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1697901e2f40839ec8e97dc05cb7d6f9afa4fb94	wikidoc	Tospovirus	Tospovirus The Tospoviruses are a genus (Topsovirus) of plant viruses within the viral family Bunyaviridae. They are the sole group of plant infecting viruses in this family, with the majority of other viruses in the Bunyaviridae infecting animals. The genus takes its name from the discovery of Tomato Spotted Wilt Virus (TSWV) in Australia in 1915. It remained the only member of the family until the early 1990's when genetic characterisation of viruses discovered in plants became more common. There are now at least twenty viral "species" in the family with more being recorded and described on a relatively regular basis. # Transmission Tospoviruses are transmitted by an insect vector, generally a thrips. The virus infects larval stage thrips, which upon adulthood, are able to infect new host plants. # Agricultural importance Plants which have been infected by a Tospovirus are incurable, and will only cause more infections if left in the field. resultingly all infected plants must be destroyed in order to prevent the spread of disease. There are a large number of families that are known to be effected by viruses of the Tospovirus genus. These include both food crops (such as peanuts, watermelons, capsicums, tomatos, zucchinis, et al.) as well as ornamental species which are important to flower farms (calla lily, impatiens, crysanthemums, iris, et al.). For a more complete list of hosts examine the Tospovirus host list at Kansas State University. # Resources - The Complete Tospovirus Resource Page at KSU - Tospoviruses:Bunyaviridae from Plant Viruses online - Tospoviruses (Family Bunyaviridae, Genus Tospovirus) An article by Scott Adkins, Tom Zitter and Tim Momol.	Tospovirus The Tospoviruses are a genus (Topsovirus) of plant viruses within the viral family Bunyaviridae. They are the sole group of plant infecting viruses in this family, with the majority of other viruses in the Bunyaviridae infecting animals. The genus takes its name from the discovery of Tomato Spotted Wilt Virus (TSWV) in Australia in 1915. It remained the only member of the family until the early 1990's when genetic characterisation of viruses discovered in plants became more common. There are now at least twenty viral "species" in the family with more being recorded and described on a relatively regular basis. # Transmission Tospoviruses are transmitted by an insect vector, generally a thrips. The virus infects larval stage thrips, which upon adulthood, are able to infect new host plants. # Agricultural importance Plants which have been infected by a Tospovirus are incurable, and will only cause more infections if left in the field. resultingly all infected plants must be destroyed in order to prevent the spread of disease. There are a large number of families that are known to be effected by viruses of the Tospovirus genus. These include both food crops (such as peanuts, watermelons, capsicums, tomatos, zucchinis, et al.) as well as ornamental species which are important to flower farms (calla lily, impatiens, crysanthemums, iris, et al.). For a more complete list of hosts examine the Tospovirus host list at Kansas State University. # Resources - The Complete Tospovirus Resource Page at KSU - Tospoviruses:Bunyaviridae from Plant Viruses online - Tospoviruses (Family Bunyaviridae, Genus Tospovirus) An article by Scott Adkins, Tom Zitter and Tim Momol. Template:Virus-plant-disease-stub	https://www.wikidoc.org/index.php/Tospovirus
e72fd73fd6818d6fb3a2a88a37d64dcb6f2c9859	wikidoc	ToxMystery	ToxMystery ToxMystery is an educational activity developed for children from 7-11 years of age. The activity teaches young people about environmental hazards in their home and helps build an understanding of not only how to recognize the hazards but how to make their own home safer. Guiding them through is an animated cat named Toxie, who reads them the information and rewards them with fun. ToxMystery was created by the United States National Library of Medicine. The History of ToxMystery ToxMystery was created by National Library of Medicine to address the need for greater understanding of household hazards by kids in the K-6 range. Recognizing the lack of environmental health resources aimed at kids, NLM sought to create a fun interface with a memorable character that could relate vital information in a way that was both enlightening and engaging. ToxMystery went live October 2006 at toxmystery.nlm.nih.gov. In addition to its Online version there is a CD-ROM that can be made available to teachers and lesson plans and activities that have been developed for the classroom. The Activity To play ToxMystery, one must have a CD-ROM version of the application (given in limited release to teachers and educational professionals) or access to the internet and the latest version of Macromedia Flash Player. To begin, the player clicks on the front door of Toxie’s house. If instructions are needed, the player can consult the “getting started” primer in the bottom button row. The object of the game is to find all of the environmental health hazards in the house. The player rolls the cursor across the rooms of the house and clicks one to explore it. The player then rolls the cursor around the individual rooms and looks for animation “hot-spots” that show where chemicals are hidden. When the player clicks on these hot spots, a question appears asking about the given location and what chemical hazard might be found there. If the player gets the question wrong, a brief explanation is given with the permission to try again. When the player gets the question right, he or she earns a “paw print” and moves forward. When all of the paw prints are earned, the room is completed and Toxie gives an animated movie. When the entire house has been finished, Toxie