therefore an alternative energy source for brain and muscle tissues. It produces a sugar high without a sugar low, making it especially suited for sweetening tea (instead of sugar). It is also a membrane stabilizer which can strengthen (and therefore help protect) neurons. - Kava-kava - The roots of the Kava-Kava plant contain Kavalactones which have GABAergic properties and are used to combat anxiety.[19] - Lemon Balm (Melissa officinalis) - Herb. Anti-depressant. - Passion Flower is used to treat depression. It is commonly combined with St. John’s Wort and Valerian, which work synergistically to reestablish the patients emotional balance without causing tachyphylaxia, hangovers, or addiction. [19] - Rhodiola Rosea - Herb. Adaptogen; elevates mood, alleviates depression. Promotes mental energy and stamina, reduces fatigue. - St John's Wort - Herb. The active components: hypericin and hyperforin, are clinically indicated to be effective in cases of mild to moderate depression, on par with synthetic drugs. However, St John's Wort is not suitable for the treatment of severe depression or suicidal tendencies. Side effects include gastrointestinal complaints and allergic reactions such as pruritus and phototoxicity. [19] - Ginseng, Siberian (Eleutherococcus senticosus) - Root. Anti-anxiety adaptogen that normalizes physical stress and mental consequences. - Selegiline (Deprenyl) - Along with Piracetam and Meclofenoxate, Deprenyl decreases the amount of lipofuscin pigment and ceroid pigment accumulations in the brain by improving cellular recycling activities.[20] Therefore, these nootropics may slow age-related diseases in the brain. Selegiline, an MAO-B inhibitor, is used as an antioxidant for the treatment of Alzheimer’s disease. [17] - Sutherlandia frutescens - Herb. Adaptogen, blood detoxifier. - Tea - Herb. Contains theophylline and theanine. Increases alpha-wave based alert relaxation (relieves stress). - Theanine - Amino acid. Found in tea. Increases serotonin and dopamine levels in the brain. Increases alpha-wave based alert relaxation. Also stimulates the GABAergic system. - Tianeptine - Anxiolytic anti-depressant. It enhances working and reference memory in rats.[21] - Vasopressin - Drug. Memory hormone produced by the pituitary gland which improves both memory encoding and recall. Rapidly counters chronic apathy syndrome and drug-induced vasopressin depletion. - Nicotinic acid (vitamin B3) - Essential nutrient. Mild enhancer of concentration and memory. Vasodilator - Mood stabilizer, with a powerful anti-anxiety effect — perhaps the best and most immediate stress reliever available (note that other forms of vitamin B do not have this effect). Side effects: gastric upset (which is easily prevented and relieved with antacids), reduced blood pressure and flushing of the skin (caused by vasodilation), and itchy sensation in the skin caused by histamine release. - Vitis vinifera (Grape Seed) Grape seed has antistress (adaptogenic) activity, protects against memory loss induced by scopolamine, is an antioxidant, has nootropic activities, and supports the traditional claims for the use of grape fruits and seeds in stress induced disorders. [22] ## Brain function and improved oxygen supply - Acetyl-L-carnitine (ALCAR) - Amino acid. Transports fatty acids through cellular membranes and cytosol into cells' mitochondria, where the fats undergo oxidation to produce ATP, the universal energy molecule. Synergistic with lipoic acid. - Chromium- stabilises blood sugar levels promoting concentration. - Coenzyme q-10 syn. Ubiquinone - increases oxygen transport through the mitochondria of the cells. - Creatine - increases brain energy levels via ATP production. - Inositol - B vitamin which synergizes with other nootropics - Lipoic acid - synergistic with Acetyl-L-carnitine. - Piracetam - improves alertness, blood flow, oxygen supply, and stroke recovery. - Pyritinol (Enerbol) - Drug. Enhances oxygen and glucose uptake in the brain, and allows glucose to pass more easily through the blood-brain barrier. It is also a powerful anti-oxidant which scavenges hydroxyl radicals created in the very processes it is involved in. - Vinpocetine - Vinpocetine increases blood circulation and metabolism in the brain. Animal studies have shown that vinpocetine can reduce the loss of neurons due to decreased blood flow. [4] - Prazosin - Alpha-blocking blood pressure medication also prescribed as an anti-PTSD medication, appears to block the increase of steroid hormones known as glucocorticoids, Oregon Health & Science University and Portland Veterans Affairs Medical Center researchers have found. Elevated levels of glucocorticoids are associated with atrophy in nerve branches where impulses are transmitted, and even nerve cell death, in the hippocampus. ## Mental agility, concentration, stamina, and focus - Adrafinil (Olmifon) - Drug. - Caffeine - Drug. improves concentration, idea production, but hinders memory encoding. Also produces the jitters. Caffeine is the most widely used psychoactive substance in the world, and may be susceptible to strong levels of tolerance. - Coffee - Bean. Contains caffeine; brewed coffee is high in antioxidants. - Nicergoline - Drug. Nicergoline is an ergoloid mesylate derivative used to treat senile dementia. It has also been found to increase mental agility and enhance clarity and perception. It increases vigilance.[8] Increases arterial flow and use of oxygen and glucose in the brain. - Nicotine - stimulus barrier (aids in concentration). Stimulus barrier rebound effect (an unpleasant side effect). - Cocaine - Drug. - Methylphenidate (Ritalin) - Drug - Dextroamphetamine - (Adderall, Dexedrine) - Drug. - Modafinil - (Provigil) - Drug. - Piracetam - improves alertness, socialization, and co-operation in the brain impaired from age, dementia, and reduced blood flow. - Phenibut - - Theophylline - - Amphetamine - aids in concentration, focus and stamina. Prescribed for ADD/ADHD - Carphedon (Phenotropil) - ## Purported memory enhancement and learning improvement All of the "nergics" listed above are purported to improve memory (encoding and recall), as do all nootropics which improve general brain performance in categories such as the brain energy and oxygen supply, and nerve growth stimulation and protection. Other agents purported to have these specific benefits are mentioned in their own sections. Other nootropics with specific effects on memory encoding and recall include: - Bacopa monniera (Brahmi) - Herb. Elevates curiosity, enhances memory and concentration.[23] Brahmi also protects against amnesia inducing chemicals such as scopolamine or loss of memory due to electro convulsive shocks.[23] It is a traditional ayurvedic medicine. - Piracetam - improves memory. Used to treat Alzheimer's, dementia, dyslexia and Down's syndrome - Rosemary - Herb. Rosemary has a very old, albeit unverified, reputation for improving memory. - Vasopressin - Hormone, prescription drug. - Dextroamphetamine- Adderall, Dexedrine.[24] - Nicotine - Improves working memory and learning[25] ## Nerve growth stimulation and brain cell protection - Acetyl-L-carnitine (ALCAR) - Amino acid. Inhibits lipofuscin formation. - Bacopa monnieri (Brahmi) - Herb. Improves protein synthesis in brain cell repair and new dendritic growth. - Selegiline (Deprenyl) - Drug. Brain cell protectant, delays senescence of brain cells, proven to increase maximum life span in laboratory rats. - Ergoloid mesylates (Hydergine) - Drug. Mimics nerve growth factor (NGF), and is a powerful anti-oxidant capable of delaying brain death in cases of heart failure and stroke by several minutes with regular use. It increases vigilance.[8] - Idebenone - stimulates nerve growth, and has same effects as Coenzyme q-10. - Inositol - Membrane stabilizer. Strengthens neurons, making them less susceptible to damage. - Pyritinol (Enerbol) - Drug. Powerful anti-oxidant which scavenges hydroxyl radicals. - Rasagiline (Azilect) - Drug. Treats Parkinson’s disease either as monotherapy (by itself) or in addition to levodopa therapy. Promotes increased and sustained levels of dopamine by selectively inhibiting an enzyme, monoamine oxidase-B. - Vitamin C - Membrane stabilizer, involved in collagen synthesis. Vitamin C is also a co-factor in the brain's production of dopamine. ## Recreational drugs with purported nootropic effects Template:Seealso - Amphetamine-type stimulants (such as Adderall, Dexedrine, Desoxyn, etc.) are Schedule II controlled substances in the United States, and Class B drugs in the United Kingdom, with comparable legal controls in effect in most countries throughout the world. They are prescribed for attention-deficit disorders, narcolepsy, and certain cases of obesity; and are issued to counteract fatigue and to enhance performance for pilots in the armed forces of the United States of America.[26][27] These also heighten alertness, mental focus, vigilance, stamina, and sex drive. They tend to be habit-forming, and exhibit side effects with prolonged or heavy use. Personal importation of amphetamine-class drugs is prohibited in many countries, and their use for recreation or for performance enhancement without a medical prescription is likewise illegal in most countries. - LSD - Schedule I / Class A drug. At higher doses, the impact of the senses on one's mind are expanded to such an overwhelming degree that what is being sensed seems qualitatively different. Many psychedelic drugs are known to produce this overwhelming effect on the mind. Aldous Huxley called this state of mind "Mind at Large". Activity in the Raphe Nuclei and Locus ceruleus increases dramatically following administration of LSD to produce extremely heightened creativity in many users. This effect on the creative process is a phenomenon that may be due to ascending traffic in the reticular activation system, which can result in stimulus overload. The longest single research project with LSD, at Spring Grove Hospital, Maryland, showed an average 10% increase in linear IQ alone.[28] Also produces hallucinogenic and entheogenic effects at doses as low as 30–40 μg (micrograms), with the likelihood of having a bad trip increasing as dose is increased if these effects are undesired. May also cause cognitive shifts, synesthesia, and flashbacks. The drug sometimes spurs long-term or even permanent changes in a user's personality and life perspective. (For more details, see Albert Hofmann: LSD - My Problem Child.) - 4-methylaminorex - Pemoline (Cylert) - Psilocybin and Psilocin - MDPV - Mescaline ## Dietary Nootropics Some regular food items are rich sources of substances with alleged nootropic benefits: - Nuts, in particular walnuts, are rich sources of alpha-linolenic acid (ALA), a type of omega-3 fatty acid. A mixture of walnuts served with dried fruit pieces is known in some regions as student food (orig. German: Studentenfutter) and is popularly recommended as a snack for students. - Oily fish, such as salmon or fresh tuna (not tuna canned in oil) are also good sources of omega-3 fatty acids such as eicosapentaenoic acid and docosahexaenoic acid, whose lack in diet has been associated with increased risk of mental illnesses such as depression, anxiety, aggressive behavior, schizophrenia, or hyper-activity in children (see omega-3 fatty acids article) ## Other nootropics - Adafenoxate - Has an anti-anxiety effect for rats[29] and possibly the same for humans. - Moderate use of alcohol - Moderate drinking has been associated with better cognitive ability than both abstention and heavy drinking.[30][31][32][33][34] - Butea frondosa - "The plant Butea frondosa has been indicated in the Indian system of medicine as a plant augmenting memory and as a rejuvenator. ... B. frondosa possesses anti-stress and weak nootropic activity."[35] - BMY 21502 - Injured animals treated with BMY-21502 at one week post-injury showed significant improvement in post-injury learning ability compared to injured animals treated with vehicle. Paradoxically, in uninjured control animals BMY-21502 treatment appeared to worsen learning scores. The results of this study indicate that BMY-21502 may be useful for attenuating the dysfunction in learning ability that occurs following traumatic brain injury. - Cabergoline (Dostinex) - A lysergic acid amide derivative, is a potent dopamine receptor agonist on D2 receptors. Maybe carcinogenic. - Celastrus paniculatus - Oil made from the seeds of this shrub are used in Ayurvedice medicine to increase memory and facilitate learning. It allegedly induces a feeling of well-being and has reported aphrodisiac effects. - Cerebrolysin - A neuroprotective nootropic agent, might affect Alzheimer's disease pathology. Currently in clinical trials - Clausenamide - Facilitated learning and memory acquisition in step down and step through tests and increased thickness of cerebral cortex and synapse density significantly in the dentate cells over pyramidel cells in hippocampal region in mice. - Coluracetam - It may also have potential use in prevention and treatment of ischemic retinopathy and retinal and optic nerve injury - Desmopressin (DDAVP) - Analog of vasopressin, a neuropeptide responsible for memory. - DHEA - Hormone created by the adrenal glands; Precursor to Estrogen and Testosterone - Dostinex - (see Cabergoline above) - Fasoracetam - A nootropic drug of the racetam family. - Essential Fatty Acids- Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are the best known. EPA in particular, has an anti-depressant function and is positively indicated in trials with autism and learning difficulties - Fipexide (Vigilor) - It protects against some memory impairing chemicals, such as diethyldithiocarbamate and clonidine.[11] - Gerovital H3 - Romanian anti-aging formula containing procaine hydrochloride, but which breaks down into PABA and DMAE. - Ginkgo biloba - Ginkgo (Ginkgo biloba), a root, is used to treat a variety of problems, including chronic cerebrovascular insufficiency, tinnitus, vertigo and peripheral arterial disease. Patients with dementia treated with ginkgo showed significant improvement of symptoms like memory loss, concentration difficulties, fatigue, anxiety and depressive mood. [19] However, because Ginkgo is a vasodilator, it ought not be taken with Aspirin, for doing so could increase the risk of bleeding. [36] Ginkgo is widely used in Europe to treat subjective tinnitus, however, there is as yet no hard evidence supporting this assertion. [36] Ginkgolides are extracts from the leaves of the tree. They produce a beneficial effect for Alzheimer’s disease, and for amyloid-B, the toxic prion protein, which suggests they could be relevant to treating those diseases. [37] - Gotu Kola - Herb and root. - Meclofenoxate - Has an anti-anxiety effect for rats[29] and possibly the same for humans. Like Fipexide, it protects against some memory impairing chemicals, such as diethyldithiocarbamate and clonidine.[11] Like many racetams, it may treat fetal alcohol syndrome.[12] - Milacemide - A glycine prodrug which is both an inhibitor and a substrate for monoamine oxidase-type B (MAO-B) and also an inhibitor of MAO-type A (MAO-A). - Nimodipine - A dihydropyridine calcium channel blocker originally developed for the treatment of high blood pressure. - Ondansetron (Zofran) - A serotonin 5-HT3 receptor antagonist used mainly as an antiemetic to treat nausea and vomiting following chemotherapy. - Phenytoin (Dilantin) - A neuroleptic and anti-siezure medication advocated by Jack Dreyfus for a variety of psychological conditions. - Phosphatidylserine- In animals, PS has been shown to attenuate many neuronal effects of aging, and to restore normal memory on a variety of tasks. [4] - Picamilon or Pikamilone - Compound of Niacin and GABA. It can pass the blood-brain barrier and increase amount of GABA in the brain. - Pregnenolone - Hormone; Precursor to DHEA; - Pyroglutamate - An amino acid shown to improve learning. - Royal Jelly - Produced by bees for the Queen. Can cause fatal allergic reactions in rare cases - Sapunifiram - Semax - A neuropeptide (stimulator of the nervous system) developed from a short fragment of ACTH, Pro8-Gly9-Pro10 ACTH(4-10). Claims of significant increase in salvation of neurons are made - Somatotropin - Growth hormone, a polypeptide containing 191 amino acids, produced by the anterior pituitary, the front section of the pituitary gland. It acts by stimulating the release of another hormone called somatomedin by the liver, thereby causing growth. - Sulbutiamine (Arcalion) - Drug - derivative of thiamine (vitamin B1) that can cross the blood-brain barrier and work as anti-fatigue and cognitive support agent. - Sunifiram - Turmeric - has possible benefits in Alzheimer's disease, cancer and liver disorders. Turmeric, under the name Avea, is becoming popular to treat depression. - Unifiram - Xanthinol Nicotinate (Complamin) - A drug that has been shown to stimulate memory and concentration, by improving blood flow to the brain.	https://www.wikidoc.org/index.php/Nootropic
f09ca6d83b257508367eafed3d71c0c62c94cfb8	wikidoc	Ritonavir	Ritonavir - 600 mg twice daily - Ritonavir should be started at no less than 300 mg twice daily and increased at 2 to 3 day intervals by 100 mg twice daily. The maximum dose of 600 mg twice daily. - Children greater than 1 month is 350 to 400 mg per m2 twice daily. - In combination with other antiretroviral agents. - Not exceed 600 mg twice daily. - Ritonavir should be started at 250 mg per m2 twice daily and increased at 2 to 3 day intervals by 50 mg per m2 twice daily. - Ritonavir is contraindicated in patients with known hypersensitivity (e.g., toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome) to ritonavir or any of its ingredients. - Co-administration of ritonavir with several classes of drugs (including sedative hypnotics, antiarrhythmics, or ergot alkaloid preparations) is contraindicated and may result in potentially serious and/or life-threatening adverse events due to possible effects of ritonavir on the hepatic metabolism of these drugs (see TABLE 2). - Voriconazole and St. John’s Wort are exceptions in that co-administration of ritonavir and voriconazole results in a significant decrease in plasma concentrations of voriconazole, and co-administration of ritonavir with St. John’s Wort may result in decreased ritonavir plasma concentrations. ## Drug Interactions - Ritonavir is a CYP3A inhibitor. - Initiating treatment with ritonavir in patients receiving medications metabolized by CYP3A or initiating medications metabolized by CYP3A in patients already maintained on ritonavir may result in increased plasma concentrations of concomitant medications. - Higher plasma concentrations of concomitant medications can result in increased or prolonged therapeutic or adverse effects, potentially leading to severe, life-threatening or fatal events. - The potential for drug-drug interactions must be considered prior to and during therapy with ritonavir. - Review of other medications taken by patients and monitoring of patients for adverse effects is recommended during therapy with ritonavir. See Table 2 for a listing of drugs that are contraindicated with ritonavir due to potentially life-threatening adverse events, significant drug interactions, or loss of virologic activity. Also, see Table 5 for a listing of drugs with established and other significant drug interactions. ## Toxicity in Preterm Neonates - Ritonavir oral solution contains the excipients alcohol (43.2% v/v) and propylene glycol (26.57% w/v). - When administered concomitantly with propylene glycol, ethanol competitively inhibits the metabolism of propylene glycol, which may lead to elevated concentrations. - Preterm neonates may be at an increased risk of propylene glycol-associated adverse events due to diminished ability to metabolize propylene glycol, thereby leading to accumulation and potential adverse events. - Postmarketing life-threatening cases of cardiac toxicity (including complete AV block, bradycardia, and cardiomyopathy), lactic acidosis, acute renal failure, CNS depression and respiratory complications leading to death have been reported, predominantly in preterm neonates receiving lopinavir/ritonavir oral solution which also contains the excipients alcohol and propylene glycol. - Ritonavir oral solution should not be used in preterm neonates in the immediate postnatal period because of possible toxicities. However, if the benefit of using ritonavir oral solution to treat HIV infection in infants immediately after birth outweighs the potential risks, infants should be monitored closely for increases in serum osmolality and serum creatinine, and for toxicity related to ritonavir oral solution including: hyperosmolality, with or without lactic acidosis, renal toxicity, CNS depression (including stupor, coma, and apnea), seizures, hypotonia, cardiac arrhythmias and ECG changes, and hemolysis. - Total amounts of alcohol and propylene glycol from all medicines that are to be given to infants should be taken into account in order to avoid toxicity from these excipients. ## Hepatic Reactions - Hepatic transaminase elevations exceeding 5 times the upper limit of normal, clinical hepatitis, and jaundice have occurred in patients receiving ritonavir alone or in combination with other antiretroviral drugs (see Table 4). There may be an increased risk for transaminase elevations in patients with underlying hepatitis B or C. Therefore, caution should be exercised when administering ritonavir to patients with pre-existing liver diseases, liver enzyme abnormalities, or hepatitis. - Increased AST/ALT monitoring should be considered in these patients, especially during the first three months of ritonavir treatment. - There have been postmarketing reports of hepatic dysfunction, including some fatalities. - These have generally occurred in patients taking multiple concomitant medications and/or with advanced AIDS. ## Pancreatitis - Pancreatitis has been observed in patients receiving ritonavir therapy, including those who developed hypertriglyceridemia. - In some cases fatalities have been observed. - Patients with advanced HIV disease may be at increased risk of elevated triglycerides and pancreatitis. - Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) or abnormalities in laboratory values (such as increased serum lipase or amylase values) suggestive of pancreatitis should occur. - Patients who exhibit these signs or symptoms should be evaluated and ritonavir therapy should be discontinued if a diagnosis of pancreatitis is made. ## Allergic Reactions/Hypersensitivity - Allergic reactions including urticaria, mild skin eruptions, bronchospasm, and angioedema have been reported. Cases of anaphylaxis, toxic epidermal necrolysis (TEN), and Stevens-Johnson syndrome have also been reported. - Discontinue treatment if severe reactions develop. ## PR Interval Prolongation - Ritonavir prolongs the PR interval in some patients. - Post marketing cases of second or third degree atrioventricular block have been reported in patients. - Ritonavir should be used with caution in patients with underlying structural heart disease, preexisting conduction system abnormalities, ischemic heart disease, cardiomyopathies, as these patients may be at increased risk for developing cardiac conduction abnormalities. - The impact on the PR interval of co-administration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers, beta-adrenergic blockers, digoxin and atazanavir) has not been evaluated. - As a result, co-administration of ritonavir with these drugs should be undertaken with caution, particularly with those drugs metabolized by CYP3A. Clinical monitoring is recommended. ## Lipid Disorders - Treatment with ritonavir therapy alone or in combination with saquinavir has resulted in substantial increases in the concentration of total cholesterol and triglycerides. Triglyceride and cholesterol testing should be performed prior to initiating ritonavir therapy and at periodic intervals during therapy. - Lipid disorders should be managed as clinically appropriate, taking into account any potential drug-drug interactions with ritonavir and HMG CoA reductase inhibitors. ## Diabetes Mellitus/Hyperglycemia - New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV-infected patients receiving protease inhibitor therapy. - Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. - In some cases, diabetic ketoacidosis has occurred. - In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established. ## Immune Reconstitution Syndrome - Immune reconstitution syndrome has been reported in HIV-infected patients treated with combination antiretroviral therapy, including ritonavir. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia, or tuberculosis), which may necessitate further evaluation and treatment. - Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment. ## Fat Redistribution - Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. - The mechanism and long-term consequences of these events are currently unknown. - A causal relationship has not been established. ## Patients with Hemophilia - There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia type A and B treated with protease inhibitors. - In some patients additional factor VIII was given. - In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced. - A causal relationship between protease inhibitor therapy and these events has not been established. ## Resistance/Cross-resistance - Varying degrees of cross-resistance among protease inhibitors have been observed. - Continued administration of ritonavir 600 mg twice daily following loss of viral suppression may increase the likelihood of cross-resistance to other protease inhibitors. ## Laboratory Tests - Ritonavir has been shown to increase triglycerides, cholesterol, SGOT (AST), SGPT (ALT), GGT, CPK, and uric acid. Appropriate laboratory testing should be performed prior to initiating ritonavir therapy and at periodic intervals or if any clinical signs or symptoms occur during therapy. ## Adult Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. - The safety of ritonavir alone and in combination with other antiretroviral agents was studied in 1,755 adult patients. Table 3 lists treatment-emergent Adverse Reactions (with possible or probable relationship to study drug) occurring in greater than or equal to 1% of adult patients receiving ritonavir in combined Phase II/IV studies. - The most frequently reported adverse drug reactions among patients receiving ritonavir alone or in combination with other antiretroviral drugs were gastrointestinal (including diarrhea, nausea, vomiting, abdominal pain (upper and lower)), neurological disturbances (including paresthesia and oral paresthesia), rash, and fatigue/asthenia. # =Pediatric Clinical Trial Experience Ritonavir has been studied in 265 pediatric patients greater than 1 month to 21 years of age. - The adverse event profile observed during pediatric clinical trials was similar to that for adult patients. - Vomiting, diarrhea, and skin rash/allergy were the only drug-related clinical adverse events of moderate to severe intensity observed in greater than or equal to 2% of pediatric patients enrolled in ritonavir clinical trials. ## Laboratory Abnormalities - The following Grade 3-4 laboratory abnormalities occurred in greater than 3% of pediatric patients who received treatment with ritonavir either alone or in combination with reverse transcriptase inhibitors: neutropenia (9%), hyperamylasemia (7%), thrombocytopenia (5%), anemia (4%), and elevated AST (3%). ## Body as a Whole - Dehydration, usually associated with gastrointestinal symptoms, and sometimes resulting in hypotension, syncope, or renal insufficiency has been reported. Syncope, orthostatic hypotension, and renal insufficiency have also been reported without known dehydration. - Co-administration of ritonavir with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system. ## Cardiovascular System - First-degree AV block - Second-degree AV block - Third-degree AV block - Right bundle branch block - Cardiac and neurologic events have been reported when ritonavir has been co-administered with disopyramide, mexiletine, nefazodone, fluoxetine, and beta blockers. - The possibility of drug interaction cannot be excluded. ## Endocrine System - Cushing's syndrome - Adrenal suppression - Reported when ritonavir has been co-administered with fluticasone propionate or budesonide. ## Nervous System - Seizure ## Skin and subcutaneous tissue disorders - Toxic epidermal necrolysis (TEN) ## Potential for ritonavir to Affect Other Drugs - Ritonavir has been found to be an inhibitor of cytochrome P450 3A (CYP3A) and may increase plasma concentrations of agents that are primarily metabolized by CYP3A. - Agents that are extensively metabolized by CYP3A and have high first pass metabolism appear to be the most susceptible to large increases in AUC (greater than 3-fold) when co-administered with ritonavir. Thus, co-administration of ritonavir with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. - Co-administration with other CYP3A substrates may require a dose adjustment or additional monitoring as shown in Table 5. - Ritonavir also inhibits CYP2D6 to a lesser extent. - Co-administration of substrates of CYP2D6 with ritonavir could result in increases (up to 2-fold) in the AUC of the other agent, possibly requiring a proportional dosage reduction. - Ritonavir also appears to induce CYP3A, CYP1A2, CYP2C9, CYP2C19, and CYP2B6 as well as other enzymes, including glucuronosyl transferase. ## Established and Other Potentially Significant Drug Interactions Table 5 provides a list of established or potentially clinically significant drug interactions. Alteration in dose or regimen may be recommended based on drug interaction studies or predicted interaction. - There are no adequate and well-controlled studies in pregnant women. - Ritonavir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. ## Animal Data - No treatment related malformations were observed when ritonavir was administered to pregnant rats or rabbits. - Developmental toxicity observed in rats (early resorptions, decreased fetal body weight and ossification delays and developmental variations) occurred at a maternally toxic dosage at an exposure equivalent to approximately 30% of that achieved with the proposed therapeutic dose. - A slight increase in the incidence of cryptorchidism was also noted in rats at an exposure approximately 22% of that achieved with the proposed therapeutic dose. - Developmental toxicity observed in rabbits (resorptions, decreased litter size and decreased fetal weights) also occurred at a maternally toxic dosage equivalent to 1.8 times the proposed therapeutic dose based on a body surface area conversion factor. - It is not known whether ritonavir is secreted in human milk. - Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving ritonavir. - In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. - No pharmacokinetic or safety data are available regarding the use of ritonavir in subjects with severe hepatic impairment (Child-Pugh Class C), therefore, ritonavir is not recommended for use in patients with severe hepatic impairment. - Total cholesterol and triglycerides elevations: Monitor prior to therapy and periodically thereafter. - Initial frequent monitoring of the INR during ritonavir and warfarin co-administration is indicated. - Use with beta blockers, caution is warranted and clinical monitoring of patients is recommended. - Caution should be exercised when co-administering ritonavir with digoxin, with appropriate monitoring of serum digoxin levels. - Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with ritonavir. - Human experience of acute overdose with ritonavir is limited. - One patient in clinical trials took ritonavir 1500 mg per day for two days. - The patient reported paresthesias which resolved after the dose was decreased. - A post-marketing case of renal failure with eosinophilia has been reported with ritonavir overdose. - The approximate lethal dose was found to be greater than 20 times the related human dose in rats and 10 times the related human dose in mice. ## Management of Overdosage - Ritonavir oral solution contains 43.2% (v/v) alcohol and 26.57% (w/v) propylene glycol. - Ingestion of the product over the recommended dose by a young child could result in significant toxicity and could potentially be lethal. - Treatment of overdose with ritonavir consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. - There is no specific antidote for overdose with ritonavir. - If indicated, elimination of unabsorbed drug should be achieved by gastric lavage; usual precautions should be observed to maintain the airway. Administration of activated charcoal may also be used to aid in removal of unabsorbed drug. - Since ritonavir is extensively metabolized by the liver and is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the drug. However, dialysis can remove both alcohol and propylene glycol in the case of overdose with ritonavir oral solution. - A Certified Poison Control Center should be consulted for up-to-date information on the management of overdose with ritonavir Inhibition of HIV protease renders the enzyme incapable of processing the gag-pol polyprotein precursor which leads to production of non-infectious immature HIV particles. ## Absorption The absolute bioavailability of ritonavir has not been determined. After a 600 mg dose of oral solution, peak concentrations of ritonavir were achieved approximately 2 hours and 4 hours after dosing under fasting and non-fasting (514 KCal; 9% fat, 12% protein, and 79% carbohydrate) conditions, respectively. Ritonavir tablets are not bioequivalent to ritonavir capsules. Under moderate fat conditions (857 kcal; 31% fat, 13% protein, 56% carbohydrates), when a single 100 mg ritonavir dose was administered as a tablet compared with a capsule, AUC(0- ∞) met equivalence criteria but mean Cmax was increased by 26% (92.8% confidence intervals: ↑15 -↑39%). No information is available comparing ritonavir tablets to ritonavir capsules under fasting conditions. When the oral solution was given under non-fasting conditions, peak ritonavir concentrations decreased 23% and the extent of absorption decreased 7% relative to fasting conditions. Dilution of the oral solution, within one hour of administration, with 240 mL of chocolate milk. Administration of a single 600 mg dose oral solution under non-fasting conditions yielded mean ± SD areas under the plasma concentration-time curve (AUCs) of 129.0 ± 39.3 mgh per mL. A food effect is observed for ritonavir tablets. Food decreased the bioavailability of the ritonavir tablets when a single 100 mg dose of ritonavir was administered. Under high fat conditions (907 kcal; 52% fat, 15% protein, 33% carbohydrates), a 23% decrease in mean AUC(0-∞) , and a 23% decrease in mean Cmax ) was observed relative to fasting conditions. Under moderate fat conditions, a 21% decrease in mean AUC(0-∞) , and a 22% decrease in mean Cmax ) was observed relative to fasting conditions. However, the type of meal administered did not change ritonavir tablet bioavailability when high fat was compared to moderate fat meals. ## Metabolism Nearly all of the plasma radioactivity after a single oral 600 mg dose of 14C-ritonavir oral solution (n = 5) was attributed to unchanged ritonavir. Five ritonavir metabolites have been identified in human urine and feces. The isopropylthiazole oxidation metabolite (M-2) is the major metabolite and has antiviral activity similar to that of parent drug; however, the concentrations of this metabolite in plasma are low. In vitro studies utilizing human liver microsomes have demonstrated that cytochrome P450 3A (CYP3A) is the major isoform involved in ritonavir metabolism, although CYP2D6 also contributes to the formation of M–2. ## Elimination In a study of five subjects receiving a 600 mg dose of 14C-ritonavir oral solution, 11.3 ± 2.8% of the dose was excreted into the urine, with 3.5 ± 1.8% of the dose excreted as unchanged parent drug. In that study, 86.4 ± 2.9% of the dose was excreted in the feces with 33.8 ± 10.8% of the dose excreted as unchanged parent drug. Upon multiple dosing, ritonavir accumulation is less than predicted from a single dose possibly due to a time and dose-related increase in clearance. ## Effects on Electrocardiogram QTcF interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg once-daily) controlled crossover study in 45 healthy adults, with 10 measurements over 12 hours on Day 3. The maximum mean (95% upper confidence bound) time-matched difference in QTcF from placebo after baseline correction was 5.5 (7.6) milliseconds (msec) for 400 mg twice-daily ritonavir. Ritonavir 400 mg twice daily resulted in Day 3 ritonavir exposure that was approximately 1.5 fold higher than observed with ritonavir 600 mg twice-daily dose at steady state. PR interval prolongation was also noted in subjects receiving ritonavir in the same study on Day 3. The maximum mean (95% confidence interval) difference from placebo in the PR interval after baseline correction was 22 (25) msec for 400 mg twice-daily ritonavir. ## Special Populations No age-related pharmacokinetic differences have been observed in adult patients (18 to 63 years). Ritonavir pharmacokinetics have not been studied in older patients. A study of ritonavir pharmacokinetics in healthy males and females showed no statistically significant differences in the pharmacokinetics of ritonavir. Pharmacokinetic differences due to race have not been identified. Steady-state pharmacokinetics were evaluated in 37 HIV-infected patients ages 2 to 14 years receiving doses ranging from 250 mg per m2 twice-daily to 400 mg per m2 twice-daily in PACTG Study 310, and in 41 HIV-infected patients ages 1 month to 2 years at doses of 350 and 450 mg per m2 twice-daily in PACTG Study 345. Across dose groups, ritonavir steady-state oral clearance (CL/F/m2) was approximately 1.5 to 1.7 times faster in pediatric patients than in adult subjects. Ritonavir concentrations obtained after 350 to 400 mg per m2 twice-daily in pediatric patients greater than 2 years were comparable to those obtained in adults receiving 600 mg (approximately 330 mg per m2) twice-daily. The following observations were seen regarding ritonavir concentrations after administration with 350 or 450 mg per m2 twice-daily in children less than 2 years of age. Higher ritonavir exposures were not evident with 450 mg per m2 twice-daily compared to the 350 mg per m2 twice-daily. Ritonavir trough concentrations were somewhat lower than those obtained in adults receiving 600 mg twice-daily. The area under the ritonavir plasma concentration time curve and trough concentrations obtained after administration with 350 or 450 mg per m2 twice-daily in children less than 2 years were approximately 16% and 60% lower, respectively, than that obtained in adults receiving 600 mg twice daily. ## Renal Impairment Ritonavir pharmacokinetics have not been studied in patients with renal impairment, however, since renal clearance is negligible, a decrease in total body clearance is not expected in patients with renal impairment. ## Hepatic Impairment Dose-normalized steady-state ritonavir concentrations in subjects with mild hepatic impairment (400 mg twice-daily, n = 6) were similar to those in control subjects dosed with 500 mg twice-daily. Dose-normalized steady-state ritonavir exposures in subjects with moderate hepatic impairment (400 mg twice-daily, n= 6) were about 40% lower than those in subjects with normal hepatic function (500 mg twice-daily, n = 6). Protein binding of ritonavir was not statistically significantly affected by mild or moderately impaired hepatic function. No dose adjustment is recommended in patients with mild or moderate hepatic impairment. However, health care providers should be aware of the potential for lower ritonavir concentrations in patients with moderate hepatic impairment and should monitor patient response carefully. Ritonavir has not been studied in patients with severe hepatic impairment. Table 7 and Table 8 summarize the effects on AUC and Cmax, with 95% confidence intervals (95% CI), of co-administration of ritonavir with a variety of drugs. For information about clinical recommendations see Table 5 in Drug Interactions (7). Carcinogenicity studies in mice and rats have been carried out on ritonavir. In male mice, at levels of 50, 100 or 200 mg per kg per day, there was a dose dependent increase in the incidence of both adenomas and combined adenomas and carcinomas in the liver. Based on AUC measurements, the exposure at the high dose was approximately 0.3-fold for males that of the exposure in humans with the recommended therapeutic dose (600 mg twice-daily). There were no carcinogenic effects seen in females at the dosages tested. The exposure at the high dose was approximately 0.6-fold for the females that of the exposure in humans. In rats dosed at levels of 7, 15 or 30 mg per kg per day there were no carcinogenic effects. In this study, the exposure at the high dose was approximately 6% that of the exposure in humans with the recommended therapeutic dose. Based on the exposures achieved in the animal studies, the significance of the observed effects is not known. However, ritonavir was found to be negative for mutagenic or clastogenic activity in a battery of in in vitro and in vivo assays including the Ames bacterial reverse mutation assay using S. typhimurium and E. coli, the mouse lymphoma assay, the mouse micronucleus test and chromosomal aberration assays in human lymphocytes. Ritonavir produced no effects on fertility in rats at drug exposures approximately 40% (male) and 60% (female) of that achieved with the proposed therapeutic dose. Higher dosages were not feasible due to hepatic toxicity. ## Advanced Patients with Prior Antiretroviral Therapy - Study 247 was a randomized, double-blind trial (with open-label follow-up) conducted in HIV-infected patients with at least nine months of prior antiretroviral therapy and baseline CD4 cell counts less than or equal to 100 cells per μL. ritonavir 600 mg twice-daily or placebo was added to each patient's baseline antiretroviral therapy regimen, which could have consisted of up to two approved antiretroviral agents. - The study accrued 1,090 patients, with mean baseline CD4 cell count at study entry of 32 cells per μL. - After the clinical benefit of ritonavir therapy was demonstrated, all patients were eligible to switch to open-label ritonavir for the duration of the follow-up period. - Median duration of double-blind therapy with ritonavir and placebo was 6 months. - The median duration of follow-up through the end of the open-label phase was 13.5 months for patients randomized to ritonavir and 14 months for patients randomized to placebo. - The cumulative incidence of clinical disease progression or death during the double-blind phase of Study 247 was 26% for patients initially randomized to ritonavir compared to 42% for patients initially randomized to placebo. - This difference in rates was statistically significant. - Cumulative mortality through the end of the open-label follow-up phase for patients enrolled in Study 247 was 18% (99/543) for patients initially randomized to ritonavir compared to 26% (142/547) for patients initially randomized to placebo. - This difference in rates was statistically significant. However, since the analysis at the end of the open-label phase includes patients in the placebo arm who were switched from placebo to ritonavir therapy, the survival benefit of ritonavir cannot be precisely estimated. - During the double-blind phase of Study 247, CD4 cell counts increases from baseline for patients randomized to ritonavir at Week 2 and Week 4 were observed. - From Week 4 and through Week 24, mean CD4 cell counts for patients randomized to ritonavir appeared to plateau. - In contrast, there was no apparent change in mean CD4 cell counts for patients randomized to placebo at any visit between baseline and Week 24 of the double-blind phase of Study 247. ## Patients without Prior Antiretroviral Therapy - In Study 245, 356 antiretroviral-naive HIV-infected patients (mean baseline CD4 = 364 cells per μL) were randomized to receive either ritonavir 600 mg twice-daily, zidovudine 200 mg three-times-daily, or a combination of these drugs. - During the double-blind phase of study 245, greater mean CD4 cell count increases were observed from baseline to Week 12 in the ritonavir-containing arms compared to the zidovudine arms. Mean CD4 cell count changes subsequently appeared to plateau through Week 24 in the ritonavir arm, whereas mean CD4 cell counts gradually diminished through Week 24 in the zidovudine and ritonavir plus zidovudine arms. - Greater mean reductions in plasma HIV-1 RNA levels were observed from baseline to Week 2 for the ritonavir-containing arms compared to the zidovudine arm. After Week 2 and through Week 24, mean plasma HIV-1 RNA levels either remained stable in the ritonavir and zidovudine arms or gradually rebounded toward baseline in the ritonavir plus zidovudine arm. - 100 mg ritonavir Ritonavir (ritonavir) tablets are white film-coated ovaloid tablets debossed with the "a" logo and the code NK. ## Ritonavir Oral Solution - 80 mg per mL Ritonavir Ritonavir (ritonavir) oral solution is an orange-colored liquid, supplied in amber-colored, multi-dose bottles containing 600 mg ritonavir per 7.5 mL marked dosage cup (80 mg per mL). 240 mL bottles (NDC 0074-1940-63). Bottles of 30 tablets each (NDC 0074-3333-30). - Store at or below 30°C (86°F). - Exposure to temperatures up to 50°C (122°F) for seven days permitted. - Dispense in original container or USP equivalent tight container (60 mL or less). - For patient use: exposure of this product to high humidity outside the original or USP equivalent tight container (60 mL or less) for longer than 2 weeks is not recommended. ## Ritonavir Oral Solution - Store ritonavir oral solution at room temperature 20°-25°C (68°-77°F). - Do not refrigerate. - Shake well before each use. - They should pay special attention to accurate administration of their dose to minimize the risk of accidental overdose or underdose of ritonavir. - They should inform their healthcare provider if their children’s weight changes in order to make sure that the child’s ritonavir dose is the correct one. - Take ritonavir with meals. - For adult patients taking ritonavir tablets, the maximum dose of 600 mg twice daily by mouth with meals should not be exceeded. - Patients should remain under the care of a physician while using ritonavir. Patients should be advised to take ritonavir and other concomitant antiretroviral therapy every day as prescribed. ritonavir must always be used in combination with other antiretroviral drugs. Patients should not alter the dose or discontinue therapy without consulting with their doctor. If a dose of ritonavir is missed patients should take the dose as soon as possible and then return to their normal schedule. However, if a dose is skipped the patient should not double the next dose. - Ritonavir is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients should remain under the care of a physician when using ritonavir. - Patients should be advised to avoid doing things that can spread HIV-1 infection to others. - Do not share needles or other injection equipment. - Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades. - Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood. - Do not breastfeed. We do not know if ritonavir can be passed to the baby through breast milk and whether it could harm the baby. Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk. - Sustained decreases in plasma HIV-1 RNA have been associated with a reduced risk of progression to AIDS and death. - Ritonavir may interact with some drugs; therefore, patients should be advised to report to their doctor the use of any other prescription, non-prescription medication or herbal products, particularly St. John's Wort. - If they are receiving estrogen-based hormonal contraceptives, additional or alternate contraceptive measures should be used during therapy with ritonavir. - Pre-existing liver disease including Hepatitis B or C can worsen with use of ritonavir. This can be seen as worsening of transaminase elevations or hepatic decompensation. Patients should be advised that their liver function tests will need to be monitored closely especially during the first several months of ritonavir treatment and that they should notify their healthcare provider if they develop the signs and symptoms of worsening liver disease including loss of appetite, abdominal pain, jaundice, and itchy skin. - Pancreatitis, including some fatalities, has been observed in patients receiving ritonavir therapy. Your patients should let you know of signs and symptoms (nausea, vomiting, and abdominal pain) that might be suggestive of pancreatitis. - Skin rashes ranging in severity from mild to Stevens-Johnson syndrome have been reported in patients receiving ritonavir. Patients should be advised to contact their healthcare provider if they develop a rash while taking ritonavir. The healthcare provider will determine if treatment should be continued or an alternative antiretroviral regimen used. - Ritonavir may produce changes in the electrocardiogram (e.g., PR prolongation). Patients should consult their physician if they experience symptoms such as dizziness, lightheadedness, abnormal heart rhythm or loss of consciousness. - Treatment with ritonavir therapy can result in substantial increases in the concentration of total cholesterol and triglycerides. - New onset of diabetes or exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported. Patients should be advised to notify their healthcare provider if they develop the signs and symptoms of diabetes mellitus including frequent urination, excessive thirst, extreme hunger or unusual weight loss and/or an increased blood sugar while on ritonavir as they may require a change in their diabetes treatment or new treatment. - Immune reconstitution syndrome has been reported in HIV-infected patients treated with combination antiretroviral therapy, including ritonavir. - Redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long term health effects of these conditions are not known at this time. - Patients with hemophilia may experience increased bleeding when treated with protease inhibitors such as ritonavir. - If they are receiving avanafil, sildenafil, tadalafil, or vardenafil for the treatment of erectile dysfunction, they may be at an increased risk of associated adverse reactions including hypotension, visual changes, and sustained erection, and should promptly report any symptoms to their doctor. They should seek medical assistance immediately if they develop a sustained penile erection lasting more than 4 hours while taking ritonavir and a PDE 5 Inhibitor. If they are currently using or planning to use avanafil or tadalafil (for the treatment of pulmonary arterial hypertension) they should ask their doctor about potential adverse reactions these medications may cause when taken with ritonavir. The doctor may choose not to keep them on avanafil, or may adjust the dose of tadalafil] while initiating treatment with ritonavir. Concomitant use of sildenafil with ritonavir is contraindicated in patients with pulmonary arterial hypertension (PAH). - Continued ritonavir therapy at a dose of 600 mg twice daily following loss of viral suppression may increase the likelihood of cross-resistance to other protease inhibitors. - ↑ "NORVIR- ritonavir tablet, film coated NORVIR- ritonavir solution". line feed character in \|title= at position 39 (help).mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}	Ritonavir - 600 mg twice daily - Ritonavir should be started at no less than 300 mg twice daily and increased at 2 to 3 day intervals by 100 mg twice daily. The maximum dose of 600 mg twice daily. - Children greater than 1 month is 350 to 400 mg per m2 twice daily. - In combination with other antiretroviral agents. - Not exceed 600 mg twice daily. - Ritonavir should be started at 250 mg per m2 twice daily and increased at 2 to 3 day intervals by 50 mg per m2 twice daily. - Ritonavir is contraindicated in patients with known hypersensitivity (e.g., toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome) to ritonavir or any of its ingredients. - Co-administration of ritonavir with several classes of drugs (including sedative hypnotics, antiarrhythmics, or ergot alkaloid preparations) is contraindicated and may result in potentially serious and/or life-threatening adverse events due to possible effects of ritonavir on the hepatic metabolism of these drugs (see TABLE 2). - Voriconazole and St. John’s Wort are exceptions in that co-administration of ritonavir and voriconazole results in a significant decrease in plasma concentrations of voriconazole, and co-administration of ritonavir with St. John’s Wort may result in decreased ritonavir plasma concentrations. ### Drug Interactions - Ritonavir is a CYP3A inhibitor. - Initiating treatment with ritonavir in patients receiving medications metabolized by CYP3A or initiating medications metabolized by CYP3A in patients already maintained on ritonavir may result in increased plasma concentrations of concomitant medications. - Higher plasma concentrations of concomitant medications can result in increased or prolonged therapeutic or adverse effects, potentially leading to severe, life-threatening or fatal events. - The potential for drug-drug interactions must be considered prior to and during therapy with ritonavir. - Review of other medications taken by patients and monitoring of patients for adverse effects is recommended during therapy with ritonavir. See Table 2 for a listing of drugs that are contraindicated with ritonavir due to potentially life-threatening adverse events, significant drug interactions, or loss of virologic activity. Also, see Table 5 for a listing of drugs with established and other significant drug interactions. ### Toxicity in Preterm Neonates - Ritonavir oral solution contains the excipients alcohol (43.2% v/v) and propylene glycol (26.57% w/v). - When administered concomitantly with propylene glycol, ethanol competitively inhibits the metabolism of propylene glycol, which may lead to elevated concentrations. - Preterm neonates may be at an increased risk of propylene glycol-associated adverse events due to diminished ability to metabolize propylene glycol, thereby leading to accumulation and potential adverse events. - Postmarketing life-threatening cases of cardiac toxicity (including complete AV block, bradycardia, and cardiomyopathy), lactic acidosis, acute renal failure, CNS depression and respiratory complications leading to death have been reported, predominantly in preterm neonates receiving lopinavir/ritonavir oral solution which also contains the excipients alcohol and propylene glycol. - Ritonavir oral solution should not be used in preterm neonates in the immediate postnatal period because of possible toxicities. However, if the benefit of using ritonavir oral solution to treat HIV infection in infants immediately after birth outweighs the potential risks, infants should be monitored closely for increases in serum osmolality and serum creatinine, and for toxicity related to ritonavir oral solution including: hyperosmolality, with or without lactic acidosis, renal toxicity, CNS depression (including stupor, coma, and apnea), seizures, hypotonia, cardiac arrhythmias and ECG changes, and hemolysis. - Total amounts of alcohol and propylene glycol from all medicines that are to be given to infants should be taken into account in order to avoid toxicity from these excipients. ### Hepatic Reactions - Hepatic transaminase elevations exceeding 5 times the upper limit of normal, clinical hepatitis, and jaundice have occurred in patients receiving ritonavir alone or in combination with other antiretroviral drugs (see Table 4). There may be an increased risk for transaminase elevations in patients with underlying hepatitis B or C. Therefore, caution should be exercised when administering ritonavir to patients with pre-existing liver diseases, liver enzyme abnormalities, or hepatitis. - Increased AST/ALT monitoring should be considered in these patients, especially during the first three months of ritonavir treatment. - There have been postmarketing reports of hepatic dysfunction, including some fatalities. - These have generally occurred in patients taking multiple concomitant medications and/or with advanced AIDS. ### Pancreatitis - Pancreatitis has been observed in patients receiving ritonavir therapy, including those who developed hypertriglyceridemia. - In some cases fatalities have been observed. - Patients with advanced HIV disease may be at increased risk of elevated triglycerides and pancreatitis. - Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) or abnormalities in laboratory values (such as increased serum lipase or amylase values) suggestive of pancreatitis should occur. - Patients who exhibit these signs or symptoms should be evaluated and ritonavir therapy should be discontinued if a diagnosis of pancreatitis is made. ### Allergic Reactions/Hypersensitivity - Allergic reactions including urticaria, mild skin eruptions, bronchospasm, and angioedema have been reported. Cases of anaphylaxis, toxic epidermal necrolysis (TEN), and Stevens-Johnson syndrome have also been reported. - Discontinue treatment if severe reactions develop. ### PR Interval Prolongation - Ritonavir prolongs the PR interval in some patients. - Post marketing cases of second or third degree atrioventricular block have been reported in patients. - Ritonavir should be used with caution in patients with underlying structural heart disease, preexisting conduction system abnormalities, ischemic heart disease, cardiomyopathies, as these patients may be at increased risk for developing cardiac conduction abnormalities. - The impact on the PR interval of co-administration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers, beta-adrenergic blockers, digoxin and atazanavir) has not been evaluated. - As a result, co-administration of ritonavir with these drugs should be undertaken with caution, particularly with those drugs metabolized by CYP3A. Clinical monitoring is recommended. ### Lipid Disorders - Treatment with ritonavir therapy alone or in combination with saquinavir has resulted in substantial increases in the concentration of total cholesterol and triglycerides. Triglyceride and cholesterol testing should be performed prior to initiating ritonavir therapy and at periodic intervals during therapy. - Lipid disorders should be managed as clinically appropriate, taking into account any potential drug-drug interactions with ritonavir and HMG CoA reductase inhibitors. ### Diabetes Mellitus/Hyperglycemia - New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV-infected patients receiving protease inhibitor therapy. - Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. - In some cases, diabetic ketoacidosis has occurred. - In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established. ### Immune Reconstitution Syndrome - Immune reconstitution syndrome has been reported in HIV-infected patients treated with combination antiretroviral therapy, including ritonavir. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia, or tuberculosis), which may necessitate further evaluation and treatment. - Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment. ### Fat Redistribution - Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. - The mechanism and long-term consequences of these events are currently unknown. - A causal relationship has not been established. ### Patients with Hemophilia - There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia type A and B treated with protease inhibitors. - In some patients additional factor VIII was given. - In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced. - A causal relationship between protease inhibitor therapy and these events has not been established. ### Resistance/Cross-resistance - Varying degrees of cross-resistance among protease inhibitors have been observed. - Continued administration of ritonavir 600 mg twice daily following loss of viral suppression may increase the likelihood of cross-resistance to other protease inhibitors. ### Laboratory Tests - Ritonavir has been shown to increase triglycerides, cholesterol, SGOT (AST), SGPT (ALT), GGT, CPK, and uric acid. Appropriate laboratory testing should be performed prior to initiating ritonavir therapy and at periodic intervals or if any clinical signs or symptoms occur during therapy. ### Adult Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. - The safety of ritonavir alone and in combination with other antiretroviral agents was studied in 1,755 adult patients. Table 3 lists treatment-emergent Adverse Reactions (with possible or probable relationship to study drug) occurring in greater than or equal to 1% of adult patients receiving ritonavir in combined Phase II/IV studies. - The most frequently reported adverse drug reactions among patients receiving ritonavir alone or in combination with other antiretroviral drugs were gastrointestinal (including diarrhea, nausea, vomiting, abdominal pain (upper and lower)), neurological disturbances (including paresthesia and oral paresthesia), rash, and fatigue/asthenia. ## =Pediatric Clinical Trial Experience Ritonavir has been studied in 265 pediatric patients greater than 1 month to 21 years of age. - The adverse event profile observed during pediatric clinical trials was similar to that for adult patients. - Vomiting, diarrhea, and skin rash/allergy were the only drug-related clinical adverse events of moderate to severe intensity observed in greater than or equal to 2% of pediatric patients enrolled in ritonavir clinical trials. ### Laboratory Abnormalities - The following Grade 3-4 laboratory abnormalities occurred in greater than 3% of pediatric patients who received treatment with ritonavir either alone or in combination with reverse transcriptase inhibitors: neutropenia (9%), hyperamylasemia (7%), thrombocytopenia (5%), anemia (4%), and elevated AST (3%). ### Body as a Whole - Dehydration, usually associated with gastrointestinal symptoms, and sometimes resulting in hypotension, syncope, or renal insufficiency has been reported. Syncope, orthostatic hypotension, and renal insufficiency have also been reported without known dehydration. - Co-administration of ritonavir with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system. ### Cardiovascular System - First-degree AV block - Second-degree AV block - Third-degree AV block - Right bundle branch block - Cardiac and neurologic events have been reported when ritonavir has been co-administered with disopyramide, mexiletine, nefazodone, fluoxetine, and beta blockers. - The possibility of drug interaction cannot be excluded. ### Endocrine System - Cushing's syndrome - Adrenal suppression - Reported when ritonavir has been co-administered with fluticasone propionate or budesonide. ### Nervous System - Seizure ### Skin and subcutaneous tissue disorders - Toxic epidermal necrolysis (TEN) ### Potential for ritonavir to Affect Other Drugs - Ritonavir has been found to be an inhibitor of cytochrome P450 3A (CYP3A) and may increase plasma concentrations of agents that are primarily metabolized by CYP3A. - Agents that are extensively metabolized by CYP3A and have high first pass metabolism appear to be the most susceptible to large increases in AUC (greater than 3-fold) when co-administered with ritonavir. Thus, co-administration of ritonavir with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. - Co-administration with other CYP3A substrates may require a dose adjustment or additional monitoring as shown in Table 5. - Ritonavir also inhibits CYP2D6 to a lesser extent. - Co-administration of substrates of CYP2D6 with ritonavir could result in increases (up to 2-fold) in the AUC of the other agent, possibly requiring a proportional dosage reduction. - Ritonavir also appears to induce CYP3A, CYP1A2, CYP2C9, CYP2C19, and CYP2B6 as well as other enzymes, including glucuronosyl transferase. ### Established and Other Potentially Significant Drug Interactions Table 5 provides a list of established or potentially clinically significant drug interactions. Alteration in dose or regimen may be recommended based on drug interaction studies or predicted interaction. - There are no adequate and well-controlled studies in pregnant women. - Ritonavir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. ### Animal Data - No treatment related malformations were observed when ritonavir was administered to pregnant rats or rabbits. - Developmental toxicity observed in rats (early resorptions, decreased fetal body weight and ossification delays and developmental variations) occurred at a maternally toxic dosage at an exposure equivalent to approximately 30% of that achieved with the proposed therapeutic dose. - A slight increase in the incidence of cryptorchidism was also noted in rats at an exposure approximately 22% of that achieved with the proposed therapeutic dose. - Developmental toxicity observed in rabbits (resorptions, decreased litter size and decreased fetal weights) also occurred at a maternally toxic dosage equivalent to 1.8 times the proposed therapeutic dose based on a body surface area conversion factor. - It is not known whether ritonavir is secreted in human milk. - Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving ritonavir. - In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. - No pharmacokinetic or safety data are available regarding the use of ritonavir in subjects with severe hepatic impairment (Child-Pugh Class C), therefore, ritonavir is not recommended for use in patients with severe hepatic impairment. - Total cholesterol and triglycerides elevations: Monitor prior to therapy and periodically thereafter. - Initial frequent monitoring of the INR during ritonavir and warfarin co-administration is indicated. - Use with beta blockers, caution is warranted and clinical monitoring of patients is recommended. - Caution should be exercised when co-administering ritonavir with digoxin, with appropriate monitoring of serum digoxin levels. - Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with ritonavir. - - Human experience of acute overdose with ritonavir is limited. - One patient in clinical trials took ritonavir 1500 mg per day for two days. - The patient reported paresthesias which resolved after the dose was decreased. - A post-marketing case of renal failure with eosinophilia has been reported with ritonavir overdose. - The approximate lethal dose was found to be greater than 20 times the related human dose in rats and 10 times the related human dose in mice. ### Management of Overdosage - Ritonavir oral solution contains 43.2% (v/v) alcohol and 26.57% (w/v) propylene glycol. - Ingestion of the product over the recommended dose by a young child could result in significant toxicity and could potentially be lethal. - Treatment of overdose with ritonavir consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. - There is no specific antidote for overdose with ritonavir. - If indicated, elimination of unabsorbed drug should be achieved by gastric lavage; usual precautions should be observed to maintain the airway. Administration of activated charcoal may also be used to aid in removal of unabsorbed drug. - Since ritonavir is extensively metabolized by the liver and is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the drug. However, dialysis can remove both alcohol and propylene glycol in the case of overdose with ritonavir oral solution. - A Certified Poison Control Center should be consulted for up-to-date information on the management of overdose with ritonavir Inhibition of HIV protease renders the enzyme incapable of processing the gag-pol polyprotein precursor which leads to production of non-infectious immature HIV particles. ### Absorption The absolute bioavailability of ritonavir has not been determined. After a 600 mg dose of oral solution, peak concentrations of ritonavir were achieved approximately 2 hours and 4 hours after dosing under fasting and non-fasting (514 KCal; 9% fat, 12% protein, and 79% carbohydrate) conditions, respectively. Ritonavir tablets are not bioequivalent to ritonavir capsules. Under moderate fat conditions (857 kcal; 31% fat, 13% protein, 56% carbohydrates), when a single 100 mg ritonavir dose was administered as a tablet compared with a capsule, AUC(0- ∞) met equivalence criteria but mean Cmax was increased by 26% (92.8% confidence intervals: ↑15 -↑39%). No information is available comparing ritonavir tablets to ritonavir capsules under fasting conditions. When the oral solution was given under non-fasting conditions, peak ritonavir concentrations decreased 23% and the extent of absorption decreased 7% relative to fasting conditions. Dilution of the oral solution, within one hour of administration, with 240 mL of chocolate milk. Administration of a single 600 mg dose oral solution under non-fasting conditions yielded mean ± SD areas under the plasma concentration-time curve (AUCs) of 129.0 ± 39.3 mg•h per mL. A food effect is observed for ritonavir tablets. Food decreased the bioavailability of the ritonavir tablets when a single 100 mg dose of ritonavir was administered. Under high fat conditions (907 kcal; 52% fat, 15% protein, 33% carbohydrates), a 23% decrease in mean AUC(0-∞) [90% confidence intervals: ↓30%-↓15%], and a 23% decrease in mean Cmax [90% confidence intervals: ↓34%-↓11%]) was observed relative to fasting conditions. Under moderate fat conditions, a 21% decrease in mean AUC(0-∞) [90% confidence intervals: ↓28%-↓13%], and a 22% decrease in mean Cmax [90% confidence intervals: ↓33%-↓9%]) was observed relative to fasting conditions. However, the type of meal administered did not change ritonavir tablet bioavailability when high fat was compared to moderate fat meals. ### Metabolism Nearly all of the plasma radioactivity after a single oral 600 mg dose of 14C-ritonavir oral solution (n = 5) was attributed to unchanged ritonavir. Five ritonavir metabolites have been identified in human urine and feces. The isopropylthiazole oxidation metabolite (M-2) is the major metabolite and has antiviral activity similar to that of parent drug; however, the concentrations of this metabolite in plasma are low. In vitro studies utilizing human liver microsomes have demonstrated that cytochrome P450 3A (CYP3A) is the major isoform involved in ritonavir metabolism, although CYP2D6 also contributes to the formation of M–2. ### Elimination In a study of five subjects receiving a 600 mg dose of 14C-ritonavir oral solution, 11.3 ± 2.8% of the dose was excreted into the urine, with 3.5 ± 1.8% of the dose excreted as unchanged parent drug. In that study, 86.4 ± 2.9% of the dose was excreted in the feces with 33.8 ± 10.8% of the dose excreted as unchanged parent drug. Upon multiple dosing, ritonavir accumulation is less than predicted from a single dose possibly due to a time and dose-related increase in clearance. ### Effects on Electrocardiogram QTcF interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg once-daily) controlled crossover study in 45 healthy adults, with 10 measurements over 12 hours on Day 3. The maximum mean (95% upper confidence bound) time-matched difference in QTcF from placebo after baseline correction was 5.5 (7.6) milliseconds (msec) for 400 mg twice-daily ritonavir. Ritonavir 400 mg twice daily resulted in Day 3 ritonavir exposure that was approximately 1.5 fold higher than observed with ritonavir 600 mg twice-daily dose at steady state. PR interval prolongation was also noted in subjects receiving ritonavir in the same study on Day 3. The maximum mean (95% confidence interval) difference from placebo in the PR interval after baseline correction was 22 (25) msec for 400 mg twice-daily ritonavir. ### Special Populations No age-related pharmacokinetic differences have been observed in adult patients (18 to 63 years). Ritonavir pharmacokinetics have not been studied in older patients. A study of ritonavir pharmacokinetics in healthy males and females showed no statistically significant differences in the pharmacokinetics of ritonavir. Pharmacokinetic differences due to race have not been identified. Steady-state pharmacokinetics were evaluated in 37 HIV-infected patients ages 2 to 14 years receiving doses ranging from 250 mg per m2 twice-daily to 400 mg per m2 twice-daily in PACTG Study 310, and in 41 HIV-infected patients ages 1 month to 2 years at doses of 350 and 450 mg per m2 twice-daily in PACTG Study 345. Across dose groups, ritonavir steady-state oral clearance (CL/F/m2) was approximately 1.5 to 1.7 times faster in pediatric patients than in adult subjects. Ritonavir concentrations obtained after 350 to 400 mg per m2 twice-daily in pediatric patients greater than 2 years were comparable to those obtained in adults receiving 600 mg (approximately 330 mg per m2) twice-daily. The following observations were seen regarding ritonavir concentrations after administration with 350 or 450 mg per m2 twice-daily in children less than 2 years of age. Higher ritonavir exposures were not evident with 450 mg per m2 twice-daily compared to the 350 mg per m2 twice-daily. Ritonavir trough concentrations were somewhat lower than those obtained in adults receiving 600 mg twice-daily. The area under the ritonavir plasma concentration time curve and trough concentrations obtained after administration with 350 or 450 mg per m2 twice-daily in children less than 2 years were approximately 16% and 60% lower, respectively, than that obtained in adults receiving 600 mg twice daily. ### Renal Impairment Ritonavir pharmacokinetics have not been studied in patients with renal impairment, however, since renal clearance is negligible, a decrease in total body clearance is not expected in patients with renal impairment. ### Hepatic Impairment Dose-normalized steady-state ritonavir concentrations in subjects with mild hepatic impairment (400 mg twice-daily, n = 6) were similar to those in control subjects dosed with 500 mg twice-daily. Dose-normalized steady-state ritonavir exposures in subjects with moderate hepatic impairment (400 mg twice-daily, n= 6) were about 40% lower than those in subjects with normal hepatic function (500 mg twice-daily, n = 6). Protein binding of ritonavir was not statistically significantly affected by mild or moderately impaired hepatic function. No dose adjustment is recommended in patients with mild or moderate hepatic impairment. However, health care providers should be aware of the potential for lower ritonavir concentrations in patients with moderate hepatic impairment and should monitor patient response carefully. Ritonavir has not been studied in patients with severe hepatic impairment. Table 7 and Table 8 summarize the effects on AUC and Cmax, with 95% confidence intervals (95% CI), of co-administration of ritonavir with a variety of drugs. For information about clinical recommendations see Table 5 in Drug Interactions (7). Carcinogenicity studies in mice and rats have been carried out on ritonavir. In male mice, at levels of 50, 100 or 200 mg per kg per day, there was a dose dependent increase in the incidence of both adenomas and combined adenomas and carcinomas in the liver. Based on AUC measurements, the exposure at the high dose was approximately 0.3-fold for males that of the exposure in humans with the recommended therapeutic dose (600 mg twice-daily). There were no carcinogenic effects seen in females at the dosages tested. The exposure at the high dose was approximately 0.6-fold for the females that of the exposure in humans. In rats dosed at levels of 7, 15 or 30 mg per kg per day there were no carcinogenic effects. In this study, the exposure at the high dose was approximately 6% that of the exposure in humans with the recommended therapeutic dose. Based on the exposures achieved in the animal studies, the significance of the observed effects is not known. However, ritonavir was found to be negative for mutagenic or clastogenic activity in a battery of in in vitro and in vivo assays including the Ames bacterial reverse mutation assay using S. typhimurium and E. coli, the mouse lymphoma assay, the mouse micronucleus test and chromosomal aberration assays in human lymphocytes. Ritonavir produced no effects on fertility in rats at drug exposures approximately 40% (male) and 60% (female) of that achieved with the proposed therapeutic dose. Higher dosages were not feasible due to hepatic toxicity. ### Advanced Patients with Prior Antiretroviral Therapy - Study 247 was a randomized, double-blind trial (with open-label follow-up) conducted in HIV-infected patients with at least nine months of prior antiretroviral therapy and baseline CD4 cell counts less than or equal to 100 cells per μL. ritonavir 600 mg twice-daily or placebo was added to each patient's baseline antiretroviral therapy regimen, which could have consisted of up to two approved antiretroviral agents. - The study accrued 1,090 patients, with mean baseline CD4 cell count at study entry of 32 cells per μL. - After the clinical benefit of ritonavir therapy was demonstrated, all patients were eligible to switch to open-label ritonavir for the duration of the follow-up period. - Median duration of double-blind therapy with ritonavir and placebo was 6 months. - The median duration of follow-up through the end of the open-label phase was 13.5 months for patients randomized to ritonavir and 14 months for patients randomized to placebo. - The cumulative incidence of clinical disease progression or death during the double-blind phase of Study 247 was 26% for patients initially randomized to ritonavir compared to 42% for patients initially randomized to placebo. - This difference in rates was statistically significant. - Cumulative mortality through the end of the open-label follow-up phase for patients enrolled in Study 247 was 18% (99/543) for patients initially randomized to ritonavir compared to 26% (142/547) for patients initially randomized to placebo. - This difference in rates was statistically significant. However, since the analysis at the end of the open-label phase includes patients in the placebo arm who were switched from placebo to ritonavir therapy, the survival benefit of ritonavir cannot be precisely estimated. - During the double-blind phase of Study 247, CD4 cell counts increases from baseline for patients randomized to ritonavir at Week 2 and Week 4 were observed. - From Week 4 and through Week 24, mean CD4 cell counts for patients randomized to ritonavir appeared to plateau. - In contrast, there was no apparent change in mean CD4 cell counts for patients randomized to placebo at any visit between baseline and Week 24 of the double-blind phase of Study 247. ### Patients without Prior Antiretroviral Therapy - In Study 245, 356 antiretroviral-naive HIV-infected patients (mean baseline CD4 = 364 cells per μL) were randomized to receive either ritonavir 600 mg twice-daily, zidovudine 200 mg three-times-daily, or a combination of these drugs. - During the double-blind phase of study 245, greater mean CD4 cell count increases were observed from baseline to Week 12 in the ritonavir-containing arms compared to the zidovudine arms. Mean CD4 cell count changes subsequently appeared to plateau through Week 24 in the ritonavir arm, whereas mean CD4 cell counts gradually diminished through Week 24 in the zidovudine and ritonavir plus zidovudine arms. - Greater mean reductions in plasma HIV-1 RNA levels were observed from baseline to Week 2 for the ritonavir-containing arms compared to the zidovudine arm. After Week 2 and through Week 24, mean plasma HIV-1 RNA levels either remained stable in the ritonavir and zidovudine arms or gradually rebounded toward baseline in the ritonavir plus zidovudine arm. - 100 mg ritonavir Ritonavir (ritonavir) tablets are white film-coated ovaloid tablets debossed with the "a" logo and the code NK. ### Ritonavir Oral Solution - 80 mg per mL Ritonavir Ritonavir (ritonavir) oral solution is an orange-colored liquid, supplied in amber-colored, multi-dose bottles containing 600 mg ritonavir per 7.5 mL marked dosage cup (80 mg per mL). 240 mL bottles (NDC 0074-1940-63). Bottles of 30 tablets each (NDC 0074-3333-30). - Store at or below 30°C (86°F). - Exposure to temperatures up to 50°C (122°F) for seven days permitted. - Dispense in original container or USP equivalent tight container (60 mL or less). - For patient use: exposure of this product to high humidity outside the original or USP equivalent tight container (60 mL or less) for longer than 2 weeks is not recommended. ### Ritonavir Oral Solution - Store ritonavir oral solution at room temperature 20°-25°C (68°-77°F). - Do not refrigerate. - Shake well before each use. - They should pay special attention to accurate administration of their dose to minimize the risk of accidental overdose or underdose of ritonavir. - They should inform their healthcare provider if their children’s weight changes in order to make sure that the child’s ritonavir dose is the correct one. - Take ritonavir with meals. - For adult patients taking ritonavir tablets, the maximum dose of 600 mg twice daily by mouth with meals should not be exceeded. - Patients should remain under the care of a physician while using ritonavir. Patients should be advised to take ritonavir and other concomitant antiretroviral therapy every day as prescribed. ritonavir must always be used in combination with other antiretroviral drugs. Patients should not alter the dose or discontinue therapy without consulting with their doctor. If a dose of ritonavir is missed patients should take the dose as soon as possible and then return to their normal schedule. However, if a dose is skipped the patient should not double the next dose. - Ritonavir is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients should remain under the care of a physician when using ritonavir. - Patients should be advised to avoid doing things that can spread HIV-1 infection to others. - Do not share needles or other injection equipment. - Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades. - Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood. - Do not breastfeed. We do not know if ritonavir can be passed to the baby through breast milk and whether it could harm the baby. Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk. - Sustained decreases in plasma HIV-1 RNA have been associated with a reduced risk of progression to AIDS and death. - Ritonavir may interact with some drugs; therefore, patients should be advised to report to their doctor the use of any other prescription, non-prescription medication or herbal products, particularly St. John's Wort. - If they are receiving estrogen-based hormonal contraceptives, additional or alternate contraceptive measures should be used during therapy with ritonavir. - Pre-existing liver disease including Hepatitis B or C can worsen with use of ritonavir. This can be seen as worsening of transaminase elevations or hepatic decompensation. Patients should be advised that their liver function tests will need to be monitored closely especially during the first several months of ritonavir treatment and that they should notify their healthcare provider if they develop the signs and symptoms of worsening liver disease including loss of appetite, abdominal pain, jaundice, and itchy skin. - Pancreatitis, including some fatalities, has been observed in patients receiving ritonavir therapy. Your patients should let you know of signs and symptoms (nausea, vomiting, and abdominal pain) that might be suggestive of pancreatitis. - Skin rashes ranging in severity from mild to Stevens-Johnson syndrome have been reported in patients receiving ritonavir. Patients should be advised to contact their healthcare provider if they develop a rash while taking ritonavir. The healthcare provider will determine if treatment should be continued or an alternative antiretroviral regimen used. - Ritonavir may produce changes in the electrocardiogram (e.g., PR prolongation). Patients should consult their physician if they experience symptoms such as dizziness, lightheadedness, abnormal heart rhythm or loss of consciousness. - Treatment with ritonavir therapy can result in substantial increases in the concentration of total cholesterol and triglycerides. - New onset of diabetes or exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported. Patients should be advised to notify their healthcare provider if they develop the signs and symptoms of diabetes mellitus including frequent urination, excessive thirst, extreme hunger or unusual weight loss and/or an increased blood sugar while on ritonavir as they may require a change in their diabetes treatment or new treatment. - Immune reconstitution syndrome has been reported in HIV-infected patients treated with combination antiretroviral therapy, including ritonavir. - Redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long term health effects of these conditions are not known at this time. - Patients with hemophilia may experience increased bleeding when treated with protease inhibitors such as ritonavir. - If they are receiving avanafil, sildenafil, tadalafil, or vardenafil for the treatment of erectile dysfunction, they may be at an increased risk of associated adverse reactions including hypotension, visual changes, and sustained erection, and should promptly report any symptoms to their doctor. They should seek medical assistance immediately if they develop a sustained penile erection lasting more than 4 hours while taking ritonavir and a PDE 5 Inhibitor. If they are currently using or planning to use avanafil or tadalafil (for the treatment of pulmonary arterial hypertension) they should ask their doctor about potential adverse reactions these medications may cause when taken with ritonavir. The doctor may choose not to keep them on avanafil, or may adjust the dose of tadalafil] while initiating treatment with ritonavir. Concomitant use of sildenafil with ritonavir is contraindicated in patients with pulmonary arterial hypertension (PAH). - Continued ritonavir therapy at a dose of 600 mg twice daily following loss of viral suppression may increase the likelihood of cross-resistance to other protease inhibitors. - ↑ "NORVIR- ritonavir tablet, film coated NORVIR- ritonavir solution". line feed character in \|title= at position 39 (help).mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}	https://www.wikidoc.org/index.php/Norvir
288b940340d3af4c3bc5466344eca12d8d078aff	wikidoc	Notochord	Notochord # Overview The notochord is a flexible, rod-shaped body found in embryos of all chordates. It is composed of cells derived from the mesoderm and defines the primitive axis of the embryo. In lower vertebrates, it persists throughout life as the main axial support of the body, while in higher vertebrates it is replaced by the vertebral column. The notochord is found on the ventral surface of the neural tube. Notochords were the first "backbones", as well, serving as support structures in chordates that lacked a bony skeleton. The very first vertebrates, such as Haikouicthys, had only a notochord. Embryos of vertebrates have notochords today, as embryonic development often happens to follow a pattern similar to the ancestral evolution of the modern animal's traits . Notochords were advantageous to primitive fish-ancestors because they were a rigid structure for muscle attachment, yet flexible enough to allow more movement than, for example, the exoskeleton of the dominant animals of that time. In humans, they eventually develop into the disks between the vertebrae. # Development Notogenesis is the development of the notochord by the epiblasts that make up the floor of the amnion cavity (Human Embryology). The notochord arises as a pouch from the mesoderm. The notochord forms during gastrulation and soon after induces the formation of the neural plate (neurulation), synchronizing the development of the neural tube. On the ventral aspect of the neural groove an axial thickening of the endoderm takes place. (In bi-pedal chordates, e.g. humans, this surface is properly referred to as the anterior surface). This thickening appears as a furrow (the chordal furrow) the margins of which anastimose (come into contact), and so convert it into a solid rod of polygonal-shaped cells (the notochord) which is then separated from the endoderm. In higher vertebrates, it extends throughout the entire length of the future vertebral column, and reaches as far as the anterior end of the midbrain, where it ends in a hook-like extremity in the region of the future dorsum sellæ of the sphenoid bone. Initially it exists between the neural tube and the endoderm of the yolk-sac, but soon becomes separated from them by the mesoderm, which grows medially and surrounds it. From the mesoderm surrounding the neural tube and notochord, the skull, vertebral column, and the membranes of the brain and medulla spinalis are developed. Postembryonic vestige of the notochord is found in the nucleus pulposus of the intervertebral disks, but not in the vertebral bodies, from which notochordal cells usually regress entirely. In humans, by the age of 4, all notochord residue is replaced by a population of chondrocyte-like cells of unclear origin. Persistence of notochordal cells within the vertebra may cause a pathologic condition- persistent notochordal canal. They are also found to persist in the nasopharyngeal space and, in such an unusual instance, may give rise to Tornwaldt's cyst. # Research Research into the notochord has played a key role in understanding the development of the central nervous system. By transplanting and expressing a second notochord near the dorsal neural tube, 180 degrees opposite of the normal notochord location, one can induce the formation of motoneurons in the dorsal tube. Motoneuron formation generally occurs in the ventral neural tube, while the dorsal tube generally forms sensory cells. The notochord secretes a protein called sonic hedgehog homolog (SHH), a key morphogen regulating organogenesis and having a critical role in signaling the development of motoneurons. The secretion of SHH by the notochord establishes the ventral pole of the dorsal-ventral axis in the developing embryo. # Additional images - Diagram of a transverse section, showing the mode of formation of the amnion in the chick. - Section through the head of a human embryo, about twelve days old, in the region of the hind-brain. - Transverse section of human embryo eight and a half to nine weeks old. # Reference - ↑ J. P. G. Urban , S. Roberts , and J. R. Ralphs. The Nucleus of the Intervertebral Disc from Development to Degeneration. Amer Zool. 2000;40(1):53-61. full text - ↑ Christopherson LR, Rabin BM, Hallam DK, Russell EJ. Persistence of the notochordal canal: MR and plain film appearance. AJNR Am J Neuroradiol. 1999 Jan;20(1):33-6. PMID 9974055 - ↑ Echelard Y, Epstein DJ, St-Jacques B, Shen L, Mohler J, McMahon JA, McMahon AP. Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell 1993;75(7):1417-30. PMID 7916661	Notochord Template:Infobox Embryology # Overview The notochord is a flexible, rod-shaped body found in embryos of all chordates. It is composed of cells derived from the mesoderm and defines the primitive axis of the embryo. In lower vertebrates, it persists throughout life as the main axial support of the body, while in higher vertebrates it is replaced by the vertebral column. The notochord is found on the ventral surface of the neural tube. Notochords were the first "backbones", as well, serving as support structures in chordates that lacked a bony skeleton. The very first vertebrates, such as Haikouicthys, had only a notochord. Embryos of vertebrates have notochords today, as embryonic development often happens to follow a pattern similar to the ancestral evolution of the modern animal's traits [this idea that 'ontogeny recapitulates phylogeny' is something of an old-fashioned concept in embryology]. Notochords were advantageous to primitive fish-ancestors because they were a rigid structure for muscle attachment, yet flexible enough to allow more movement than, for example, the exoskeleton of the dominant animals of that time. In humans, they eventually develop into the disks between the vertebrae. # Development Notogenesis is the development of the notochord by the epiblasts that make up the floor of the amnion cavity (Human Embryology). The notochord arises as a pouch from the mesoderm. The notochord forms during gastrulation and soon after induces the formation of the neural plate (neurulation), synchronizing the development of the neural tube. On the ventral aspect of the neural groove an axial thickening of the endoderm takes place. (In bi-pedal chordates, e.g. humans, this surface is properly referred to as the anterior surface). This thickening appears as a furrow (the chordal furrow) the margins of which anastimose (come into contact), and so convert it into a solid rod of polygonal-shaped cells (the notochord) which is then separated from the endoderm. In higher vertebrates, it extends throughout the entire length of the future vertebral column, and reaches as far as the anterior end of the midbrain, where it ends in a hook-like extremity in the region of the future dorsum sellæ of the sphenoid bone. Initially it exists between the neural tube and the endoderm of the yolk-sac, but soon becomes separated from them by the mesoderm, which grows medially and surrounds it. From the mesoderm surrounding the neural tube and notochord, the skull, vertebral column, and the membranes of the brain and medulla spinalis are developed. Postembryonic vestige of the notochord is found in the nucleus pulposus of the intervertebral disks, but not in the vertebral bodies, from which notochordal cells usually regress entirely. In humans, by the age of 4, all notochord residue is replaced by a population of chondrocyte-like cells of unclear origin[1]. Persistence of notochordal cells within the vertebra may cause a pathologic condition- persistent notochordal canal[2]. They are also found to persist in the nasopharyngeal space and, in such an unusual instance, may give rise to Tornwaldt's cyst. # Research Research into the notochord has played a key role in understanding the development of the central nervous system. By transplanting and expressing a second notochord near the dorsal neural tube, 180 degrees opposite of the normal notochord location, one can induce the formation of motoneurons in the dorsal tube. Motoneuron formation generally occurs in the ventral neural tube, while the dorsal tube generally forms sensory cells. The notochord secretes a protein called sonic hedgehog homolog (SHH), a key morphogen regulating organogenesis and having a critical role in signaling the development of motoneurons[3]. The secretion of SHH by the notochord establishes the ventral pole of the dorsal-ventral axis in the developing embryo. # Additional images - Diagram of a transverse section, showing the mode of formation of the amnion in the chick. - Section through the head of a human embryo, about twelve days old, in the region of the hind-brain. - Transverse section of human embryo eight and a half to nine weeks old. # Reference - ↑ J. P. G. Urban , S. Roberts , and J. R. Ralphs. The Nucleus of the Intervertebral Disc from Development to Degeneration. Amer Zool. 2000;40(1):53-61. full text - ↑ Christopherson LR, Rabin BM, Hallam DK, Russell EJ. Persistence of the notochordal canal: MR and plain film appearance. AJNR Am J Neuroradiol. 1999 Jan;20(1):33-6. PMID 9974055 - ↑ Echelard Y, Epstein DJ, St-Jacques B, Shen L, Mohler J, McMahon JA, McMahon AP. Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell 1993;75(7):1417-30. PMID 7916661 # External links - Template:EmbryologyUNC Template:Development of nervous system ca:Notocordi cs:Struna hřbetní de:Chorda dorsalis eo:Notokordo it:Notocorda Template:WH Template:WS	https://www.wikidoc.org/index.php/Notochord