appears and offers the player a printable certificate of completion. The Goals of ToxMystery ToxMystery seeks to not only educate K-6 learners but to also give a hand to parents and teachers to ensure that they have proper resources on environmental health. Parents can click on the “Parent Resources” tab to find links to other NLM projects and pages. “Teacher’s Resources” contains the entire lesson plans with ToxMystery as the focus, as well as worksheets and activities that students can color and create. Links: - ToxMystery - The National Library of Medicine	ToxMystery ToxMystery is an educational activity developed for children from 7-11 years of age. The activity teaches young people about environmental hazards in their home and helps build an understanding of not only how to recognize the hazards but how to make their own home safer. Guiding them through is an animated cat named Toxie, who reads them the information and rewards them with fun. ToxMystery was created by the United States National Library of Medicine. The History of ToxMystery ToxMystery was created by National Library of Medicine to address the need for greater understanding of household hazards by kids in the K-6 range. Recognizing the lack of environmental health resources aimed at kids, NLM sought to create a fun interface with a memorable character that could relate vital information in a way that was both enlightening and engaging. ToxMystery went live October 2006 at toxmystery.nlm.nih.gov. In addition to its Online version there is a CD-ROM that can be made available to teachers and lesson plans and activities that have been developed for the classroom. The Activity To play ToxMystery, one must have a CD-ROM version of the application (given in limited release to teachers and educational professionals) or access to the internet and the latest version of Macromedia Flash Player. To begin, the player clicks on the front door of Toxie’s house. If instructions are needed, the player can consult the “getting started” primer in the bottom button row. The object of the game is to find all of the environmental health hazards in the house. The player rolls the cursor across the rooms of the house and clicks one to explore it. The player then rolls the cursor around the individual rooms and looks for animation “hot-spots” that show where chemicals are hidden. When the player clicks on these hot spots, a question appears asking about the given location and what chemical hazard might be found there. If the player gets the question wrong, a brief explanation is given with the permission to try again. When the player gets the question right, he or she earns a “paw print” and moves forward. When all of the paw prints are earned, the room is completed and Toxie gives an animated movie. When the entire house has been finished, Toxie appears and offers the player a printable certificate of completion. The Goals of ToxMystery ToxMystery seeks to not only educate K-6 learners but to also give a hand to parents and teachers to ensure that they have proper resources on environmental health. Parents can click on the “Parent Resources” tab to find links to other NLM projects and pages. “Teacher’s Resources” contains the entire lesson plans with ToxMystery as the focus, as well as worksheets and activities that students can color and create. Links: - ToxMystery - The National Library of Medicine	https://www.wikidoc.org/index.php/ToxMystery
acb0ddbb9c16f519da23c1f52f7da9d14d9e25e4	wikidoc	Toxicology	Toxicology For Overdosage Contact Poison Control at 1-800-222-1222 Report a side effect to the FDA at MedWatch Read more about MedWatch here For information on Drug Overdoses: Poisoning and drug overdose here Search for Drug-Drug Interactions Toxicology (from the Greek words toxicos and logos) is the study of the adverse effects of chemicals on living organisms. It is the study of symptoms, mechanisms, treatments and detection of poisoning, especially the poisoning of people. # History Mathieu Orfila is considered to be the modern father of toxicology, having given the subject its first formal treatment in 1813 in his Trait des poisons, also called Toxicologie generate. However, Theophrastus Phillipus Auroleus Bombastus von Hohenheim (1493 - 1541) (also referred to as Paracelsus, from his belief that he was above or beyond the work of Celsus - the Roman physician from the first century) is widely regarded as "the father" of toxicology. He is credited with the classic toxicology soundbite "All things are poison and nothing is without poison; only the dose makes a thing a poison." The original German reads: "Alle Dinge sind Gift und nichts ist ohne Gift; allein die Dosis macht, dass ein Ding kein Gift ist." This is often condensed to "The dose makes the poison". The term LD50 refers to the dose of a toxic substance that kills 50 percent of a test population (typically rats or other surrogates when the test concerns human toxicity). LD50 estimations in animals are no longer required for regulatory submissions as a part of pre-clinical development package. # Relationship between dose and toxicity Toxicology studies the relationship between dose and its effects on the living organism. The chief criterion regarding the toxicity of a chemical is the dose, i.e. the amount of exposure to the substance. Almost all substances are toxic under the right conditions as Paracelsus, the father of modern toxicology said, “Sola dosis facit venenum” (only dose makes the poison). Paracelsus, who lived in the 16th century, was the first person to explain the dose-response relationship of toxic substances. Even a benign substance like water can cause harm in excessive amounts. "Dr. Adrian Cohen was saddened, but not surprised, to hear about the 28-year-old woman who died earlier this month after drinking nearly two gallons of water to try to win a radio station contest." # Toxicity of Metabolites Many substances regarded as poisons are toxic only indirectly. An example is "wood alcohol," or methanol, which is chemically converted to formaldehyde and formic acid in the liver. It is the formaldehyde and formic acid that cause the toxic effects of methanol exposure. Many drug molecules are made toxic in the liver, a good example being acetaminophen (paracetamol), especially in the presence of alcohol. The genetic variability of certain liver enzymes makes the toxicity of many compounds differ between one individual and the next. Because demands placed on one liver enzyme can induce activity in another, many molecules become toxic only in combination with others. A family of activities that engages many toxicologists includes identifying which liver enzymes convert a molecule into a poison, what are the toxic products of the conversion and under what conditions and in which individuals this conversion takes place.	Toxicology Editor-In-Chief: Scott Everett, M.D., Pharm. D. Assistant Professor of Emergency Medicine, Wake Forest University Baptist Medical Center, Winston Salem, NC Email Dr. Everett by clicking here For Overdosage Contact Poison Control at 1-800-222-1222 Report a side effect to the FDA at MedWatch Read more about MedWatch here For information on Drug Overdoses: Poisoning and drug overdose here Search for Drug-Drug Interactions Toxicology (from the Greek words toxicos and logos) is the study of the adverse effects of chemicals on living organisms.[1] It is the study of symptoms, mechanisms, treatments and detection of poisoning, especially the poisoning of people. # History Mathieu Orfila is considered to be the modern father of toxicology, having given the subject its first formal treatment in 1813 in his Trait des poisons, also called Toxicologie generate. However, Theophrastus Phillipus Auroleus Bombastus von Hohenheim (1493 - 1541) (also referred to as Paracelsus, from his belief that he was above or beyond the work of Celsus - the Roman physician from the first century) is widely regarded as "the father" of toxicology. He is credited with the classic toxicology soundbite "All things are poison and nothing is without poison; only the dose makes a thing a poison." The original German reads: "Alle Dinge sind Gift und nichts ist ohne Gift; allein die Dosis macht, dass ein Ding kein Gift ist." This is often condensed to "The dose makes the poison". The term LD50 refers to the dose of a toxic substance that kills 50 percent of a test population (typically rats or other surrogates when the test concerns human toxicity). LD50 estimations in animals are no longer required for regulatory submissions as a part of pre-clinical development package. # Relationship between dose and toxicity Toxicology studies the relationship between dose and its effects on the living organism. The chief criterion regarding the toxicity of a chemical is the dose, i.e. the amount of exposure to the substance. Almost all substances are toxic under the right conditions as Paracelsus, the father of modern toxicology said, “Sola dosis facit venenum” (only dose makes the poison). Paracelsus, who lived in the 16th century, was the first person to explain the dose-response relationship of toxic substances. Even a benign substance like water can cause harm in excessive amounts. "Dr. Adrian Cohen was saddened, but not surprised, to hear about the 28-year-old woman who died earlier this month after drinking nearly two gallons of water to try to win a radio station contest." [2] # Toxicity of Metabolites Many substances regarded as poisons are toxic only indirectly. An example is "wood alcohol," or methanol, which is chemically converted to formaldehyde and formic acid in the liver. It is the formaldehyde and formic acid that cause the toxic effects of methanol exposure. Many drug molecules are made toxic in the liver, a good example being acetaminophen (paracetamol), especially in the presence of alcohol. The genetic variability of certain liver enzymes makes the toxicity of many compounds differ between one individual and the next. Because demands placed on one liver enzyme can induce activity in another, many molecules become toxic only in combination with others. A family of activities that engages many toxicologists includes identifying which liver enzymes convert a molecule into a poison, what are the toxic products of the conversion and under what conditions and in which individuals this conversion takes place.	https://www.wikidoc.org/index.php/Toxicological
03900f83fefcd466d04f45a8af6273938b5f061c	wikidoc	Trametinib	Trametinib # 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 Trametinib is an kinase inhibitor that is FDA approved for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. Common adverse reactions include decreased left ventricular ejection fraction (LVEF), pneumonitis, renal failure, diarrhea, and rash. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Trametinib ® as a single agent is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test . - Trametinib, in combination with dabrafenib, is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. This indication is based on the demonstration of durable response rate . Improvement in disease-related symptoms or overall survival has not been demonstrated for Trametinib in combination with dabrafenib. - Limitation of use: Trametinib as a single agent is not indicated for treatment of patients who have received prior BRAF-inhibitor therapy - Select patients for treatment of unresectable or metastatic melanoma with Trametinib based on presence of BRAF V600E or V600K mutation in tumor specimens . - The recommended dosage regimens of Trametinib are: - 2 mg orally taken once daily as a single agent - 2 mg orally taken once daily in combination with dabrafenib 150 mg orally taken twice daily - Continue treatment until disease progression or unacceptable toxicity occurs. Take Trametinib as a single agent, or Trametinib in combination with dabrafenib, at least 1 hour before or 2 hours after a meal . Do not take a missed dose of Trametinib within 12 hours of the next dose of Trametinib . When administered in combination with dabrafenib, take the once daily dose of Trametinib at the same time each day with either the morning dose or the evening dose of dabrafenib. - For New Primary Cutaneous Malignancies: No dose modifications are required. - For New Primary Non-Cutaneous Malignancies: No dose modifications are required for Trametinib . If used in combination with dabrafenib, permanently discontinue dabrafenib in patients who develop RAS mutation-positive non-cutaneous malignancies. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Trametinib in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Trametinib in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Trametinib in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Trametinib in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Trametinib in pediatric patients. # Contraindications - None. # Warnings - Review the Full Prescribing Information for dabrafenib prior to initiation of Trametinib in combination with dabrafenib. The following serious adverse reactions of dabrafenib as a single agent, which may occur when Trametinib is used in combination with dabrafenib, are not described in the Full Prescribing Information for Trametinib : - Tumor promotion in patients with BRAF wild-type melanoma - Hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency - New primary malignancies, cutaneous and non-cutaneous, can occur when Trametinib is used in combination with dabrafenib and with dabrafenib as a single agent . - In Trial 2, the incidence of basal cell carcinoma was increased in patients receiving Trametinib in combination with dabrafenib, with an incidence of 9% (5/55) in patients receiving Trametinib in combination with dabrafenib compared with 2% (1/53) in patients receiving dabrafenib as a single agent. The range of time to diagnosis of basal cell carcinoma was 28 to 249 days in patients receiving Trametinib in combination with dabrafenib and was 197 days for the patient receiving dabrafenib as a single agent. - Cutaneous squamous cell carcinomas (SCC), including keratoacanthoma, occurred in 7% of patients receiving Trametinib in combination with dabrafenib and 19% of patients receiving dabrafenib as a single agent. The range of time to diagnosis of cuSCC was 136 to 197 days in the combination arm and was 9 to 197 days in the arm receiving dabrafenib as a single agent. - New primary melanoma occurred in 2% (1/53) of patients receiving dabrafenib and in none of the 55 patients receiving Trametinib in combination with dabrafenib. - Perform dermatologic evaluations prior to initiation of Trametinib in combination with dabrafenib, every 2 months while on therapy, and for up to 6 months following discontinuation of the combination. No dose modifications of Trametinib or dabrafenib are recommended in patients who develop new primary cutaneous malignancies. - Based on its mechanism of action, dabrafenib may promote growth and development of malignancies with activation of RAS through mutation or other mechanisms . In patients receiving Trametinib in combination with dabrafenib, four cases of non-cutaneous malignancies were identified: KRAS mutation-positive pancreatic adenocarcinoma (n = 1), recurrent NRAS mutation-positive colorectal carcinoma (n = 1), head and neck carcinoma (n = 1), and glioblastoma (n = 1). Monitor patients receiving the combination closely for signs or symptoms of non-cutaneous malignancies. If used in combination with dabrafenib, no dose modification is required for Trametinib in patients who develop non-cutaneous malignancies. Permanently discontinue dabrafenib in patients who develop RAS mutation-positive non-cutaneous malignancies. - Hemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur when Trametinib is used in combination with dabrafenib. - In Trial 2, treatment with Trametinib in combination with dabrafenib resulted in an increased incidence and severity of any hemorrhagic events: 16% (9/55) of patients treated with Trametinib in combination with dabrafenib compared with 2% (1/53) of patients treated with dabrafenib as a single agent. The major hemorrhagic events of intracranial or gastric hemorrhage occurred in 5% (3/55) of patients treated with Trametinib in combination with dabrafenib compared with none of the 53 patients treated with dabrafenib as a single agent. Intracranial hemorrhage was fatal in two (4%) patients receiving the combination of Trametinib and dabrafenib. - Permanently discontinue Trametinib , and also permanently discontinue dabrafenib if administered in combination, for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve. Withhold Trametinib for up to 3 weeks for Grade 3 hemorrhagic events; if improved resume at a lower dose level. Withhold dabrafenib for Grade 3 hemorrhagic events; if improved resume at a lower dose level. - Venous thromboembolism can occur when Trametinib is used in combination with dabrafenib. - In Trial 2, treatment with Trametinib in combination with dabrafenib resulted in an increased incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE): 7% (4/55) of patients treated with Trametinib in combination with dabrafenib compared with none of the 53 patients treated with dabrafenib as a single agent. Pulmonary embolism was fatal in one (2%) patient receiving the combination of Trametinib and dabrafenib. - Advise patients to immediately seek medical care if they develop symptoms of DVT or PE, such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue Trametinib and dabrafenib for life threatening PE. Withhold Trametinib for uncomplicated DVT and PE for up to 