01a68441045c278a1e6f0699d6e8525118df1b2b	wikidoc	Nucleolus	Nucleolus In cell biology, the nucleolus (plural nucleoli) is a sub-organelle of the cell nucleus, which itself is an organelle. A main function of the nucleolus is the production and assembly of ribosome components. The nucleolus is roughly spherical, and is surrounded by a layer of condensed chromatin. No membrane separates the nucleolus from the nucleoplasm. Nucleoli are made of protein and ribosomal DNA (rDNA) sequences of chromosomes. The rDNA is a fundamental component since it serves as the template for transcription of the ribosomal RNA (rRNA) for inclusion in new ribosomes. Most plant and animal cells have one or more nucleoli, but some cell types do not have any. Since nucleoli carry out the production and maturation of ribosomes, large numbers of ribosomes are found inside them. In addition to ribosome biogenesis, nucleoli are believed to have other roles in cellular activity. Nucleoli fragment during cell reproduction (they can no longer be seen in metaphase of mitosis, when the chromosome copies separate). After the daughter cells complete their separation, the fragments of nucleoli fuse together around the nucleolus organizer regions (NORs) of the chromosomes. # Structure Study of the structure of the nucleolus has mainly concentrated on its RNA (Ribonucleic acid) synthesis area. The nucleolus includes fibrillar centers (FC), dense fibrillar components (DFC), granular components (GC) and rDNA. Other components are interstices and chromatin inclusions. The nucleolus can be observed with the light microscope, and was much studied in the nineteenth century; its structure has more recently been clarified using the electron microscope. ## Fibrillar center (FC) It is made up by a network of fine (4-5 nm thick) Fibrils. The shape of an FC is typically roughly globular, with the diameter ranging from about 50nm to 1 μm. The number and size of FCs per nucleolus is variable, and changes with cellular activity and the need for ribosome production. Cells with lower cellular activity usually have fewer FC than others. ## Dense Fibrillar Component (DFC) This component is also made up by very fine (3-5 nm) and densely packed fibrils. DFCs usually surround FCs when they are present and form a meshwork. As this is particularly true for activated states, the amount of DFC roughly reflects the nucleolar engagement in ribosome biogenesis. Sometimes this meshwork occupies large areas of the nucleolus, occasionally interspersed with small FCs. During S phase of cell cycle, the increase in upstream binding factor (UBF) association may be due to the increase in its ability to compete with the histones for binding to the rDNA. ## Granular component (GC) The granular component appears to consist of small granules with a diameter of about 15 nm. They typically form a mass surrounding the fibrillar complexes and embed the FCs and DFC. Thus a transition zone between DFC and GC can be observed. Although nucleolus is not membrane-bound, due to the presence of GC the border with the surrounding chromatin and nucleoplasm is usually distinct. ## Ribosomal DNA (rDNA) rDNA is a set of tandemly-repeated genes coding for preribosomal RNA. Because these genes have the ability to initiate the formation of nucleoli during interphase, these segments of the chromosomes are called nucleolus organizer regions or NORs. In the human genome, there are tandem repeats of the rDNA sequence on the short arms of each of the two copies of chromosomes 13, 14, 15, 21 and 22. # Functions The main role of the nucleolus is considered to be ribosome biogenesis, since its fundamental component rDNA codes for preribosomal RNA. Additionally, recent research pointed out that the nucleolus is also responsible for the trafficking of various prominent small RNA species. The nucleolus helps them during their maturation process and route to their final cellular destination. Moreover, although nucleoli become invisible during cell division, more recent studies have found that they are involved in cell cycle regulation. Several of its non-traditional roles include interaction with viral components, the regulation of tumor suppressor and oncogene activities, signal recognition particle assembly, the modification of small RNA strands, the control of aging and modulating telomerase function.	Nucleolus In cell biology, the nucleolus (plural nucleoli) is a sub-organelle of the cell nucleus, which itself is an organelle. A main function of the nucleolus is the production and assembly of ribosome components. The nucleolus is roughly spherical, and is surrounded by a layer of condensed chromatin. No membrane separates the nucleolus from the nucleoplasm. Nucleoli are made of protein and ribosomal DNA (rDNA) sequences of chromosomes. The rDNA is a fundamental component since it serves as the template for transcription of the ribosomal RNA (rRNA) for inclusion in new ribosomes. Most plant and animal cells have one or more nucleoli, but some cell types do not have any. Since nucleoli carry out the production and maturation of ribosomes, large numbers of ribosomes are found inside them. In addition to ribosome biogenesis, nucleoli are believed to have other roles in cellular activity. Nucleoli fragment during cell reproduction (they can no longer be seen in metaphase of mitosis, when the chromosome copies separate). After the daughter cells complete their separation, the fragments of nucleoli fuse together around the nucleolus organizer regions (NORs) of the chromosomes. # Structure Study of the structure of the nucleolus has mainly concentrated on its RNA (Ribonucleic acid) synthesis area. The nucleolus includes fibrillar centers (FC), dense fibrillar components (DFC), granular components (GC) and rDNA. Other components are interstices and chromatin inclusions. The nucleolus can be observed with the light microscope, and was much studied in the nineteenth century; its structure has more recently been clarified using the electron microscope. ## Fibrillar center (FC) It is made up by a network of fine (4-5 nm thick) Fibrils. The shape of an FC is typically roughly globular, with the diameter ranging from about 50nm to 1 μm. The number and size of FCs per nucleolus is variable, and changes with cellular activity and the need for ribosome production. Cells with lower cellular activity usually have fewer FC than others. ## Dense Fibrillar Component (DFC) This component is also made up by very fine (3-5 nm) and densely packed fibrils. DFCs usually surround FCs when they are present and form a meshwork. As this is particularly true for activated states, the amount of DFC roughly reflects the nucleolar engagement in ribosome biogenesis. Sometimes this meshwork occupies large areas of the nucleolus, occasionally interspersed with small FCs. During S phase of cell cycle, the increase in upstream binding factor (UBF) association may be due to the increase in its ability to compete with the histones for binding to the rDNA. ## Granular component (GC) The granular component appears to consist of small granules with a diameter of about 15 nm. They typically form a mass surrounding the fibrillar complexes and embed the FCs and DFC. Thus a transition zone between DFC and GC can be observed. Although nucleolus is not membrane-bound, due to the presence of GC the border with the surrounding chromatin and nucleoplasm is usually distinct. ## Ribosomal DNA (rDNA) rDNA is a set of tandemly-repeated genes coding for preribosomal RNA. Because these genes have the ability to initiate the formation of nucleoli during interphase, these segments of the chromosomes are called nucleolus organizer regions or NORs. In the human genome, there are tandem repeats of the rDNA sequence on the short arms of each of the two copies of chromosomes 13, 14, 15, 21 and 22. # Functions The main role of the nucleolus is considered to be ribosome biogenesis, since its fundamental component rDNA codes for preribosomal RNA. Additionally, recent research pointed out that the nucleolus is also responsible for the trafficking of various prominent small RNA species. The nucleolus helps them during their maturation process and route to their final cellular destination. Moreover, although nucleoli become invisible during cell division, more recent studies have found that they are involved in cell cycle regulation. Several of its non-traditional roles include interaction with viral components, the regulation of tumor suppressor and oncogene activities, signal recognition particle assembly, the modification of small RNA strands, the control of aging and modulating telomerase function.	https://www.wikidoc.org/index.php/Nucleoli
dc022f9712c72d6495ed259e8e1e12f18d99da57	wikidoc	Nucleolin	Nucleolin Nucleolin is a protein that in humans is encoded by the NCL gene. # Gene The human NCL gene is located on chromosome 2 and consists of 14 exons with 13 introns and spans approximately 11kb. The intron 11 of the NCL gene encodes a small nucleolar RNA, termed U20. # Function Nucleolin (NCL), a eukaryotic nucleolar phosphoprotein, is involved in the synthesis and maturation of ribosomes. The protein is located mainly in dense fibrillar regions of the nucleolus. Nucleolin is also able to act as a transcriptional coactivator with Chicken Ovalbumin Upstream Promoter Transcription Factor II (COUP-TFII). # Clinical significance Midkine and pleiotrophin bind to cell-surface nucleolin as a low affinity receptor. This binding can inhibit HIV infection. Nucleolin at the cell surface is the receptor for the Respiratory Syncytial Virus (RSV) fusion protein. Interference with the nucleolin - RSV fusion protein interaction has been shown to be therapeutic against RSV infection in cell cultures and animal models. # Interactions Nucleolin has been shown to interact with: - CSNK2A2, - Centaurin, alpha 1, - HuR, - NPM1, - P53, - PPP1CB, - S100A11, - Sjogren syndrome antigen B, - TOP1, and - Telomerase reverse transcriptase.	Nucleolin Nucleolin is a protein that in humans is encoded by the NCL gene.[1][2] # Gene The human NCL gene is located on chromosome 2 and consists of 14 exons with 13 introns and spans approximately 11kb. The intron 11 of the NCL gene encodes a small nucleolar RNA, termed U20.[3] # Function Nucleolin (NCL), a eukaryotic nucleolar phosphoprotein, is involved in the synthesis and maturation of ribosomes.[3] The protein is located mainly in dense fibrillar regions of the nucleolus. Nucleolin is also able to act as a transcriptional coactivator with Chicken Ovalbumin Upstream Promoter Transcription Factor II (COUP-TFII).[4] # Clinical significance Midkine and pleiotrophin bind to cell-surface nucleolin as a low affinity receptor. This binding can inhibit HIV infection.[5][6] Nucleolin at the cell surface is the receptor for the Respiratory Syncytial Virus (RSV) fusion protein.[7] Interference with the nucleolin - RSV fusion protein interaction has been shown to be therapeutic against RSV infection in cell cultures and animal models.[8][9][10] # Interactions Nucleolin has been shown to interact with: - CSNK2A2,[11] - Centaurin, alpha 1,[12] - HuR,[13] - NPM1,[14] - P53,[15] - PPP1CB,[16] - S100A11,[17] - Sjogren syndrome antigen B,[18] - TOP1,[19][20] and - Telomerase reverse transcriptase.[21]	https://www.wikidoc.org/index.php/Nucleolin
54c59e9defdd8b43945a02d75e534c1d1f626f59	wikidoc	Nucleosol	Nucleosol # Overview The structural and functional unit of all known living organisms is the cell. Eukaryotic cells of which humans are composed contain membrane-bound compartments. The most important among these is the cell nucleus. It is the "control center" for each cell that has at least one. Separating the nucleus from the cellular cytoplasm is the double-membraned structure of the nuclear envelope. Inside the nuclear membrane, including attached to the inner layer of this membrane, are a variety of substances serving special purposes. Depending on conditions, for a time, some of these compose the nucleosol, some compose the nucleohyaloplasm, and still others compose the nucleoplasm. Those substances and the special conditions present, even if temporary, in water can be the nucleosol. The nucleus cannot succeed in its efforts to control the cell without the special properties of the nucleosol. # Introduction Generally, in chemistry a fluid suspension of a colloidal solid in a liquid is referred to as a sol. Whereas, a solution is a liquid mixture of a minor component (the solute) distributed uniformly within the major component (the solvent). In the nucleosol the liquid is water and the solvent is also water. Using the water (data page) and the atomic radii of the elements (data page), a water molecule is approximately 120 x 187 pm in maximum diameters (average 154 pm). For its small size a water molecule (H2O), 18 Da, at about 38°C, under 1 atm of pressure (about 101325 kgm-1s-2), in large enough numbers to produce a liquid exhibits a high viscosity, short-range order, clustering, and miscibility. The molecule is polar enough to produce and maintain ions when in a liquid. Liquid water can also dissolve organic compounds such as carbohydrates, fatty acids, amino acids, nucleobases, nucleosides, nucleotides, and peptides. Diffusion of molecules, ions, or particles in liquid water is depended upon by most living organisms. In cell biology, diffusion is the main form of transport for the smaller necessary materials such as amino acids within cells. Metabolism and respiration rely in part upon diffusion in addition to bulk or active processes. For example, in the alveoli of mammalian lungs, due to differences in partial pressures across the alveolar-capillary membrane, oxygen diffuses into the blood (another water-based liquid) and carbon dioxide diffuses out. Diffusion in liquid water depends on the lateral speed of the water molecule within liquid water. The lateral speed of a water molecule within liquid water appears to be unknown but can be estimated.Template:Wiktionarypar A plasm is a formative or formed material; i.e., something molded. Usually a formed material keeps it shape once the mold is removed. Should something be glassy or transparent it can be said to be hyaloid. Whether a fluid is molded or liquid is often a matter of viscosity and whether a fluid is transparent, translucent, or opaque is often a matter of absorption. Before any internal molding exists within the nucleus or when any portion of the existing nucleoskeleton is dissolved and reconstructed elsewhere, genes within the euchromatin are transcribed, mRNAs are synthesized, and the mers that are to become new portions of the nucleoskeleton become part of the nucleosol: actins (microfilaments), lamins (intermediate filaments), and tubulins (microtubules). In addition to internal molding by the nucleoskeleton there are local increases in viscosity due to macromolecular crowding that help to compose the nucleohyaloplasm and the nucleoplasm of which it is a part. # Water Water, whether a gas (water vapor) or liquid, is an amorphous substance. The chemical bonding within many amorphous substances can produce short-range order while there is long-range disorder. The short-range order is often a symmetrical arrangement of polyhedra. The long-range disorder can be approached with the disordered arrangement of space-filling polyhedra. These polyhedra are bonded together in a solid and undergo bond breaking through the transitions from solid to fluid. A model based on the configuron is an approach to understanding the viscosity changes that occur with changes in temperature. In the kinetic theory of gases (such as water vapor) there is a correlation between average energy (Eav) and temperature (T): Eav = 3/2 kT with Eav = 1/2 mvav2. ⇒ vav2 = 3kT/m. For a water molecule m = 18 Da, or 2.9913 x 10-23 gmolecule-1. ⇒ vrms = √3kT/m = √3·1.382x10-23 J/K·306 K/(0.018 kg/6.022x1023) = 651 ms-1 at 33°C. vrms is the root mean square velocity. However, water in the nucleosol is a liquid, not a gas. For example, vrms (O2) in air at 25°C is 482.1 ms-1. ## Enthalpy of vaporization for water The enthalpy of vaporization for water at 25°C is 44 kJmol-1. The enthalpy of vaporization can be viewed as the energy required to overcome the intermolecular interactions in water. The molecules in liquid water are held together by relatively strong hydrogen bonds. But care must be taken, however, when using enthalpies of vaporization to measure the strength of intermolecular forces, as these forces may persist to an extent in the gas phase (as is the case with hydrogen fluoride), and so the calculated value of the bond strength will be too low. With water the enthalpy of vaporization is larger than the available kinetic energy suggested by the ideal gas law: Eav = 3/2 kT with Eav = 1/2 mvav2. The lateral speed of a water molecule estimated using the enthalpy of vaporization is ~2,210 ms-1. For water vapor at 25°C, by the ideal gas law, vrms = 643 ms-1. ## Enthalpy of flow for liquid water As a liquid much of the available kinetic energy is expressed through additional degrees of freedom. Some of this energy is in the form of intermolecular bonds. These bonds are a resistance to flow. Water has a resistance to flow that is considered relatively "thin", having a lower viscosity than other liquids such as vegetable oil. At 25°C, water has a nominal viscosity of 1.0 × 10-3 Pa∙s and motor oil has a nominal apparent viscosity of 250 × 10-3 Pa∙s. Because of its density of \rho = 1 g/cm3 (varies slightly with temperature), and its dynamic viscosity near 1 mPa·s, the viscosity values of water are, to rough precision, all powers of ten: Dynamic viscosity: Kinematic viscosity: {\nu} = {\mu}/{\rho}, where {\rho} is the density (kg/m3). In water - viscosity is independent of pressure (except at very high pressure); and - viscosity tends to fall as temperature increases: from 1.79 cP to 0.28 cP in the temperature range from 0°C to 100°C; see temperature dependence of liquid viscosity for more details. The viscosity of water is 8.94 × 10−4 Pa·s or 8.94 × 10−3 dyn·s/cm2 or 10−1 cP at about 25 °C. As a function of temperature T (K): μ(Pa·s) = A × 10B/(T−C) where A=2.414 × 10−5 Pa·s ; B = 247.8 K ; and C = 140 K. Whereas, for a gas such as air, the viscosity is much lower and also depends mostly on temperature. At 15.0 °C, the viscosity of air is 1.78 × 10−5 kg/(m·s) or 1.78 × 10−4 cP. One can get the viscosity of air as a function of temperature from the Gas Viscosity Calculator. Viscous flow, which results from viscosity, in amorphous materials such as water is a thermally activated process: where QL is the activation energy in the liquid state, T is temperature, R is the molar gas constant and AL is approximately a constant. With where Hm is the enthalpy of motion of the broken hydrogen bonds. Hm ~ 1/2 mvav2. Here, the energy of motion for flow suggests a lateral speed of ~1590 ms-1. Because of its small molecular size and ability to quickly rearrange, it cannot be made amorphous without resorting to specialized hyperquenching techniques. These produce amorphous ice, which has a quenching rate in the range of metallic glasses. The higher the temperature of an amorphous material the higher the configuron concentration. The higher the configuron concentration the lower the viscosity. As configurons form percolating clusters, an amorphous solid can transition to a liquid. This clustering facilitates viscous flow. Thermodynamic parameters of configurons can be found from viscosity-temperature relationships. ## Short-range order Like a liquid an amorphous solid has a topologically disordered distribution of particles but elastic properties of an isotropic solid. The symmetry similarity of both liquid and solid phases cannot explain the qualitative differences in their behavior. Due to chemical bonding characteristics amorphous solids such as glasses do possess a high degree of short-range order with respect to local atomic polyhedra. The amorphous structure of glassy silica has no long range order but shows local ordering with respect to the tetrahedral arrangement of oxygen atoms around silicon atoms. The most ubiquitous, and perhaps simplest, example of a hydrogen bond is found between water molecules. This intermolecular hydrogen bonding is responsible for the high boiling point of water (100 °C) due to the high number of hydrogen bonds each molecule can have relative to its low molecular mass, and the great strength of these bonds. The length of hydrogen bonds depends on bond strength, temperature, and pressure. The bond strength itself is dependent on temperature, pressure, bond angle, and environment (usually characterized by local dielectric constant). The typical length of a hydrogen bond (H-bond) in water is 1.97 Å (197 pm). Every water molecule can be H-bonded with up to four other molecules, as shown in the figure (two through its two lone pairs, and two through its two hydrogen atoms.) Water has a very high boiling point, melting point and viscosity compared to other similar substances not conjoined by hydrogen bonds. The exact number of hydrogen bonds in which a molecule in liquid water participates fluctuates with time and depends on the temperature. From liquid water simulations at 25 °C, each water molecule may participate in an average of 3.59 hydrogen bonds. At 100 °C, this number apparently decreases to 3.24 due to the increased molecular motion and decreased density, while at 0 °C, the average number of hydrogen bonds increases to 3.69. A more recent study found a much smaller number of hydrogen bonds: 2.357 at 25 °C. The differences may be due to the use of a different method for defining and counting the hydrogen bonds. Where the bond strengths are more equivalent, one might instead find the atoms of two interacting water molecules partitioned into two polyatomic ions of opposite charge, specifically hydroxide (OH−) and hydronium (H3O+). (Hydronium ions are also known as 'hydroxonium' ions.) Indeed, in pure water under conditions of standard temperature and pressure, this latter formulation is applicable only rarely; on average about one in every 5.5 × 108 molecules gives up a proton to another water molecule, in accordance with the value of the dissociation constant for water under such conditions. It is a crucial part of the uniqueness of water. It can be that a single hydrogen atom participates in two hydrogen bonds, rather than one. This type of bonding is called "bifurcated". It was suggested that a bifurcated hydrogen atom is an essential step in water reorientation. ## Water clusters In chemistry a water cluster is a discrete hydrogen bonded assembly or cluster of molecules of water . These clusters have been found experimentally or predicted in silico in various forms of water; in ice, in crystal lattices and in bulk liquid water, the simplest one being the water dimer (W2). Water manifests itself as clusters. Water clusters are also implicated in the stabilization of certain supramolecular structures. Supramolecular forces include hydrogen bonding that result in molecular self-assembly, folding, and mechanically-interlocked molecular architectures. In silico, cyclic water clusters (H2O)n are found with n = 3 to 6. Many isomeric forms seem to exist for the hexamer: from ring, book, bag, cage, to prism shape with nearly identical energy. Two cage-like isomers exist for heptamers and octamers: either cyclic or in the shape of a cube. Even larger clusters are predicted: the fullerene-like cluster W28 is called bucky water and even for a 280 water molecule monster icosahedral network (with each water molecule coordinated to 4 others) there is found a local energy minimum. When water is trapped in a liquid helium environment the hexamer occurs as a cyclic planar assembly but in the gas-phase it is the cage form and in an organic host (water trapped in the crystal lattice of an organic compound) the hexamer occurs as a conformation reminiscent of a cyclohexane chair. Cubic configurations for clusters in the range W8-W10 have been found. Another heptamer (cyclic twisted nonplanar) is the conformation for water as a hydrate in a crystal structure. Recent research has revealed that liquid water at ambient conditions has two distinct structures, either a very disordered or a very tetrahedral (clusters) at any temperature, which are spatially separated. As temperature increases the very tetrahedral structure concentration decreases and the very disordered increases. ## Glass transition temperature of water The glass transition temperature for water is about 136 K or -137°C. Factors in the formation of amorphous ice include ingredients that form a heterogenous mixture with water (such as is used in the production of ice cream), pressure (which may convert one form into another), and cryoprotectants that lower its freezing point and increase viscosity. Melting low-density amorphous ice (LDA) between 140 and 210 K through its transition temperature shows that it is more viscous than normal water. LDA has a density of 0.94 g/cm³, less dense than the densest water (1.00 g/cm³ at 277 K), but denser than ordinary ice. Amorphous ice is used in some scientific experiments, especially in electron cryomicroscopy of biomolecules. The individual molecules can be preserved for imaging in a state close to what they are in liquid water. ## Enthalpy of motion for water configurons A simple estimate of QL can be obtained by using the two temperatures 0°C and 100°C, where µ=1.79 x 10-3 Pa·s at 0°C and 0.28 x 10-3 Pa·s at 100°C, and solving for AL and QL. AL = 7.7 x 10-7 Pa·s and QL = 18 kJmol-1. R=8.314472 JK-1mol-1. Temperature is in K (273.15 + °C). QL includes the energy to break the hydrogen bond and move the configuron, as such HM ≤ QL. Using AL and QL to calculate the viscosity of water and comparing the calculated values to the experimentally determined ones for a range of temperature values shows that there is a systematic deviation at the higher temperatures. As the data for the viscosity of water vapor is available, AV and QV can be estimated: AV ~ 1.2 x 10-4 Pa·s and QV ~ - 6.0 kJmol-1. This added to the calculated configuron contribution improves the fit to the liquid water viscosity data remarkably well, suggesting that like other gas molecules mixed into water, water vapor can also be. But, here again the enthalpy of motion for water configurons suggests an average lateral speed of 1410 ms-1 and the enthalpy of dissolved water molecules suggests ~816 ms-1 which is also too high. ## Average speed for water molecules Although a liquid, some idea of the average speed for water molecules can be estimated using the self-diffusion coefficients for water at various temperatures. In the gas phase, \, \lambda is often defined as the diffusional mean free path, by assuming a simple approximate relation is exact: D = \frac{1}{2}\lambda \,v, where \, v is the root mean square (rms) speed of the gas molecules: v = \sqrt {{3\, k\, T}\over{m}} where \, m is the mass of the diffusing species. This approximate equation becomes exact when used to define the diffusional mean free path. If the diffusional mean free path were nominally the same number of µm as vrms, then, with the apparent self-diffusion coefficients (ADCs) ranging from 0.58 x 10-9 to 1.23 x 10-9 m2s-1, an approximate vrms would range from 34-50 µms-1 for λ from 34-50 µm. So if in liquid water λ is much greater, then vrms may be much less. The self-diffusion coefficient, D, for pure liquid water has been measured for temperatures between 2°C and 225°C at pressures up to 1.75 kbar. The average speeds of translation for various small molecules having the same kinetic energy as a water molecule, when water is at 500 nms-1, m = 18 Da, are Pi at 200 nms-1, m = 96 Da, adenosine (Ado) at 100 nms-1, m = 267 Da, and EC 3.1.3.5 at 6 nms-1, m = 140 kDa (homodimer), for the reaction: Ado + Pi H2O + AMP, although EC 3.1.3.5 (70 kDa) may not occur within the nucleosol. But EC 3.1.3.5 NT5C1A cytosolic 5'-nucleotidase 1A, m = 41 kDa can, with 82 kDa as a homodimer. But, if the average speed of lateral translation for a water molecule were on the order of 500 nms-1, an average cell could not operate ~64,000 RNA polymerase II transcription units by diffusion of ATP, CTP, GTP, and UTP to the RNA polymerase II transcription locations to produce, e.g., the mRNA of dystrophin, at the rate needed of ~42 NTPs per second. For a lateral speed of ~37 µms-1 of a water molecule, an average cell could operate ~14,400 transcription units by diffusion, ~75 µms-1, ~28,800 transcription units, and ~167 µms-1, ~64,000 transcription units. This in turn suggests λs of ~32, ~15, and ~6.9 µm. Signal transduction also depends on the lateral speed of a water molecule (diffusion) to succeed. With completion times on the order of a few minutes, this would mean the speed of a water molecule is on the order of 15 µms-1 and not much faster due to benefits from concentration. Increased lateral speed of a water molecule much above ~35 µms-1 may make signal transduction occur too quickly. The diffusion of solutes and macromolecules in aqueous cellular compartments such as the nucleosol within the nucleoplasm and the nucleus is required for numerous processes including metabolism, signaling and protein-protein interactions. Diffusion of small molecules through the cytosol is about fourfold slower than in pure water, due mostly to collisions with large numbers of macromolecules. Recent measurements have indicated unexpectedly high mobilities (µ) of small solutes and macromolecules. By the Einstein relation, \mu = \frac{q}{k\, T}D, where thus, approximately, for water, solutes and macromolecules, mobilities are directly proportional to vrms: \mu = \frac{q}{2k\, T}\lambda \,v_{\rm rms}. # Miscible molecules Miscible molecules such as O2, CO2, N2, and NH3 occur in any bodily fluid. These molecules are mixed into the liquid, but not turned into ions. Water contains only 1/20 parts O2. N2 mixes into the bloodstream and body fats. # Inorganic ions The inorganic ions in the nucleosol should be very similar in type and concentration to the cytosol as each sol is free to interdiffuse with the other. Relative to the outside of a cell, the concentration of Ca2+ is low. In addition to sodium and potassium ions the nucleosol also contains Mg2+. Some of these magnesium ions are associated with incoming ribonucleoside triphosphate (NTP) as they enter the catalytic center for transcription by RNA polymerase (RNAP) II. The remaining typical ions found in any cytosol include chloride and bicarbonate. Intranuclear posttranscriptional modifications such as mRNA editing convert cytidine to uridine within some mRNA. This conversion by enzyme EC 3.5.4.5 though infrequent releases ammonia or produces ammonium (NH4+) in solution. This enzyme is Zn2+ dependent. The zinc ion in the active site plays a central role in the proposed catalytic mechanism, activating a water molecule to form a hydroxide ion (OH-) that performs a nucleophilic attack on the substrate. Cells also maintain an intracellular iron ion (Fe2+) homeostasis. Cu2+ serves as a cofactor. Iron homeostasis involves interconversions of Fe2+ with Fe3+. When a nucleotide is incorporated into a growing DNA or RNA strand by a polymerase, pyrophosphate (PPi) is released. The pyrophosphate anion has the structure P2O74−, and is an acid anhydride of phosphate. It is unstable in aqueous solution and in the absence of enzymic catalysis hydrolyzes extremely slowly into inorganic phosphate HPO42− (orthophosphate, Pi) in all but highly acidic media. Enzyme EC 3.6.1.1 catalyzes the hydrolysis of PPi to Pi: PPi + H2O 2 Pi. The enzyme is Mg2+ binding, occurs in the cytosol, has a 33 kDa form, and no NLS. The enzymes of EC 3.6.1.1, in general, exist as homooligomers. Unless otherwise noted, minor ion concentrations are from the List of human blood components. # Carbohydrates Of the carbohydrates, monosaccharides and oligosaccharides are water soluble. Polysaccharides on the other hand tend to be insoluble in water. As to alcohols, there are two opposing solubility trends: the tendency of the polar OH to promote solubility in water, and of the carbon chain to resist it. Thus, methanol, ethanol, and propanol are miscible in water because the hydroxyl group wins out over the short carbon chain. Butanol, with a four-carbon chain, is moderately soluble because of a balance between the two trends. Alcohols of five or more carbons (pentanol and higher) are effectively insoluble in water because of the hydrocarbon chain's dominance. # Fatty acids Short chain carboxylic acids such as formic acid and acetic acid are miscible with water and dissociate to form reasonably strong acids (pKa 3.77 and 4.76, respectively). Longer-chain fatty acids do not show a great change in pKa. Nonanoic acid, for example, has a pKa of 4.96. However, as the chain length increases the solubility of the fatty acids in water decreases very rapidly, so that the longer-chain fatty acids have very little effect on the pH of a solution. When the body uses stored fat as a source of energy, glycerol and fatty acids are released into the bloodstream. The glycerol component can be converted to glucose by the liver and provides energy for cellular metabolism. # Amino acids The average mass range for amino acids: 75 - 222 Da. By comparison a water molecule is 18 Da. In addition to the proteinogenic standard amino acids, there are a number of other amino acids (aa) involved in the synthesis of the proteinogenic aa: citrulline (Cit), cystathionine (Cth), homocysteine (Hcy), ornithine (Orn), sarcosine (Sar) and taurine (Tau), for example. As Tau does not contain a carboxyl group it is not an aa, but since in its place it does contain a sulfonate group, it may be called an amino sulfonic acid. # Nucleobases Purine (Pur) 120 Da is not a protein. The purines are the most widely distributed naturally occurring nitrogen-containing heterocycle. The purine nucleobases include adenine (A) 135 Da, hypoxanthine (Hx) 136 Da, guanine (G) 151 Da, and xanthine (Xan) 152 Da. The pyrimidines include pyrimidine (Pyr) 80 Da, also a heterocycle and naturally occurring, cytosine (C) 111 Da, uracil (U) 112 Da, thymine (T) 126 Da, and queuine (Q) 275 Da. # Nucleosides Nucleosides are glycosylamines, a nucleobase linked to a ribose or deoxyribose ring. Examples include purines: adenosine (Ado) 267 Da, guanosine (Guo) 283 Da, and inosine (Ino) 268 Da, and pyrimidines: cytidine (Cyd) 243 Da, thymidine (Thd) 242 Da, uridine (Urd) 244 Da, and queuosine (Quo) 409 Da. When the nucleobase is attached to deoxyribose, a 'd' is placed in front of the abbreviation, e.g., dCyd is deoxycytidine 227 Da and the molar mass decreases by one oxygen from Cyd. # Nucleotides Nucleotides such as orotidine 5'-monophosphate (OMP) range in size from 176 Da (OMP) to 523 Da (GTP). The purine nucleotides involved in RNA or DNA synthesis include: inosine monophosphate (IMP), adenosine triphosphate (ATP), and guanosine triphosphate (GTP). The pyrimidine nucleotides involved include OMP, cytidine triphosphate (CTP), uridine triphosphate (UTP), and thymidine triphosphate (TTP) for DNA in place of UTP. Although rare, higher phosphates do occur such as adenosine tetraphosphate (Ap4) 587 Da. The deoxyribonucleotides have a 'd' in front, like dCTP, except for the thymidine deoxyribonucleotides. # Cofactors Many cofactors are involved in the synthesis of amino acids and nucleotides. They range in size from ascorbic acid (ASA) 176 Da and biotin (BIO) 244 Da, which are vitamins, to nicotinamide adenine dinucleotide phosphate (NADP) 744 Da and flavin adenine dinucleotide (FAD) 785 Da. One of the coenzymes essential for the synthesis of amino acids is nicotinamide adenine dinucleotide (NAD) 663 Da. Besides assembling NAD+ de novo from simple amino acid precursors, cells also salvage preformed compounds containing nicotinamide. The three natural compounds containing the nicotinamide ring and used in these salvage metabolic pathways are nicotinic acid (Na), nicotinamide (Nam) and nicotinamide riboside (NR). These compounds are also produced within cells, when the nicotinamide group is released from NAD+ in ADP-ribose transfer reactions. Indeed, the enzymes involved in these salvage pathways appear to be concentrated in the cell nucleus, which may compensate for the high level of reactions that consume NAD+ in this organelle. Nicotinamide mononucleotide adenylyl transferase 1 (NMNAT1) (EC 2.7.7.1) catalyzes a key step of NAD synthesis. It has a nuclear localization signal (NLS). NMNAT1 may be a substrate for nuclear kinases. # Peptides Peptides are short polymers formed from the linking, in a defined order, of α-amino acids. Proteins are polypeptide molecules (or consist of multiple polypeptide subunits). The distinction is that peptides are short and polypeptides/proteins are long. The digestion of dietary proteins produces dipeptides which are absorbed more rapidly than aa. A dipeptide is a molecule consisting of two amino acids joined by a single peptide bond. Examples of dipeptides include carnosine (Car) 244 Da, of the amino acids β-alanine (β-Ala) and histidine (His), homocarnosine (Hcn) 258 Da consisting of γ-aminobutyric acid (GABA) and His, and anserine (Ans) 240 Da. ## Oligopeptides Some tripeptides and tetrapeptides are synthesized in humans. Oligopeptides can range up to 40 aa (9 kDa) generally. ## Small proteins (polypeptides) Due to the size limitation of the nuclear pore, these polypeptides would range from 9 kDa to <70 kDa and not need or have a NLS. For example, emerin 18 kDa (no NLS) mediates inner nuclear membrane anchorage to the nuclear lamina, regulates the flux of beta-catenin into the nucleus, and interacts with nuclear actin. On the other hand, LEMD1 (20.3 kDa) is involved in the glutamine (Gln) metabolic process and has a NLS. Many of the polypeptides are enzymes including peptidases and kinases. ## Proteases Carnosinase occurs as EC 3.4.13.3 (Xaa-His dipeptidase) with Zn2+ as cofactor, 3.4.13.18 (cytosol nonspecific dipeptidase) with Zn2+ as cofactor and Mn2+ activation, and 3.4.13.20 (beta-Ala-His dipeptidase), activated by Cd2+ and citrate, catalyzing the reaction Car + H2O His + β-Ala. It is intracellular to the cytosol and can occur in 14 kDa, 35 kDa, and 44 kDa sizes, often forming a homodimer. As a nonspecific dipeptidase, it degrades a number of dipeptides including Car, Ans and Hcn as EC 3.4.13.3 and EC 3.4.13.20 per the reaction: Hcn + H2O γ-aminobutyric acid (GABA) + His. Oligopeptides can be degraded by aminopeptidases such as EC 3.4.11.6 19-68 kDa forms (intracellular to the cytosol) with Zn2+ as cofactor and activation by Cl- per the reactions: -ligopeptide (n) + H2O Lys + oligopeptide (n-1) -ligopeptide (n) + H2O Arg + oligopeptide (n-1). ## Synthases Enzymes EC 2.3.1.37 (cofactor: pyridoxal phosphate, PLP) aminolevulinate, delta-, synthase 1 (ALAS1) and aminolevulinate, delta-, synthase 2 (ALAS2) anabolically synthesize glycine (Gly) from the amino acid 5-amino-4-oxovaleric acid (ALA) in the two-step reaction: 5-aminolevulinate (C5H9NO3) (ALA) + CO2 2-amino-3-oxoadipate (C6H9NO5) 2-amino-3-oxoadipate + CoA (C21H36N7O16P3S) succinyl-CoA (C25H40N7O19P3S) + Gly 5-aminolevulinate + CoA + CO2 succinyl-CoA + Gly The mRNA for ALAS1 is 82 kDa, the intracellular precursor is a homodimer of 71 kDa, and the mitochondrial mature protein is 65 kDa. But, ALAS1 also occurs in a 30 kDa form. CTP synthase EC 6.3.4.2 is the final step in the de novo synthesis of CTP from UTP. As a monomer 67 kDa or dimer it is inactive because three monomers contribute to ligand binding at the active site. The active form is a homotetramer (a dimer of dimers), with no NLS, intracellular to the cytosol, for the following reactions. UTP + Gln + ATP + H2O CTP + Glu + ADP + Pi ATP + UTP + NH3 ADP + Pi + CTP The reactions 2 ATP + HCO3- + NH3 2 ADP + Pi + carbamoyl phosphate (multistep) Gln + H2O Glu + NH3 2 ADP + Pi + Glu + carbamoyl phosphate 2 ATP + Gln + HCO3- + H2O are catalyzed by EC 6.3.5.5 carbamoyl-phosphate synthase II (CAD). It has no NLS, occurs as a homohexamer, uses Zn2+ as a cofactor and is intracellular to the nucleus. It does occur in a 22 kDa form. ## Kinases EC 3.6.1.5 (cofactor: Ca2+) catalyzes the following reactions: AMP + Pi ADP + H2O AMP + 2 Pi ATP + 2 H2O ADP + Pi ATP + H2O CMP + Pi CDP + H2O CMP + 2 Pi CTP + 2 H2O CDP + Pi CTP + H2O GMP + Pi GDP + H2O GMP + 2 Pi GTP + 2 H2O GDP + Pi GTP + H2O UMP + Pi UDP + H2O UMP + 2 Pi UTP + 2 H2O UDP + Pi UTP + H2O Ca2+ or Mg2+ can serve as activating ions. ENTPD1 (CD39) is a 56 kDa protein. CD39 associates with RanBPM (RANBP9). RANBP9 (90 kDa) binds Ran, a small GTP binding protein that is essential for the translocation of RNA and proteins through the nuclear pore complex. RanBPM localizes in the nucleus and cytoplasm, but RanBPM has no NLS. CANT1 (EC 3.6.1.6 and 3.6.1.5) 49 kDa catalyzes similar reactions: a nucleotide + Pi a nucleoside diphosphate + H2O, also acting on IDP, GDP, UDP and on D-ribose 5-diphosphate. ENTPD7 (EC 3.6.1.-) occurs in the mouse nucleus. Enzymes 2.4.2.7 adenine phosphoribosyltransferase (APRT) 19.4 kDa (forms a dimer, 38.8 kDa) is intracellular (cytoplasm) and 2.4.2.8 hypoxanthine phosphoribosyltransferase 1 (HPRT1) 24 kDa (forms a tetramer, 96 kDa) is intracellular (cytosolic) catalyze the following reaction: Adenine + 5-phospho-alpha-D-ribose 1-diphosphate (PRPP) AMP + PPi Neither APRT nor HPRT1 has a NLS. APRT is a dimer in solution at pH 6.5, but a monomer at pH 8.0, and like HPRT1 needs Mg2+, or Mn2+. Enzymes EC 3.6.1.5 ATP pyrophosphohydrolase, ADPase/ADP synthase ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1) 56 kDa catalyzes the conversion of AMP into ADP (see below). Cofactor: Ca2+. Ca2+ or Mg2+ can serve as activating ions. Also acts on ADP, and on other nucleoside triphosphates and diphosphates. AMP + Pi ADP + H2O Enzymes EC 2.7.4.6 nucleoside-diphosphate kinases A, B, C, D (NDKA-D) catalyzes the following reaction inside the nucleosol as it is intracellular (nucleus) and each gene is translated as a 7-11 kDa particle. However, these kinases exist either as tetramers (28-44 kDa) in bacteria or hexamers (42-66 kDa). Once the hexamer has formed the particle may be too big to pass through the nuclear pores. NDKA has been shown to mediate transcription, associate with a promoter region of a gene, and be a member of the SET or INHAT complex which can modulate gene expression. Nucleoside-diphosphate kinase does form nuclear and cytoplasmic hexamers. NDKA-D do not have a NLS. ADP + GTP ATP + GDP ## Transaminases In catabolic transamination, with PLP as a cofactor, EC 2.6.1.2 transfers the amine from glutamic acid (glutamate) (Glu) to alanine (Ala) via a two step reaction: PLP + Glu pyridoxamine monophosphate (PMP) + α-ketoglutarate (2-oxoglutarate) PMP + pyruvate PLP + Ala pyruvate + Glu Ala + 2-oxoglutarate. Although this enzyme has several different names, e.g., alanine transaminase, glutamic-pyruvate transaminase (GPT), or alanine aminotransferase, it can occur as a monomer of 55 kDa or homodimer of 101 kDa, and as either a cytosolic (GPT1), or mitochondrial form (GPT2). ## Synthetases The reactions ATP + Glu + NH3 (or NH4+) ADP + Pi + Gln ATP + Asp + NH4+ ADP + Pi + Asn ATP + Asp + NH4+ AMP + PPi + Asn are catalyzed by the enzyme EC 6.3.1.2 glutamine synthetase (GS), glutamine-ammonia ligase (GLUL). GLUL 42 kDa is intracellular, occurs as a homooctamer, also as 12 kDa and 22 kDa forms, and complexes with phosphate, ADP, and Mn2+. # Histone pools in the nucleosol Histones H2A, H2B, H3, and H4 are in the nucleosol, and H2B, H3, and H4 are also in the cytosol. # Enzyme activity EC 2.4.1.101 (UDP-N-acetylglucosaminyl transferase) occurs and is active in the nuclesol. Briefly, any enzyme that can occur as a monomer small enough to pass through the nuclear pore complex before it becomes a dimer or larger oligomer or polymer can occur and act in the nucleosol, whether it has a NLS or not. # Exonucleosol proteins Keratin type II cytoskeletal 80 (KRT80) as a monomer is 51 kDa (variant 2) and thereby can diffuse into the nucleosol, variant 3 is 54 kDA, and variant 1 is 47 kDa. KRT80 is an intermediate filament protein that makes up one of the major structural fibers of epithelial cells. While keratin type I cytoskeletal 13 (KRT13) is usually paired with keratin type II cytoskeletal 4 (KRT4) 64 kDa, KRT13 has a 46 kDa variant 2 and a 39 kDA variant (KRT-13-201). Keratins only assemble as heteropolymers: a type I and a type II protein forming a heterodimer. Polo-like kinase 1 (PLK1) phosphorylizes KRT4 at serine 157. PLK1 27 kDa occurs in the nucleoplasm and cytosol, is ATP binding, and engages in protein amino acid phosphorylation. PLK1 associates with, binds to, and phosphorylates alpha-, beta- and gamma-tubulins in interphase independent of the microtubule polymerization state. Intermediate filaments (IFs) are composed of proteins (40-210 kDa) that self-assemble into complex cytoskeletal fibers. Inside an interphase cell, ~5% of the total intermediate filament protein exists in a soluble tetrameric form. Newly synthesized intermediate filament protein is soluble and self-assembly proceeds at concentrations >40-50 µg/ml. Homodimers of IF proteins can form and be added to already forming IFs but cannot assemble into IFs themselves. # History of the nucleosol While earlier articles or book sections may exist mentioning the term "nucleosol", a book from 1970 online refers to the nucleosol. # Acknowledgements The content on this page was first contributed by: Henry A. Hoff. Initial content for this page in some instances came from Wikipedia.	Nucleosol Editor-In-Chief: Henry A. Hoff # Overview The structural and functional unit of all known living organisms is the cell. Eukaryotic cells of which humans are composed contain membrane-bound compartments. The most important among these is the cell nucleus. It is the "control center" for each cell that has at least one. Separating the nucleus from the cellular cytoplasm is the double-membraned structure of the nuclear envelope. Inside the nuclear membrane, including attached to the inner layer of this membrane, are a variety of substances serving special purposes. Depending on conditions, for a time, some of these compose the nucleosol, some compose the nucleohyaloplasm, and still others compose the nucleoplasm. Those substances and the special conditions present, even if temporary, in water can be the nucleosol. The nucleus cannot succeed in its efforts to control the cell without the special properties of the nucleosol. # Introduction Generally, in chemistry a fluid suspension of a colloidal solid in a liquid is referred to as a sol. Whereas, a solution is a liquid mixture of a minor component (the solute) distributed uniformly within the major component (the solvent). In the nucleosol the liquid is water and the solvent is also water. Using the water (data page) and the atomic radii of the elements (data page), a water molecule is approximately 120 x 187 pm in maximum diameters (average 154 pm). For its small size a water molecule (H2O), 18 Da, at about 38°C, under 1 atm of pressure (about 101325 kgm-1s-2), in large enough numbers to produce a liquid exhibits a high viscosity, short-range order, clustering, and miscibility. The molecule is polar enough to produce and maintain ions when in a liquid. Liquid water can also dissolve organic compounds such as carbohydrates, fatty acids, amino acids, nucleobases, nucleosides, nucleotides, and peptides. Diffusion of molecules, ions, or particles in liquid water is depended upon by most living organisms. In cell biology, diffusion is the main form of transport for the smaller necessary materials such as amino acids within cells.[1] Metabolism and respiration rely in part upon diffusion in addition to bulk or active processes. For example, in the alveoli of mammalian lungs, due to differences in partial pressures across the alveolar-capillary membrane, oxygen diffuses into the blood (another water-based liquid) and carbon dioxide diffuses out. Diffusion in liquid water depends on the lateral speed of the water molecule within liquid water. The lateral speed of a water molecule within liquid water appears to be unknown but can be estimated.Template:Wiktionarypar A plasm is a formative or formed material; i.e., something molded. Usually a formed material keeps it shape once the mold is removed. Should something be glassy or transparent it can be said to be hyaloid. Whether a fluid is molded or liquid is often a matter of viscosity and whether a fluid is transparent, translucent, or opaque is often a matter of absorption. Before any internal molding exists within the nucleus or when any portion of the existing nucleoskeleton is dissolved and reconstructed elsewhere, genes within the euchromatin are transcribed, mRNAs are synthesized, and the mers that are to become new portions of the nucleoskeleton become part of the nucleosol: actins (microfilaments), lamins (intermediate filaments), and tubulins (microtubules). In addition to internal molding by the nucleoskeleton there are local increases in viscosity due to macromolecular crowding that help to compose the nucleohyaloplasm and the nucleoplasm of which it is a part. # Water Water, whether a gas (water vapor) or liquid, is an amorphous substance. The chemical bonding within many amorphous substances can produce short-range order while there is long-range disorder. The short-range order is often a symmetrical arrangement of polyhedra. The long-range disorder can be approached with the disordered arrangement of space-filling polyhedra. These polyhedra are bonded together in a solid and undergo bond breaking through the transitions from solid to fluid. A model based on the configuron is an approach to understanding the viscosity changes that occur with changes in temperature. In the kinetic theory of gases (such as water vapor) there is a correlation between average energy (Eav) and temperature (T): Eav = 3/2 kT with Eav = 1/2 mvav2. ⇒ vav2 = 3kT/m. For a water molecule m = 18 Da, or 2.9913 x 10-23 gmolecule-1. ⇒ vrms = √3kT/m = √3·1.382x10-23 J/K·306 K/(0.018 kg/6.022x1023) = 651 ms-1 at 33°C. vrms is the root mean square velocity. However, water in the nucleosol is a liquid, not a gas. For example, vrms (O2) in air at 25°C is 482.1 ms-1. ## Enthalpy of vaporization for water The enthalpy of vaporization for water at 25°C is 44 kJmol-1. The enthalpy of vaporization can be viewed as the energy required to overcome the intermolecular interactions in water. The molecules in liquid water are held together by relatively strong hydrogen bonds. But care must be taken, however, when using enthalpies of vaporization to measure the strength of intermolecular forces, as these forces may persist to an extent in the gas phase (as is the case with hydrogen fluoride), and so the calculated value of the bond strength will be too low. With water the enthalpy of vaporization is larger than the available kinetic energy suggested by the ideal gas law: Eav = 3/2 kT with Eav = 1/2 mvav2. The lateral speed of a water molecule estimated using the enthalpy of vaporization is ~2,210 ms-1. For water vapor at 25°C, by the ideal gas law, vrms = 643 ms-1. ## Enthalpy of flow for liquid water As a liquid much of the available kinetic energy is expressed through additional degrees of freedom. Some of this energy is in the form of intermolecular bonds. These bonds are a resistance to flow. Water has a resistance to flow that is considered relatively "thin", having a lower viscosity than other liquids such as vegetable oil. At 25°C, water has a nominal viscosity of 1.0 × 10-3 Pa∙s and motor oil has a nominal apparent viscosity of 250 × 10-3 Pa∙s.