3 weeks; if improved, Trametinib may be resumed at a lower dose level. Do not modify the dose of dabrafenib . - Cardiomyopathy can occur when Trametinib is administered as a single agent or when used in combination with dabrafenib. - In Trial 1, cardiomyopathy (defined as cardiac failure, left ventricular dysfunction, or decreased left ventricular ejection fraction ) occurred in 7% (14/211) of patients treated with Trametinib ; no chemotherapy-treated patients in Trial 1 developed cardiomyopathy. In Trial 2, cardiomyopathy occurred in 9% (5/55) of patients treated with Trametinib in combination with dabrafenib and in none of patients treated with dabrafenib as a single agent. The median time to onset of cardiomyopathy in patients treated with Trametinib was 63 days (range: 16 to 156 days) for Trial 1 and 86 days (range: 27 to 253 days) for Trial 2. - Cardiomyopathy was identified within the first month of treatment with Trametinib in 5 of 14 patients in Trial 1 and in 2 of 5 patients in Trial 2. Development of cardiomyopathy resulted in dose reduction (7/211) and/or discontinuation (4/211) of study drug in Trial 1, and resulted in dose reduction (4/55) and/or dose interruption (1/55) in Trial 2. Cardiomyopathy resolved in 10 of 14 (71%) patients in Trial 1 and in all 5 patients in Trial 2. - Across clinical trials of Trametinib administered either as a single agent (N = 329), or in combination with dabrafenib (N = 202), 11% and 8% of patients, respectively, developed evidence of cardiomyopathy (decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF ≥10% below baseline). Five percent and 2% in single-agent and in combination trials, respectively, demonstrated a decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of ≥20% below baseline. - Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of Trametinib as a single agent and in combination with dabrafenib, one month after initiation, and then at 2- to 3-month intervals while on treatment. Withhold treatment with Trametinib for up to 4 weeks if absolute LVEF value decreases by 10% from pretreatment values and is less than the lower limit of normal. For symptomatic cardiomyopathy or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue Trametinib and withhold dabrafenib. Resume dabrafenib at the same dose upon recovery of cardiac function . - Across all clinical trials of Trametinib , the incidence of RVO was 0.2% (4/1,749). RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma. - Urgently (within 24 hours) perform ophthalmological evaluation for patient-reported loss of vision or other visual disturbances. Permanently discontinue Trametinib in patients with documented RVO. If Trametinib is used in combination with dabrafenib, do not modify dabrafenib dose . - Retinal pigment epithelial detachment (RPED) can occur when Trametinib is administered as a single agent or when used in combination with dabrafenib. - In Trial 1 and Trial 2, ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment. - In Trial 1, one patient (0.5%) receiving Trametinib developed RPED and no cases of RPED were identified in chemotherapy-treated patients. Across all clinical trials of Trametinib , the incidence of RPED was 0.8% (14/1,749). Retinal detachments were often bilateral and multifocal, occurring in the macular region of the retina. RPED led to reduction in visual acuity that resolved after a median of 11.5 days (range: 3 to 71 days) following the interruption of dosing with Trametinib , although Ocular Coherence Tomography (OCT) abnormalities persisted beyond a month in at least several cases. - In Trial 2, one patient (2%) receiving Trametinib in combination with dabrafenib developed RPED. - Perform ophthalmological evaluation at any time a patient reports visual disturbances and compare with baseline, if available. Withhold Trametinib if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume Trametinib at a lower dose level. Discontinue Trametinib if no improvement after 3 weeks. If Trametinib is used in combination with dabrafenib, do not modify the dose of dabrafenib - Uveitis and iritis can occur when Trametinib is used in combination with dabrafenib and with dabrafenib as a single agent . - Uveitis occurred in 1% (2/202) of patients treated with Trametinib in combination with dabrafenib. - Symptomatic treatment employed in clinical trials included steroid and mydriatic ophthalmic drops. Monitor patients for visual signs and symptoms of uveitis (e.g., change in vision, photophobia, eye pain). If diagnosed, withhold dabrafenib for up to 6 weeks until uveitis/iritis resolves to Grade 0-1. If not improved, permanently discontinue dabrafenib. If Trametinib is used in combination with dabrafenib, do not modify the dose of Trametinib . - In clinical trials of Trametinib (N = 329) as a single agent, ILD or pneumonitis occurred in 2% of patients. In Trial 1, 2% (5/211) of patients treated with Trametinib developed ILD or pneumonitis; all five patients required hospitalization. The median time to first presentation of ILD or pneumonitis was 160 days (range: 60 to 172 days). - Withhold Trametinib in patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Permanently discontinue Trametinib for patients diagnosed with treatment-related ILD or pneumonitis.If Trametinib is used in combination with dabrafenib, do not modify the dose of dabrafenib . - Serious febrile reactions and fever of any severity accompanied by hypotension, rigors or chills, dehydration, or renal failure, can occur when Trametinib is used in combination with dabrafenib and with dabrafenib as a single agent . - The incidence and severity of pyrexia are increased when Trametinib is used in combination with dabrafenib compared with dabrafenib as a single agent . - In Trial 2, the incidence of fever (serious and non-serious) was 71% (39/55) in patients treated with Trametinib in combination with