[2] Because of its density of <math>\rho</math> = 1 g/cm3 (varies slightly with temperature), and its dynamic viscosity near 1 mPa·s, the viscosity values of water are, to rough precision, all powers of ten: Dynamic viscosity: Kinematic viscosity: <math>{\nu}</math> = <math>{\mu}</math>/<math>{\rho}</math>, where <math>{\rho}</math> is the density (kg/m3). In water - viscosity is independent of pressure (except at very high pressure); and - viscosity tends to fall as temperature increases: from 1.79 cP to 0.28 cP in the temperature range from 0°C to 100°C; see temperature dependence of liquid viscosity for more details. The viscosity of water is 8.94 × 10−4 Pa·s or 8.94 × 10−3 dyn·s/cm2 or 10−1 cP at about 25 °C. As a function of temperature T (K): μ(Pa·s) = A × 10B/(T−C) where A=2.414 × 10−5 Pa·s ; B = 247.8 K ; and C = 140 K. Whereas, for a gas such as air, the viscosity is much lower and also depends mostly on temperature. At 15.0 °C, the viscosity of air is 1.78 × 10−5 kg/(m·s) or 1.78 × 10−4 cP. One can get the viscosity of air as a function of temperature from the Gas Viscosity Calculator. Viscous flow, which results from viscosity, in amorphous materials such as water is a thermally activated process:[3] where QL is the activation energy in the liquid state, T is temperature, R is the molar gas constant and AL is approximately a constant. With where Hm is the enthalpy of motion of the broken hydrogen bonds. Hm ~ 1/2 mvav2. Here, the energy of motion for flow suggests a lateral speed of ~1590 ms-1. Because of its small molecular size and ability to quickly rearrange, it cannot be made amorphous without resorting to specialized hyperquenching techniques. These produce amorphous ice, which has a quenching rate in the range of metallic glasses.[4] The higher the temperature of an amorphous material the higher the configuron concentration. The higher the configuron concentration the lower the viscosity. As configurons form percolating clusters, an amorphous solid can transition to a liquid. This clustering facilitates viscous flow. Thermodynamic parameters of configurons can be found from viscosity-temperature relationships.[4] ## Short-range order Like a liquid an amorphous solid has a topologically disordered distribution of particles but elastic properties of an isotropic solid. The symmetry similarity of both liquid and solid phases cannot explain the qualitative differences in their behavior. Due to chemical bonding characteristics amorphous solids such as glasses do possess a high degree of short-range order with respect to local atomic polyhedra.[5] The amorphous structure of glassy silica has no long range order but shows local ordering with respect to the tetrahedral arrangement of oxygen atoms around silicon atoms. The most ubiquitous, and perhaps simplest, example of a hydrogen bond is found between water molecules. This intermolecular hydrogen bonding is responsible for the high boiling point of water (100 °C) due to the high number of hydrogen bonds each molecule can have relative to its low molecular mass, and the great strength of these bonds. The length of hydrogen bonds depends on bond strength, temperature, and pressure. The bond strength itself is dependent on temperature, pressure, bond angle, and environment (usually characterized by local dielectric constant). The typical length of a hydrogen bond (H-bond) in water is 1.97 Å (197 pm). Every water molecule can be H-bonded with up to four other molecules, as shown in the figure (two through its two lone pairs, and two through its two hydrogen atoms.) Water has a very high boiling point, melting point and viscosity compared to other similar substances not conjoined by hydrogen bonds. The exact number of hydrogen bonds in which a molecule in liquid water participates fluctuates with time and depends on the temperature. From liquid water simulations at 25 °C, each water molecule may participate in an average of 3.59 hydrogen bonds.[6] At 100 °C, this number apparently decreases to 3.24 due to the increased molecular motion and decreased density, while at 0 °C, the average number of hydrogen bonds increases to 3.69.[6] A more recent study found a much smaller number of hydrogen bonds: 2.357 at 25 °C.[7] The differences may be due to the use of a different method for defining and counting the hydrogen bonds. Where the bond strengths are more equivalent, one might instead find the atoms of two interacting water molecules partitioned into two polyatomic ions of opposite charge, specifically hydroxide (OH−) and hydronium (H3O+). (Hydronium ions are also known as 'hydroxonium' ions.) Indeed, in pure water under conditions of standard temperature and pressure, this latter formulation is applicable only rarely; on average about one in every 5.5 × 108 molecules gives up a proton to another water molecule, in accordance with the value of the dissociation constant for water under such conditions. It is a crucial part of the uniqueness of water. It can be that a single hydrogen atom participates in two hydrogen bonds, rather than one. This type of bonding is called "bifurcated". It was suggested that a bifurcated hydrogen atom is an essential step in water reorientation.[8] ## Water clusters In chemistry a water cluster is a discrete hydrogen bonded assembly or cluster of molecules of water [9]. These clusters have been found experimentally or predicted in silico in various forms of water; in ice, in crystal lattices and in bulk liquid water, the simplest one being the water dimer (W2). Water manifests itself as clusters. Water clusters are also implicated in the stabilization of certain supramolecular structures. Supramolecular forces include hydrogen bonding that result in molecular self-assembly, folding, and mechanically-interlocked molecular architectures.[10] In silico, cyclic water clusters (H2O)n are found with n = 3 to 6. Many isomeric forms seem to exist for the hexamer: from ring, book, bag, cage, to prism shape with nearly identical energy. Two cage-like isomers exist for heptamers and octamers: either cyclic or in the shape of a cube. Even larger clusters are predicted: the fullerene-like cluster W28 is called bucky water and even for a 280 water molecule monster icosahedral network (with each water molecule coordinated to 4 others) there is found a local energy minimum. When water is trapped in a liquid helium environment the hexamer occurs as a cyclic planar assembly but in the gas-phase it is the cage form and in an organic host (water trapped in the crystal lattice of an organic compound) the hexamer occurs as a conformation reminiscent of a cyclohexane chair. Cubic configurations for clusters in the range W8-W10 have been found. Another heptamer (cyclic twisted nonplanar) is the conformation for water as a hydrate in a crystal structure.[11] Recent research has revealed that liquid water at ambient conditions has two distinct structures, either a very disordered or a very tetrahedral (clusters) at any temperature, which are spatially separated.[12] As temperature increases the very tetrahedral structure concentration decreases and the very disordered increases. ## Glass transition temperature of water The glass transition temperature for water is about 136 K or -137°C. Factors in the formation of amorphous ice include ingredients that form a heterogenous mixture with water (such as is used in the production of ice cream), pressure (which may convert one form into another), and cryoprotectants that lower its freezing point and increase viscosity. Melting low-density amorphous ice (LDA) between 140 and 210 K through its transition temperature shows that it is more viscous than normal water.[13] LDA has a density of 0.94 g/cm³, less dense than the densest water (1.00 g/cm³ at 277 K), but denser than ordinary ice. Amorphous ice is used in some scientific experiments, especially in electron cryomicroscopy of biomolecules.[14] The individual molecules can be preserved for imaging in a state close to what they are in liquid water. ## Enthalpy of motion for water configurons A simple estimate of QL can be obtained by using the two temperatures 0°C and 100°C, where µ=1.79 x 10-3 Pa·s at 0°C and 0.28 x 10-3 Pa·s at 100°C, and solving for AL and QL. AL = 7.7 x 10-7 Pa·s and QL = 18 kJmol-1. R=8.314472 JK-1mol-1. Temperature is in K (273.15 + °C). QL includes the energy to break the hydrogen bond and move the configuron, as such HM ≤ QL. Using AL and QL to calculate the viscosity of water and comparing the calculated values to the experimentally determined ones for a range of temperature values shows that there is a systematic deviation at the higher temperatures. As the data for the viscosity of water vapor is available, AV and QV can be estimated: AV ~ 1.2 x 10-4 Pa·s and QV ~ - 6.0 kJmol-1. This added to the calculated configuron contribution improves the fit to the liquid water viscosity data remarkably well, suggesting that like other gas molecules mixed into water, water vapor can also be.[15] But, here again the enthalpy of motion for water configurons suggests an average lateral speed of 1410 ms-1 and the enthalpy of dissolved water molecules suggests ~816 ms-1 which is also too high. ## Average speed for water molecules Although a liquid, some idea of the average speed for water molecules can be estimated using the self-diffusion coefficients for water at various temperatures. In the gas phase, <math>\, \lambda</math> is often defined as the diffusional mean free path, by assuming a simple approximate relation is exact: <math>D = \frac{1}{2}\lambda \,v</math>, where <math>\, v</math> is the root mean square (rms) speed of the gas molecules: <math>v = \sqrt {{3\, k\, T}\over{m}}</math> where <math>\, m</math> is the mass of the diffusing species. This approximate equation becomes exact when used to define the diffusional mean free path. If the diffusional mean free path were nominally the same number of µm as vrms, then, with the apparent self-diffusion coefficients (ADCs) ranging from 0.58 x 10-9 to 1.23 x 10-9 m2s-1[16], an approximate vrms would range from 34-50 µms-1 for λ from 34-50 µm. So if in liquid water λ is much greater, then vrms may be much less. The self-diffusion coefficient, D, for pure liquid water has been measured for temperatures between 2°C and 225°C at pressures up to 1.75 kbar.[17] The average speeds of translation for various small molecules having the same kinetic energy as a water molecule, when water is at 500 nms-1, m = 18 Da, are Pi at 200 nms-1, m = 96 Da, adenosine (Ado) at 100 nms-1, m = 267 Da, and EC 3.1.3.5 at 6 nms-1, m = 140 kDa (homodimer), for the reaction: Ado + Pi <=> H2O + AMP, although EC 3.1.3.5 (70 kDa) may not occur within the nucleosol. But EC 3.1.3.5 NT5C1A cytosolic 5'-nucleotidase 1A, m = 41 kDa[18] can, with 82 kDa as a homodimer. But, if the average speed of lateral translation for a water molecule were on the order of 500 nms-1, an average cell could not operate ~64,000 RNA polymerase II transcription units by diffusion of ATP, CTP, GTP, and UTP to the RNA polymerase II transcription locations to produce, e.g., the mRNA of dystrophin, at the rate needed of ~42 NTPs per second. For a lateral speed of ~37 µms-1 of a water molecule, an average cell could operate ~14,400 transcription units by diffusion, ~75 µms-1, ~28,800 transcription units, and ~167 µms-1, ~64,000 transcription units. This in turn suggests λs of ~32, ~15, and ~6.9 µm. Signal transduction also depends on the lateral speed of a water molecule (diffusion) to succeed. With completion times on the order of a few minutes, this would mean the speed of a water molecule is on the order of 15 µms-1 and not much faster due to benefits from concentration. Increased lateral speed of a water molecule much above ~35 µms-1 may make signal transduction occur too quickly. The diffusion of solutes and macromolecules in aqueous cellular compartments such as the nucleosol within the nucleoplasm and the nucleus is required for numerous processes including metabolism, signaling and protein-protein interactions.[19] Diffusion of small molecules through the cytosol is about fourfold slower than in pure water, due mostly to collisions with large numbers of macromolecules.[19] Recent measurements have indicated unexpectedly high mobilities (µ) of small solutes and macromolecules.[19] By the Einstein relation, <math>\mu = \frac{q}{k\, T}D</math>, where thus, approximately, for water, solutes and macromolecules, mobilities are directly proportional to vrms: <math>\mu = \frac{q}{2k\, T}\lambda \,v_{\rm rms}</math>. # Miscible molecules Miscible molecules such as O2, CO2, N2, and NH3 occur in any bodily fluid. These molecules are mixed into the liquid, but not turned into ions. Water contains only 1/20 parts O2. N2 mixes into the bloodstream and body fats. # Inorganic ions The inorganic ions in the nucleosol should be very similar in type and concentration to the cytosol as each sol is free to interdiffuse with the other. Relative to the outside of a cell, the concentration of Ca2+ is low.[21] In addition to sodium and potassium ions the nucleosol also contains Mg2+[22]. Some of these magnesium ions are associated with incoming ribonucleoside triphosphate (NTP) as they enter the catalytic center for transcription by RNA polymerase (RNAP) II.[22] The remaining typical ions found in any cytosol include chloride and bicarbonate.[20] Intranuclear posttranscriptional modifications such as mRNA editing convert cytidine to uridine within some mRNA.[23] This conversion by enzyme EC 3.5.4.5 though infrequent releases ammonia[24] or produces ammonium (NH4+) in solution. This enzyme is Zn2+ dependent. The zinc ion in the active site plays a central role in the proposed catalytic mechanism, activating a water molecule to form a hydroxide ion (OH-) that performs a nucleophilic attack on the substrate.[25] Cells also maintain an intracellular iron ion (Fe2+) homeostasis.[26] Cu2+ serves as a cofactor.[27] Iron homeostasis involves interconversions of Fe2+ with Fe3+. When a nucleotide is incorporated into a growing DNA or RNA strand by a polymerase, pyrophosphate (PPi) is released. The pyrophosphate anion has the structure P2O74−, and is an acid anhydride of phosphate. It is unstable in aqueous solution and in the absence of enzymic catalysis hydrolyzes extremely slowly into inorganic phosphate HPO42− (orthophosphate, Pi) in all but highly acidic media.[28] Enzyme EC 3.6.1.1 catalyzes the hydrolysis of PPi to Pi: PPi + H2O <=> 2 Pi. The enzyme is Mg2+ binding, occurs in the cytosol, has a 33 kDa form, and no NLS. The enzymes of EC 3.6.1.1, in general, exist as homooligomers. Unless otherwise noted, minor ion concentrations are from the List of human blood components. # Carbohydrates Of the carbohydrates, monosaccharides and oligosaccharides are water soluble. Polysaccharides on the other hand tend to be insoluble in water. As to alcohols, there are two opposing solubility trends: the tendency of the polar OH to promote solubility in water, and of the carbon chain to resist it. Thus, methanol, ethanol, and propanol are miscible in water because the hydroxyl group wins out over the short carbon chain. Butanol, with a four-carbon chain, is moderately soluble because of a balance between the two trends. Alcohols of five or more carbons (pentanol and higher) are effectively insoluble in water because of the hydrocarbon chain's dominance. # Fatty acids Short chain carboxylic acids such as formic acid and acetic acid are miscible with water and dissociate to form reasonably strong acids (pKa 3.77 and 4.76, respectively). Longer-chain fatty acids do not show a great change in pKa. Nonanoic acid, for example, has a pKa of 4.96. However, as the chain length increases the solubility of the fatty acids in water decreases very rapidly, so that the longer-chain fatty acids have very little effect on the pH of a solution. When the body uses stored fat as a source of energy, glycerol and fatty acids are released into the bloodstream. The glycerol component can be converted to glucose by the liver and provides energy for cellular metabolism. # Amino acids The average mass range for amino acids: 75 - 222 Da. By comparison a water molecule is 18 Da. In addition to the proteinogenic standard amino acids, there are a number of other amino acids (aa) involved in the synthesis of the proteinogenic aa: citrulline (Cit), cystathionine (Cth), homocysteine (Hcy), ornithine (Orn), sarcosine (Sar) and taurine (Tau), for example. As Tau does not contain a carboxyl group it is not an aa, but since in its place it does contain a sulfonate group, it may be called an amino sulfonic acid. # Nucleobases Purine (Pur) 120 Da is not a protein. The purines are the most widely distributed naturally occurring nitrogen-containing heterocycle.[40] The purine nucleobases include adenine (A) 135 Da, hypoxanthine (Hx) 136 Da, guanine (G) 151 Da, and xanthine (Xan) 152 Da. The pyrimidines include pyrimidine (Pyr) 80 Da, also a heterocycle and naturally occurring, cytosine (C) 111 Da, uracil (U) 112 Da, thymine (T) 126 Da, and queuine (Q) 275 Da. # Nucleosides Nucleosides are glycosylamines, a nucleobase linked to a ribose or deoxyribose ring. Examples include purines: adenosine (Ado) 267 Da, guanosine (Guo) 283 Da, and inosine (Ino) 268 Da, and pyrimidines: cytidine (Cyd) 243 Da, thymidine (Thd) 242 Da, uridine (Urd) 244 Da, and queuosine (Quo) 409 Da. When the nucleobase is attached to deoxyribose, a 'd' is placed in front of the abbreviation, e.g., dCyd is deoxycytidine 227 Da and the molar mass decreases by one oxygen from Cyd. # Nucleotides Nucleotides such as orotidine 5'-monophosphate (OMP) range in size from 176 Da (OMP) to 523 Da (GTP). The purine nucleotides involved in RNA or DNA synthesis include: inosine monophosphate (IMP), adenosine triphosphate (ATP), and guanosine triphosphate (GTP). The pyrimidine nucleotides involved include OMP, cytidine triphosphate (CTP), uridine triphosphate (UTP), and thymidine triphosphate (TTP) for DNA in place of UTP. Although rare, higher phosphates do occur such as adenosine tetraphosphate (Ap4) 587 Da. The deoxyribonucleotides have a 'd' in front, like dCTP, except for the thymidine deoxyribonucleotides. # Cofactors Many cofactors are involved in the synthesis of amino acids and nucleotides. They range in size from ascorbic acid (ASA) 176 Da and biotin (BIO) 244 Da, which are vitamins, to nicotinamide adenine dinucleotide phosphate (NADP) 744 Da and flavin adenine dinucleotide (FAD) 785 Da. One of the coenzymes essential for the synthesis of amino acids is nicotinamide adenine dinucleotide (NAD) 663 Da. Besides assembling NAD+ de novo from simple amino acid precursors, cells also salvage preformed compounds containing nicotinamide. The three natural compounds containing the nicotinamide ring and used in these salvage metabolic pathways are nicotinic acid (Na), nicotinamide (Nam) and nicotinamide riboside (NR).[41] These compounds are also produced within cells, when the nicotinamide group is released from NAD+ in ADP-ribose transfer reactions. Indeed, the enzymes involved in these salvage pathways appear to be concentrated in the cell nucleus, which may compensate for the high level of reactions that consume NAD+ in this organelle.[42] Nicotinamide mononucleotide adenylyl transferase 1 (NMNAT1) (EC 2.7.7.1) catalyzes a key step of NAD synthesis.[43] It has a nuclear localization signal (NLS).[43] NMNAT1 may be a substrate for nuclear kinases.[43] # Peptides Peptides are short polymers formed from the linking, in a defined order, of α-amino acids. Proteins are polypeptide molecules (or consist of multiple polypeptide subunits). The distinction is that peptides are short and polypeptides/proteins are long. The digestion of dietary proteins produces dipeptides which are absorbed more rapidly than aa. A dipeptide is a molecule consisting of two amino acids joined by a single peptide bond. Examples of dipeptides include carnosine (Car) 244 Da, of the amino acids β-alanine (β-Ala) and histidine (His), homocarnosine (Hcn) 258 Da consisting of γ-aminobutyric acid (GABA) and His, and anserine (Ans) 240 Da. ## Oligopeptides Some tripeptides and tetrapeptides are synthesized in humans. Oligopeptides can range up to 40 aa (9 kDa) generally. ## Small proteins (polypeptides) Due to the size limitation of the nuclear pore, these polypeptides would range from 9 kDa to <70 kDa and not need or have a NLS. For example, emerin 18 kDa (no NLS) mediates inner nuclear membrane anchorage to the nuclear lamina, regulates the flux of beta-catenin into the nucleus, and interacts with nuclear actin.[44][45][46] On the other hand, LEMD1 (20.3 kDa) is involved in the glutamine (Gln) metabolic process[47] and has a NLS.[48] Many of the polypeptides are enzymes including peptidases and kinases. ## Proteases Carnosinase occurs as EC 3.4.13.3 (Xaa-His dipeptidase) with Zn2+ as cofactor, 3.4.13.18 (cytosol nonspecific dipeptidase) with Zn2+ as cofactor and Mn2+ activation, and 3.4.13.20 (beta-Ala-His dipeptidase), activated by Cd2+ and citrate, catalyzing the reaction Car + H2O <=> His + β-Ala. It is intracellular to the cytosol and can occur in 14 kDa, 35 kDa, and 44 kDa sizes, often forming a homodimer. As a nonspecific dipeptidase, it degrades a number of dipeptides including Car[49], Ans and Hcn[49] as EC 3.4.13.3 and EC 3.4.13.20 per the reaction: Hcn + H2O <=> γ-aminobutyric acid (GABA) + His. Oligopeptides can be degraded by aminopeptidases such as EC 3.4.11.6 19-68 kDa forms (intracellular to the cytosol) with Zn2+ as cofactor and activation by Cl- per the reactions: oligopeptide (n) + H2O <=> Lys + oligopeptide (n-1) oligopeptide (n) + H2O <=> Arg + oligopeptide (n-1). ## Synthases Enzymes EC 2.3.1.37 (cofactor: pyridoxal phosphate, PLP) aminolevulinate, delta-, synthase 1 (ALAS1) and aminolevulinate, delta-, synthase 2 (ALAS2) anabolically synthesize glycine (Gly) from the amino acid 5-amino-4-oxovaleric acid (ALA) in the two-step reaction: 5-aminolevulinate (C5H9NO3) (ALA) + CO2 <=> 2-amino-3-oxoadipate (C6H9NO5) + 2-amino-3-oxoadipate + CoA (C21H36N7O16P3S) <=> succinyl-CoA (C25H40N7O19P3S) + Gly = 5-aminolevulinate + CoA + CO2 <=> succinyl-CoA + Gly The mRNA for ALAS1 is 82 kDa, the intracellular precursor is a homodimer of 71 kDa, and the mitochondrial mature protein is 65 kDa. But, ALAS1 also occurs in a 30 kDa form.[50] CTP synthase EC 6.3.4.2 is the final step in the de novo synthesis of CTP from UTP. As a monomer 67 kDa or dimer it is inactive because three monomers contribute to ligand binding at the active site.[51] The active form is a homotetramer (a dimer of dimers), with no NLS, intracellular to the cytosol,[51][52] for the following reactions. UTP + Gln + ATP + H2O <=> CTP + Glu + ADP + Pi ATP + UTP + NH3 <=> ADP + Pi + CTP The reactions 2 ATP + HCO3- + NH3 <=> 2 ADP + Pi + carbamoyl phosphate (multistep)[53] Gln + H2O <=> Glu + NH3[54] 2 ADP + Pi + Glu + carbamoyl phosphate <=> 2 ATP + Gln + HCO3- + H2O[55] are catalyzed by EC 6.3.5.5 carbamoyl-phosphate synthase II (CAD). It has no NLS, occurs as a homohexamer, uses Zn2+ as a cofactor and is intracellular to the nucleus.[56] It does occur in a 22 kDa form.[57] ## Kinases EC 3.6.1.5 (cofactor: Ca2+) catalyzes the following reactions: AMP + Pi <=> ADP + H2O AMP + 2 Pi <=> ATP + 2 H2O ADP + Pi <=> ATP + H2O CMP + Pi <=> CDP + H2O CMP + 2 Pi <=> CTP + 2 H2O CDP + Pi <=> CTP + H2O GMP + Pi <=> GDP + H2O GMP + 2 Pi <=> GTP + 2 H2O GDP + Pi <=> GTP + H2O UMP + Pi <=> UDP + H2O UMP + 2 Pi <=> UTP + 2 H2O UDP + Pi <=> UTP + H2O Ca2+ or Mg2+ can serve as activating ions. ENTPD1 (CD39) is a 56 kDa protein.[58] CD39 associates with RanBPM (RANBP9).[59] RANBP9 (90 kDa)[60] binds Ran, a small GTP binding protein that is essential for the translocation of RNA and proteins through the nuclear pore complex.[61] RanBPM localizes in the nucleus and cytoplasm,[59] but RanBPM has no NLS. CANT1 (EC 3.6.1.6 and 3.6.1.5) 49 kDa[62] catalyzes similar reactions: a nucleotide + Pi <=> a nucleoside diphosphate + H2O, also acting on IDP, GDP, UDP and on D-ribose 5-diphosphate.[63] ENTPD7 (EC 3.6.1.-) occurs in the mouse nucleus.[64] Enzymes 2.4.2.7 adenine phosphoribosyltransferase (APRT) 19.4 kDa (forms a dimer, 38.8 kDa) is intracellular (cytoplasm)[65] and 2.4.2.8 hypoxanthine phosphoribosyltransferase 1 (HPRT1) 24 kDa (forms a tetramer, 96 kDa) is intracellular (cytosolic)[66] catalyze the following reaction: Adenine + 5-phospho-alpha-D-ribose 1-diphosphate (PRPP) <=> AMP + PPi Neither APRT nor HPRT1 has a NLS. APRT is a dimer in solution at pH 6.5, but a monomer at pH 8.0, and like HPRT1 needs Mg2+, or Mn2+.[67] Enzymes EC 3.6.1.5 ATP pyrophosphohydrolase, ADPase[68]/ADP synthase[69] ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1) 56 kDa catalyzes the conversion of AMP into ADP (see below). Cofactor: Ca2+.[70] Ca2+ or Mg2+ can serve as activating ions. Also acts on ADP, and on other nucleoside triphosphates and diphosphates.[70] AMP + Pi <=> ADP + H2O Enzymes EC 2.7.4.6 nucleoside-diphosphate kinases A, B, C, D (NDKA-D) catalyzes the following reaction inside the nucleosol as it is intracellular (nucleus)[71] and each gene is translated as a 7-11 kDa particle[72]. However, these kinases exist either as tetramers (28-44 kDa) in bacteria or hexamers (42-66 kDa).[73] Once the hexamer has formed the particle may be too big to pass through the nuclear pores. NDKA has been shown to mediate transcription, associate with a promoter region of a gene, and be a member of the SET or INHAT complex which can modulate gene expression.[74] Nucleoside-diphosphate kinase does form nuclear and cytoplasmic hexamers.[75] NDKA-D do not have a NLS. ADP + GTP <=> ATP + GDP ## Transaminases In catabolic transamination, with PLP as a cofactor, EC 2.6.1.2 transfers the amine from glutamic acid (glutamate) (Glu) to alanine (Ala) via a two step reaction: PLP + Glu <=> pyridoxamine monophosphate (PMP) + α-ketoglutarate (2-oxoglutarate) + PMP + pyruvate <=> PLP + Ala = pyruvate + Glu <=> Ala + 2-oxoglutarate. Although this enzyme has several different names, e.g., alanine transaminase, glutamic-pyruvate transaminase (GPT), or alanine aminotransferase, it can occur as a monomer of 55 kDa or homodimer of 101 kDa, and as either a cytosolic (GPT1), or mitochondrial form (GPT2). ## Synthetases The reactions ATP + Glu + NH3 (or NH4+) <=> ADP + Pi + Gln ATP + Asp + NH4+ <=> ADP + Pi + Asn ATP + Asp + NH4+ <=> AMP + PPi + Asn are catalyzed by the enzyme EC 6.3.1.2 glutamine synthetase (GS), glutamine-ammonia ligase (GLUL). GLUL 42 kDa is intracellular, occurs as a homooctamer,[76] also as 12 kDa and 22 kDa forms,[77] and complexes with phosphate, ADP, and Mn2+. # Histone pools in the nucleosol Histones H2A, H2B, H3, and H4 are in the nucleosol, and H2B, H3, and H4 are also in the cytosol.[78] # Enzyme activity EC 2.4.1.101 (UDP-N-acetylglucosaminyl transferase) occurs and is active in the nuclesol.[79] Briefly, any enzyme that can occur as a monomer small enough to pass through the nuclear pore complex before it becomes a dimer or larger oligomer or polymer can occur and act in the nucleosol, whether it has a NLS or not. # Exonucleosol proteins Keratin type II cytoskeletal 80 (KRT80) as a monomer is 51 kDa (variant 2) and thereby can diffuse into the nucleosol, variant 3 is 54 kDA, and variant 1 is 47 kDa. KRT80 is an intermediate filament protein that makes up one of the major structural fibers of epithelial cells.[80] While keratin type I cytoskeletal 13 (KRT13) is usually paired with keratin type II cytoskeletal 4 (KRT4) 64 kDa, KRT13 has a 46 kDa variant 2 and a 39 kDA variant (KRT-13-201).[81] Keratins only assemble as heteropolymers: a type I and a type II protein forming a heterodimer. Polo-like kinase 1 (PLK1) phosphorylizes KRT4 at serine 157.[82] PLK1 27 kDa occurs in the nucleoplasm and cytosol, is ATP binding, and engages in protein amino acid phosphorylation.[83] PLK1 associates with, binds to, and phosphorylates alpha-, beta- and gamma-tubulins in interphase independent of the microtubule polymerization state.[84] Intermediate filaments (IFs) are composed of proteins (40-210 kDa) that self-assemble into complex cytoskeletal fibers.[85] Inside an interphase cell, ~5% of the total intermediate filament protein exists in a soluble tetrameric form.[86] Newly synthesized intermediate filament protein is soluble and self-assembly proceeds at concentrations >40-50 µg/ml.[86] Homodimers of IF proteins can form and be added to already forming IFs but cannot assemble into IFs themselves.[86] # History of the nucleosol While earlier articles or book sections may exist mentioning the term "nucleosol", a book from 1970 online refers to the nucleosol.[87] # Acknowledgements The content on this page was first contributed by: Henry A. Hoff. Initial content for this page in some instances came from Wikipedia.	https://www.wikidoc.org/index.php/Nucleosol
a9a2e97aff9c0bb7f1f219f21987c35248804bc1	wikidoc	Nutrament	Nutrament A nutritional vitamin drink supplied by Novartis Labs, Nutrament was originally distributed by Mead Johnson & Company, beginning in 1960. Current flavors on the market are vanilla, chocolate, strawberry, coconut, banana, cappucino, and eggnog. The product is supplied as individual servings in pull-top cans. In official records, it is described as "Nutritionally Complete Food Consisting Principally of Milk Solids, Maltose-Dextrins, Soy Flour, Sucrose." Late in the 1960s, a powdered form was offered for mixing with milk, but that brand registration was not renewed in 1988 and officially expired in 1992, still owned by Mead Johnson. Mead Johnson also marketed a "dietary supplement" under the same brand in 1985, and registered the brand "Nutrament The Energy and Fitness Drink" in 1996. Nutrament was purchased from Mead Johnson & Company effective February 13, 2004.	Nutrament A nutritional vitamin drink supplied by Novartis Labs, Nutrament was originally distributed by Mead Johnson & Company, beginning in 1960. Current flavors on the market are vanilla, chocolate, strawberry, coconut, banana, cappucino, and eggnog. The product is supplied as individual servings in pull-top cans. In official records, it is described as "Nutritionally Complete Food Consisting Principally of Milk Solids, Maltose-Dextrins, Soy Flour, Sucrose." Late in the 1960s, a powdered form was offered for mixing with milk, but that brand registration was not renewed in 1988 and officially expired in 1992, still owned by Mead Johnson. Mead Johnson also marketed a "dietary supplement" under the same brand in 1985, and registered the brand "Nutrament The Energy and Fitness Drink" in 1996. Nutrament was purchased from Mead Johnson & Company effective February 13, 2004. Template:Food-product-stub	https://www.wikidoc.org/index.php/Nutrament
7c4ff237bd2144fd8d462017531710eeddf738bf	wikidoc	Nutrilite	Nutrilite Nutrilite is a brand of vitamin, mineral and dietary supplements created in 1934 by Dr. Carl F. Rehnborg. Nutrilite products are currently manufactured by Access Business Group, a subsidiary of Alticor who's products are sold via the Amway and Quixtar Corporations worldwide. The Nutrilite brand is known as Nutriway in Denmark, Finland, Norway, Sweden, Turkey, Australia and New Zealand. The founders of Amway began selling Nutrilite products in 1949. Amway bought a controlling interest in the company in 1972, and took over complete ownership in 1994. Nutrilite's vitamin and mineral products are distributed exclusively by Quixtar affiliates known as Independent Business Owners (IBO) in North America and Amway IBOs in more than 90 other countries and territories. Amway, Quixtar, and Access Business Group, are subsidiaries of Alticor. Nutrilite claims to be the only global vitamin and mineral brand to grow, harvest and process plants on their own certified organic farms, although Nutrilite states that their products may sometimes have ingredients from plants grown not at their own farms. Nutrilite farming techniques include soil solarization, an integrated pest management system and utilize sustainable agricultural production systems. Nutrilite's organic farms are located in California, Washington State, Mexico, and Brazil.. Many Nutrilite products sold in other countries are also manufactured locally, for example in India.IBOs can sell these products at any price they choose to. In 2001, five Nutrilite products were the first dietary supplements to be certified by NSF International. # Spokespersons Nutrilite has signed 2006 World Male Athlete of the Year and men's 100m sprint world record holder, Asafa Powell of Jamaica, 110m men's hurdles World Record Holder, Olympic and World Champion Liu Xiang of China, 2006 World Female Athlete of the Year Sanya Richards of the USA, and American Pole Vault Champion Jennifer Stuczynski as spokespersons for the brand.	Nutrilite Nutrilite is a brand of vitamin, mineral and dietary supplements created in 1934 by Dr. Carl F. Rehnborg. Nutrilite products are currently manufactured by Access Business Group, a subsidiary of Alticor who's products are sold via the Amway and Quixtar Corporations worldwide. The Nutrilite brand is known as Nutriway in Denmark, Finland, Norway, Sweden, Turkey, Australia and New Zealand. The founders of Amway began selling Nutrilite products in 1949. Amway bought a controlling interest in the company in 1972, and took over complete ownership in 1994.[1] Nutrilite's vitamin and mineral products are distributed exclusively by Quixtar affiliates known as Independent Business Owners (IBO) in North America and Amway IBOs in more than 90 other countries and territories. Amway, Quixtar, and Access Business Group, are subsidiaries of Alticor. Nutrilite claims to be the only global vitamin and mineral brand to grow, harvest and process plants on their own certified organic farms, although Nutrilite states that their products may sometimes have ingredients from plants grown not at their own farms.[2] Nutrilite farming techniques include soil solarization, an integrated pest management system and utilize sustainable agricultural production systems. Nutrilite's organic farms are located in California, Washington State, Mexico, and Brazil.[3]. Many Nutrilite products sold in other countries are also manufactured locally, for example in India.[4]IBOs can sell these products at any price they choose to. In 2001, five Nutrilite products were the first dietary supplements to be certified by NSF International.[5] # Spokespersons Nutrilite has signed 2006 World Male Athlete of the Year and men's 100m sprint world record holder, Asafa Powell of Jamaica, 110m men's hurdles World Record Holder, Olympic and World Champion Liu Xiang of China, 2006 World Female Athlete of the Year Sanya Richards of the USA, and American Pole Vault Champion Jennifer Stuczynski as spokespersons for the brand.[6][7][8]	https://www.wikidoc.org/index.php/Nutrilite
d5d4654315276a8ae0bdf216f67a016f8f5a964d	wikidoc	Obestatin	Obestatin Obestatin is a hormone that is produced in specialized epithelial cells of the stomach and small intestine of several mammals including humans. Obestatin was originally identified as an anorectic peptide, but its effect on food intake remains controversial. # Discovery Obestatin was discovered using a bioinformatics approach: by computer search of the sequenced genomes of several organisms. # Structure The obestatin structure to the right was determined by NMR. The length of the polypeptide was found to be 24 residues with a secondary structure 29% helical. Specifically 2 helices and 7 residues are formed. # Gene and transcription Obestatin is encoded by the same gene that encodes ghrelin, a peptide hormone. The mRNA produced from the GHRL gene has four exons. Five products of similar structure and function arise: the first is the 117-amino acid preproghrelin. (It is homologous to promotilin; both are members of the motilin family). It is cleaved to produce proghrelin which is cleaved to produce a 28-amino acid ghrelin (unacylated) and C-ghrelin(acylated). Obestatin is presumed to be cleaved from C-ghrelin. # Receptor It was originally proposed that GPR39 functioned as an obestatin receptor, however more recent findings suggest that this is unlikely. # Blood levels As yet no biochemical studies of circulating obestatin have been carried out. # Function Obestatin opposes the actions of ghrelin which are growth hormone secretion and increased appetite. The purpose of producing two hormones with opposing effects is not clear: removing the ghrelin gene from mice did not significantly reduce food intake. No secretory convertase is capable of cleaving the recombinant proghrelin precursor by cleavage at the single basic residue required for generation of the obestatin sequence. Thus the physiological generation of this particular peptide sequence remains unproven. Obestatin has opposite action to ghrelin on food intake and plays a role in energy balance. Circuit-resistance exercise resulted in a significant change in GH levels, but had no effect on plasma Obestatin levels. # Clinical significance Studies on the obestatin/ghrelin ratio in the gastrointestinal tract and plasma are associated with some diseases such as irritable bowel syndrome (IBS), obesity, Prader–Willi syndrome, and type II diabetes mellitus.	Obestatin Obestatin is a hormone that is produced in specialized epithelial cells of the stomach and small intestine of several mammals including humans.[2] Obestatin was originally identified as an anorectic peptide, but its effect on food intake remains controversial.[3] # Discovery Obestatin was discovered using a bioinformatics approach: by computer search of the sequenced genomes of several organisms.[4] # Structure The obestatin structure to the right was determined by NMR. The length of the polypeptide was found to be 24 residues with a secondary structure 29% helical. Specifically 2 helices and 7 residues are formed.[1] # Gene and transcription Obestatin is encoded by the same gene that encodes ghrelin, a peptide hormone. The mRNA produced from the GHRL gene has four exons. Five products of similar structure and function arise: the first is the 117-amino acid preproghrelin. (It is homologous to promotilin; both are members of the motilin family). It is cleaved to produce proghrelin which is cleaved to produce a 28-amino acid ghrelin (unacylated) and C-ghrelin(acylated). Obestatin is presumed to be cleaved from C-ghrelin.[5] # Receptor It was originally proposed that GPR39 functioned as an obestatin receptor, however more recent findings suggest that this is unlikely.[6] # Blood levels As yet no biochemical studies of circulating obestatin have been carried out. # Function Obestatin opposes the actions of ghrelin which are growth hormone secretion and increased appetite.[3] The purpose of producing two hormones with opposing effects is not clear: removing the ghrelin gene from mice did not significantly reduce food intake. No secretory convertase is capable of cleaving the recombinant proghrelin precursor by cleavage at the single basic residue required for generation of the obestatin sequence.[7] Thus the physiological generation of this particular peptide sequence remains unproven. Obestatin has opposite action to ghrelin on food intake and plays a role in energy balance.[8] Circuit-resistance exercise resulted in a significant change in GH levels, but had no effect on plasma Obestatin levels.[9] # Clinical significance Studies on the obestatin/ghrelin ratio in the gastrointestinal tract and plasma are associated with some diseases such as irritable bowel syndrome (IBS),[10] obesity,[11] Prader–Willi syndrome,[12] and type II diabetes mellitus.[13][14]	https://www.wikidoc.org/index.php/Obestatin
40109c833cb663c00ecf6ca9f5c0f26b05f82d4c	wikidoc	Obidoxime	Obidoxime # Overview Obidoxime is a member of the oxime family used to treat nerve gas poisoning. Oximes are drugs known for their ability to reverse the binding of organophosphorus compounds to the enzyme acetylcholinesterase (AChE). AChE is an enzyme that removes acetylcholine from the synapse after it creates the required stimulation on the next nerve cell. If it gets inhibited, acetylcholine is not removed after the stimulation and multiple stimulations are made, resulting in muscle contractions and paralysis. Organophosphates (such as nerve gases) are well-known inhibitors of AChE. They bind to a specific place on the enzyme and prevent it from functioning normally by changing the OH group on the serine residue and by protonating (quaternary nitrogen, R4N+) the nearby nitrogen atom located in the histidine residue. # Function Oximes such as obidoxime, pralidoxime and asoxime (HI-6) are used to restore enzyme functionality. They have greater affinity for the organic phosphate residue than the enzyme and they remove the phosphate group, restore the OH to serine and turn nitrogen from histidine back into its R3N form (tertiary nitrogen). This results in full enzyme recovery and the phosphate-oxime compound is eliminated from the organism via urine. # Side effects Oximes like these do have side effects and they include liver damage, kidney damage, nausea, vomiting, but they are very efficient antidotes to nerve gas poisoning. Usually treatment of poisoning includes the use of atropine, which can slow down the action of the poison, giving more time to apply the oxime.	Obidoxime Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Obidoxime is a member of the oxime family used to treat nerve gas poisoning. Oximes are drugs known for their ability to reverse the binding of organophosphorus compounds to the enzyme acetylcholinesterase (AChE).[1] AChE is an enzyme that removes acetylcholine from the synapse after it creates the required stimulation on the next nerve cell. If it gets inhibited, acetylcholine is not removed after the stimulation and multiple stimulations are made, resulting in muscle contractions and paralysis. Organophosphates (such as nerve gases) are well-known inhibitors of AChE. They bind to a specific place on the enzyme and prevent it from functioning normally by changing the OH group on the serine residue and by protonating (quaternary nitrogen, R4N+) the nearby nitrogen atom located in the histidine residue. # Function Oximes such as obidoxime, pralidoxime and asoxime (HI-6) are used to restore enzyme functionality. They have greater affinity for the organic phosphate residue than the enzyme and they remove the phosphate group, restore the OH to serine and turn nitrogen from histidine back into its R3N form (tertiary nitrogen). This results in full enzyme recovery and the phosphate-oxime compound is eliminated from the organism via urine. # Side effects Oximes like these do have side effects and they include liver damage, kidney damage, nausea, vomiting, but they are very efficient antidotes to nerve gas poisoning. Usually treatment of poisoning includes the use of atropine, which can slow down the action of the poison, giving more time to apply the oxime.	https://www.wikidoc.org/index.php/Obidoxime
fdb59cc6a93247ee812db9d43d828b5aa41c9b01	wikidoc	Ocularist	Ocularist An ocularist is someone who specializes in the fabrication and fitting of ocular prostheses for people who have lost an eye or eyes due to trauma or illness. The fabrication process for a custom made eye typically includes taking an impression of the eye socket, shaping a plastic shell, painting the iris and then fitting the ocular prostheses. In addition to creating the prosthetic eye, they show the patient how to care for and handle the prosthesis. Ocularists may develop their skills from various background disciplines, for example medical, optometry, dental, nursing, biology, medical arts and illustration. # United States Training and registration varies. There is not a specific training program of study to become an "ocularist" at the present time. This field is practiced in many places by maxillofacial prosthodontists who are dentists who have undergone 3-4 years of specialty residency training. There are also technicians who practice this field as well after learning how to make artificial eyes through an apprenticeship program approved by the American Society of Ocularists or Anaplastologists.	Ocularist An ocularist is someone who specializes in the fabrication and fitting of ocular prostheses for people who have lost an eye or eyes due to trauma or illness. The fabrication process for a custom made eye typically includes taking an impression of the eye socket, shaping a plastic shell, painting the iris and then fitting the ocular prostheses. In addition to creating the prosthetic eye, they show the patient how to care for and handle the prosthesis. Ocularists may develop their skills from various background disciplines, for example medical, optometry, dental, nursing, biology, medical arts and illustration. # United States Training and registration varies. There is not a specific training program of study to become an "ocularist" at the present time. This field is practiced in many places by maxillofacial prosthodontists who are dentists who have undergone 3-4 years of specialty residency training. There are also technicians who practice this field as well after learning how to make artificial eyes through an apprenticeship program approved by the American Society of Ocularists or Anaplastologists.	https://www.wikidoc.org/index.php/Ocularist
aaaa4f259ea6c2dc990e3de67d0af4c371d77e43	wikidoc	Oculotect	Oculotect Oculotect is used in the treatment of dry eye syndrome, also called 'Keratoconjunctivitis sicca (KCS), keratitis sicca or xerophthalmia. It is available over the counter and is usually found in the form of sterile eye drops or ointment. It contains retinol, which is vital for the eyes, and povidone (polyvidone) 5%. Ocolutect does not contain preservatives. # Indications for use Relief of dry eye symptoms; as a tear substitute when preservative use may be contraindicated or considered inadvisable. It is also sometimes used for the treatment of corneal ulcers as it covers the cornea with a protective layer and helps in the healing process. It can also help contact lens wearers who complain of dry eyes. Patients with severe occular allergies may experience dry eyes and the medication is particularly useful in such cases as it blocks out allergens such as pollens and dust mites. # Contraindication/s Known allergy (sensitivity) to any of the eye drops ingredients . # Specific precautions The drug has not been tested on animals, children or pregnant patients, so it is advisable to consult an ophthalmologist before using Ocultect. # Adverse drug reactions Since the drug does not contain active chemical ingredients, no adverse reactions are expected. Blurred vision, itching and burning sensation can sometimes appear shortly after application. These are usually short-lived and should not be a cause for concern. # External link	Oculotect Oculotect is used in the treatment of dry eye syndrome, also called 'Keratoconjunctivitis sicca (KCS), keratitis sicca or xerophthalmia. It is available over the counter and is usually found in the form of sterile eye drops or ointment. It contains retinol, which is vital for the eyes, and povidone (polyvidone) 5%. Ocolutect does not contain preservatives. # Indications for use Relief of dry eye symptoms; as a tear substitute when preservative use may be contraindicated or considered inadvisable. It is also sometimes used for the treatment of corneal ulcers as it covers the cornea with a protective layer and helps in the healing process. It can also help contact lens wearers who complain of dry eyes. Patients with severe occular allergies may experience dry eyes and the medication is particularly useful in such cases as it blocks out allergens such as pollens and dust mites. # Contraindication/s Known allergy (sensitivity) to any of the eye drops ingredients . # Specific precautions The drug has not been tested on animals, children or pregnant patients, so it is advisable to consult an ophthalmologist before using Ocultect. # Adverse drug reactions Since the drug does not contain active chemical ingredients, no adverse reactions are expected. Blurred vision, itching and burning sensation can sometimes appear shortly after application. These are usually short-lived and should not be a cause for concern. # External link http://www.netdoctor.co.uk/medicines/100001914.html Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Oculotect