dabrafenib and 26% (14/53) in patients treated with dabrafenib as a single agent. Serious febrile reactions and fever of any severity accompanied by hypotension, rigors, or chills occurred in 25% (14/55) of patients treated with Trametinib in combination with dabrafenib compared with 2% (1/53) of patients treated with dabrafenib as a single agent. Fever was complicated with chills/rigors in 51% (28/55), dehydration in 9% (5/55), renal failure in 4% (2/55), and syncope in 4% (2/55) of patients in Trial 2. In patients treated with Trametinib in combination with dabrafenib, the median time to initial onset of fever was 30 days compared with 19 days in patients treated with dabrafenib as a single agent; the median duration of fever was 6 days with the combination compared with 4 days with dabrafenib as a single agent. - Across clinical trials of Trametinib administered in combination with dabrafenib (N = 202), the incidence of pyrexia was 57% (116/202). - Withhold dabrafenib for fever of 101.3ºF or higher. Withhold Trametinib for fever higher than 104ºF. Withhold dabrafenib and Trametinib for any serious febrile reaction or fever accompanied by hypotension, rigors or chills, dehydration, or renal failure, and evaluate for signs and symptoms of infection. Refer to Table 2 for recommended dose modifications for adverse reactions . Prophylaxis with antipyretics may be required when resuming Trametinib or dabrafenib. - Serious skin toxicity can occur when Trametinib is administered as a single agent or when used in combination with dabrafenib. Serious skin toxicity can also occur with dabrafenib as a single agent. - In Trial 1, the overall incidence of any skin toxicity, the most common of which were rash, dermatitis acneiform rash, palmar-plantar erythrodysesthesia syndrome, and erythema, was 87% in patients treated with Trametinib and 13% in chemotherapy-treated patients. Severe skin toxicity occurred in 12% of patients treated with Trametinib . Skin toxicity requiring hospitalization occurred in 6% of patients treated with Trametinib , most commonly for secondary infections of the skin requiring intravenous antibiotics or severe skin toxicity without secondary infection. In comparison, no patients treated with chemotherapy required hospitalization for severe skin toxicity or infections of the skin. The median time to onset of skin toxicity in patients treated with Trametinib was 15 days (range: 1 to 221 days) and median time to resolution of skin toxicity was 48 days (range: 1 to 282 days). Reductions in the dose of Trametinib were required in 12% and permanent discontinuation of Trametinib was required in 1% of patients with skin toxicity. - In Trial 2, the incidence of any skin toxicity was similar for patients receiving Trametinib in combination with dabrafenib (65% ) compared with patients receiving dabrafenib as a single agent (68% ). The median time to onset of skin toxicity in patients treated with Trametinib in combination with dabrafenib was 37 days (range: 1 to 225 days) and median time to resolution of skin toxicity was 33 days (range: 3 to 421 days). No patient required dose reduction or permanent discontinuation of Trametinib or dabrafenib for skin toxicity. - Across clinical trials of Trametinib administered in combination with dabrafenib (n = 202), severe skin toxicity and secondary infection of the skin requiring hospitalization occurred in 2.5% (5/202) of patients treated with Trametinib in combination with dabrafenib. - Withhold Trametinib , and dabrafenib if used in combination, for intolerable or severe skin toxicity. Trametinib and dabrafenib may be resumed at lower dose levels in patients with improvement or recovery from skin toxicity within 3 weeks . - Hyperglycemia can occur when Trametinib is used in combination with dabrafenib and with dabrafenib as a single agent. Hyperglycemia requiring an increase in the dose of, or initiation of insulin or oral hypoglycemic agent therapy occurred with dabrafenib as a single agent . - In Trial 2, the incidence of Grade 3 hyperglycemia based on laboratory values was 5% (3/55) in patients treated with Trametinib in combination with dabrafenib compared with 2% (1/53) in patients treated with dabrafenib as a single agent. - Monitor serum glucose levels as clinically appropriate during treatment with Trametinib in combination with dabrafenib in patients with pre-existing diabetes or hyperglycemia. Advise patients to report symptoms of severe hyperglycemia. - Based on its mechanism of action, Trametinib can cause fetal harm when administered to a pregnant woman. Trametinib was embryotoxic and abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 0.3 times the human exposure at the recommended clinical dose. 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 a fetus . - Advise female patients of reproductive potential to use highly effective contraception during treatment with Trametinib and for 4 months after treatment. Advise patients to use a highly effective non-hormonal method of contraception when Trametinib is administered in combination with dabrafenib, since dabrafenib can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking Trametinib # Adverse Reactions ## Clinical Trials Experience - The following adverse reactions are discussed in greater detail in another section of the label: - New Primary Malignancies - Hemorrhage - Venous Thromboembolism - Cardiomyopathy - Ocular Toxicities - Interstitial Lung Disease - Serious Febrile Reactions - Serious Skin Toxicity - Hyperglycemia - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. - The data described in the Warnings and Precautions section and below reflect exposure to Trametinib as a single agent and in combination with dabrafenib. Trametinib as a single agent was evaluated in 329 patients including 107 (33%) exposed for greater than or equal to 6 months and 30 (9%) exposed