b9bb575c3d240c729d6ca737762cd46c69acf532	wikidoc	Oenothera	Oenothera Oenothera is a genus of about 125 species of annual, biennial and perennial herbaceous flowering plants, native to North and South America. It is the type genus of the family Onagraceae. Common names include evening primrose, suncups, and sundrops. The species vary in size from small alpine plants 10 cm tall (e.g. O. acaulis from Chile), to vigorous lowland species growing to 3 m (e.g. O. stubbei from Mexico). The leaves form a basal rosette at ground level and spiral up to the flowering stems; the leaves are dentate or deeply lobed (pinnatifid). The flowers open in the evening, hence the name "evening primrose", and are yellow in most species but white, purple, pink or red in a few; there are four petals. One of the most distinctive features of the flower is the stigma with four branches, forming an X shape. Pollination is by Lepidoptera (moths) and bees; like many members of the Onagraceae, however, the pollen grains are loosely held together by viscin threads (see photo below), meaning that only bees that are morphologically specialized to gather this pollen can effectively pollinate the flowers (it cannot be held effectively in a typical bee scopa). Furthermore, the flowers are open at a time when most bee species are inactive, so the bees which visit Oenothera are also compelled to be vespertine temporal specialists. The seeds ripen from late summer to fall. Oenothera species are used as food plants by the larvae of some Lepidoptera species including Schinia felicitata and Schinia florida, both of which feed exclusively on the genus, the former exclusively on O. deltoides. In the wild, evening primroses acts as primary colonizers, springing up wherever a patch of bare, undisturbed ground may be found. This means that they tend to be found in poorer environments such as dunes, roadsides, railway embankments and wasteland. It often occurs as a casual, eventually being out-competed by other species. The genus Oenothera may have originated in Mexico and Central America. During the Pleistocene era a succession of ice ages swept down across North America, with intervening warm periods. This was repeated for four ice ages, with four separate waves of colonization, each hybridizing with the remnants of the previous waves. This generated a present-day population that is very rich in genetic diversity, spread right across the North American continent. It was originally assigned to the genus Onagra, which gave the family Onagraceae its name. Onagra (meaning "(food of) onager") was first used in botany in 1587, and in English in Philip Miller's 1754 Gardeners Dictionary: Abridged. Its modern name Oenothera was published by Carolus Linnaeus in his Systema Naturae. William Baird suggests that since oeno means "wine" in Greek it refers to the fact that the root of the edible Oenothera biennis was used as a wine flavor additive. # Cultivation and uses Young roots can be eaten like a vegetable (with a peppery flavour), or the shoots can be eaten as a salad. The whole plant was used to prepare an infusion with astringent and sedative properties. It was considered to be effective in healing asthmatic coughs, gastro-intestinal disorders, whooping cough and as a sedative pain-killer. Poultices containing O. biennis were at one time used to ease bruises and speed wound healing. One of the common names for Oenothera, "Kings cureall", reflects the wide range of healing powers ascribed to this plant, although it should be noted that its efficacy for these purposes has not been demonstrated in clinical trials. The mature seeds contain approximately 7-10% gamma-linolenic acid, a rare essential fatty acid. The O. biennis seed oil is used to reduce the pains of premenstrual stress syndrome. Gamma-linolenic acid also shows promise against breast cancer. Evening Primroses are very popular ornamental plants in gardens. For propagation, the seeds can be sown in situ from late spring to early summer. The plant will grow successfully in fertile soils if competing species are kept at bay. Evening primrose species can be planted in any ordinary, dry, well-drained garden soil (preferly sandy loam) in an open site that is sunny to partly shady. They are fairly drought-resistant. The first plants to arrive in Europe reached Padua from Virginia in 1614 and were described by the English botanist John Goodyer in 1621. Some species are now also naturalized in parts of Europe and Asia, and can be grown as far north as 65° N in Finland. The UK National Council for the Conservation of Plants and Gardens, based at Wisley, maintains an Oenothera collection as part of its National Collections scheme.	Oenothera Oenothera is a genus of about 125 species of annual, biennial and perennial herbaceous flowering plants, native to North and South America. It is the type genus of the family Onagraceae. Common names include evening primrose, suncups, and sundrops. The species vary in size from small alpine plants 10 cm tall (e.g. O. acaulis from Chile), to vigorous lowland species growing to 3 m (e.g. O. stubbei from Mexico). The leaves form a basal rosette at ground level and spiral up to the flowering stems; the leaves are dentate or deeply lobed (pinnatifid). The flowers open in the evening, hence the name "evening primrose", and are yellow in most species but white, purple, pink or red in a few; there are four petals. One of the most distinctive features of the flower is the stigma with four branches, forming an X shape.[1] Pollination is by Lepidoptera (moths) and bees; like many members of the Onagraceae, however, the pollen grains are loosely held together by viscin threads (see photo below), meaning that only bees that are morphologically specialized to gather this pollen can effectively pollinate the flowers (it cannot be held effectively in a typical bee scopa). Furthermore, the flowers are open at a time when most bee species are inactive, so the bees which visit Oenothera are also compelled to be vespertine temporal specialists. The seeds ripen from late summer to fall. Oenothera species are used as food plants by the larvae of some Lepidoptera species including Schinia felicitata and Schinia florida, both of which feed exclusively on the genus, the former exclusively on O. deltoides. In the wild, evening primroses acts as primary colonizers, springing up wherever a patch of bare, undisturbed ground may be found. This means that they tend to be found in poorer environments such as dunes, roadsides, railway embankments and wasteland. It often occurs as a casual, eventually being out-competed by other species. The genus Oenothera may have originated in Mexico and Central America. During the Pleistocene era a succession of ice ages swept down across North America, with intervening warm periods. This was repeated for four ice ages, with four separate waves of colonization, each hybridizing with the remnants of the previous waves. This generated a present-day population that is very rich in genetic diversity, spread right across the North American continent. It was originally assigned to the genus Onagra, which gave the family Onagraceae its name. Onagra (meaning "(food of) onager") was first used in botany in 1587, and in English in Philip Miller's 1754 Gardeners Dictionary: Abridged. Its modern name Oenothera was published by Carolus Linnaeus in his Systema Naturae. William Baird suggests that since oeno means "wine" in Greek it refers to the fact that the root of the edible Oenothera biennis was used as a wine flavor additive.[citation needed] # Cultivation and uses Young roots can be eaten like a vegetable (with a peppery flavour), or the shoots can be eaten as a salad. The whole plant was used to prepare an infusion with astringent and sedative properties. It was considered to be effective in healing asthmatic coughs, gastro-intestinal disorders, whooping cough and as a sedative pain-killer. Poultices containing O. biennis were at one time used to ease bruises and speed wound healing. One of the common names for Oenothera, "Kings cureall", reflects the wide range of healing powers ascribed to this plant, although it should be noted that its efficacy for these purposes has not been demonstrated in clinical trials. The mature seeds contain approximately 7-10% gamma-linolenic acid, a rare essential fatty acid. The O. biennis seed oil is used to reduce the pains of premenstrual stress syndrome. Gamma-linolenic acid also shows promise against breast cancer.[2] Evening Primroses are very popular ornamental plants in gardens. For propagation, the seeds can be sown in situ from late spring to early summer. The plant will grow successfully in fertile soils if competing species are kept at bay. Evening primrose species can be planted in any ordinary, dry, well-drained garden soil (preferly sandy loam) in an open site that is sunny to partly shady. They are fairly drought-resistant. The first plants to arrive in Europe reached Padua from Virginia in 1614 and were described by the English botanist John Goodyer in 1621. Some species are now also naturalized in parts of Europe and Asia, and can be grown as far north as 65° N in Finland. The UK National Council for the Conservation of Plants and Gardens, based at Wisley, maintains an Oenothera collection as part of its National Collections scheme.	https://www.wikidoc.org/index.php/Oenothera
7734d6023ccf4aac0d25ce3d826abdec31e2c03e	wikidoc	Ohm's law	Ohm's law Ohm's law states that, in an electrical circuit, the current passing through a conductor between two points is directly proportional to the potential difference (i.e. voltage drop or voltage) across the two points, and inversely proportional to the resistance between them. The mathematical equation that describes this relationship is: where I is the current in amperes, V is the potential difference between two points of interest in volts, and R is a circuit parameter, measured in ohms (which is equivalent to volts per ampere), and is called the resistance. The potential difference is also known as the voltage drop, and is sometimes denoted by U, E or emf (electromotive force) instead of V. The law was named after the physicist Georg Ohm, who, in a treatise published in 1827, described measurements of applied voltage, and current passing through, simple electrical circuits containing various lengths of wire, and presented a slightly more complex equation than the one above to explain his experimental results. The above equation is the modern form of Ohm's law; it could not exist until the ohm itself was defined (1861, 1864). Well before Georg Ohm's work, Henry Cavendish found experimentally (January 1781) that current varies in direct proportion to applied voltage, but he did not communicate his results to other scientists at the time. The resistance of most resistive devices (resistors) is constant over a large range of values of current and voltage. When a resistor is used under these conditions, the resistor is referred to as an ohmic device because a single value for the resistance suffices to describe the resistive behavior of the device over the range. When sufficiently high voltages are applied to a resistor, forcing a high current to flow through it, the device is no longer ohmic because its resistance, when measured under such electrically stressed conditions, is different (typically greater) from the value measured under standard conditions (see temperature effects, below). Ohm's law, in the form above, is an extremely useful equation in the field of electrical/electronic engineering because it describes how voltage, current and resisitance are interrelated on a macroscopic level, that is, commonly, as circuit elements in an electrical circuit. Physicists who study the electrical properties of matter at the microsopic level use a closely related and more general vector equation, sometimes also referred to as Ohm's law, having variables that are closely related to the I, V and R scalar variables of Ohm's law, but are each functions of position within the conductor. See the Physics section and the Relation to heat conduction section below. # Elementary description and use Electrical circuits consist of electrical devices connected by wires (or other suitable conductors). (See the article electrical circuits for some basic combinations.) The above diagram shows one of the simplest electrical circuits that can be constructed. One electrical device is shown as a circle with + and - terminals, which represents a voltage source such as a battery. The other device is illustrated by a zig-zag symbol and has an R beside it. This symbol represents a resistor, and the R designates its resistance. The + or positive terminal of the voltage source is connected to one of the terminals of the resistor using a wire of negligible resistance, and through this wire a current I is shown to be passing, in a specified direction illustrated by the arrow. The other terminal of the resistor is connected to the - or negative terminal of the voltage source by a second wire. This configuration forms a complete circuit because all the current that leaves one terminal of the voltage source must return to the other terminal of the voltage source. (While not shown, because electrical engineers assume that it exists, there is an implied current I, and an arrow pointing to the left, associated with the second wire.) Voltage is the electrical force that moves (negatively charged) electrons through wires and electrical devices, current is the rate of electron flow, and resistance is the property of a resistor (or other device that obeys Ohm's law) that limits current to an amount proportional to the applied voltage. So, for a given resistance R (ohms), and a given voltage V (volts) established across the resistance, Ohm's law provides the equation (I=V/R) for calculating the current that must flow through the resistor (or device). The 'conductor' mentioned by Ohm's law is a circuit element across which the voltage is measured. Resistors are conductors that slow down the passage of electric charge. A resistor with a high value of resistance, say greater than 10 megaohms, is a poor conductor, while a resistor with a low value, say less than 0.1 ohm, is a good conductor. (Insulators are materials that, for most practical purposes, do not allow a current to flow when a voltage is applied.) In a circuit diagram like the one above, the various components may be joined by connectors, contacts, welds or solder joints of various kinds, but for simplicity these connections are usually not shown. # Physics Physicists often use the continuum form of Ohm's Law: \mathbf{J} = \sigma \cdot \mathbf{E} where J is the current density (current per unit area, unlike the simpler I, units of amperes, of Ohm's law), σ is the conductivity (which can be a tensor in anisotropic materials) and E is the electric field (units of volts per meter, unlike the simpler V, units of volts, of Ohms's law). While the notation above does not explicitly depict the variables, each are vectors and each are functions of three position variables. (Normally, and in some places below, the dot means the vector dot product. Here the dot just means multiplication.) That is, in the case of J, using cartesian coordinates, there are actually three separate equations, one for each component of the vector, each equation having three independent position variables. For example, the components of J in the x, y and z directions would be Jx(x,y,z), Jy(x,y,z) and Jz(x,y,z). The common form used in circuit design is the macroscopic, averaged-out version of Ohm's actual equation, and can be derived thusly: the potential difference between two points is defined as -r, in the case where the electric field is independent of the choice of path (as it is in a circuit), {\|\Delta V\|} = {E}{L} where L is the distance between points of interest. since the current per unit area, J, is equal to I/A, Ohm's Law becomes: The Electrical Resistance of a conductor is defined in terms of conductivity, length, and cross sectional area: From this, it can be seen that Ohm's law takes on the more familiar, yet macroscopic and averaged version: The continuum form of the equation is only valid in the reference frame of the conducting material. If the material is moving at velocity v relative to a magnetic field B, a term must be added as follows \mathbf{J} = \sigma \cdot \left( \mathbf{E} + \mathbf{v}\times\mathbf{B} \right) The analogy to the Lorentz force is obvious, and in fact Ohm's law can be derived from the Lorentz force and the assumption that there is a drag on the charge carriers proportional to their velocity. A perfect metal lattice would have no resistivity, but a real metal has crystallographic defects, impurities, multiple isotopes, and thermal motion of the atoms. Electrons scatter from all of these, resulting in resistance to their flow. Ohm's law is sufficient to derive both Kirchhoff's voltage law (KVL) and Kirchhoff's current law (KCL). Let us first examine only the right-hand side of the equation: and calculate the line integral around a closed contour: Applying Stokes's theorem, we can write over the surface bounded by the countour: but, since E is the gradient of a scalar potential, yielding: and gradients are irrotational, we have: thereby proving KCL. Returning to the original formulation of Ohm's law: and forming the closed line integrals again: and recalling from Maxwell's equations that curl(H) = J: we apply Stokes's theorem to obtain: From our preceding derivation, we know that the right-hand side evaluates to zero: thus proving that the net current flow through an open surface is zero, which restates KCL. # How electrical and electronic engineers use Ohm's law Ohm's Law is one of the equations used in the analysis of electrical circuits, whether the analysis is done by engineers or computers. Even though, today, computers running electronic computer aided design and analysis programs do the bulk of the work predicting and optimizing the performance of electrical circuits (in particular, those circuits to be fabricated on silicon chips), most electrical engineers still use Ohm's Law every working day. Whether designing or debugging an electrical circuit, electrical engineers must have a working knowledge of the practical aspects of Ohm's law. Virtually all electronic circuits have resistive elements which are almost always considered ideal ohmic devices, i.e. they obey Ohm's Law. From the engineer's point of view, resistors (devices that "resist" the flow of electrical current) develop a voltage across their terminal conductors (e.g. the two wires emerging from the device) proportional to the amount of current flowing through the device. More specifically, the voltage measured across a resistor at a given instant is strictly proportional to the current passing through the resistor at that instant. When a functioning electrical circuit drives a current I, measured in amperes, through a resistor of resistance R, the voltage that develops across the resistor is I R, the value of R serving as the proportionality factor. (That current must have been supplied by a circuit element functioning as a current source and it must be passed on to a circuit element that serves as a current sink.) Thus resistors act like current-to-voltage converters (just as springs act like displacement-to-force converters). Similarly, a circuit may incorporate a resistor (of resistance R) designed to function as a voltage-to-current converter. In such a circuit, a desired voltage V is established across the resistor in order to force a current I exactly equal to 1/R times V to flow through the resistor. The DC resistance of a resistor is always a positive quantity, and the current flowing through a resistor generates (waste) heat in the resistor as it does in one of Ohm's wires. Voltages can be either positive or negative, and are always measured with respect to a reference point. When we say that a point in a circuit has a certain voltage, it is understood that this voltage is really a voltage difference (a two terminal measurement) and that there is an understood, or explicitly stated, reference point, often called ground or common. Currents can be either positive or negative, the sign of the current indicating the direction of current flow. Current flow in a wire consists of the slow drift of electrons due to the influence of a voltage established between two points on the wire. Since the resistance of a resistor is always positive and the equation describing Ohm's law does not in itself constrain R to be positive (by being written as: \|V\|=\|I\| R), there is the potential for computing a negative value for R. Using measurements of voltage and current that are made correctly, the sign of a computed R is never negative. When a negative R is computed based on a measurement of the voltage drop across a resistor and a measurement of the current passing through the resistor, then one of the two measurements must have been made improperly. When circuits are analyzed, the direction of flow of current between circuit elements may not be known or obvious. In this case, the direction of the current is assigned arbitrarily. Should a sign error (one that implies a negative resistance) arise during the analysis, the error is resolved by asserting that the initially assigned direction of current was incorrect, and that the actual direction of current is in the direction opposite to the initially assigned direction. Non-ohmic and active components may actually have negative differential resistance, a subject discussed in its own article. The word 'differential' is key, though often omitted, because it describes the characteristics of an interesting portion of the I vs. V curve of the non-ohmic device. At no time is the 'static' resistance itself negative. Certain powered circuit devices, constructed as two terminal devices and tested as if they were a resistor (by applying a voltage across the two terminals while measuring the current), may exhibit actual negative resistance. Ohm's law is not intended to apply to such devices. Further the law of conservation of energy is not violated because there is an integrated source of power. Ohm's law applies to conductors whose resistance is (substantially) independent of the applied voltage (or equivalently the injected current). That is, Ohm's law only applies to the linear portion of the I vs. V curve centered around the origin. The equation is just too simple to encompass devices described by a more complicated I vs. V relationship. The blue line in the I vs. V graph at right represents ohmic devices because current is directly (linearly) proportional to the applied voltage. The slope of the blue line is 1/R. The graph's red line represents a non-ohmic device such as a lamp filament because as more voltage is applied, heating the filament, the filament's resistance rises, forcing the (magnitude of the) slope to decrease. The graph's yellow line illustrates the I vs. V characteristics of a non-ohmic two terminal circuit having semi-conductor components (such as paralleled and oppositely oriented diodes). ## Hydraulic analogs While the terms voltage, current and resistance are fairly intuitive terms, beginning students of electrical engineering might find the analog terms for water flow helpful. Water pressure, measured by pascals (or PSI), is the analog of voltage because establishing a water pressure difference between two points along a (horizontal) pipe causes water to flow. Water flow rate, as in liters (or gallons) of water per minute, is the analog of current, as in coulombs per second. Finally, flow restrictors — such as apertures placed in pipes between points where the water pressure is measured — are the analog of resistors. We say that the rate of water flow through an aperture restrictor is proportional to the difference in water pressure across the restrictor. Similarly, the rate of flow of electrical charge, i.e. the electrical current, passing through an electrical resistor is proportional to the difference in voltage measured across the resistor. ## Sheet resistance Thin metal films, usually deposited on insulating substrates, are used for various purposes, the electrical current traveling parallel to the plane of the film. When describing the electrical resistivity of such devices, the term ohms-per-square is used. See sheet resistance. # Temperature effects When the temperature of the conductor increases, the collisions between electrons and atoms increase. Thus as a substance heats up because of electricity flowing through it (or by any heating process), the resistance will usually increase. The exception is semiconductors. The resistance of an Ohmic substance depends on temperature in the following way: R = \frac{L}{A} \cdot \rho = \frac{L}{A} \cdot \rho_0 (\alpha (T - T_0) + 1) where ρ is the resistivity, L is the length of the conductor, A is its cross-sectional area, T is its temperature, T_0 is a reference temperature (usually room temperature), and \rho_0 and \alpha are constants specific to the material of interest. In the above expression, we have assumed that L and A remain unchanged within the temperature range. It is worth mentioning that temperature dependence does not make a substance non-ohmic, because at a given temperature, R does not vary with voltage or current (V / I = \mathrm{constant}). Intrinsic semiconductors exhibit the opposite temperature behavior, becoming better conductors as the temperature increases. This occurs because the electrons are bumped to the conduction energy band by the thermal energy, where they can flow freely and in doing so they leave behind holes in the valence band which can also flow freely. Extrinsic semiconductors have much more complex temperature behaviour. First the electrons (or holes) leave the donors (or acceptors) giving a decreasing resistance. Then there is a fairly flat phase in which the semiconductor is normally operated where almost all of the donors (or acceptors) have lost their electrons (or holes) but the number of electrons that have jumped right over the energy gap is negligible compared to the number of electrons (or holes) from the donors (or acceptors). Finally as the temperature increases further the carriers that jump the energy gap becomes the dominant figure and the material starts behaving like an intrinsic semiconductor. # Strain (mechanical) effects Just as the resistance of a conductor depends upon temperature, the resistance of a conductor depends upon strain. By placing a conductor under tension (a form of strain), which means to mechanically stretch the conductor, the length of the section of conductor under tension increases and its cross-sectional area decreases. Both these effects contribute to increasing the resistance of the strained section of conductor. Under compression (the other form of strain), the resistance of the strained section of conductor decreases. See the discussion on strain gauges for details about devices constructed to take advantage of this effect. # AC circuits For an AC circuit Ohm's law can be written \mathbf{V} = \mathbf{I} \cdot \mathbf{Z}, where V and I are the oscillating phasor voltage and current respectively and Z is the complex impedance for the frequency of oscillation. In a transmission line, the phasor form of Ohm's law above breaks down because of reflections. In a lossless transmission line, the ratio of voltage and current follows the complicated expression Z(d) = Z_0 \frac{Z_L + j Z_0 \tan(\beta d)}{Z_0 + j Z_L \tan(\beta d)} where d is the distance from the load impedance Z_L measured in wavelengths, β is the wavenumber of the line, and Z_0 is the characteristic impedance of the line. # Relation to heat conduction Ohm's principle predicts the flow of electrical charge (i.e. current) in electrical conductors when subjected to the influence of voltage differences; Jean-Baptiste-Joseph Fourier's principle predicts the flow of heat in heat conductors when subjected to the influence of temperature differences. The same equation describes both phenomena, the equation's variables taking on different meanings in the two cases. Specifically, solving a heat conduction (Fourier) problem with temperature (the driving "force") and flux of heat (the rate of flow of the driven "quantity", i.e. heat energy) variables also solves an analogous electrical conduction (Ohm) problem having electric potential (the driving "force") and electric current (the rate of flow of the driven "quantity", i.e. charge) variables. The basis of Fourier's work was his clear conception and definition of thermal conductivity. He assumed that, all else being the same, the flux of heat is strictly proportional to the gradient of temperature. Although undoubtedly true for small temperature gradients, strictly proportional behavior will be lost when real materials (e.g. ones having a thermal conductivity that is a function of temperature) are subjected to large temperature gradients. A similar assumption is made in the statement of Ohm's law: other things being alike, the strength of the current at each point is proportional to the gradient of electric potential. The accuracy of the assumption that flow is proportional to the gradient is more readily tested, using modern measurement methods, for the electrical case than for the heat case.	Ohm's law Template:Two other uses Ohm's law states that, in an electrical circuit, the current passing through a conductor between two points is directly proportional to the potential difference (i.e. voltage drop or voltage) across the two points, and inversely proportional to the resistance between them. The mathematical equation that describes this relationship is: where I is the current in amperes, V is the potential difference between two points of interest in volts, and R is a circuit parameter, measured in ohms (which is equivalent to volts per ampere), and is called the resistance. The potential difference is also known as the voltage drop, and is sometimes denoted by U, E or emf (electromotive force) instead of V.[1] The law was named after the physicist Georg Ohm, who, in a treatise published in 1827, described measurements of applied voltage, and current passing through, simple electrical circuits containing various lengths of wire, and presented a slightly more complex equation than the one above to explain his experimental results. The above equation is the modern form of Ohm's law; it could not exist until the ohm itself was defined (1861, 1864). Well before Georg Ohm's work, Henry Cavendish found experimentally (January 1781) that current varies in direct proportion to applied voltage, but he did not communicate his results to other scientists at the time.[2] The resistance of most resistive devices (resistors) is constant over a large range of values of current and voltage. When a resistor is used under these conditions, the resistor is referred to as an ohmic device because a single value for the resistance suffices to describe the resistive behavior of the device over the range. When sufficiently high voltages are applied to a resistor, forcing a high current to flow through it, the device is no longer ohmic because its resistance, when measured under such electrically stressed conditions, is different (typically greater) from the value measured under standard conditions (see temperature effects, below). Ohm's law, in the form above, is an extremely useful equation in the field of electrical/electronic engineering because it describes how voltage, current and resisitance are interrelated on a macroscopic level, that is, commonly, as circuit elements in an electrical circuit. Physicists who study the electrical properties of matter at the microsopic level use a closely related and more general vector equation, sometimes also referred to as Ohm's law, having variables that are closely related to the I, V and R scalar variables of Ohm's law, but are each functions of position within the conductor. See the Physics section and the Relation to heat conduction section below. # Elementary description and use Electrical circuits consist of electrical devices connected by wires (or other suitable conductors). (See the article electrical circuits for some basic combinations.) The above diagram shows one of the simplest electrical circuits that can be constructed. One electrical device is shown as a circle with + and - terminals, which represents a voltage source such as a battery. The other device is illustrated by a zig-zag symbol and has an R beside it. This symbol represents a resistor, and the R designates its resistance. The + or positive terminal of the voltage source is connected to one of the terminals of the resistor using a wire of negligible resistance, and through this wire a current I is shown to be passing, in a specified direction illustrated by the arrow. The other terminal of the resistor is connected to the - or negative terminal of the voltage source by a second wire. This configuration forms a complete circuit because all the current that leaves one terminal of the voltage source must return to the other terminal of the voltage source. (While not shown, because electrical engineers assume that it exists, there is an implied current I, and an arrow pointing to the left, associated with the second wire.) Voltage is the electrical force that moves (negatively charged) electrons through wires and electrical devices, current is the rate of electron flow, and resistance is the property of a resistor (or other device that obeys Ohm's law) that limits current to an amount proportional to the applied voltage. So, for a given resistance R (ohms), and a given voltage V (volts) established across the resistance, Ohm's law provides the equation (I=V/R) for calculating the current that must flow through the resistor (or device). The 'conductor' mentioned by Ohm's law is a circuit element across which the voltage is measured. Resistors are conductors that slow down the passage of electric charge. A resistor with a high value of resistance, say greater than 10 megaohms, is a poor conductor, while a resistor with a low value, say less than 0.1 ohm, is a good conductor. (Insulators are materials that, for most practical purposes, do not allow a current to flow when a voltage is applied.) In a circuit diagram like the one above, the various components may be joined by connectors, contacts, welds or solder joints of various kinds, but for simplicity these connections are usually not shown. # Physics Physicists often use the continuum form of Ohm's Law: \mathbf{J} = \sigma \cdot \mathbf{E} </math> where J is the current density (current per unit area, unlike the simpler I, units of amperes, of Ohm's law), σ is the conductivity (which can be a tensor in anisotropic materials) and E is the electric field (units of volts per meter, unlike the simpler V, units of volts, of Ohms's law). While the notation above does not explicitly depict the variables, each are vectors and each are functions of three position variables. (Normally, and in some places below, the dot means the vector dot product. Here the dot just means multiplication.) That is, in the case of J, using cartesian coordinates, there are actually three separate equations, one for each component of the vector, each equation having three independent position variables. For example, the components of J in the x, y and z directions would be Jx(x,y,z), Jy(x,y,z) and Jz(x,y,z). The common form used in circuit design is the macroscopic, averaged-out version of Ohm's actual equation, and can be derived thusly: the potential difference between two points is defined as or, in the case where the electric field is independent of the choice of path (as it is in a circuit), <math>{\|\Delta V\|} = {E}{L}</math> where L is the distance between points of interest. since the current per unit area, J, is equal to <math>I/A</math>, Ohm's Law becomes: The Electrical Resistance of a conductor is defined in terms of conductivity, length, and cross sectional area: From this, it can be seen that Ohm's law takes on the more familiar, yet macroscopic and averaged version: The continuum form of the equation is only valid in the reference frame of the conducting material. If the material is moving at velocity v relative to a magnetic field B, a term must be added as follows \mathbf{J} = \sigma \cdot \left( \mathbf{E} + \mathbf{v}\times\mathbf{B} \right) </math> The analogy to the Lorentz force is obvious, and in fact Ohm's law can be derived from the Lorentz force and the assumption that there is a drag on the charge carriers proportional to their velocity. A perfect metal lattice would have no resistivity, but a real metal has crystallographic defects, impurities, multiple isotopes, and thermal motion of the atoms. Electrons scatter from all of these, resulting in resistance to their flow. Ohm's law is sufficient to derive both Kirchhoff's voltage law (KVL) and Kirchhoff's current law (KCL). Let us first examine only the right-hand side of the equation: and calculate the line integral around a closed contour: Applying Stokes's theorem, we can write over the surface bounded by the countour: but, since E is the gradient of a scalar potential, yielding: and gradients are irrotational, we have: thereby proving KCL. Returning to the original formulation of Ohm's law: and forming the closed line integrals again: and recalling from Maxwell's equations that <math>curl(H) = J</math>: we apply Stokes's theorem to obtain: From our preceding derivation, we know that the right-hand side evaluates to zero: thus proving that the net current flow through an open surface is zero, which restates KCL. # How electrical and electronic engineers use Ohm's law Ohm's Law is one of the equations used in the analysis of electrical circuits, whether the analysis is done by engineers or computers. Even though, today, computers running electronic computer aided design and analysis programs do the bulk of the work predicting and optimizing the performance of electrical circuits (in particular, those circuits to be fabricated on silicon chips), most electrical engineers still use Ohm's Law every working day. Whether designing or debugging an electrical circuit, electrical engineers must have a working knowledge of the practical aspects of Ohm's law. Virtually all electronic circuits have resistive elements which are almost always considered ideal ohmic devices, i.e. they obey Ohm's Law. From the engineer's point of view, resistors (devices that "resist" the flow of electrical current) develop a voltage across their terminal conductors (e.g. the two wires emerging from the device) proportional to the amount of current flowing through the device. More specifically, the voltage measured across a resistor at a given instant is strictly proportional to the current passing through the resistor at that instant. When a functioning electrical circuit drives a current I, measured in amperes, through a resistor of resistance R, the voltage that develops across the resistor is I R, the value of R serving as the proportionality factor. (That current must have been supplied by a circuit element functioning as a current source and it must be passed on to a circuit element that serves as a current sink.) Thus resistors act like current-to-voltage converters (just as springs act like displacement-to-force converters). Similarly, a circuit may incorporate a resistor (of resistance R) designed to function as a voltage-to-current converter. In such a circuit, a desired voltage V is established across the resistor in order to force a current I exactly equal to 1/R times V to flow through the resistor. The DC resistance of a resistor is always a positive quantity, and the current flowing through a resistor generates (waste) heat in the resistor as it does in one of Ohm's wires. Voltages can be either positive or negative, and are always measured with respect to a reference point. When we say that a point in a circuit has a certain voltage, it is understood that this voltage is really a voltage difference (a two terminal measurement) and that there is an understood, or explicitly stated, reference point, often called ground or common. Currents can be either positive or negative, the sign of the current indicating the direction of current flow. Current flow in a wire consists of the slow drift of electrons due to the influence of a voltage established between two points on the wire. Since the resistance of a resistor is always positive and the equation describing Ohm's law does not in itself constrain R to be positive (by being written as: \|V\|=\|I\| R), there is the potential for computing a negative value for R. Using measurements of voltage and current that are made correctly, the sign of a computed R is never negative. When a negative R is computed based on a measurement of the voltage drop across a resistor and a measurement of the current passing through the resistor, then one of the two measurements must have been made improperly. When circuits are analyzed, the direction of flow of current between circuit elements may not be known or obvious. In this case, the direction of the current is assigned arbitrarily. Should a sign error (one that implies a negative resistance) arise during the analysis, the error is resolved by asserting that the initially assigned direction of current was incorrect, and that the actual direction of current is in the direction opposite to the initially assigned direction. Non-ohmic and active components may actually have negative differential resistance, a subject discussed in its own article. The word 'differential' is key, though often omitted, because it describes the characteristics of an interesting portion of the I vs. V curve of the non-ohmic device. At no time is the 'static' resistance itself negative. Certain powered circuit devices, constructed as two terminal devices and tested as if they were a resistor (by applying a voltage across the two terminals while measuring the current), may exhibit actual negative resistance. Ohm's law is not intended to apply to such devices. Further the law of conservation of energy is not violated because there is an integrated source of power. Ohm's law applies to conductors whose resistance is (substantially) independent of the applied voltage (or equivalently the injected current). That is, Ohm's law only applies to the linear portion of the I vs. V curve centered around the origin. The equation is just too simple to encompass devices described by a more complicated I vs. V relationship. The blue line in the I vs. V graph at right represents ohmic devices because current is directly (linearly) proportional to the applied voltage. The slope of the blue line is 1/R. The graph's red line represents a non-ohmic device such as a lamp filament because as more voltage is applied, heating the filament, the filament's resistance rises, forcing the (magnitude of the) slope to decrease. The graph's yellow line illustrates the I vs. V characteristics of a non-ohmic two terminal circuit having semi-conductor components (such as paralleled and oppositely oriented diodes). ## Hydraulic analogs While the terms voltage, current and resistance are fairly intuitive terms, beginning students of electrical engineering might find the analog terms for water flow helpful. Water pressure, measured by pascals (or PSI), is the analog of voltage because establishing a water pressure difference between two points along a (horizontal) pipe causes water to flow. Water flow rate, as in liters (or gallons) of water per minute, is the analog of current, as in coulombs per second. Finally, flow restrictors — such as apertures placed in pipes between points where the water pressure is measured — are the analog of resistors. We say that the rate of water flow through an aperture restrictor is proportional to the difference in water pressure across the restrictor. Similarly, the rate of flow of electrical charge, i.e. the electrical current, passing through an electrical resistor is proportional to the difference in voltage measured across the resistor. ## Sheet resistance Thin metal films, usually deposited on insulating substrates, are used for various purposes, the electrical current traveling parallel to the plane of the film. When describing the electrical resistivity of such devices, the term ohms-per-square is used. See sheet resistance. # Temperature effects When the temperature of the conductor increases, the collisions between electrons and atoms increase. Thus as a substance heats up because of electricity flowing through it (or by any heating process), the resistance will usually increase. The exception is semiconductors. The resistance of an Ohmic substance depends on temperature in the following way: R = \frac{L}{A} \cdot \rho = \frac{L}{A} \cdot \rho_0 (\alpha (T - T_0) + 1) </math> where ρ is the resistivity, L is the length of the conductor, A is its cross-sectional area, T is its temperature, <math>T_0</math> is a reference temperature (usually room temperature), and <math>\rho_0</math> and <math>\alpha</math> are constants specific to the material of interest. In the above expression, we have assumed that L and A remain unchanged within the temperature range. It is worth mentioning that temperature dependence does not make a substance non-ohmic, because at a given temperature, R does not vary with voltage or current (<math>V / I = \mathrm{constant}</math>). Intrinsic semiconductors exhibit the opposite temperature behavior, becoming better conductors as the temperature increases. This occurs because the electrons are bumped to the conduction energy band by the thermal energy, where they can flow freely and in doing so they leave behind holes in the valence band which can also flow freely. Extrinsic semiconductors have much more complex temperature behaviour. First the electrons (or holes) leave the donors (or acceptors) giving a decreasing resistance. Then there is a fairly flat phase in which the semiconductor is normally operated where almost all of the donors (or acceptors) have lost their electrons (or holes) but the number of electrons that have jumped right over the energy gap is negligible compared to the number of electrons (or holes) from the donors (or acceptors). Finally as the temperature increases further the carriers that jump the energy gap becomes the dominant figure and the material starts behaving like an intrinsic semiconductor. # Strain (mechanical) effects Just as the resistance of a conductor depends upon temperature, the resistance of a conductor depends upon strain. By placing a conductor under tension (a form of strain), which means to mechanically stretch the conductor, the length of the section of conductor under tension increases and its cross-sectional area decreases. Both these effects contribute to increasing the resistance of the strained section of conductor. Under compression (the other form of strain), the resistance of the strained section of conductor decreases. See the discussion on strain gauges for details about devices constructed to take advantage of this effect. # AC circuits For an AC circuit Ohm's law can be written <math>\mathbf{V} = \mathbf{I} \cdot \mathbf{Z}</math>, where V and I are the oscillating phasor voltage and current respectively and Z is the complex impedance for the frequency of oscillation. In a transmission line, the phasor form of Ohm's law above breaks down because of reflections. In a lossless transmission line, the ratio of voltage and current follows the complicated expression Z(d) = Z_0 \frac{Z_L + j Z_0 \tan(\beta d)}{Z_0 + j Z_L \tan(\beta d)} </math>, where d is the distance from the load impedance <math>Z_L</math> measured in wavelengths, β is the wavenumber of the line, and <math>Z_0</math> is the characteristic impedance of the line. # Relation to heat conduction Ohm's principle predicts the flow of electrical charge (i.e. current) in electrical conductors when subjected to the influence of voltage differences; Jean-Baptiste-Joseph Fourier's principle predicts the flow of heat in heat conductors when subjected to the influence of temperature differences. The same equation describes both phenomena, the equation's variables taking on different meanings in the two cases. Specifically, solving a heat conduction (Fourier) problem with temperature (the driving "force") and flux of heat (the rate of flow of the driven "quantity", i.e. heat energy) variables also solves an analogous electrical conduction (Ohm) problem having electric potential (the driving "force") and electric current (the rate of flow of the driven "quantity", i.e. charge) variables. The basis of Fourier's work was his clear conception and definition of thermal conductivity. He assumed that, all else being the same, the flux of heat is strictly proportional to the gradient of temperature. Although undoubtedly true for small temperature gradients, strictly proportional behavior will be lost when real materials (e.g. ones having a thermal conductivity that is a function of temperature) are subjected to large temperature gradients. A similar assumption is made in the statement of Ohm's law: other things being alike, the strength of the current at each point is proportional to the gradient of electric potential. The accuracy of the assumption that flow is proportional to the gradient is more readily tested, using modern measurement methods, for the electrical case than for the heat case.	https://www.wikidoc.org/index.php/Ohm%27s_law