for greater than or equal to one year. Trametinib as a single agent was studied in open-label, single-arm trials (N = 118) or in an open-label, randomized, active-controlled trial (N = 211). The median age was 54 years, 60% were male, >99% were white, and all patients had metastatic melanoma. All patients received 2 mg once-daily doses of Trametinib . The incidence of RPED and RVO are obtained from the 1,749 patients from all clinical trials with Trametinib . - The safety of Trametinib in combination with dabrafenib was evaluated in Trial 2 and other trials consisting of 202 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma who received Trametinib 2 mg orally once daily in combination with dabrafenib 150 mg orally twice daily until disease progression or unacceptable toxicity. Among these 202 patients, 68 (34%) were exposed to Trametinib and 66 (33%) were exposed to dabrafenib for greater than 6 to 12 months while 36 (18%) were exposed to Trametinib and 40 (20%) were exposed to dabrafenib for greater than one year. The median age was 54 years, 57% were male and >99% were white. - Table 3 presents adverse reactions identified from analyses of Trial 1, a randomized, open-label trial of patients with BRAF V600E or V600K mutation-positive melanoma receiving Trametinib (N = 211) 2 mg orally once daily or chemotherapy (N = 99) (either dacarbazine 1,000 mg/m2 every 3 weeks or paclitaxel 175 mg/m2 every 3 weeks) . Patients with abnormal LVEF, history of acute coronary syndrome within 6 months, or current evidence of Class II or greater congestive heart failure (New York Heart Association) were excluded from Trial 1. The median duration of treatment with Trametinib was 4.3 months. In Trial 1, 9% of patients receiving Trametinib experienced adverse reactions resulting in permanent discontinuation of trial medication. The most common adverse reactions resulting in permanent discontinuation of Trametinib were decreased left ventricular ejection fraction (LVEF), pneumonitis, renal failure, diarrhea, and rash. Adverse reactions led to dose reductions in 27% of patients treated with Trametinib . Rash and decreased LVEF were the most common reasons cited for dose reductions of Trametinib . - Table 5 presents adverse reactions from Trial 2, a multicenter, open-label, randomized trial of 162 patients with BRAF V600E or V600K mutation-positive melanoma receiving Trametinib 2 mg once daily in combination with dabrafenib 150 mg twice daily (N = 55), Trametinib 1 mg once daily in combination with dabrafenib 150 mg twice daily (N = 54), and dabrafenib as a single agent 150 mg twice daily (N = 53) . Patients with abnormal LVEF, history of acute coronary syndrome within 6 months, current evidence of Class II or greater congestive heart failure (New York Heart Association), history of RVO, or RPED, QTc interval ≥480 msec, treatment refractory hypertension, uncontrolled arrhythmias, history of pneumonitis or interstitial lung disease, or a known history of G6PD deficiency were excluded. The median duration of treatment was 10.9 months for both Trametinib (2-mg once-daily treatment group) and dabrafenib when used in combination, 10.6 months for both Trametinib (1-mg once-daily treatment group) and dabrafenib when used in combination, and 6.1 months for dabrafenib as a single agent. - In Trial 2, 13% of patients receiving Trametinib in combination with dabrafenib at the recommended dose experienced adverse reactions resulting in permanent discontinuation of trial medication(s). The most common adverse reaction resulting in permanent discontinuation was pyrexia (4%). Adverse reactions led to dose reductions in 49% and dose interruptions in 67% of patients treated with Trametinib in combination with dabrafenib. Pyrexia, chills, and nausea were the most common reasons cited for dose reductions, and pyrexia, chills, and decreased ejection fraction were the most common reasons cited for dose interruptions of Trametinib and dabrafenib when used in combination. - QT Prolongation: In Trial 2, QTcF prolongation to >500 msec occurred in 4% (2/55) of patients treated with Trametinib in combination with dabrafenib and in 2% (1/53) of patients treated with dabrafenib as a single agent. The QTcF was increased more than 60 msec from baseline in 13% (7/55) of patients treated with Trametinib in combination with dabrafenib and 2% (1/53) of patients treated with dabrafenib as a single agent. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Trametinib in the drug label. # Drug Interactions - No formal clinical trials have been conducted to evaluate human cytochrome P450 (CYP) enzyme-mediated drug interactions with trametinib . - Coadministration of Trametinib 2 mg once daily and dabrafenib 150 mg twice daily resulted in no clinically relevant pharmacokinetic drug interactions . - Refer to the Full Prescribing Information for dabrafenib for further details on the drug interaction potential of dabrafenib. Avoid concurrent administration of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 with dabrafenib. If concomitant use of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors or loss of efficacy when taking strong inducers. Concomitant use of dabrafenib with agents that are sensitive substrates of CYP3A4, CYP2C8, CYP2C9, CYP2C19, or CYP2B6 may result in loss of efficacy of these agents. Substitute for these medications or monitor patients for loss of efficacy if use of these medications is unavoidable. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D - Trametinib can cause fetal harm when administered to a pregnant woman. Trametinib was embryotoxic and abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 0.3 times the human exposure at the recommended clinical dose. 