ae248bdcb5f3f0d8274827d05445eaf2397d9ea5	wikidoc	Oily fish	Oily fish # Overview Oily fish, oil-rich fish or pelagic fish are those fish which have oils throughout the fillet and in the belly cavity around the gut, rather than only in the liver like white fish. Oily fish fillets may contain up to 30 percent oil, although this figure varies both within and between species. Oily fish generally swim in the pelagic zones of the oceans. Oily fish are a good source of Vitamins A and D as well as being rich in omega 3 fatty acids. For this reason the consumption of oily fish has been identified as more beneficial to humans than white fish. Amongst other benefits, studies suggest that the omega 3 fatty acids in oily fish may help sufferers of depression, reduce the likelihood of heart disease and improve inflammatory conditions such as arthritis. # Research ## Dementia French research published in 2002 in the British Medical Journal followed 1,674 elderly residents of southern France for seven years, studying their consumption meat versus seafood and the presence of dementia symptoms. The conclusion was that people who ate fish at least once a week had a significantly lower risk of being diagnosed with dementia over a seven-year period, though the study was uncertain if fish consumption protected against dementia, or if dementia prevented the participants from consuming more fish. Individuals with higher education also had a lower risk of dementia and higher consumption of fish, and the relationship between the three factors is uncertain. ## Cardiovascular health Consuming oily fish twice per week may also help prevent sudden death due to myocardial infarction by preventing cardiac arrhythmia. The eicosapentaenoic acid found in fish oils appears to dramatically reduce inflammation through conversion within the body to resolvins, with beneficial effects for the cardiovascular system and arthritis. # Recommended consumption In 1994, the UK Committee on Medical Aspects of Food and Nutrition Policy (COMA) recommended that people should eat at least two portions of fish per week, one of which should be oily fish. In 2004 the UK Food Standards Agency published advice on the recommended minimum and maximum quantities of oily fish to be eaten per week, to balance the beneficial qualities of the Omega 3 fatty acids against the potential dangers of ingesting methylmercury (MeHg). The EPAs Exposure Reference Dose (RfI) for MeHg is 0.1 micrograms per kg body weight per day. The corresponding limit of blood mercury is 5.8 micrograms per liter. The recommendations on maximum consumption of oily fish were up to four portions (1 portion = 140g, or approx 4.9 ounces) a week for men, boys, and women past childbearing age, and up to two portions a week for women of childbearing age, including pregnant and breastfeeding women, and girls. There is no recommended limit on the consumption of white fish. The United States Environmental Protection Agency (EPA)and the USDA current guidelines (as of 2007) sets a limit only on consumption of fatty fish with greater than one part per million of methylmercury. Specifically tilefish, king mackrel, shark and swordfish (and some fish caught in local waters). There are limits, however, for nursing/pregnant women and children under the age of 6. This population should completely avoid high MeHg fish (those listed above) and limit consumption of moderate and low MeHg fish to less than or equal to 12oz per week. Albacore tuna should be limited to 6 oz or less per week. (info available at: www.epa.gov/waterscience/fish/states.htm) # Oils from fish or plants as a source of omega-3 fatty acids Concerns about contamination, diet or supply have led to investigation of plant sources of omega-3 fatty acids, notably flax and hempseed oil. Lactating women who supplemented their diet with flaxseed oil showed increases in blood and breastmilk concentration of alpha-linolenic acid and eicosapentaenoic acid but no changes to concentrations of docosahexaenoic acid.	Oily fish Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Oily fish, oil-rich fish or pelagic fish are those fish which have oils throughout the fillet and in the belly cavity around the gut, rather than only in the liver like white fish. Oily fish fillets may contain up to 30 percent oil, although this figure varies both within and between species. Oily fish generally swim in the pelagic zones of the oceans. Oily fish are a good source of Vitamins A and D as well as being rich in omega 3 fatty acids. For this reason the consumption of oily fish has been identified as more beneficial to humans than white fish. Amongst other benefits, studies suggest that the omega 3 fatty acids in oily fish may help sufferers of depression, reduce the likelihood of heart disease and improve inflammatory conditions such as arthritis. # Research ## Dementia French research published in 2002 in the British Medical Journal followed 1,674 elderly residents of southern France for seven years, studying their consumption meat versus seafood and the presence of dementia symptoms. The conclusion was that people who ate fish at least once a week had a significantly lower risk of being diagnosed with dementia over a seven-year period,[1] though the study was uncertain if fish consumption protected against dementia, or if dementia prevented the participants from consuming more fish. Individuals with higher education also had a lower risk of dementia and higher consumption of fish, and the relationship between the three factors is uncertain. ## Cardiovascular health Consuming oily fish twice per week may also help prevent sudden death due to myocardial infarction by preventing cardiac arrhythmia.[2] The eicosapentaenoic acid found in fish oils appears to dramatically reduce inflammation through conversion within the body to resolvins, with beneficial effects for the cardiovascular system and arthritis.[3] # Recommended consumption In 1994, the UK Committee on Medical Aspects of Food and Nutrition Policy (COMA) recommended that people should eat at least two portions of fish per week, one of which should be oily fish. In 2004 the UK Food Standards Agency published advice on the recommended minimum and maximum quantities of oily fish to be eaten per week, to balance the beneficial qualities of the Omega 3 fatty acids against the potential dangers of ingesting methylmercury (MeHg). The EPAs Exposure Reference Dose (RfI) for MeHg is 0.1 micrograms per kg body weight per day. The corresponding limit of blood mercury is 5.8 micrograms per liter. The recommendations on maximum consumption of oily fish were up to four portions (1 portion = 140g, or approx 4.9 ounces) a week for men, boys, and women past childbearing age, and up to two portions a week for women of childbearing age, including pregnant and breastfeeding women, and girls. There is no recommended limit on the consumption of white fish. The United States Environmental Protection Agency (EPA)and the USDA current guidelines (as of 2007) sets a limit only on consumption of fatty fish with greater than one part per million of methylmercury. Specifically tilefish, king mackrel, shark and swordfish (and some fish caught in local waters). There are limits, however, for nursing/pregnant women and children under the age of 6. This population should completely avoid high MeHg fish (those listed above) and limit consumption of moderate and low MeHg fish to less than or equal to 12oz per week. Albacore tuna should be limited to 6 oz or less per week. (info available at: www.epa.gov/waterscience/fish/states.htm) # Oils from fish or plants as a source of omega-3 fatty acids Concerns about contamination, diet or supply have led to investigation of plant sources of omega-3 fatty acids, notably flax and hempseed oil. Lactating women who supplemented their diet with flaxseed oil showed increases in blood and breastmilk concentration of alpha-linolenic acid and eicosapentaenoic acid but no changes to concentrations of docosahexaenoic acid.[4]	https://www.wikidoc.org/index.php/Oily_fish
f7e698fe063b6697f3b34e4ae2dc2065c263e226	wikidoc	Olbas oil	Olbas oil Olbas oil is a brand name for a nasal decongestant, manufactured under licence by G. R. Lane Health Products Ltd in England (license holder) and Penn Herb Company Ltd in the United States. It is a mixture of essential plant oils: cajuput, clove, eucalyptus, juniper berry, levomenthol, peppermint and wintergreen. Olbas oil originated in Basel, Switzerland in the 19th century. As well as providing bronchial and nasal relief - hence its popularity for common cold sufferers - it can soothe muscles and joints of sufferers in conditions such as arthritis and spinal pain. Olbas is available in its original oil form, and is now also available in other forms such as nasal inhaler, herbal tea (US), herbal bath, cough syrup (US), cough drops (US),sport massage oil (US), and an analgesic salve. There is also a formulation for children available in the UK. Its British manufacturer also claims it is used as a cat repellent to discourage damage to flowerbeds, furniture, etc. Olbas oil is effective for coughs colds and for suffers of hayfever.	Olbas oil Olbas oil is a brand name for a nasal decongestant, manufactured under licence by G. R. Lane Health Products Ltd in England (license holder) and Penn Herb Company Ltd in the United States. It is a mixture of essential plant oils: cajuput, clove, eucalyptus, juniper berry, levomenthol, peppermint and wintergreen. Olbas oil originated in Basel, Switzerland in the 19th century. As well as providing bronchial and nasal relief - hence its popularity for common cold sufferers - it can soothe muscles and joints of sufferers in conditions such as arthritis and spinal pain. Olbas is available in its original oil form, and is now also available in other forms such as nasal inhaler, herbal tea (US), herbal bath, cough syrup (US), cough drops (US),sport massage oil (US), and an analgesic salve. There is also a formulation for children available in the UK. Its British manufacturer also claims it is used as a cat repellent to discourage damage to flowerbeds, furniture, etc. Olbas oil is effective for coughs colds and for suffers of hayfever. # External links - Olbas website of G.R. Lane Health Products Ltd - Olbas website of Penn Herb Company Ltd Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Olbas_oil
4b2f9a680df5a7491b275ca2e1329b9cbedbb5fe	wikidoc	Olfaction	Olfaction Olfaction (also known as olfactics or smell) refers to the sense of smell. This sense is mediated by specialized sensory cells of the nasal cavity of vertebrates, and, by analogy, sensory cells of the antennae of invertebrates. For air-breathing animals, the olfactory system detects volatile or, in the case of the accessory olfactory system, fluid-phase chemicals. For water-dwelling organisms, e.g., fish or crustaceans, the chemicals are present in the surrounding aqueous medium. Olfaction, along with taste, is a form of chemoreception. The chemicals themselves which activate the olfactory system, generally at very low concentrations, are called odors. # History As described by the Roman philosopher Lucretius (1st Century BCE), different odors are attributed to different shapes and sizes of odor molecules that stimulate the olfactory organ. The modern counterpart to that theory was the cloning of olfactory receptor proteins by Linda B. Buck and Richard Axel (who were awarded the Nobel Prize in 2004), and subsequent pairing of odor molecules to specific receptor proteins. Each odor receptor molecule recognizes only a particular molecular feature or class of odor molecules. Mammals have about a thousand genes expressing for odor reception. Of these genes, only a portion are functional odor receptors. Humans have far fewer active odor receptor genes than other mammals and primates Each olfactory receptor neuron expresses only one functional odor receptor. Odor receptor nerve cells function like a key-lock system: If the airborne molecules of a certain chemical can fit into the lock, the nerve cell will respond. There are, at present, a number of competing theories regarding the mechanism of odor coding and perception. According to shape theory, each receptor detects a feature of the odor molecule. Weak-shape theory, known as odotope theory, suggests that different receptors detect only small pieces of molecules, and these minimal inputs are combined to form a larger olfactory perception (similar to the way visual perception is built up of smaller, information-poor sensations, combined and refined to create a detailed overall perception). An alternative theory, the vibration theory proposed by Luca Turin, posits that odor receptors detect the frequencies of vibrations of odor molecules in the infrared range by electron tunnelling. However, the behavioral predictions of this theory have been called into question. As of yet, there is no theory that explains olfactory perception completely. # Olfactory system ## Olfactory epithelium In vertebrates smells are sensed by olfactory sensory neurons in the olfactory epithelium. The proportion of olfactory epithelium compared to respiratory epithelium (not innervated) gives an indication of the animal's olfactory sensitivity. Humans have about 10 cm² of olfactory epithelium, whereas some dogs have 170 cm2. A dog's olfactory epithelium is also considerably more densely innervated, with a hundred times more receptors per square centimetre. Molecules of odorants passing through the superior nasal concha of the nasal passages dissolve in the mucus lining the superior portion of the cavity and are detected by olfactory receptors on the dendrites of the olfactory sensory neurons. This may occur by diffusion or by the binding of the odorant to odorant binding proteins. The mucus overlying the epithelium contains mucopolysaccharides, salts, enzymes, and antibodies (these are highly important, as the olfactory neurons provide a direct passage for infection to pass to the brain). In insects smells are sensed by olfactory sensory neurons in the chemosensory sensilla, which are present in insect antenna, palps and tarsa, but also on other parts of the insect body. Odorants penetrate into the cuticle pores of chemosensory sensilla and get in contact with insect Odorant binding proteins (OBPs) or Chemosensory proteins (CSPs), before activating the sensory neurons. ## Receptor neuron The process of how the binding of the ligand (odor molecule or odorant) to the receptor leads to an action potential in the receptor neuron is via a second messenger pathway depending on the organism. In mammals the odorants stimulate adenylate cyclase to synthesize cAMP via a G protein called Golf. cAMP, which is the second messenger here, opens a cyclic nucleotide-gated ion channel (CNG) producing an influx of cations (largely Ca2+ with some Na+) into the cell, slightly depolarising it. The Ca2+ in turn opens a Ca2+-activated chloride channel, leading to efflux of Cl-, further depolarising the cell and triggering an action potential. Ca2+ is then extruded through a sodium-calcium exchanger. A calcium-calmodulin complex also acts to inhibit the binding of cAMP to the cAMP-dependent channel, thus contributing to olfactory adaptation. This mechanism of transduction is somewhat unique, in that cAMP works by directly binding to the ion channel rather than through activation of protein kinase A. It is similar to the transduction mechanism for photoreceptors, in which the second messenger cGMP works by directly binding to ion channels, suggesting that maybe one of these receptors was evolutionarily adapted into the other. There are also considerable similarities in the immediate processing of stimuli by lateral inhibition. Averaged activity of the receptor neuron to an odor can be measured by an electroolfactogram in vertebrates or an electroantenogram in insects. The receptor neurons in the nose are particularly interesting because they are the only direct recipient of stimuli in all of the senses which are nerves. Senses like hearing, tasting, and, to some extent, touch use cilia or other indirect pressure to stimulate nerves, and sight uses the chemical Rhodopsin to stimulate the mind. ## Olfactory bulb projections Olfactory sensory neurons project axons to the brain within the olfactory nerve, (cranial nerve I). These axons pass to the olfactory bulb through the cribriform plate, which in-turn projects olfactory information to the olfactory cortex and other areas. The axons from the olfactory receptors converge in the olfactory bulb within small (~50 micrometers in diameter) structures called glomeruli. Mitral cells in the olfactory bulb form synapses with the axons within glomeruli and send the information about the odor to multiple other parts of the olfactory system in the brain, where multiple signals may be processed to form a synthesized olfactory perception. There is a large degree of convergence here, with twenty-five thousand axons synapsing on one hundred or so mitral cells, and with each of these mitral cells projecting to multiple glomeruli. Mitral cells also project to periglomerular cells and granular cells that inhibit the mitral cells surrounding it (lateral inhibition). Granular cells also mediate inhibition and excitation of mitral cells through pathways from centrifugal fibres and the anterior olfactory nuclei. The mitral cells leave the olfactory bulb in the lateral olfactory tract, which synapses on five major regions of the cerebrum: the anterior olfactory nucleus, the olfactory tubercle, the amygdala, the piriform cortex, and the entorhinal cortex. The anterior olfactory nucleus projects, via the anterior commissure, to the contralateral olfactory bulb, inhibiting it. The piriform cortex projects to the medial dorsal nucleus of the thalamus, which then projects to the orbitofrontal cortex. The orbitofrontal cortex mediates conscious perception of the odor. The 3-layered piriform cortex projects to a number of thalamic and hypothalamic nuclei, the hippocampus and amygdala and the orbitofrontal cortex but its function is largely unknown. The entorhinal cortex projects to the amygdala and is involved in emotional and autonomic responses to odor. It also projects to the hippocampus and is involved in motivation and memory. Odor information is easily stored in long-term memory and has strong connections to emotional memory. This is possibly due to the olfactory system's close anatomical ties to the limbic system and hippocampus, areas of the brain that have long been known to be involved in emotion and place memory, respectively. Since any one receptor is responsive to various odorants, and there is a great deal of convergence at the level of the olfactory bulb, it seems strange that human beings are able to distinguish so many different odors. It seems that there must be a highly-complex form of processing occurring; however, as it can be shown that, while many neurons in the olfactory bulb (and even the pyriform cortex and amygdala) are responsive to many different odors, half the neurons in the orbitofrontal cortex are responsive only to one odor, and the rest to only a few. It has been shown through microelectrode studies that each individual odor gives a particular specific spatial map of excitation in the olfactory bulb. It is possible that, through spatial encoding, the brain is able to distinguish specific odors. However, temporal coding must be taken into account. Over time, the spatial maps change, even for one particular odor, and the brain must be able to process these details as well. In insects smells are sensed by sensilla located on the antenna and first processed by the antennal lobe (analogous to the olfactory bulb), and next by the mushroom bodies. ## Pheromonal olfaction Many animals, including most mammals and reptiles, have two distinct and segregated olfactory systems: a main olfactory system, which detects volatile stimuli, and an accessory olfactory system, which detects fluid-phase stimuli. Behavioral evidence suggests that these fluid-phase stimuli often function as pheromones, although pheromones can also be detected by the main olfactory system. In the accessory olfactory system, stimuli are detected by the vomeronasal organ, located in the vomer, between the nose and the mouth. Snakes use it to smell prey, sticking their tongue out and touching it to the organ. Some mammals make a face called flehmen to direct air to this organ. In women, the sense of olfaction is strongest around the time of ovulation, significantly stronger than during other phases of the menstrual cycle and also stronger than the sense in males. The MHC genes (known as HLA in humans) are a group of genes present in many animals and important for the immune system; in general, offspring from parents with differing MHC genes have a stronger immune system. Fish, mice and female humans are able to smell some aspect of the MHC genes of potential sex partners and prefer partners with MHC genes different from their own. ## Olfaction and taste Olfaction, taste and trigeminal receptors together contribute to flavor. The human tongue can distinguish only among five distinct qualities of taste, while the nose can distinguish among hundreds of substances, even in minute quantities. ## Disorders of olfaction The following are disorders of olfaction: - Anosmia - lack of ability to smell - Hyposmia - decreased ability to smell - Phantosmia - "hallucinated smell", often unpleasant in nature - Dysosmia - things smell differently than they should - Hyperosmia - an abnormally acute sense of smell # Quantifying olfaction in industry Scientists have devised methods for quantifying the intensity of odors, particularly for the purpose of analyzing unpleasant or objectionable odors released by an industrial source into a community. Since the 1800s, industrial countries have encountered incidents where proximity of an industrial source or landfill produced adverse reactions to nearby residents regarding airborne odor. The basic theory of odor analysis is to measure what extent of dilution with "pure" air is required before the sample in question is rendered indistinguishable from the "pure" or reference standard. Since each person perceives odor differently, an "odor panel" composed of several different people is assembled, each sniffing the same sample of diluted specimen air. A field olfactometer can be utilized to determine the magnitude of an odor. One example is the Nasal Ranger field olfactometer, which is often utilized in odor studies. Many air management districts in the USA have numerical standards of acceptability for the intensity of odor that is allowed to cross into a residential property. For example, the Bay Area Air Quality Management District has applied its standard in regulating numerous industries, landfills, and sewage treatment plants. Example applications this district has engaged are the San Mateo, California wastewater treatment plant; the Shoreline Amphitheatre in Mountain View, California; and the IT Corporation waste ponds, Martinez, California. # Olfaction in non-human animals The importance and sensitivity of smell varies among different organisms; most mammals have a good sense of smell, whereas most birds do not, except the tubenoses (e.g., petrels and albatrosses), and the kiwis. Among mammals, it is well-developed in the carnivores and ungulates, who must always be aware of each other, and in those, such as the moles, that smell for their food. Dogs in general have a nose approximately a hundred thousand to a million times more sensitive than a human's. Scenthounds as a group can smell one to ten million times more acutely than a human, and Bloodhounds, which have the keenest sense of smell of any dogs, have noses ten to a hundred million times more sensitive than a human's. They were bred for the specific purpose of tracking humans, and can detect a scent trail a few days old. The second-most-sensitive nose is possessed by the Basset Hound, which was bred to track and hunt rabbits and other small animals. The sense of smell is less-developed in the catarrhine primates (Catarrhini), and nonexistent in cetaceans, which compensate with a well-developed sense of taste. In some prosimians, such as the Red-bellied Lemur, scent glands occur atop the head. In many species, olfaction is highly tuned to pheromones; a male silkworm moth, for example, can sense a single molecule of bombykol. Fish too have a well-developed sense of smell, even though they inhabit an aquatic environment. Salmon utilize their sense of smell to identify and return to their home stream waters. Catfish use their sense of smell to identify other individual catfish and to maintain a social hierarchy. Many fishes use the sense of smell to identify mating partners or to alert to the presence of food. Insects primarily use their antennae for olfaction. Sensory neurons in the antenna generate odor-specific electrical signals called spikes in response to odor. They process these signals from the sensory neurons in the antennal lobe followed by the mushroom bodies and lateral horn of the brain. The antennae have the sensory neurons in the sensilla and they have their axons terminating in the antennal lobes where they synapse with other neurons there in semidelineated (with membrane boundaries) called glomeruli. These antennal lobes have two kinds of neurons, projection neurons (excitatory) and local neurons (inhibitory). The projection neurons send their axon terminals to mushroom body and lateral horn (both of which are part of the protocerebrum of the insects), and local neurons have no axons. Recordings from projection neurons show in some insects strong specialization and discrimination for the odors presented (especially for the projection neurons of the macroglomeruli, a specialized complex of glomeruli responsible for the pheromones detection). Processing beyond this level is not exactly known though some preliminary results are available.	Olfaction Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Olfaction (also known as olfactics or smell) refers to the sense of smell. This sense is mediated by specialized sensory cells of the nasal cavity of vertebrates, and, by analogy, sensory cells of the antennae of invertebrates. For air-breathing animals, the olfactory system detects volatile or, in the case of the accessory olfactory system, fluid-phase chemicals. For water-dwelling organisms, e.g., fish or crustaceans, the chemicals are present in the surrounding aqueous medium. Olfaction, along with taste, is a form of chemoreception. The chemicals themselves which activate the olfactory system, generally at very low concentrations, are called odors. # History As described by the Roman philosopher Lucretius (1st Century BCE), different odors are attributed to different shapes and sizes of odor molecules that stimulate the olfactory organ. The modern counterpart to that theory was the cloning of olfactory receptor proteins by Linda B. Buck and Richard Axel (who were awarded the Nobel Prize in 2004), and subsequent pairing of odor molecules to specific receptor proteins. Each odor receptor molecule recognizes only a particular molecular feature or class of odor molecules. Mammals have about a thousand genes expressing for odor reception.[1] Of these genes, only a portion are functional odor receptors. Humans have far fewer active odor receptor genes than other mammals and primates[2] Each olfactory receptor neuron expresses only one functional odor receptor. Odor receptor nerve cells function like a key-lock system: If the airborne molecules of a certain chemical can fit into the lock, the nerve cell will respond. There are, at present, a number of competing theories regarding the mechanism of odor coding and perception. According to shape theory, each receptor detects a feature of the odor molecule. Weak-shape theory, known as odotope theory, suggests that different receptors detect only small pieces of molecules, and these minimal inputs are combined to form a larger olfactory perception (similar to the way visual perception is built up of smaller, information-poor sensations, combined and refined to create a detailed overall perception)[3]. An alternative theory, the vibration theory proposed by Luca Turin[4][5], posits that odor receptors detect the frequencies of vibrations of odor molecules in the infrared range by electron tunnelling. However, the behavioral predictions of this theory have been called into question.[6] As of yet, there is no theory that explains olfactory perception completely. # Olfactory system ## Olfactory epithelium In vertebrates smells are sensed by olfactory sensory neurons in the olfactory epithelium. The proportion of olfactory epithelium compared to respiratory epithelium (not innervated) gives an indication of the animal's olfactory sensitivity. Humans have about 10 cm² of olfactory epithelium, whereas some dogs have 170 cm2. A dog's olfactory epithelium is also considerably more densely innervated, with a hundred times more receptors per square centimetre. Molecules of odorants passing through the superior nasal concha of the nasal passages dissolve in the mucus lining the superior portion of the cavity and are detected by olfactory receptors on the dendrites of the olfactory sensory neurons. This may occur by diffusion or by the binding of the odorant to odorant binding proteins. The mucus overlying the epithelium contains mucopolysaccharides, salts, enzymes, and antibodies (these are highly important, as the olfactory neurons provide a direct passage for infection to pass to the brain). In insects smells are sensed by olfactory sensory neurons in the chemosensory sensilla, which are present in insect antenna, palps and tarsa, but also on other parts of the insect body. Odorants penetrate into the cuticle pores of chemosensory sensilla and get in contact with insect Odorant binding proteins (OBPs) or Chemosensory proteins (CSPs), before activating the sensory neurons. ## Receptor neuron The process of how the binding of the ligand (odor molecule or odorant) to the receptor leads to an action potential in the receptor neuron is via a second messenger pathway depending on the organism. In mammals the odorants stimulate adenylate cyclase to synthesize cAMP via a G protein called Golf. cAMP, which is the second messenger here, opens a cyclic nucleotide-gated ion channel (CNG) producing an influx of cations (largely Ca2+ with some Na+) into the cell, slightly depolarising it. The Ca2+ in turn opens a Ca2+-activated chloride channel, leading to efflux of Cl-, further depolarising the cell and triggering an action potential. Ca2+ is then extruded through a sodium-calcium exchanger. A calcium-calmodulin complex also acts to inhibit the binding of cAMP to the cAMP-dependent channel, thus contributing to olfactory adaptation. This mechanism of transduction is somewhat unique, in that cAMP works by directly binding to the ion channel rather than through activation of protein kinase A. It is similar to the transduction mechanism for photoreceptors, in which the second messenger cGMP works by directly binding to ion channels, suggesting that maybe one of these receptors was evolutionarily adapted into the other. There are also considerable similarities in the immediate processing of stimuli by lateral inhibition. Averaged activity of the receptor neuron to an odor can be measured by an electroolfactogram in vertebrates or an electroantenogram in insects. The receptor neurons in the nose are particularly interesting because they are the only direct recipient of stimuli in all of the senses which are nerves. Senses like hearing, tasting, and, to some extent, touch use cilia or other indirect pressure to stimulate nerves, and sight uses the chemical Rhodopsin to stimulate the mind. ## Olfactory bulb projections Olfactory sensory neurons project axons to the brain within the olfactory nerve, (cranial nerve I). These axons pass to the olfactory bulb through the cribriform plate, which in-turn projects olfactory information to the olfactory cortex and other areas. The axons from the olfactory receptors converge in the olfactory bulb within small (~50 micrometers in diameter) structures called glomeruli. Mitral cells in the olfactory bulb form synapses with the axons within glomeruli and send the information about the odor to multiple other parts of the olfactory system in the brain, where multiple signals may be processed to form a synthesized olfactory perception. There is a large degree of convergence here, with twenty-five thousand axons synapsing on one hundred or so mitral cells, and with each of these mitral cells projecting to multiple glomeruli. Mitral cells also project to periglomerular cells and granular cells that inhibit the mitral cells surrounding it (lateral inhibition). Granular cells also mediate inhibition and excitation of mitral cells through pathways from centrifugal fibres and the anterior olfactory nuclei. The mitral cells leave the olfactory bulb in the lateral olfactory tract, which synapses on five major regions of the cerebrum: the anterior olfactory nucleus, the olfactory tubercle, the amygdala, the piriform cortex, and the entorhinal cortex. The anterior olfactory nucleus projects, via the anterior commissure, to the contralateral olfactory bulb, inhibiting it. The piriform cortex projects to the medial dorsal nucleus of the thalamus, which then projects to the orbitofrontal cortex. The orbitofrontal cortex mediates conscious perception of the odor. The 3-layered piriform cortex projects to a number of thalamic and hypothalamic nuclei, the hippocampus and amygdala and the orbitofrontal cortex but its function is largely unknown. The entorhinal cortex projects to the amygdala and is involved in emotional and autonomic responses to odor. It also projects to the hippocampus and is involved in motivation and memory. Odor information is easily stored in long-term memory and has strong connections to emotional memory. This is possibly due to the olfactory system's close anatomical ties to the limbic system and hippocampus, areas of the brain that have long been known to be involved in emotion and place memory, respectively. Since any one receptor is responsive to various odorants, and there is a great deal of convergence at the level of the olfactory bulb, it seems strange that human beings are able to distinguish so many different odors. It seems that there must be a highly-complex form of processing occurring; however, as it can be shown that, while many neurons in the olfactory bulb (and even the pyriform cortex and amygdala) are responsive to many different odors, half the neurons in the orbitofrontal cortex are responsive only to one odor, and the rest to only a few. It has been shown through microelectrode studies that each individual odor gives a particular specific spatial map of excitation in the olfactory bulb. It is possible that, through spatial encoding, the brain is able to distinguish specific odors. However, temporal coding must be taken into account. Over time, the spatial maps change, even for one particular odor, and the brain must be able to process these details as well. In insects smells are sensed by sensilla located on the antenna and first processed by the antennal lobe (analogous to the olfactory bulb), and next by the mushroom bodies. ## Pheromonal olfaction Many animals, including most mammals and reptiles, have two distinct and segregated olfactory systems: a main olfactory system, which detects volatile stimuli, and an accessory olfactory system, which detects fluid-phase stimuli. Behavioral evidence suggests that these fluid-phase stimuli often function as pheromones, although pheromones can also be detected by the main olfactory system. In the accessory olfactory system, stimuli are detected by the vomeronasal organ, located in the vomer, between the nose and the mouth. Snakes use it to smell prey, sticking their tongue out and touching it to the organ. Some mammals make a face called flehmen to direct air to this organ. In women, the sense of olfaction is strongest around the time of ovulation, significantly stronger than during other phases of the menstrual cycle and also stronger than the sense in males.[7] The MHC genes (known as HLA in humans) are a group of genes present in many animals and important for the immune system; in general, offspring from parents with differing MHC genes have a stronger immune system. Fish, mice and female humans are able to smell some aspect of the MHC genes of potential sex partners and prefer partners with MHC genes different from their own.[8][9] ## Olfaction and taste Olfaction, taste and trigeminal receptors together contribute to flavor. The human tongue can distinguish only among five distinct qualities of taste, while the nose can distinguish among hundreds of substances, even in minute quantities. ## Disorders of olfaction The following are disorders of olfaction:[10] - Anosmia - lack of ability to smell - Hyposmia - decreased ability to smell - Phantosmia - "hallucinated smell", often unpleasant in nature - Dysosmia - things smell differently than they should - Hyperosmia - an abnormally acute sense of smell # Quantifying olfaction in industry Scientists have devised methods for quantifying the intensity of odors, particularly for the purpose of analyzing unpleasant or objectionable odors released by an industrial source into a community. Since the 1800s, industrial countries have encountered incidents where proximity of an industrial source or landfill produced adverse reactions to nearby residents regarding airborne odor. The basic theory of odor analysis is to measure what extent of dilution with "pure" air is required before the sample in question is rendered indistinguishable from the "pure" or reference standard. Since each person perceives odor differently, an "odor panel" composed of several different people is assembled, each sniffing the same sample of diluted specimen air. A field olfactometer can be utilized to determine the magnitude of an odor. One example is the Nasal Ranger field olfactometer, which is often utilized in odor studies. [2] Many air management districts in the USA have numerical standards of acceptability for the intensity of odor that is allowed to cross into a residential property. For example, the Bay Area Air Quality Management District has applied its standard in regulating numerous industries, landfills, and sewage treatment plants. Example applications this district has engaged are the San Mateo, California wastewater treatment plant; the Shoreline Amphitheatre in Mountain View, California; and the IT Corporation waste ponds, Martinez, California. # Olfaction in non-human animals The importance and sensitivity of smell varies among different organisms; most mammals have a good sense of smell, whereas most birds do not, except the tubenoses (e.g., petrels and albatrosses), and the kiwis. Among mammals, it is well-developed in the carnivores and ungulates, who must always be aware of each other, and in those, such as the moles, that smell for their food. Dogs in general have a nose approximately a hundred thousand to a million times more sensitive than a human's. Scenthounds as a group can smell one to ten million times more acutely than a human, and Bloodhounds, which have the keenest sense of smell of any dogs, have noses ten to a hundred million times more sensitive than a human's. They were bred for the specific purpose of tracking humans, and can detect a scent trail a few days old. The second-most-sensitive nose is possessed by the Basset Hound, which was bred to track and hunt rabbits and other small animals. The sense of smell is less-developed in the catarrhine primates (Catarrhini), and nonexistent in cetaceans, which compensate with a well-developed sense of taste. In some prosimians, such as the Red-bellied Lemur, scent glands occur atop the head. In many species, olfaction is highly tuned to pheromones; a male silkworm moth, for example, can sense a single molecule of bombykol. Fish too have a well-developed sense of smell, even though they inhabit an aquatic environment. Salmon utilize their sense of smell to identify and return to their home stream waters. Catfish use their sense of smell to identify other individual catfish and to maintain a social hierarchy. Many fishes use the sense of smell to identify mating partners or to alert to the presence of food. Insects primarily use their antennae for olfaction. Sensory neurons in the antenna generate odor-specific electrical signals called spikes in response to odor. They process these signals from the sensory neurons in the antennal lobe followed by the mushroom bodies and lateral horn of the brain. The antennae have the sensory neurons in the sensilla and they have their axons terminating in the antennal lobes where they synapse with other neurons there in semidelineated (with membrane boundaries) called glomeruli. These antennal lobes have two kinds of neurons, projection neurons (excitatory) and local neurons (inhibitory). The projection neurons send their axon terminals to mushroom body and lateral horn (both of which are part of the protocerebrum of the insects), and local neurons have no axons. Recordings from projection neurons show in some insects strong specialization and discrimination for the odors presented (especially for the projection neurons of the macroglomeruli, a specialized complex of glomeruli responsible for the pheromones detection). Processing beyond this level is not exactly known though some preliminary results are available.	https://www.wikidoc.org/index.php/Olfaction
25edaac5670a7a5668eb14973d494c79403df7fb	wikidoc	Patisiran	Patisiran # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Patisiran is a transthyretin-directed small interfering RNA that is FDA approved for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults. Common adverse reactions include upper respiratory tract infections and infusion-related reactions. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Indication - Patisiran is indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults. Dosage - For patients weighing less than 100 kg, the recommended dosage is 0.3 mg/kg every 3 weeks by intravenous infusion. For patients weighing 100 kg or more, the recommended dosage is 30 mg. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding patisiran Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding patisiran Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and effectiveness in pediatric patients have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding patisiran Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding patisiran Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications None. # Warnings - Infusion-related reactions (IRRs) have been observed in patients treated with patisiran. In clinical studies, all patients received premedication with a corticosteroid, acetaminophen, and antihistamines (H1 and H2 blockers) to reduce the risk of IRRs. In a controlled clinical study, 19% of patisiran-treated patients experienced IRRs, compared to 9% of placebo-treated patients. Among patisiran-treated patients who experienced an IRR, 79% experienced the first IRR within the first 2 infusions. The frequency of IRRs decreased over time. IRRs led to infusion interruption in 5% of patients. IRRs resulted in permanent discontinuation of patisiran in less than 1% of patients in clinical studies. Across clinical studies, the most common symptoms (reported in greater than 2% of patients) of IRRs with patisiran were flushing, back pain, nausea, abdominal pain, dyspnea, and headache. One patient in the patisiran expanded access program had a severe adverse reaction of hypotension and syncope during a patisiran infusion. - Patients should receive premedications on the day of patisiran infusion, at least 60 minutes prior to the start of infusion. Monitor patients during the infusion for signs and symptoms of IRRs. If an IRR occurs, consider slowing or interrupting the patisiran infusion and instituting medical management (e.g., corticosteroids or other symptomatic treatment), as clinically indicated. If the infusion is interrupted, consider resuming at a slower infusion rate only if symptoms have resolved. In the case of a serious or life-threatening IRR, the infusion should be discontinued and not resumed. - Some patients who experience IRRs may benefit from a slower infusion rate or additional or higher doses of one or more of the premedications with subsequent infusions to reduce the risk of IRRs. - Patisiran treatment leads to a decrease in serum vitamin A levels. Supplementation at the recommended daily allowance of vitamin A is advised for patients taking patisiran. Higher doses than the recommended daily allowance of vitamin A should not be given to try to achieve normal serum vitamin A levels during treatment with patisiran, as serum vitamin A levels do not reflect the total vitamin A in the body. - Patients should be referred to an ophthalmologist if they develop ocular symptoms suggestive of vitamin A deficiency (e.g., night blindness). # Adverse Reactions ## Clinical Trials Experience - Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of patisiran cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. - A total of 224 patients with polyneuropathy caused by hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) received patisiran in the placebo-controlled and open-label clinical studies, including 186 patients exposed for at least 1 year, 137 patients exposed for at least 2 years, and 52 patients exposed for at least 3 years. In the placebo-controlled study, 148 patients received patisiran for up to 18 months (mean exposure 17.7 months). Baseline demographic and disease characteristics were generally similar between treatment groups. The median age of study patients was 62 years and 74% were male. Seventy-two percent of study patients were Caucasian, 23% were Asian, 2% were Black, and 2% were reported as other. At baseline, 46% of patients were in Stage 1 of the disease and 53% were in Stage 2. Forty-three percent of patients had Val30Met mutations in the transthyretin gene; the remaining patients had 38 other point mutations. Sixty-two percent of patisiran-treated patients had non-Val30Met mutations, compared to 48% of the placebo-treated patients. - Upper respiratory tract infections and infusion-related reactions were the most common adverse reactions. One patient (0.7%) discontinued patisiran because of an infusion-related reaction. - Table 1 lists the adverse reactions that occurred in at least 5% of patients in the patisiran-treated group and that occurred at least 3% more frequently than in the placebo-treated group in the randomized controlled clinical trial. - Four serious adverse reactions of atrioventricular (AV) heart block (2.7%) occurred in patisiran-treated patients, including 3 cases of complete AV block. No serious adverse reactions of AV block were reported in placebo-treated patients. - Ocular adverse reactions that occurred in 5% or less of patisiran-treated patients in the controlled clinical trial, but in at least 2% of patisiran-treated patients, and more frequently than on placebo, include dry eye (5% vs. 3%), blurred vision (3% vs. 1%), and vitreous floaters (2% vs. 1%). - Extravasation was observed in less than 0.5% of infusions in clinical studies, including cases that were reported as serious. Signs and symptoms included phlebitis or thrombophlebitis, infusion or injection site swelling, dermatitis (subcutaneous inflammation), cellulitis, erythema or injection site redness, burning sensation, or injection site pain. ## Immunogenicity - The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. In addition, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to patisiran in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. - Anti-drug antibodies to patisiran were evaluated by measuring antibodies specific to PEG2000-C-DMG, a lipid component exposed on the surface of patisiran. In the placebo-controlled and open-label clinical studies, 7 of 194 (3.6%) patients with hATTR amyloidosis developed anti-drug antibodies during treatment with patisiran. One additional patient had pre-existing anti-drug antibodies. There was no evidence of an effect of anti-drug antibodies on clinical efficacy, safety, or the pharmacokinetic or pharmacodynamic profiles of patisiran. Although these data do not demonstrate an impact of anti-drug antibody development on the efficacy or safety of patisiran in these patients, the available data are too limited to make definitive conclusions. ## Postmarketing Experience There is limited information regarding Patisiran Postmarketing Experience in the drug label. # Drug Interactions There is limited information regarding Patisiran Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Risk Summary - There are no available data on patisiran use in pregnant women to inform a drug-associated risk of adverse developmental outcomes. Patisiran treatment leads to a decrease in serum vitamin A levels, and vitamin A supplementation is advised for patients taking patisiran. Vitamin A is essential for normal embryofetal development; however, excessive levels of vitamin A are associated with adverse developmental effects. The effects on the fetus of a reduction in maternal serum TTR caused by patisiran and of vitamin A supplementation are unknown. - In animal studies, intravenous administration of patisiran lipid complex (patisiran-LC) to pregnant rabbits resulted in developmental toxicity (embryofetal mortality and reduced fetal body weight) at doses that were also associated with maternal toxicity. No adverse developmental effects were observed when patisiran-LC or a rodent-specific (pharmacologically active) surrogate were administered to pregnant rats. - In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Animal Data - Intravenous administration of patisiran-LC (0, 0.15, 0.50, or 1.5 mg/kg) or a rodent-specific (pharmacologically active) surrogate (1.5 mg/kg) to female rats every week for two weeks prior to mating and continuing throughout organogenesis resulted in no adverse effects on fertility or embryofetal development. - Intravenous administration of patisiran-LC (0, 0.1, 0.3, or 0.6 mg/kg) to pregnant rabbits every week during the period of organogenesis produced no adverse effects on embryofetal development. In a separate study, patisiran-LC (0, 0.3, 1, or 2 mg/kg), administered to pregnant rabbits every week during the period of organogenesis, resulted in embryofetal mortality and reduced fetal body weight at the mid and high doses, which were associated with maternal toxicity. - Intravenous administration of patisiran-LC (0, 0.15, 0.50, or 1.5 mg/kg) or a rodent-specific surrogate (1.5 mg/kg) to pregnant rats every week throughout pregnancy and lactation resulted in no adverse developmental effects on the offspring. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Patisiran in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Patisiran during labor and delivery. ### Nursing Mothers Risk Summary - There is no information regarding the presence of patisiran in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for patisiran and any potential adverse effects on the breastfed infant from patisiran or from the underlying maternal condition. - In lactating rats, patisiran was not detected in milk; however, the lipid components (DLin-MC3-DMA and PEG2000-C-DMG) were present in milk. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use - No dose adjustment is required in patients ≥65 years old. A total of 62 patients ≥65 years of age, including 9 patients ≥75 years of age, received patisiran in the placebo-controlled study. No overall differences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. ### Gender There is no FDA guidance on the use of Patisiran with respect to specific gender populations. ### Race There is no FDA guidance on the use of Patisiran with respect to specific racial populations. ### Renal Impairment - No dose adjustment is necessary in patients with mild or moderate renal impairment (estimated glomerular filtration rate ≥30 to <90 mL/min/1.73m2). Patisiran has not been studied in patients with severe renal impairment or end-stage renal disease. ### Hepatic Impairment - No dose adjustment is necessary in patients with mild hepatic impairment (bilirubin ≤1 × ULN and AST >1 × ULN, or bilirubin >1.0 to 1.5 × ULN). Patisiran has not been studied in patients with moderate or severe hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Patisiran in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Patisiran in patients who are immunocompromised. # Administration and Monitoring ### Administration - Patisiran should be administered by a healthcare professional. - Patisiran is administered via intravenous (IV) infusion. Dosing is based on actual body weight. - For patients weighing less than 100 kg, the recommended dosage is 0.3 mg/kg once every 3 weeks. - For patients weighing 100 kg or more, the recommended dosage is 30 mg once every 3 weeks. Missed Dose - If a dose is missed, administer patisiran as soon as possible. If patisiran is administered within 3 days of the missed dose, continue dosing according to the patient's original schedule. If patisiran is administered more than 3 days after the missed dose, continue dosing every 3 weeks thereafter. - If patisiran is administered within 3 days of the missed dose, continue dosing according to the patient's original schedule. - If patisiran is administered more than 3 days after the missed dose, continue dosing every 3 weeks thereafter. - All patients should receive premedication prior to patisiran administration to reduce the risk of infusion-related reactions (IRRs). Each of the following premedications should be given on the day of patisiran infusion at least 60 minutes prior to the start of infusion: Intravenous corticosteroid (e.g., dexamethasone 10 mg, or equivalent) Oral acetaminophen (500 mg) Intravenous H1 blocker (e.g., diphenhydramine 50 mg, or equivalent) Intravenous H2 blocker (e.g., ranitidine 50 mg, or equivalent) - Intravenous corticosteroid (e.g., dexamethasone 10 mg, or equivalent) - Oral acetaminophen (500 mg) - Intravenous H1 blocker (e.g., diphenhydramine 50 mg, or equivalent) - Intravenous H2 blocker (e.g., ranitidine 50 mg, or equivalent) - For premedications not available or not tolerated intravenously, equivalents may be administered orally. - For patients who are tolerating their patisiran infusions but experiencing adverse reactions related to the corticosteroid premedication, the corticosteroid may be reduced by 2.5 mg increments to a minimum dose of 5 mg of dexamethasone (intravenous), or equivalent. - Some patients may require additional or higher doses of one or more of the premedications to reduce the risk of IRRs. - Patisiran must be filtered and diluted prior to intravenous infusion. The diluted solution for infusion should be prepared by a healthcare professional using aseptic technique as follows: Remove patisiran from the refrigerator and allow to warm to room temperature. Do not shake or vortex. Inspect visually for particulate matter and discoloration. Do not use if discoloration or foreign particles are present. Patisiran is a white to off-white, opalescent, homogeneous solution. A white to off-white coating may be observed on the inner surface of the vial, typically at the liquid-headspace interface. Product quality is not impacted by presence of the white to off-white coating. Calculate the required dose of patisiran based on the recommended weight-based dosage. Withdraw the entire contents of one or more vials into a single sterile syringe. Filter patisiran through a sterile 0.45 micron polyethersulfone (PES) syringe filter into a sterile container. Withdraw the required volume of filtered patisiran from the sterile container using a sterile syringe. Dilute the required volume of filtered patisiran into an infusion bag containing 0.9% Sodium Chloride Injection, USP for a total volume of 200 mL. Use infusion bags that are di(2-ethylhexyl)phthalate-free (DEHP-free). Gently invert the bag to mix the solution. Do not shake. Do not mix or dilute with other drugs. Discard any unused portion of patisiran. Patisiran does not contain preservatives. The diluted solution should be administered immediately after preparation. If not used immediately, store in the infusion bag at room temperature (up to 30°C ) for up to 16 hours (including infusion time). Do not freeze. - Remove patisiran from the refrigerator and allow to warm to room temperature. Do not shake or vortex. - Inspect visually for particulate matter and discoloration. Do not use if discoloration or foreign particles are present. Patisiran is a white to off-white, opalescent, homogeneous solution. A white to off-white coating may be observed on the inner surface of the vial, typically at the liquid-headspace interface. Product quality is not impacted by presence of the white to off-white coating. - Calculate the required dose of patisiran based on the recommended weight-based dosage. - Withdraw the entire contents of one or more vials into a single sterile syringe. - Filter patisiran through a sterile 0.45 micron polyethersulfone (PES) syringe filter into a sterile container. - Withdraw the required volume of filtered patisiran from the sterile container using a sterile syringe. - Dilute the required volume of filtered patisiran into an infusion bag containing 0.9% Sodium Chloride Injection, USP for a total volume of 200 mL. Use infusion bags that are di(2-ethylhexyl)phthalate-free (DEHP-free). - Gently invert the bag to mix the solution. Do not shake. Do not mix or dilute with other drugs. - Discard any unused portion of patisiran. - Patisiran does not contain preservatives. The diluted solution should be administered immediately after preparation. If not used immediately, store in the infusion bag at room temperature (up to 30°C ) for up to 16 hours (including infusion time). Do not freeze. - Use a dedicated line with an infusion set containing a 1.2 micron polyethersulfone (PES) in-line infusion filter. Use infusion sets and lines that are DEHP-free. Infuse the diluted solution of patisiran intravenously, via an ambulatory infusion pump, over approximately 80 minutes, at an initial infusion rate of approximately 1 mL/min for the first 15 minutes, then increase to approximately 3 mL/min for the remainder of the infusion. The duration of infusion may be extended in the event of an IRR . Administer only through a free-flowing venous access line. Monitor the infusion site for possible infiltration during drug administration. Suspected extravasation should be managed according to local standard practice for non-vesicants. Observe the patient during the infusion and, if clinically indicated, following the infusion. After completion of the infusion, flush the intravenous administration set with 0.9% Sodium Chloride Injection, USP to ensure that all patisiran has been administered. - Use a dedicated line with an infusion set containing a 1.2 micron polyethersulfone (PES) in-line infusion filter. Use infusion sets and lines that are DEHP-free. - Infuse the diluted solution of patisiran intravenously, via an ambulatory infusion pump, over approximately 80 minutes, at an initial infusion rate of approximately 1 mL/min for the first 15 minutes, then increase to approximately 3 mL/min for the remainder of the infusion. The duration of infusion may be extended in the event of an IRR . - Administer only through a free-flowing venous access line. Monitor the infusion site for possible infiltration during drug administration. Suspected extravasation should be managed according to local standard practice for non-vesicants. - Observe the patient during the infusion and, if clinically indicated, following the infusion. - After completion of the infusion, flush the intravenous administration set with 0.9% Sodium Chloride Injection, USP to ensure that all patisiran has been administered. ### Monitoring There is limited information regarding Patisiran Monitoring in the drug label. # IV Compatibility - Patisiran is administered as an intravenous injection. # Overdosage There is limited information regarding Patisiran overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action - Patisiran is a double-stranded siRNA that causes degradation of mutant and wild-type TTR mRNA through RNA interference, which results in a reduction of serum TTR protein and TTR protein deposits in tissues. ## Structure - Onpattro contains patisiran, a double-stranded small interfering ribonucleic acid (siRNA), formulated as a lipid complex for delivery to hepatocytes. Patisiran specifically binds to a genetically conserved sequence in the 3' untranslated region (3'UTR) of mutant and wild-type transthyretin (TTR) messenger RNA (mRNA). - The molecular formula of patisiran sodium is C412H480N148Na40O290P40 and the molecular weight is 14304 Da. - The structural formula is: ## Pharmacodynamics - The pharmacodynamic effects of patisiran were evaluated in hATTR amyloidosis patients treated with 0.3 mg/kg patisiran via intravenous infusion once every 3 weeks. - Mean serum TTR was reduced by approximately 80% within 10 to 14 days after a single dose. With repeat dosing every 3 weeks, mean reductions of serum TTR after 9 and 18 months of treatment were 83% and 84%, respectively. The mean maximum reduction of serum TTR over 18 months was 88%. Similar TTR reductions were observed regardless of TTR mutation, sex, age, or race. In a dose-ranging study, greater TTR reduction was maintained over the dosing interval with the recommended dosing regimen of 0.3 mg/kg every 3 weeks compared to 0.3 mg/kg every 4 weeks. - Serum TTR is a carrier of retinol binding protein, which is involved in the transport of vitamin A in the blood. Mean reductions in serum retinol binding protein of 45% and serum vitamin A of 62% were observed over 18 months. ## Pharmacokinetics - Following a single intravenous administration, systemic exposure to patisiran increases in a linear and dose-proportional manner over the range of 0.01 to 0.5 mg/kg. Greater than 95% of patisiran in the circulation is associated with the lipid complex. At the recommended dosing regimen of 0.3 mg/kg every 3 weeks, steady state is reached by 24 weeks of treatment. The estimated mean ± SD steady state peak concentrations (Cmax), trough concentrations (Ctrough), and area under the curve (AUCτ) were 7.15 ± 2.14 µg/mL, 0.021 ± 0.044 µg/mL, and 184 ± 159 µg∙h/mL, respectively. The accumulation of AUCτ was 3.2-fold at steady state, compared to the first dose. In the placebo-controlled study, inter-patient variability in patisiran exposure did not result in differences in clinical efficacy (mNIS+7 change from baseline) or safety (adverse events, serious adverse events). Distribution - Plasma protein binding of patisiran is low, with ≤2.1% binding observed in vitro with human serum albumin and human α1-acid glycoprotein. Patisiran distributes primarily to the liver. At the recommended dosing regimen of 0.3 mg/kg every 3 weeks, the mean ± SD steady state volume of distribution of patisiran (Vss) was 0.26 ± 0.20 L/kg. Elimination - The terminal elimination half-life (mean ± SD) of patisiran is 3.2 ± 1.8 days. Patisiran is mainly cleared through metabolism, and the total body clearance (mean ± SD) at steady state (CLss) is 3.0 ± 2.5 mL/h/kg. Metabolism - Patisiran is metabolized by nucleases to nucleotides of various lengths. Excretion - Less than 1% of the administered dose of patisiran is excreted unchanged into urine. Specific Populations - Age, race (non-Caucasian vs. Caucasian), and sex had no impact on the steady state pharmacokinetics of patisiran or TTR reduction. Population pharmacokinetic and pharmacodynamic analyses indicated no impact of mild or moderate renal impairment (eGFR ≥30 to 1 × ULN, or bilirubin >1.0 to 1.5 × ULN) on patisiran exposure or TTR reduction. Patisiran has not been studied in patients with severe renal impairment, end-stage renal disease, moderate or severe hepatic impairment, or in patients with prior liver transplant. Drug Interaction Studies - No formal clinical drug interaction studies have been performed. The components of patisiran are not inhibitors or inducers of cytochrome P450 enzymes or transporters. Patisiran is not a substrate of cytochrome P450 enzymes. In a population pharmacokinetic analysis, concomitant use of strong or moderate CYP3A inducers and inhibitors did not impact the pharmacokinetic parameters of patisiran. Patisiran is not expected to cause drug-drug interactions or to be affected by inhibitors or inducers of cytochrome P450 enzymes. ## Nonclinical Toxicology Carcinogenesis - Patisiran-LC was not carcinogenic in TgRasH2 mice when administered at intravenous (IV) doses of 0, 0.5, 2, or 6 mg/kg every two weeks for 26 weeks. Mutagenesis - Patisiran-LC was negative for genotoxicity in in vitro (bacterial mutagenicity assay, chromosomal aberration assay in human peripheral blood lymphocytes) and in vivo (mouse bone marrow micronucleus) assays. Impairment of Fertility - Intravenous (IV) administration of patisiran-LC (0, 0.03, 0.1, or 0.3 mg/kg) or a rodent-specific (pharmacologically active) surrogate (0.1 mg/kg) to male rats every two weeks prior to and throughout mating to untreated females produced no adverse effects on fertility. - Intravenous administration of patisiran-LC (0, 0.15, 0.50, or 1.5 mg/kg) or a rodent-specific (pharmacologically active) surrogate (1.5 mg/kg) to female rats every week for two weeks prior to mating and continuing throughout organogenesis resulted in no adverse effects on fertility or on embryofetal development. - Intravenous administration of patisiran-LC (0, 0.3, 1, or 2 mg/kg) to adult monkeys every three weeks for 39 weeks produced no adverse effects on male reproductive organs or on sperm morphology or count. # Clinical Studies - The efficacy of patisiran was demonstrated in a randomized, double-blind, placebo-controlled, multicenter clinical trial in adult patients with polyneuropathy caused by hATTR amyloidosis (NCT 01960348). Patients were randomized in a 2:1 ratio to receive patisiran 0.3 mg/kg (N=148) or placebo (N=77), respectively, via intravenous infusion once every 3 weeks for 18 months. All patients received premedication with a corticosteroid, acetaminophen, and H1 and H2 blockers. Ninety-three percent of patisiran-treated patients and 62% of placebo-treated patients completed 18 months of the assigned treatment. - The primary efficacy endpoint was the change from baseline to Month 18 in the modified Neuropathy Impairment Score +7 (mNIS+7). The mNIS+7 is an objective assessment of neuropathy and comprises the NIS and Modified +7 (+7) composite scores. In the version of the mNIS+7 used in the trial, the NIS objectively measures deficits in cranial nerve function, muscle strength, and reflexes, and the +7 assesses postural blood pressure, quantitative sensory testing, and peripheral nerve electrophysiology. The maximum possible score was 304 points, with higher scores representing a greater severity of disease. - The clinical meaningfulness of effects on the mNIS+7 was assessed by the change from baseline to Month 18 in Norfolk Quality of Life-Diabetic Neuropathy (QoL-DN) total score. The Norfolk QoL-DN scale is a patient-reported assessment that evaluates the subjective experience of neuropathy in the following domains: physical functioning/large fiber neuropathy, activities of daily living, symptoms, small fiber neuropathy, and autonomic neuropathy. The version of the Norfolk QoL-DN that was used in the trial had a total score range from -4 to 136, with higher scores representing greater impairment. - The changes from baseline to Month 18 on both the mNIS+7 and the Norfolk QoL-DN significantly favored patisiran (Table 2, Figure 1 and Figure 3). The distributions of changes in mNIS+7 and Norfolk QoL-DN scores from baseline to Month 18 by percent of patients are shown in Figure 2 and Figure 4, respectively. - The changes from baseline to Month 18 in modified body mass index (mBMI) and gait speed (10-meter walk test) significantly favored patisiran (Table 2). - A decrease in mNIS+7 indicates improvement. - Δ indicates between-group treatment difference, shown as the LS mean difference (95% CI) for patisiran – placebo. - mNIS+7 change scores are rounded to the nearest whole number; last available post-baseline scores were used. - Categories are mutually exclusive; patients who died before 18 months are summarized in the "Death" category only. - A decrease in Norfolk QoL-DN score indicates improvement. - Δ indicates between-group treatment difference, shown as the LS mean difference (95% CI) for patisiran – placebo. - Norfolk QoL-DN change scores are rounded to the nearest whole number; last available post-baseline scores were used. - Categories are mutually exclusive; patients who died before 18 months are summarized in the "Death" category only. - Patients receiving patisiran experienced similar improvements relative to placebo in mNIS+7 and Norfolk QoL-DN score across all subgroups including age, sex, race, region, NIS score, Val30Met mutation status, and disease stage. # How Supplied - Patisiran is a sterile, preservative-free, white to off-white, opalescent, homogeneous solution for intravenous infusion supplied as a 10 mg/5 mL (2 mg/mL) solution in a single-dose glass vial. The vial stopper is not made with natural rubber latex. Patisiran is available in cartons containing one single-dose vial each. ## Storage - Store at 2°C to 8°C (36°F to 46°F). Do not freeze. Discard vial if it has been frozen. - If refrigeration is not available, patisiran can be stored at room temperature up to 25°C (up to 77°F) for up to 14 days. - For storage conditions of patisiran after dilution in the infusion bag, see Administration & Monitoring # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Infusion-Related Reactions - Inform patients about the signs and symptoms of infusion-related reactions (e.g., flushing, dyspnea, chest pain, rash, increased heart rate, facial edema). Advise patients to contact their healthcare provider immediately if they experience signs and symptoms of infusion-related reactions. Recommended Vitamin A Supplementation - Inform patients that patisiran treatment leads to a decrease in vitamin A levels measured in the serum. Instruct patients to take the recommended daily allowance of vitamin A. Advise patients to contact their healthcare provider if they experience ocular symptoms suggestive of vitamin A deficiency (e.g., night blindness) and refer them to an ophthalmologist if they develop these symptoms. Pregnancy - Instruct patients that if they are pregnant or plan to become pregnant while taking patisiran they should inform their healthcare provider. Advise female patients of childbearing potential of the potential risk to the fetus. # Precautions with Alcohol Alcohol-Patisiran interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names Onpattro # Look-Alike Drug Names There is limited information regarding Patisiran Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Patisiran Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Zach Leibowitz [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Patisiran is a transthyretin-directed small interfering RNA that is FDA approved for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults. Common adverse reactions include upper respiratory tract infections and infusion-related reactions. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Indication - Patisiran is indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults. Dosage - For patients weighing less than 100 kg, the recommended dosage is 0.3 mg/kg every 3 weeks by intravenous infusion. For patients weighing 100 kg or more, the recommended dosage is 30 mg. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding patisiran Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding patisiran Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and effectiveness in pediatric patients have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding patisiran Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding patisiran Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications None. # Warnings - Infusion-related reactions (IRRs) have been observed in patients treated with patisiran. In clinical studies, all patients received premedication with a corticosteroid, acetaminophen, and antihistamines (H1 and H2 blockers) to reduce the risk of IRRs. In a controlled clinical study, 19% of patisiran-treated patients experienced IRRs, compared to 9% of placebo-treated patients. Among patisiran-treated patients who experienced an IRR, 79% experienced the first IRR within the first 2 infusions. The frequency of IRRs decreased over time. IRRs led to infusion interruption in 5% of patients. IRRs resulted in permanent discontinuation of patisiran in less than 1% of patients in clinical studies. Across clinical studies, the most common symptoms (reported in greater than 2% of patients) of IRRs with patisiran were flushing, back pain, nausea, abdominal pain, dyspnea, and headache. One patient in the patisiran expanded access program had a severe adverse reaction of hypotension and syncope during a patisiran infusion. - Patients should receive premedications on the day of patisiran infusion, at least 60 minutes prior to the start of infusion. Monitor patients during the infusion for signs and symptoms of IRRs. If an IRR occurs, consider slowing or interrupting the patisiran infusion and instituting medical management (e.g., corticosteroids or other symptomatic treatment), as clinically indicated. If the infusion is interrupted, consider resuming at a slower infusion rate only if symptoms have resolved. In the case of a serious or life-threatening IRR, the infusion should be discontinued and not resumed. - Some patients who experience IRRs may benefit from a slower infusion rate or additional or higher doses of one or more of the premedications with subsequent infusions to reduce the risk of IRRs. - Patisiran treatment leads to a decrease in serum vitamin A levels. Supplementation at the recommended daily allowance of vitamin A is advised for patients taking patisiran. Higher doses than the recommended daily allowance of vitamin A should not be given to try to achieve normal serum vitamin A levels during treatment with patisiran, as serum vitamin A levels do not reflect the total vitamin A in the body. - Patients should be referred to an ophthalmologist if they develop ocular symptoms suggestive of vitamin A deficiency (e.g., night blindness). # Adverse Reactions ## Clinical Trials Experience - Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of patisiran cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. - A total of 224 patients with polyneuropathy caused by hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) received patisiran in the placebo-controlled and open-label clinical studies, including 186 patients exposed for at least 1 year, 137 patients exposed for at least 2 years, and 52 patients exposed for at least 3 years. In the placebo-controlled study, 148 patients received patisiran for up to 18 months (mean exposure 17.7 months). Baseline demographic and disease characteristics were generally similar between treatment groups. The median age of study patients was 62 years and 74% were male. Seventy-two percent of study patients were Caucasian, 23% were Asian, 2% were Black, and 2% were reported as other. At baseline, 46% of patients were in Stage 1 of the disease and 53% were in Stage 2. Forty-three percent of patients had Val30Met mutations in the transthyretin gene; the remaining patients had 38 other point mutations. Sixty-two percent of patisiran-treated patients had non-Val30Met mutations, compared to 48% of the placebo-treated patients. - Upper respiratory tract infections and infusion-related reactions were the most common adverse reactions. One patient (0.7%) discontinued patisiran because of an infusion-related reaction. - Table 1 lists the adverse reactions that occurred in at least 5% of patients in the patisiran-treated group and that occurred at least 3% more frequently than in the placebo-treated group in the randomized controlled clinical trial. - Four serious adverse reactions of atrioventricular (AV) heart block (2.7%) occurred in patisiran-treated patients, including 3 cases of complete AV block. No serious adverse reactions of AV block were reported in placebo-treated patients. - Ocular adverse reactions that occurred in 5% or less of patisiran-treated patients in the controlled clinical trial, but in at least 2% of patisiran-treated patients, and more frequently than on placebo, include dry eye (5% vs. 3%), blurred vision (3% vs. 1%), and vitreous floaters (2% vs. 1%). - Extravasation was observed in less than 0.5% of infusions in clinical studies, including cases that were reported as serious. Signs and symptoms included phlebitis or thrombophlebitis, infusion or injection site swelling, dermatitis (subcutaneous inflammation), cellulitis, erythema or injection site redness, burning sensation, or injection site pain. ## Immunogenicity - The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. In addition, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to patisiran in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. - Anti-drug antibodies to patisiran were evaluated by measuring antibodies specific to PEG2000-C-DMG, a lipid component exposed on the surface of patisiran. In the placebo-controlled and open-label clinical studies, 7 of 194 (3.6%) patients with hATTR amyloidosis developed anti-drug antibodies during treatment with patisiran. One additional patient had pre-existing anti-drug antibodies. There was no evidence of an effect of anti-drug antibodies on clinical efficacy, safety, or the pharmacokinetic or pharmacodynamic profiles of patisiran. Although these data do not demonstrate an impact of anti-drug antibody development on the efficacy or safety of patisiran in these patients, the available data are too limited to make definitive conclusions. ## Postmarketing Experience There is limited information regarding Patisiran Postmarketing Experience in the drug label. # Drug Interactions There is limited information regarding Patisiran Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Risk Summary - There are no available data on patisiran use in pregnant women to inform a drug-associated risk of adverse developmental outcomes. Patisiran treatment leads to a decrease in serum vitamin A levels, and vitamin A supplementation is advised for patients taking patisiran. Vitamin A is essential for normal embryofetal development; however, excessive levels of vitamin A are associated with adverse developmental effects. The effects on the fetus of a reduction in maternal serum TTR caused by patisiran and of vitamin A supplementation are unknown. - In animal studies, intravenous administration of patisiran lipid complex (patisiran-LC) to pregnant rabbits resulted in developmental toxicity (embryofetal mortality and reduced fetal body weight) at doses that were also associated with maternal toxicity. No adverse developmental effects were observed when patisiran-LC or a rodent-specific (pharmacologically active) surrogate were administered to pregnant rats. - In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Animal Data - Intravenous administration of patisiran-LC (0, 0.15, 0.50, or 1.5 mg/kg) or a rodent-specific (pharmacologically active) surrogate (1.5 mg/kg) to female rats every week for two weeks prior to mating and continuing throughout organogenesis resulted in no adverse effects on fertility or embryofetal development. - Intravenous administration of patisiran-LC (0, 0.1, 0.3, or 0.6 mg/kg) to pregnant rabbits every week during the period of organogenesis produced no adverse effects on embryofetal development. In a separate study, patisiran-LC (0, 0.3, 1, or 2 mg/kg), administered to pregnant rabbits every week during the period of organogenesis, resulted in embryofetal mortality and reduced fetal body weight at the mid and high doses, which were associated with maternal toxicity. - Intravenous administration of patisiran-LC (0, 0.15, 0.50, or 1.5 mg/kg) or a rodent-specific surrogate (1.5 mg/kg) to pregnant rats every week throughout pregnancy and lactation resulted in no adverse developmental effects on the offspring. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Patisiran in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Patisiran during labor and delivery. ### Nursing Mothers Risk Summary - There is no information regarding the presence of patisiran in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for patisiran and any potential adverse effects on the breastfed infant from patisiran or from the underlying maternal condition. - In lactating rats, patisiran was not detected in milk; however, the lipid components (DLin-MC3-DMA and PEG2000-C-DMG) were present in milk. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use - No dose adjustment is required in patients ≥65 years old. A total of 62 patients ≥65 years of age, including 9 patients ≥75 years of age, received patisiran in the placebo-controlled study. No overall differences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. ### Gender There is no FDA guidance on the use of Patisiran with respect to specific gender populations. ### Race There is no FDA guidance on the use of Patisiran with respect to specific racial populations. ### Renal Impairment - No dose adjustment is necessary in patients with mild or moderate renal impairment (estimated glomerular filtration rate [eGFR] ≥30 to <90 mL/min/1.73m2). Patisiran has not been studied in patients with severe renal impairment or end-stage renal disease. ### Hepatic Impairment - No dose adjustment is necessary in patients with mild hepatic impairment (bilirubin ≤1 × ULN and AST >1 × ULN, or bilirubin >1.0 to 1.5 × ULN). Patisiran has not been studied in patients with moderate or severe hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Patisiran in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Patisiran in patients who are immunocompromised. # Administration and Monitoring ### Administration - Patisiran should be administered by a healthcare professional. - Patisiran is administered via intravenous (IV) infusion. Dosing is based on actual body weight. - For patients weighing less than 100 kg, the recommended dosage is 0.3 mg/kg once every 3 weeks. - For patients weighing 100 kg or more, the recommended dosage is 30 mg once every 3 weeks. Missed Dose - If a dose is missed, administer patisiran as soon as possible. If patisiran is administered within 3 days of the missed dose, continue dosing according to the patient's original schedule. If patisiran is administered more than 3 days after the missed dose, continue dosing every 3 weeks thereafter. - If patisiran is administered within 3 days of the missed dose, continue dosing according to the patient's original schedule. - If patisiran is administered more than 3 days after the missed dose, continue dosing every 3 weeks thereafter. - All patients should receive premedication prior to patisiran administration to reduce the risk of infusion-related reactions (IRRs). Each of the following premedications should be given on the day of patisiran infusion at least 60 minutes prior to the start of infusion: Intravenous corticosteroid (e.g., dexamethasone 10 mg, or equivalent) Oral acetaminophen (500 mg) Intravenous H1 blocker (e.g., diphenhydramine 50 mg, or equivalent) Intravenous H2 blocker (e.g., ranitidine 50 mg, or equivalent) - Intravenous corticosteroid (e.g., dexamethasone 10 mg, or equivalent) - Oral acetaminophen (500 mg) - Intravenous H1 blocker (e.g., diphenhydramine 50 mg, or equivalent) - Intravenous H2 blocker (e.g., ranitidine 50 mg, or equivalent) - For premedications not available or not tolerated intravenously, equivalents may be administered orally. - For patients who are tolerating their patisiran infusions but experiencing adverse reactions related to the corticosteroid premedication, the corticosteroid may be reduced by 2.5 mg increments to a minimum dose of 5 mg of dexamethasone (intravenous), or equivalent. - Some patients may require additional or higher doses of one or more of the premedications to reduce the risk of IRRs. - Patisiran must be filtered and diluted prior to intravenous infusion. The diluted solution for infusion should be prepared by a healthcare professional using aseptic technique as follows: Remove patisiran from the refrigerator and allow to warm to room temperature. Do not shake or vortex. Inspect visually for particulate matter and discoloration. Do not use if discoloration or foreign particles are present. Patisiran is a white to off-white, opalescent, homogeneous solution. A white to off-white coating may be observed on the inner surface of the vial, typically at the liquid-headspace interface. Product quality is not impacted by presence of the white to off-white coating. Calculate the required dose of patisiran based on the recommended weight-based dosage. Withdraw the entire contents of one or more vials into a single sterile syringe. Filter patisiran through a sterile 0.45 micron polyethersulfone (PES) syringe filter into a sterile container. Withdraw the required volume of filtered patisiran from the sterile container using a sterile syringe. Dilute the required volume of filtered patisiran into an infusion bag containing 0.9% Sodium Chloride Injection, USP for a total volume of 200 mL. Use infusion bags that are di(2-ethylhexyl)phthalate-free (DEHP-free). Gently invert the bag to mix the solution. Do not shake. Do not mix or dilute with other drugs. Discard any unused portion of patisiran. Patisiran does not contain preservatives. The diluted solution should be administered immediately after preparation. If not used immediately, store in the infusion bag at room temperature (up to 30°C [86°F]) for up to 16 hours (including infusion time). Do not freeze. - Remove patisiran from the refrigerator and allow to warm to room temperature. Do not shake or vortex. - Inspect visually for particulate matter and discoloration. Do not use if discoloration or foreign particles are present. Patisiran is a white to off-white, opalescent, homogeneous solution. A white to off-white coating may be observed on the inner surface of the vial, typically at the liquid-headspace interface. Product quality is not impacted by presence of the white to off-white coating. - Calculate the required dose of patisiran based on the recommended weight-based dosage. - Withdraw the entire contents of one or more vials into a single sterile syringe. - Filter patisiran through a sterile 0.45 micron polyethersulfone (PES) syringe filter into a sterile container. - Withdraw the required volume of filtered patisiran from the sterile container using a sterile syringe. - Dilute the required volume of filtered patisiran into an infusion bag containing 0.9% Sodium Chloride Injection, USP for a total volume of 200 mL. Use infusion bags that are di(2-ethylhexyl)phthalate-free (DEHP-free). - Gently invert the bag to mix the solution. Do not shake. Do not mix or dilute with other drugs. - Discard any unused portion of patisiran. - Patisiran does not contain preservatives. The diluted solution should be administered immediately after preparation. If not used immediately, store in the infusion bag at room temperature (up to 30°C [86°F]) for up to 16 hours (including infusion time). Do not freeze. - Use a dedicated line with an infusion set containing a 1.2 micron polyethersulfone (PES) in-line infusion filter. Use infusion sets and lines that are DEHP-free. Infuse the diluted solution of patisiran intravenously, via an ambulatory infusion pump, over approximately 80 minutes, at an initial infusion rate of approximately 1 mL/min for the first 15 minutes, then increase to approximately 3 mL/min for the remainder of the infusion. The duration of infusion may be extended in the event of an IRR [see WARNINGS AND PRECAUTIONS]. Administer only through a free-flowing venous access line. Monitor the infusion site for possible infiltration during drug administration. Suspected extravasation should be managed according to local standard practice for non-vesicants. Observe the patient during the infusion and, if clinically indicated, following the infusion. After completion of the infusion, flush the intravenous administration set with 0.9% Sodium Chloride Injection, USP to ensure that all patisiran has been administered. - Use a dedicated line with an infusion set containing a 1.2 micron polyethersulfone (PES) in-line infusion filter. Use infusion sets and lines that are DEHP-free. - Infuse the diluted solution of patisiran intravenously, via an ambulatory infusion pump, over approximately 80 minutes, at an initial infusion rate of approximately 1 mL/min for the first 15 minutes, then increase to approximately 3 mL/min for the remainder of the infusion. The duration of infusion may be extended in the event of an IRR [see WARNINGS AND PRECAUTIONS]. - Administer only through a free-flowing venous access line. Monitor the infusion site for possible infiltration during drug administration. Suspected extravasation should be managed according to local standard practice for non-vesicants. - Observe the patient during the infusion and, if clinically indicated, following the infusion. - After completion of the infusion, flush the intravenous administration set with 0.9% Sodium Chloride Injection, USP to ensure that all patisiran has been administered. ### Monitoring There is limited information regarding Patisiran Monitoring in the drug label. # IV Compatibility - Patisiran is administered as an intravenous injection. # Overdosage There is limited information regarding Patisiran overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action - Patisiran is a double-stranded siRNA that causes degradation of mutant and wild-type TTR mRNA through RNA interference, which results in a reduction of serum TTR protein and TTR protein deposits in tissues. ## Structure - Onpattro contains patisiran, a double-stranded small interfering ribonucleic acid (siRNA), formulated as a lipid complex for delivery to hepatocytes. Patisiran specifically binds to a genetically conserved sequence in the 3' untranslated region (3'UTR) of mutant and wild-type transthyretin (TTR) messenger RNA (mRNA). - The molecular formula of patisiran sodium is C412H480N148Na40O290P40 and the molecular weight is 14304 Da. - The structural formula is: ## Pharmacodynamics - The pharmacodynamic effects of patisiran were evaluated in hATTR amyloidosis patients treated with 0.3 mg/kg patisiran via intravenous infusion once every 3 weeks. - Mean serum TTR was reduced by approximately 80% within 10 to 14 days after a single dose. With repeat dosing every 3 weeks, mean reductions of serum TTR after 9 and 18 months of treatment were 83% and 84%, respectively. The mean maximum reduction of serum TTR over 18 months was 88%. Similar TTR reductions were observed regardless of TTR mutation, sex, age, or race. In a dose-ranging study, greater TTR reduction was maintained over the dosing interval with the recommended dosing regimen of 0.3 mg/kg every 3 weeks compared to 0.3 mg/kg every 4 weeks. - Serum TTR is a carrier of retinol binding protein, which is involved in the transport of vitamin A in the blood. Mean reductions in serum retinol binding protein of 45% and serum vitamin A of 62% were observed over 18 months. ## Pharmacokinetics - Following a single intravenous administration, systemic exposure to patisiran increases in a linear and dose-proportional manner over the range of 0.01 to 0.5 mg/kg. Greater than 95% of patisiran in the circulation is associated with the lipid complex. At the recommended dosing regimen of 0.3 mg/kg every 3 weeks, steady state is reached by 24 weeks of treatment. The estimated mean ± SD steady state peak concentrations (Cmax), trough concentrations (Ctrough), and area under the curve (AUCτ) were 7.15 ± 2.14 µg/mL, 0.021 ± 0.044 µg/mL, and 184 ± 159 µg∙h/mL, respectively. The accumulation of AUCτ was 3.2-fold at steady state, compared to the first dose. In the placebo-controlled study, inter-patient variability in patisiran exposure did not result in differences in clinical efficacy (mNIS+7 change from baseline) or safety (adverse events, serious adverse events). Distribution - Plasma protein binding of patisiran is low, with ≤2.1% binding observed in vitro with human serum albumin and human α1-acid glycoprotein. Patisiran distributes primarily to the liver. At the recommended dosing regimen of 0.3 mg/kg every 3 weeks, the mean ± SD steady state volume of distribution of patisiran (Vss) was 0.26 ± 0.20 L/kg. Elimination - The terminal elimination half-life (mean ± SD) of patisiran is 3.2 ± 1.8 days. Patisiran is mainly cleared through metabolism, and the total body clearance (mean ± SD) at steady state (CLss) is 3.0 ± 2.5 mL/h/kg. Metabolism - Patisiran is metabolized by nucleases to nucleotides of various lengths. Excretion - Less than 1% of the administered dose of patisiran is excreted unchanged into urine. Specific Populations - Age, race (non-Caucasian vs. Caucasian), and sex had no impact on the steady state pharmacokinetics of patisiran or TTR reduction. Population pharmacokinetic and pharmacodynamic analyses indicated no impact of mild or moderate renal impairment (eGFR ≥30 to <90 mL/min/1.73m2) or mild hepatic impairment (bilirubin ≤1 × ULN and AST >1 × ULN, or bilirubin >1.0 to 1.5 × ULN) on patisiran exposure or TTR reduction. Patisiran has not been studied in patients with severe renal impairment, end-stage renal disease, moderate or severe hepatic impairment, or in patients with prior liver transplant. Drug Interaction Studies - No formal clinical drug interaction studies have been performed. The components of patisiran are not inhibitors or inducers of cytochrome P450 enzymes or transporters. Patisiran is not a substrate of cytochrome P450 enzymes. In a population pharmacokinetic analysis, concomitant use of strong or moderate CYP3A inducers and inhibitors did not impact the pharmacokinetic parameters of patisiran. Patisiran is not expected to cause drug-drug interactions or to be affected by inhibitors or inducers of cytochrome P450 enzymes. ## Nonclinical Toxicology Carcinogenesis - Patisiran-LC was not carcinogenic in TgRasH2 mice when administered at intravenous (IV) doses of 0, 0.5, 2, or 6 mg/kg every two weeks for 26 weeks. Mutagenesis - Patisiran-LC was negative for genotoxicity in in vitro (bacterial mutagenicity assay, chromosomal aberration assay in human peripheral blood lymphocytes) and in vivo (mouse bone marrow micronucleus) assays. Impairment of Fertility - Intravenous (IV) administration of patisiran-LC (0, 0.03, 0.1, or 0.3 mg/kg) or a rodent-specific (pharmacologically active) surrogate (0.1 mg/kg) to male rats every two weeks prior to and throughout mating to untreated females produced no adverse effects on fertility. - Intravenous administration of patisiran-LC (0, 0.15, 0.50, or 1.5 mg/kg) or a rodent-specific (pharmacologically active) surrogate (1.5 mg/kg) to female rats every week for two weeks prior to mating and continuing throughout organogenesis resulted in no adverse effects on fertility or on embryofetal development. - Intravenous administration of patisiran-LC (0, 0.3, 1, or 2 mg/kg) to adult monkeys every three weeks for 39 weeks produced no adverse effects on male reproductive organs or on sperm morphology or count. # Clinical Studies - The efficacy of patisiran was demonstrated in a randomized, double-blind, placebo-controlled, multicenter clinical trial in adult patients with polyneuropathy caused by hATTR amyloidosis (NCT 01960348). Patients were randomized in a 2:1 ratio to receive patisiran 0.3 mg/kg (N=148) or placebo (N=77), respectively, via intravenous infusion once every 3 weeks for 18 months. All patients received premedication with a corticosteroid, acetaminophen, and H1 and H2 blockers. Ninety-three percent of patisiran-treated patients and 62% of placebo-treated patients completed 18 months of the assigned treatment. - The primary efficacy endpoint was the change from baseline to Month 18 in the modified Neuropathy Impairment Score +7 (mNIS+7). The mNIS+7 is an objective assessment of neuropathy and comprises the NIS and Modified +7 (+7) composite scores. In the version of the mNIS+7 used in the trial, the NIS objectively measures deficits in cranial nerve function, muscle strength, and reflexes, and the +7 assesses postural blood pressure, quantitative sensory testing, and peripheral nerve electrophysiology. The maximum possible score was 304 points, with higher scores representing a greater severity of disease. - The clinical meaningfulness of effects on the mNIS+7 was assessed by the change from baseline to Month 18 in Norfolk Quality of Life-Diabetic Neuropathy (QoL-DN) total score. The Norfolk QoL-DN scale is a patient-reported assessment that evaluates the subjective experience of neuropathy in the following domains: physical functioning/large fiber neuropathy, activities of daily living, symptoms, small fiber neuropathy, and autonomic neuropathy. The version of the Norfolk QoL-DN that was used in the trial had a total score range from -4 to 136, with higher scores representing greater impairment. - The changes from baseline to Month 18 on both the mNIS+7 and the Norfolk QoL-DN significantly favored patisiran (Table 2, Figure 1 and Figure 3). The distributions of changes in mNIS+7 and Norfolk QoL-DN scores from baseline to Month 18 by percent of patients are shown in Figure 2 and Figure 4, respectively. - The changes from baseline to Month 18 in modified body mass index (mBMI) and gait speed (10-meter walk test) significantly favored patisiran (Table 2). - A decrease in mNIS+7 indicates improvement. - Δ indicates between-group treatment difference, shown as the LS mean difference (95% CI) for patisiran – placebo. - mNIS+7 change scores are rounded to the nearest whole number; last available post-baseline scores were used. - Categories are mutually exclusive; patients who died before 18 months are summarized in the "Death" category only. - A decrease in Norfolk QoL-DN score indicates improvement. - Δ indicates between-group treatment difference, shown as the LS mean difference (95% CI) for patisiran – placebo. - Norfolk QoL-DN change scores are rounded to the nearest whole number; last available post-baseline scores were used. - Categories are mutually exclusive; patients who died before 18 months are summarized in the "Death" category only. - Patients receiving patisiran experienced similar improvements relative to placebo in mNIS+7 and Norfolk QoL-DN score across all subgroups including age, sex, race, region, NIS score, Val30Met mutation status, and disease stage. # How Supplied - Patisiran is a sterile, preservative-free, white to off-white, opalescent, homogeneous solution for intravenous infusion supplied as a 10 mg/5 mL (2 mg/mL) solution in a single-dose glass vial. The vial stopper is not made with natural rubber latex. Patisiran is available in cartons containing one single-dose vial each. ## Storage - Store at 2°C to 8°C (36°F to 46°F). Do not freeze. Discard vial if it has been frozen. - If refrigeration is not available, patisiran can be stored at room temperature up to 25°C (up to 77°F) for up to 14 days. - For storage conditions of patisiran after dilution in the infusion bag, see Administration & Monitoring # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Infusion-Related Reactions - Inform patients about the signs and symptoms of infusion-related reactions (e.g., flushing, dyspnea, chest pain, rash, increased heart rate, facial edema). Advise patients to contact their healthcare provider immediately if they experience signs and symptoms of infusion-related reactions. Recommended Vitamin A Supplementation - Inform patients that patisiran treatment leads to a decrease in vitamin A levels measured in the serum. Instruct patients to take the recommended daily allowance of vitamin A. Advise patients to contact their healthcare provider if they experience ocular symptoms suggestive of vitamin A deficiency (e.g., night blindness) and refer them to an ophthalmologist if they develop these symptoms. Pregnancy - Instruct patients that if they are pregnant or plan to become pregnant while taking patisiran they should inform their healthcare provider. Advise female patients of childbearing potential of the potential risk to the fetus. # Precautions with Alcohol Alcohol-Patisiran interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names Onpattro # Look-Alike Drug Names There is limited information regarding Patisiran Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Onpattro
4ef131d4e0315b2bb38be72ad3daf5b1825221ec	wikidoc	Oogenesis	Oogenesis # Overview Oogenesis or rarely oögenesis is the creation of an ovum (egg cell). It is the female process of gametogenesis. It involves the various stages of immature ova. # Oogenesis in mammals In mammals, oogenesis occurs in the ovarian follicle of the ovary. It is interesting to note that such an important process in animal life cycles is done completely without the aid of spindle-coordinating centrosomes. It consists of several processes: oocytogenesis, ootidogenesis and the final maturity to form an ovum. Folliculogenesis is a separate process during ootidogenesis. ## Creation of oogonia The creation of oogonia traditionally doesn't belong to oogenesis, but to the common path of gametogenesis together with spermatogenesis. ## Oocytogenesis Oogenesis starts with oogonial transformation into primary oocytes, called oocytogenesis. Oocytogenesis is completed either before or shortly after birth. ### Number of primary oocytes It is commonly said that when oocytogenesis is completed, no additional primary oocytes are created, in contrast to the male spermatogenesis, where gametocytes are continuously created. In other words, oocytes reaches their maximum at ~20 weeks of gestational age, when there are approximately seven million of them. Recently, however, two publications have challenged the ovarian biology dogma that a finite number of oocytes are set around the time of birth. Renewal of ovarian follicles from germline stem cells (originating from bone marrow and peripheral blood) was reported in the postnatal mouse ovary. Due to the revolutionary nature of these claims, further experiments are required to examine the dynamics of small follicle formation. ## Ootidogenesis The succeeding ootidogenesis is the step in which the primary oocyte turns into an ootid. It is achieved by meiosis. The primary oocyte is even defined from its role to undergo meiosis. However, although this process begins at prenatal age, it stops at prophase I. In in late fetal life, all oocytes, still primary oocytes, have taken this halt in development, called dictyate. First after menarche they continue to develop, although only a few does so every menstrual cycle. ### Meiosis I Meiosis I of ootidogenesis starts at embryonic age, but halts in dictyate until puberty. For those primary oocytes continuing to develop in each menstrual cycle, however, synapsis occurs and tetrads form, enabling and crossing over. As a result of meiosis I, the primary oocyte becomes the secondary oocyte and the first polar body. ### Meiosis II Immediately after meiosis I, the haploid secondary oocyte initiates meiosis II. However, this, too is halted, and it's halted in the metaphase of meiosis II. However, this only lasts until fertilization, if such occurs. When meiosis II is completed, an ootid and another polar body is created. ### Folliculogenesis Synchronously as ootidogenesis, the ovarian follicle surrounding it develops from a primordial follicle to a preovulatory one. ## Maturation into ovum Both polar bodies at the end of Meiosis II disintegrate leaving only the ootid which undergoes maturation and eventually matures into an ovum. # Oogenesis in non-mammals Many protists produce egg cells in structures termed archegonia. Some algae and the oomycetes produce eggs in oogonia. In the brown alga Fucus, all four egg cells survive oogenesis, which is an exception to the rule that generally only one product of female meiosis survives to maturity. In plants, oogenesis occurs inside the female gametophyte via mitosis. In many plants such as bryophytes, ferns, and gymnosperms, egg cells are formed in archegonia. In flowering plants, the female gametophyte has been reduced to an eight-celled embryo sac within the ovule inside the ovary of the flower. Oogenesis occurs within the embryo sac and leads to the formation of a single egg cell per ovule. In ascaris, the oocyte does not even begin meiosis until the sperm touches it, in contrast to mammals, where meiosis is completed in the menstrual cycle.	Oogenesis Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Oogenesis or rarely oögenesis is the creation of an ovum (egg cell). It is the female process of gametogenesis. It involves the various stages of immature ova. # Oogenesis in mammals In mammals, oogenesis occurs in the ovarian follicle of the ovary. It is interesting to note that such an important process in animal life cycles is done completely without the aid of spindle-coordinating centrosomes. It consists of several processes: oocytogenesis, ootidogenesis and the final maturity to form an ovum. Folliculogenesis is a separate process during ootidogenesis. ## Creation of oogonia The creation of oogonia traditionally doesn't belong to oogenesis, but to the common path of gametogenesis together with spermatogenesis. ## Oocytogenesis Oogenesis starts with oogonial transformation into primary oocytes, called oocytogenesis[1]. Oocytogenesis is completed either before or shortly after birth. ### Number of primary oocytes It is commonly said that when oocytogenesis is completed, no additional primary oocytes are created, in contrast to the male spermatogenesis, where gametocytes are continuously created. In other words, oocytes reaches their maximum at ~20[2] weeks of gestational age, when there are approximately seven million of them. Recently, however, two publications have challenged the ovarian biology dogma that a finite number of oocytes are set around the time of birth.[3][4] Renewal of ovarian follicles from germline stem cells (originating from bone marrow and peripheral blood) was reported in the postnatal mouse ovary. Due to the revolutionary nature of these claims, further experiments are required to examine the dynamics of small follicle formation. ## Ootidogenesis The succeeding ootidogenesis is the step in which the primary oocyte turns into an ootid. It is achieved by meiosis. The primary oocyte is even defined from its role to undergo meiosis[5]. However, although this process begins at prenatal age, it stops at prophase I. In in late fetal life, all oocytes, still primary oocytes, have taken this halt in development, called dictyate. First after menarche they continue to develop, although only a few does so every menstrual cycle. ### Meiosis I Meiosis I of ootidogenesis starts at embryonic age, but halts in dictyate until puberty. For those primary oocytes continuing to develop in each menstrual cycle, however, synapsis occurs and tetrads form, enabling and crossing over. As a result of meiosis I, the primary oocyte becomes the secondary oocyte and the first polar body. ### Meiosis II Immediately after meiosis I, the haploid secondary oocyte initiates meiosis II. However, this, too is halted, and it's halted in the metaphase of meiosis II. However, this only lasts until fertilization, if such occurs. When meiosis II is completed, an ootid and another polar body is created. ### Folliculogenesis Synchronously as ootidogenesis, the ovarian follicle surrounding it develops from a primordial follicle to a preovulatory one. ## Maturation into ovum Both polar bodies at the end of Meiosis II disintegrate leaving only the ootid which undergoes maturation and eventually matures into an ovum. # Oogenesis in non-mammals Many protists produce egg cells in structures termed archegonia. Some algae and the oomycetes produce eggs in oogonia. In the brown alga Fucus, all four egg cells survive oogenesis, which is an exception to the rule that generally only one product of female meiosis survives to maturity. In plants, oogenesis occurs inside the female gametophyte via mitosis. In many plants such as bryophytes, ferns, and gymnosperms, egg cells are formed in archegonia. In flowering plants, the female gametophyte has been reduced to an eight-celled embryo sac within the ovule inside the ovary of the flower. Oogenesis occurs within the embryo sac and leads to the formation of a single egg cell per ovule. In ascaris, the oocyte does not even begin meiosis until the sperm touches it, in contrast to mammals, where meiosis is completed in the menstrual cycle.	https://www.wikidoc.org/index.php/Oocytogenesis
da4a9c5e977c774acd740fe0c93a1da5265f9d66	wikidoc	Opacifier	Opacifier An opacifier is a substance added to a material in order to make the ensuing system opaque. An example of a chemical opacifier is tin dioxide (SnO2), which is used to opacify ceramic glazes. Opacifiers must have a refractive index (RI) substantially different from the system. Conversely, clarity may be achieved in a system by choosing components with very similar refractive indices. Opacifiers must also form small particles in the system. Opacifiers are generally inert. Sometimes opacifiers are added to medical implants to make them visible under X-ray imaging. This is especially true in the case of most polymers which are often unrecognizable in the body when viewed using X-rays. In solid (composite) rocket motors, the primary method of heat transfer into the propellant grain from the combustion process is by radiation, and opacifiers such as "lamp black" may be added to the propellant mixture to ensure the heat does not penetrate far below the surface of the grain, which could cause detonation.	Opacifier An opacifier is a substance added to a material in order to make the ensuing system opaque. An example of a chemical opacifier is tin dioxide (SnO2), which is used to opacify ceramic glazes.[1] Opacifiers must have a refractive index (RI) substantially different from the system. Conversely, clarity may be achieved in a system by choosing components with very similar refractive indices.[2] Opacifiers must also form small particles in the system. Opacifiers are generally inert. Sometimes opacifiers are added to medical implants to make them visible under X-ray imaging. This is especially true in the case of most polymers which are often unrecognizable in the body when viewed using X-rays. In solid (composite) rocket motors, the primary method of heat transfer into the propellant grain from the combustion process is by radiation, and opacifiers such as "lamp black" may be added to the propellant mixture to ensure the heat does not penetrate far below the surface of the grain, which could cause detonation.	https://www.wikidoc.org/index.php/Opacifier
f7f6f9c90f2094ace2bd6256e51aa9d8956c56d9	wikidoc	Opipramol	Opipramol # Overview Opipramol (Insidon, Pramolan, Ensidon, Oprimol) is an antidepressant and anxiolytic used in Germany and other European countries. Although it is a member of the tricyclic antidepressants, opipramol's primary mechanism of action is much different in comparison. Most TCAs act as reuptake inhibitors, but opipramol does not, and instead acts as a sigma receptor agonist, among other properties. It is an iminostilbene derivative, belonging to dibenzazepine group. Opipramol was developed by Schindler and Blattner in 1961. # Medical uses Opipramol is typically used in the treatment of generalized anxiety disorder (GAD) and somatoform disorders. Its anxiolysis becomes prominent after only one to two weeks of chronic administration. Upon first commencing treatment, opipramol is rather sedating in nature due to its antihistamine properties, but this effect becomes less prominent with time. Opipramols sigma-1 agonistic effects likely impart potent antitussive effects, many other sigma-1 agonists (ex. codeine, hydrocodone, and dextromethorphan) are used for this purpose. # Pregnancy and lactation Experimental animal studies did not indicate injurious effects of opipramol on the embryonic development or the fertility. Opipramol should be prescribed during pregnancy, particularly in the first trimester, only for compelling indication. Opipramol should not be used during lactation period, since the active ingredient passes into the milk in small quantities. # Pharmacology Opipramol acts as a high affinity sigma receptor agonist, primarily at the σ1 subtype, but also at the σ2 subtype with somewhat lower affinity. It is this property which is responsible for its therapeutic benefits against anxiety and depression. Opipramol also acts as a low to moderate affinity antagonist for the D2, 5-HT2, H1, H2, and muscarinic acetylcholine receptors. H1 and H2 receptor antagonism account for its antihistamine effects, and muscarinic acetylcholine receptor antagonism is responsible for its anticholinergic properties. Sigma receptors as a set of proteins located in the endoplasmic reticulum, σ1 receptors play key role in potentiating intracellular calcium mobilization thereby acting as sensor or modulator of calcium signalling. Occupancy of σ1 receptors by agonists causes translocation of the receptor from endoplasmic reticulum to peripheral areas (membranes) where the σ1 receptors and neurotransmitter release. The biphasic action initially makes prompt improvement of tension, anxiety and insomnia. Opipramol is a tranquilizer with a thymoleptic component. After sub-chronic treatment, opipramol is significantly down-regulated to σ2 but not σ1 sites. # Pharmacokinetics Opipramol is rapidly and completely absorbed by the gastrointestinal tract. Its terminal plasma half life is 6–11 hours. After single oral administration of 50 mg, the peak plasma concentration of the drug is reached after 3.3 hours and amounts to 15.6 ng/ml. After single oral administration of 100 mg the maximum plasma concentration is reached after 3 hours and amounts to 33.2 ng/ml. The bioavailability of opipramol amounts to 94%. The plasma protein binding amounts to approximately 91% and the volume distribution is approximately 10 L/kg. Opipramol is partially metabolized in liver as deshydroxy ethyl-opipramol. Metabolization occurs through CYP2D6-isoenzyme. Elimination is 70% renally and 10% unaltered. Remaining portion is eliminated through faeces. # Adverse effects Opipramol is a well-tolerated drug and produces fewer side effects than SSRIs and SNRIs. ## Paradoxical reactions The frequently (≥1% to <10%) reported adverse reactions with opipramol especially at the beginning of the treatment includes fatigue, dry mouth, blocked nose, hypotension and orthostatic dysregulation. The adverse reactions reported occasionally(≥0.1% to <1%) includes dizziness, stupor, micturition disturbances, accommodation disturbances, tremor, weight gain, thirst, allergic skin reactions (rash, uriticaria), abnormal ejaculation, erectile impotence, constipation, transient increase in liver enzyme activities, tachycardia and palpilations. Rarely (≥0.01% to <0.1%) reported adverse reaction includes excitation, headache, parethesia especially in elderly patients, restlessness, sweating, sleep disturbances, oedema, galactorrhea, urine blockage, nausea and vomiting, collapse conditions, stimulation conducting disturbances, intensification of present heart insufficiency, blood profile changes particularly leukopenia, confusion, delirium, stomach complaints, taste disturbance and paralytic ileus especially with sudden discontinuation of a longer term high dose therapy. Very rarely (<0.01%) adverse reaction includes seizures, motor disorder, (akathisia, dyskinesia), ataxia, polyneuropathy, glaucoma, anxiety, hairfall, agranulocytosis, severe liver dysfunction after long term treatment, jaundice and chronic liver damage. ## Overdosage Symptoms of intoxications includes drowsiness, insomnia, stupor, agitation, coma, transient confusion, increased axiety, ataxia, convulsions, oligouria, anuria, tachycardia or bradycardia, arrhythmia, AV block, hypotension, shock, respiratory depression, rarely, cardiac arrest. As therapy of intoxication, specific antidote is not available, removal of the drug by vomiting or gastric lavage should be done. Continuous cardiovascular monitoring for at least 48 hours should be done. In case of respiratory failure due to overdose, intubation and artificial respiration should be done. During severe hypotension due to overdose, corresponding recumbent positioning, plasma expander, dopamine or dobutamine as drops-infusion should be initiated. In heart rhythm disturbances, individualized treatment should be done where appropriate pacemaker and compensation in low potassium levels and possible acidosis should be done. While in convulsions due to overdose, administration of intravenous diazepam or another anti-convulsant agent such as phenobarbital or paraldehyde should be done though intensification of existing respiratory insufficiency, hypotension or coma may happen. ## Drug interactions The therapy with Opipramol indicates an additional therapy with neuroleptics, hypnotics and tranquilizers (e.g. Barbiturates, Benzodiazepines). Therefore, it should be noted that some specific reactions, particularly CNS depressant effects could be intensified and an intensification of common side effects may occur. If necessary the dosage may be reduced. Co-administration with alcohol can cause stupor. MAO Inhibitors should be discontinued at least 14 days before the treatment with Opipramol. Concomitant use of Opipramol with β-blockers, antiarrhythmics (of class 1c), as well as drugs from tricyclic antidepressant group and preparations which influence the microsomal enzyme system, can lead to change in plasma concentration of these drugs. Co-administration of neuroleptics (example- haloperidol, risperidone) can increase the plasma concentration. Barbiturates and anticonvulsants can reduce the plasma concentration of Opipramol and thereby weaken the therapeutic effect. # Contraindications - In patients with hypersensitivity to opipramol dihydrochloride or an other component of the formulation. - Acute alcohol, soporofics, analgesics and antidepressant intoxications. - Acute urinary retention - Acute delirium - Untreated narrow-angle glaucoma - Prostate hypertrophy with residual urinary retention. - Paralytic ileus - Pre-existing higher grade AV blockages or diffuse supra ventricular or ventricular stimulus conduction disturbances. - Combination with monoamine oxidase inhibitor.	Opipramol Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Opipramol (Insidon, Pramolan, Ensidon, Oprimol) is an antidepressant and anxiolytic used in Germany and other European countries.[2][3] Although it is a member of the tricyclic antidepressants, opipramol's primary mechanism of action is much different in comparison.[3] Most TCAs act as reuptake inhibitors, but opipramol does not, and instead acts as a sigma receptor agonist, among other properties.[3] It is an iminostilbene derivative, belonging to dibenzazepine group. Opipramol was developed by Schindler and Blattner in 1961.[4] # Medical uses Opipramol is typically used in the treatment of generalized anxiety disorder (GAD) and somatoform disorders.[1][2] Its anxiolysis becomes prominent after only one to two weeks of chronic administration. Upon first commencing treatment, opipramol is rather sedating in nature due to its antihistamine properties, but this effect becomes less prominent with time. Opipramols sigma-1 agonistic effects likely impart potent antitussive effects, many other sigma-1 agonists (ex. codeine, hydrocodone, and dextromethorphan) are used for this purpose. # Pregnancy and lactation Experimental animal studies did not indicate injurious effects of opipramol on the embryonic development or the fertility. Opipramol should be prescribed during pregnancy, particularly in the first trimester, only for compelling indication. Opipramol should not be used during lactation period, since the active ingredient passes into the milk in small quantities. # Pharmacology Opipramol acts as a high affinity sigma receptor agonist, primarily at the σ1 subtype, but also at the σ2 subtype with somewhat lower affinity.[2] It is this property which is responsible for its therapeutic benefits against anxiety and depression.[3] Opipramol also acts as a low to moderate affinity antagonist for the D2, 5-HT2, H1, H2, and muscarinic acetylcholine receptors. H1 and H2 receptor antagonism account for its antihistamine effects, and muscarinic acetylcholine receptor antagonism is responsible for its anticholinergic properties.[2] Sigma receptors as a set of proteins located in the endoplasmic reticulum, σ1 receptors play key role in potentiating intracellular calcium mobilization thereby acting as sensor or modulator of calcium signalling. Occupancy of σ1 receptors by agonists causes translocation of the receptor from endoplasmic reticulum to peripheral areas (membranes) where the σ1 receptors and neurotransmitter release. The biphasic action initially makes prompt improvement of tension, anxiety and insomnia. Opipramol is a tranquilizer with a thymoleptic component. After sub-chronic treatment, opipramol is significantly down-regulated to σ2 but not σ1 sites.[1] # Pharmacokinetics Opipramol is rapidly and completely absorbed by the gastrointestinal tract. Its terminal plasma half life is 6–11 hours. After single oral administration of 50 mg, the peak plasma concentration of the drug is reached after 3.3 hours and amounts to 15.6 ng/ml. After single oral administration of 100 mg the maximum plasma concentration is reached after 3 hours and amounts to 33.2 ng/ml. The bioavailability of opipramol amounts to 94%. The plasma protein binding amounts to approximately 91% and the volume distribution is approximately 10 L/kg. Opipramol is partially metabolized in liver as deshydroxy ethyl-opipramol. Metabolization occurs through CYP2D6-isoenzyme. Elimination is 70% renally and 10% unaltered. Remaining portion is eliminated through faeces.[1] # Adverse effects Opipramol is a well-tolerated drug and produces fewer side effects than SSRIs and SNRIs. ## Paradoxical reactions The frequently (≥1% to <10%) reported adverse reactions with opipramol especially at the beginning of the treatment includes fatigue, dry mouth, blocked nose, hypotension and orthostatic dysregulation. The adverse reactions reported occasionally(≥0.1% to <1%) includes dizziness, stupor, micturition disturbances, accommodation disturbances, tremor, weight gain, thirst, allergic skin reactions (rash, uriticaria), abnormal ejaculation, erectile impotence, constipation, transient increase in liver enzyme activities, tachycardia and palpilations. Rarely (≥0.01% to <0.1%) reported adverse reaction includes excitation, headache, parethesia especially in elderly patients, restlessness, sweating, sleep disturbances, oedema, galactorrhea, urine blockage, nausea and vomiting, collapse conditions, stimulation conducting disturbances, intensification of present heart insufficiency, blood profile changes particularly leukopenia, confusion, delirium, stomach complaints, taste disturbance and paralytic ileus especially with sudden discontinuation of a longer term high dose therapy. Very rarely (<0.01%) adverse reaction includes seizures, motor disorder, (akathisia, dyskinesia), ataxia, polyneuropathy, glaucoma, anxiety, hairfall, agranulocytosis, severe liver dysfunction after long term treatment, jaundice and chronic liver damage. ## Overdosage Symptoms of intoxications includes drowsiness, insomnia, stupor, agitation, coma, transient confusion, increased axiety, ataxia, convulsions, oligouria, anuria, tachycardia or bradycardia, arrhythmia, AV block, hypotension, shock, respiratory depression, rarely, cardiac arrest. As therapy of intoxication, specific antidote is not available, removal of the drug by vomiting or gastric lavage should be done. Continuous cardiovascular monitoring for at least 48 hours should be done. In case of respiratory failure due to overdose, intubation and artificial respiration should be done. During severe hypotension due to overdose, corresponding recumbent positioning, plasma expander, dopamine or dobutamine as drops-infusion should be initiated. In heart rhythm disturbances, individualized treatment should be done where appropriate pacemaker and compensation in low potassium levels and possible acidosis should be done. While in convulsions due to overdose, administration of intravenous diazepam or another anti-convulsant agent such as phenobarbital or paraldehyde should be done though intensification of existing respiratory insufficiency, hypotension or coma may happen. ## Drug interactions The therapy with Opipramol indicates an additional therapy with neuroleptics, hypnotics and tranquilizers (e.g. Barbiturates, Benzodiazepines). Therefore, it should be noted that some specific reactions, particularly CNS depressant effects could be intensified and an intensification of common side effects may occur. If necessary the dosage may be reduced. Co-administration with alcohol can cause stupor. MAO Inhibitors should be discontinued at least 14 days before the treatment with Opipramol. Concomitant use of Opipramol with β-blockers, antiarrhythmics (of class 1c), as well as drugs from tricyclic antidepressant group and preparations which influence the microsomal enzyme system, can lead to change in plasma concentration of these drugs. Co-administration of neuroleptics (example- haloperidol, risperidone) can increase the plasma concentration. Barbiturates and anticonvulsants can reduce the plasma concentration of Opipramol and thereby weaken the therapeutic effect. # Contraindications - In patients with hypersensitivity to opipramol dihydrochloride or an other component of the formulation. - Acute alcohol, soporofics, analgesics and antidepressant intoxications. - Acute urinary retention - Acute delirium - Untreated narrow-angle glaucoma - Prostate hypertrophy with residual urinary retention. - Paralytic ileus - Pre-existing higher grade AV blockages or diffuse supra ventricular or ventricular stimulus conduction disturbances. - Combination with monoamine oxidase inhibitor.	https://www.wikidoc.org/index.php/Opipramol
83c9b8348c6e183683e1cf9fc5f2e7012ae96526	wikidoc	Opium Law	Opium Law The Opium Law(or Opium Wet in Dutch) is the section of the Dutch Law which covers nearly all psychotropic drugs. All non-psychotropic, but prescription-only drugs are covered by the Medicine Act. # Origin and history In 1912, a global Opiumconference took place in the Hague, where agreements were made about the trade in opium, this initiated the introduction of the Opium Law, which took place 7 years later. In 1919, the first Opium Law(later known as List I of the Opium Law) was introduced, and on 12 may 1928 the second Opium Law(later known as List II of the Opium Law) was introduced. The first Opium Law was created to regulate drugs with a high addiction or abuse factor, or who are physically harmful. As the name referred to, the main reason for introduction was to regulate the Opium trade, and later to control various other addictive drugs like morphine, cocaine, heroin, barbiturates, amphetamines and several decades later, benzodiazepines, which were used both medically and recreationally. Except for the addition of new drugs to List I and II of the Opium Law, the Opium Law stayed unchanged until 1976. After the rise of a new youth culture which revolved much around the use of mind altering drugs like cannabis and LSD, and with hashish being openly used, a change of law was needed by the government, to properly control all drugs, but with a clear definition between drugs with an unacceptable degree of adictiveness or physical harm(known as hard drugs), and drugs with an acceptable degree of addictiveness or physical harm(known as soft drugs). In 1976 these changes officially took effect, and the Opium Law was edited to included the new changes of law. In the same year, a decision was also made by the Dutch government not too prosecute cannabis and hashish dealers, under the condition that they didn't sell hard drugs, didn't advertise and they were only allowed to carry a certain amount of cannabis or hashish. In 1980, the decision to not prosecute cannabis and hashish dealers, under certain conditions, was publicly announced by the Dutch government. Many people thereby concluded that this decision would also allow the sale in coffeeshops, and coffeeshops began selling cannabis and hashish. This led to an enormous rise in the number of coffeeshops in the 80's and 90's, and because of this, new regulations were demanded by the government to regulate the sale of cannabis products by coffeeshops. In 1996 the laws were changed again to include new regulations for coffeeshops. The terms coffeeshops had to follow were: - No advertisement - No hard drugs - No entrance to coffeeshops by persons under the age of 18 - No sale of more than 5 grams of cannabis products per person, per day Since 1996, no new changes have been made to the Opium Law. New guidelines for coffeeshops have been made, but they are not covered by the Opium Law. # List I drugs The following drugs and intermediates are classified as List I drugs of the Opium Law: - acetorphine - acetyl-alfa-methylfentanyl - acetyldihydrocodeine - acethylmethadol - alfacetylmethadol - alfameprodine - alfamethadol - alfa-methylfentanyl - alfa-methylthiofentanyl - alfaprodine - alfentanil - allylprodine - amphetamine - amineptine - anileridine - benzethidine - benzylmorphine - betacethylmethadol - beta-hydroxy-3-methylfentanyl - beta-hydroxyfentanyl - betameprodine - betamethadol - betaprodine - bezitramide - bolkaf (all parts of the papaver somniferum plant, after harvesting, excluding seeds) - brolamphetamine - cathinone - 2C-B (2,5-dimethoxy-4-bromophenethylamine) - 2C-I (2,5-dimethoxy-4-iodophenethylamine) - 2C-T-2 (2,5-dimethoxy-4-ethylthiophenethylamine) - 2C-T-7 (2,5-dimethoxy-4-(n)-propylthiophenethylamine) - clonitazene - coca leaf (leafs of the plants of the species Erythroxylon) - cocaine - codeine - codoxim - concentrate of bolkaf (the material obtained by subjecting bolkaf to a treatment for the concentration of it's alkaloids) - desomorphine - dexamphetamine - dextromoramide - dextropropoxyphene - diampromide - diethylthiambutene - DET (N,N-diethyltryptamine) - diphenoxide - diphenoxylate - dihydrocodeine - dihydroethorphine - dihydromorphine - dimepheptanol - dimenoxadol - DMA (2,5-dimethoxyamphetamine) - DOET (2,5-dimethoxy-4-ethylamphetamine) - DOM (2,5-dimethoxy-4-methylamphetamine) - dimethylthiambutene - DMT (N,N-dimethyltryptamine) - dioxaphetylbutyrate - dipipanone - DMHP (1,2-dimethylheptyl-delta-3-THC) - drotebanol - ecgonine(3-hydroxy-2-tropanecarbonic acid) - MDEA (N-ethyl-3,4-methylenedioxyamphetamine) - ethylmethylthiambutene - ethylmorphine - eticyclidine - etonitazene - etorphine - etoxeridine - etryptamine - fentanyl - folcodiene - furethidine - hemp oil (concentrate of plants from the Cannabis species (hemp) obtained by extraction of hemp or hashish, if not mixed with oil) - heroin (diamorphine) - hydrocodone - hydromorphinol - hydromorphone - MDOH (N-hydroxy-methylenedioxyamphetamine) - hydroxypethidine - isomethadone - ketobemidone - levamphetamine - levophenacylmorphan - levomethamphetamine - levomethorphan - levomoramide - levorphanol - lysergide - mecloqualon - mescaline (3,4,5-trimethoxyphenethylamine) - methamphetamine - methamphetamine racemate - metazocine - methadone - methadone-intermediate (4-cyano-2-dimethylamino-4,4-diphenylbutane) - methaqualon - methcathinone - MMDA (2-methoxy-4,5-methylenedioxyamphetamine) - 4-methylaminorex - methyldesorphine - methyldihydromorphine - MDMA (3,4-methylenedioxymethamphetamine) - methylphenidate - 3-methylfentanyl - MPPP (1-methyl-4-phenyl-4-piperidinol propionate ester) - 4-MTA (4-methylthioamphetamine) - 3-methylthiofentanyl - metopon - moramide-intermediate (2-methyl-3-morpholino-1,1-diphenylpropane-carbonic acid) - morferidine - morphine - morphine-methobromide - morphine-N-oxide - myrophine - nicocodiene - nicodicodine - nicomorphine - noracymethadol - norcodeine - norlevorphanol - normethadone - normorphine - norpipanone - opium (the harvested milk, obtained from the plant Papaver somniferum) - oxycodone - oxymorphone - para-fluorfentanyl - parahexyl - PMA (para-methoxyamphetamine) - PMMA(para-methoxymethamphetamine) - PEPAP (1-fenethyl-4-fenyl-4-piperidinolacetate ester) - pethidine - pethidine-intermediate A (4-cyano-1-methyl-4-phenylpiperidine) - pethidine-intermediate B (4-phenylpiperidine-4-carbonic acid ethylester) - pethidine-intermediate C (1-methyl-4-phenylpiperidine-4-carbonic acid) - phenadoxon - phenampromide - phenazocine - phencyclidine - phenetylline - phenmetrazine - phenomorphan - phenoperidine - piminodine - piritramide - proheptazine - properidine - propiram - psilocine - psilocybine - racemethorphan - racemoramide - racemorphan - remifentanil - rolicyclidine - secobarbital - sufentanil - tenamphetamine - tenocyclidine - tetrahydrocannabinol - thebacon - thebaïne - thiofentanyl - tilidine - TMA-2 (2,4,5-trimethoxyamphetamine) - trimeperidine - TMA (3,4,5-trimethoxyamfetamine) - zipeprol The esters and derivatives of ecgonine, which can be turned into ecgonine and cocaine; The mono- and di-alkylamine-, the pyrollidine- and morpholinederivates of lysergic acid, and the thereby introduction of methyl-, acetyl- or halogengroups obtained substances; Fiveworthy nitrogen-substituted morphinederivates, of which morphine-N-oxide-derivatives, like codeine-N-oxide; The isomeres and stereoisomeres of tetrahydrocannabinol; The ethers, esters and enantiomeres of the above mentioned substances, with exception of dextromethorphan (INN) as enantiomere of levomethorphan and racemethorphan, and with exception of dextrorphanol (INN) as enantiomere of levorphanol and racemorphan; Formulations which contain one or more of the above mentioned substances. # List II drugs The following drugs are classified as List II drugs of the Opium Law: - allobarbital - alprazolam - amobarbital - amphepramon - aminorex - barbital - benzphetamine - bromazepam - brotizolam - buprenorphine - butalbital - butobarbital - camazepam - cathine - chlordiazepoxide - clobazam - clonazepam - clorazepate - clotiazepam - cloxazolam - cyclobarbital - delorazepam - diazepam - estazolam - ethchlorvynol - ethinamate - ethylloflazepate - ethylamphetamine - fludiazepam - flunitrazepam - flurazepam - GHB (4-hydroxybutyric acid) - gluthethimide - halazepam - haloxazolam - hashish (a usually solid mixture of the excreted resin obtained from plants of the Cannabis species (hemp), with plant materials of these plants) - hemp (all parts of the plant from the Cannabis species (hemp), of which the resin has not been extracted, with exception of the seeds) - ketazolam - lefetamine - loprazolam - lorazepam - lormetazepam - mazindole - medazepam - mephenorex - meprobamate - mesocarb - methylphenobarbital - methyprylon - midazolam - nimetazepam - nitrazepam - nordiazepam - oxazepam - oxazolam - pemoline - pentazocine - pentobarbital - phencamfamine - phendimetrazine - phenobarbital - phenproporex - phentermine - pinazepam - pipradrol - prazepam - pyrovalerone - secbutabarbital - temazepam - tetrazepam - triazolam - vinylbital - zolpidem Formulations which contain one or more of the above mentioned substances, with exception of hemp oil. # Medical use Even though List I substances are officially classified as hard drugs, several of them are often prescribed by licensed doctors. For example, nearly all opioids are List I drugs, but they are commonly prescribed to cancer and HIV patients, as well as sufferers of chronic pain, although prescriptions for opioids are very scarce due to fear of misuse, and they are only prescribed in situations where they are certainly needed, like the terminally ill. Two stimulants who are both prescribed for ADD/ADHD and narcolepsy; dexamphetamine and methylphenidate, are also List I drugs of the Opium Law. On the other hand, all barbiturates except for secobarbital are List II drugs, while none of them, except for phenobarbital, are prescribed today. In theory, a licensed doctor could prescribe any substance he/she thinks is needed for the correct of his/her patient, both List I and List II substances of the Opium Law, though substances which aren't available as commercial pharmaceutical preparations have to be custom prepared by the designated pharmacy. All prescriptions for List I and List II substances of the Opium Law(except for amobarbital, buprenorphine, butalbital, cathine, cyclobarbital, flunitrazepam, gluthethimide, hemp, pentazocine and pentobarbital) have to be written in full in letters, and have to contain the name and initials, address, city and telephone number of the licensed prescriber issuing the prescriptions, as well as the name and initials, address and city of the person the prescription is issued to. If the prescription is issued for an animal, the data of the owner should be used instead, and a description of the animal has to be included on the prescription.	Opium Law Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Template:Editor help The Opium Law(or Opium Wet in Dutch) is the section of the Dutch Law which covers nearly all psychotropic drugs. All non-psychotropic, but prescription-only drugs are covered by the Medicine Act. # Origin and history In 1912, a global Opiumconference took place in the Hague, where agreements were made about the trade in opium, this initiated the introduction of the Opium Law, which took place 7 years later. In 1919, the first Opium Law(later known as List I of the Opium Law) was introduced, and on 12 may 1928 the second Opium Law(later known as List II of the Opium Law) was introduced. The first Opium Law was created to regulate drugs with a high addiction or abuse factor, or who are physically harmful. As the name referred to, the main reason for introduction was to regulate the Opium trade, and later to control various other addictive drugs like morphine, cocaine, heroin, barbiturates, amphetamines and several decades later, benzodiazepines, which were used both medically and recreationally. Except for the addition of new drugs to List I and II of the Opium Law, the Opium Law stayed unchanged until 1976. After the rise of a new youth culture which revolved much around the use of mind altering drugs like cannabis and LSD, and with hashish being openly used, a change of law was needed by the government, to properly control all drugs, but with a clear definition between drugs with an unacceptable degree of adictiveness or physical harm(known as hard drugs), and drugs with an acceptable degree of addictiveness or physical harm(known as soft drugs). In 1976 these changes officially took effect, and the Opium Law was edited to included the new changes of law. In the same year, a decision was also made by the Dutch government not too prosecute cannabis and hashish dealers, under the condition that they didn't sell hard drugs, didn't advertise and they were only allowed to carry a certain amount of cannabis or hashish. In 1980, the decision to not prosecute cannabis and hashish dealers, under certain conditions, was publicly announced by the Dutch government. Many people thereby concluded that this decision would also allow the sale in coffeeshops, and coffeeshops began selling cannabis and hashish. This led to an enormous rise in the number of coffeeshops in the 80's and 90's, and because of this, new regulations were demanded by the government to regulate the sale of cannabis products by coffeeshops. In 1996 the laws were changed again to include new regulations for coffeeshops. The terms coffeeshops had to follow were: - No advertisement - No hard drugs - No entrance to coffeeshops by persons under the age of 18 - No sale of more than 5 grams of cannabis products per person, per day Since 1996, no new changes have been made to the Opium Law. New guidelines for coffeeshops have been made, but they are not covered by the Opium Law. [2] # List I drugs The following drugs and intermediates are classified as List I drugs of the Opium Law: - acetorphine - acetyl-alfa-methylfentanyl - acetyldihydrocodeine - acethylmethadol - alfacetylmethadol - alfameprodine - alfamethadol - alfa-methylfentanyl - alfa-methylthiofentanyl - alfaprodine - alfentanil - allylprodine - amphetamine - amineptine - anileridine - benzethidine - benzylmorphine - betacethylmethadol - beta-hydroxy-3-methylfentanyl - beta-hydroxyfentanyl - betameprodine - betamethadol - betaprodine - bezitramide - bolkaf (all parts of the papaver somniferum plant, after harvesting, excluding seeds) - brolamphetamine - cathinone - 2C-B (2,5-dimethoxy-4-bromophenethylamine) - 2C-I (2,5-dimethoxy-4-iodophenethylamine) - 2C-T-2 (2,5-dimethoxy-4-ethylthiophenethylamine) - 2C-T-7 (2,5-dimethoxy-4-(n)-propylthiophenethylamine) - clonitazene - coca leaf (leafs of the plants of the species Erythroxylon) - cocaine - codeine - codoxim - concentrate of bolkaf (the material obtained by subjecting bolkaf to a treatment for the concentration of it's alkaloids) - desomorphine - dexamphetamine - dextromoramide - dextropropoxyphene - diampromide - diethylthiambutene - DET (N,N-diethyltryptamine) - diphenoxide - diphenoxylate - dihydrocodeine - dihydroethorphine - dihydromorphine - dimepheptanol - dimenoxadol - DMA (2,5-dimethoxyamphetamine) - DOET (2,5-dimethoxy-4-ethylamphetamine) - DOM (2,5-dimethoxy-4-methylamphetamine) - dimethylthiambutene - DMT (N,N-dimethyltryptamine) - dioxaphetylbutyrate - dipipanone - DMHP (1,2-dimethylheptyl-delta-3-THC) - drotebanol - ecgonine(3-hydroxy-2-tropanecarbonic acid) - MDEA (N-ethyl-3,4-methylenedioxyamphetamine) - ethylmethylthiambutene - ethylmorphine - eticyclidine - etonitazene - etorphine - etoxeridine - etryptamine - fentanyl - folcodiene - furethidine - hemp oil (concentrate of plants from the Cannabis species (hemp) obtained by extraction of hemp or hashish, if not mixed with oil) - heroin (diamorphine) - hydrocodone - hydromorphinol - hydromorphone - MDOH (N-hydroxy-methylenedioxyamphetamine) - hydroxypethidine - isomethadone - ketobemidone - levamphetamine - levophenacylmorphan - levomethamphetamine - levomethorphan - levomoramide - levorphanol - lysergide - mecloqualon - mescaline (3,4,5-trimethoxyphenethylamine) - methamphetamine - methamphetamine racemate - metazocine - methadone - methadone-intermediate (4-cyano-2-dimethylamino-4,4-diphenylbutane) - methaqualon - methcathinone - MMDA (2-methoxy-4,5-methylenedioxyamphetamine) - 4-methylaminorex - methyldesorphine - methyldihydromorphine - MDMA (3,4-methylenedioxymethamphetamine) - methylphenidate - 3-methylfentanyl - MPPP (1-methyl-4-phenyl-4-piperidinol propionate ester) - 4-MTA (4-methylthioamphetamine) - 3-methylthiofentanyl - metopon - moramide-intermediate (2-methyl-3-morpholino-1,1-diphenylpropane-carbonic acid) - morferidine - morphine - morphine-methobromide - morphine-N-oxide - myrophine - nicocodiene - nicodicodine - nicomorphine - noracymethadol - norcodeine - norlevorphanol - normethadone - normorphine - norpipanone - opium (the harvested milk, obtained from the plant Papaver somniferum) - oxycodone - oxymorphone - para-fluorfentanyl - parahexyl - PMA (para-methoxyamphetamine) - PMMA(para-methoxymethamphetamine) - PEPAP (1-fenethyl-4-fenyl-4-piperidinolacetate ester) - pethidine - pethidine-intermediate A (4-cyano-1-methyl-4-phenylpiperidine) - pethidine-intermediate B (4-phenylpiperidine-4-carbonic acid ethylester) - pethidine-intermediate C (1-methyl-4-phenylpiperidine-4-carbonic acid) - phenadoxon - phenampromide - phenazocine - phencyclidine - phenetylline - phenmetrazine - phenomorphan - phenoperidine - piminodine - piritramide - proheptazine - properidine - propiram - psilocine - psilocybine - racemethorphan - racemoramide - racemorphan - remifentanil - rolicyclidine - secobarbital - sufentanil - tenamphetamine - tenocyclidine - tetrahydrocannabinol - thebacon - thebaïne - thiofentanyl - tilidine - TMA-2 (2,4,5-trimethoxyamphetamine) - trimeperidine - TMA (3,4,5-trimethoxyamfetamine) - zipeprol The esters and derivatives of ecgonine, which can be turned into ecgonine and cocaine; The mono- and di-alkylamine-, the pyrollidine- and morpholinederivates of lysergic acid, and the thereby introduction of methyl-, acetyl- or halogengroups obtained substances; Fiveworthy nitrogen-substituted morphinederivates, of which morphine-N-oxide-derivatives, like codeine-N-oxide; The isomeres and stereoisomeres of tetrahydrocannabinol; The ethers, esters and enantiomeres of the above mentioned substances, with exception of dextromethorphan (INN) as enantiomere of levomethorphan and racemethorphan, and with exception of dextrorphanol (INN) as enantiomere of levorphanol and racemorphan; Formulations which contain one or more of the above mentioned substances.[3] # List II drugs The following drugs are classified as List II drugs of the Opium Law: - allobarbital - alprazolam - amobarbital - amphepramon - aminorex - barbital - benzphetamine - bromazepam - brotizolam - buprenorphine - butalbital - butobarbital - camazepam - cathine - chlordiazepoxide - clobazam - clonazepam - clorazepate - clotiazepam - cloxazolam - cyclobarbital - delorazepam - diazepam - estazolam - ethchlorvynol - ethinamate - ethylloflazepate - ethylamphetamine - fludiazepam - flunitrazepam - flurazepam - GHB (4-hydroxybutyric acid) - gluthethimide - halazepam - haloxazolam - hashish (a usually solid mixture of the excreted resin obtained from plants of the Cannabis species (hemp), with plant materials of these plants) - hemp (all parts of the plant from the Cannabis species (hemp), of which the resin has not been extracted, with exception of the seeds) - ketazolam - lefetamine - loprazolam - lorazepam - lormetazepam - mazindole - medazepam - mephenorex - meprobamate - mesocarb - methylphenobarbital - methyprylon - midazolam - nimetazepam - nitrazepam - nordiazepam - oxazepam - oxazolam - pemoline - pentazocine - pentobarbital - phencamfamine - phendimetrazine - phenobarbital - phenproporex - phentermine - pinazepam - pipradrol - prazepam - pyrovalerone - secbutabarbital - temazepam - tetrazepam - triazolam - vinylbital - zolpidem Formulations which contain one or more of the above mentioned substances, with exception of hemp oil. [4] # Medical use Even though List I substances are officially classified as hard drugs, several of them are often prescribed by licensed doctors. For example, nearly all opioids are List I drugs, but they are commonly prescribed to cancer and HIV patients, as well as sufferers of chronic pain, although prescriptions for opioids are very scarce due to fear of misuse, and they are only prescribed in situations where they are certainly needed, like the terminally ill. Two stimulants who are both prescribed for ADD/ADHD and narcolepsy; dexamphetamine and methylphenidate, are also List I drugs of the Opium Law. On the other hand, all barbiturates except for secobarbital are List II drugs, while none of them, except for phenobarbital, are prescribed today. In theory, a licensed doctor could prescribe any substance he/she thinks is needed for the correct of his/her patient, both List I and List II substances of the Opium Law, though substances which aren't available as commercial pharmaceutical preparations have to be custom prepared by the designated pharmacy. [5] All prescriptions for List I and List II substances of the Opium Law(except for amobarbital, buprenorphine, butalbital, cathine, cyclobarbital, flunitrazepam, gluthethimide, hemp, pentazocine and pentobarbital) have to be written in full in letters, and have to contain the name and initials, address, city and telephone number of the licensed prescriber issuing the prescriptions, as well as the name and initials, address and city of the person the prescription is issued to. If the prescription is issued for an animal, the data of the owner should be used instead, and a description of the animal has to be included on the prescription. [6] Template:Uncategorized Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Opium_Law

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