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. - In reproductive toxicity studies, administration of trametinib to rats during the period of organogenesis resulted in decreased fetal weights at doses greater than or equal to 0.031 mg/kg/day (approximately 0.3 times the human exposure based on AUC at the recommended dose). In rats, at a dose resulting in exposures 1.8-fold higher than the human exposure at the recommended dose, there was maternal toxicity and an increase in post-implantation loss. - In pregnant rabbits, administration of trametinib during the period of organogenesis resulted in decreased fetal body weight and increased incidence of variations in ossification at doses greater than or equal to 0.039 mg/kg/day (approximately 0.08 times the human exposure at the recommended dose based on AUC). In rabbits administered trametinib at 0.15 mg/kg/day (approximately 0.3 times the human exposure at the recommended dose based on AUC) there was an increase in post-implantation loss, including total loss of pregnancy, compared with control animals. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Trametinib in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Trametinib during labor and delivery. ### Nursing Mothers - It is not known whether this drug is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from Trametinib , 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 Trametinib as a single agent or in combination with dabrafenib have not been established in pediatric patients. - Adequate juvenile animal studies using trametinib have not been completed. In a repeat-dose toxicity study in juvenile rats, an increased incidence of kidney cysts and tubular deposits were noted at doses as low as 0.2 times the human exposure at the recommended adult dose of dabrafenib based on AUC. Additionally, forestomach hyperplasia, decreased bone length, and early vaginal opening were noted at doses as low as 0.8 times the human exposure at the recommended adult dose based on AUC. ### Geriatic Use - Clinical trials of Trametinib as a single agent did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In Trial 1, 49 patients (23%) were 65 years of age and older, and 9 patients (4%) were 75 years of age and older. - Across all clinical trials of Trametinib administered in combination with dabrafenib, there was an insufficient number of patients aged 65 years and over to determine whether they respond differently from younger patients. In Trial 2, 11 patients (20%) were 65 years of age and older, and 2 patients (4%) were 75 years of age and older. ### Gender There is no FDA guidance on the use of Trametinib with respect to specific gender populations. ### Race There is no FDA guidance on the use of Trametinib with respect to specific racial populations. ### Renal Impairment - No formal clinical trial has been conducted to evaluate the effect of renal impairment on the pharmacokinetics of trametinib. No dose adjustment is recommended in patients with mild or moderate renal impairment based on a population pharmacokinetic analysis . The appropriate dose of Trametinib has not been established in patients with severe renal impairment. ### Hepatic Impairment - No formal clinical trial has been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of trametinib. No dose adjustment is recommended in patients with mild hepatic impairment based on a population pharmacokinetic analysis - The appropriate dose of Trametinib has not been established in patients with moderate or severe hepatic impairment. ### Females of Reproductive Potential and Males - Females: Trametinib can cause fetal harm when administered during pregnancy. Advise female patients of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of Trametinib . When Trametinib is used in combination with dabrafenib, counsel patients to use a non-hormonal method of contraception since dabrafenib can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking Trametinib . - Females: Trametinib may impair fertility in female patients . - Males: Effects on spermatogenesis have been observed in animals treated with dabrafenib. Advise male patients of the potential risk for impaired spermatogenesis, and to seek counseling on fertility and family planning options prior to starting treatment with Trametinib in combination with dabrafenib. ### Immunocompromised Patients There is no FDA guidance one the use of Trametinib in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Trametinib in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Trametinib in the drug label. # Overdosage - There were no reported cases of overdosage with Trametinib . The highest doses of Trametinib evaluated in clinical trials were 4 mg orally once daily and 10 mg administered orally once daily on 2 consecutive days followed by 3 mg once daily. In seven patients treated on one of these two schedules, there were two cases of retinal pigment epithelial detachments for an incidence of 28%. Since trametinib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with Trametinib . # Pharmacology ## Mechanism of Action - Trametinib is a reversible inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activation and of MEK1 and MEK2 kinase activity. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation. BRAF V600E mutations result in constitutive activation of the BRAF pathway which includes MEK1 and MEK2. Trametinib inhibits BRAF V600 mutation-positive melanoma cell growth in vitro and in vivo. - Trametinib and dabrafenib target two different tyrosine kinases in the RAS/RAF/MEK/ERK pathway. Use of trametinib and dabrafenib in combination resulted in greater growth inhibition of BRAF V600 mutation-positive melanoma cell lines in vitro and prolonged inhibition of tumor growth in BRAF V600 mutation positive melanoma xenografts compared with either drug alone. ## Structure - Trametinib dimethyl sulfoxide is a kinase inhibitor. The chemical name is acetamide, N--3,4,6,7-tetrahydro-6,8-dimethyl- 2,4,7-trioxopyridopyrimidin-1(2H)-yl]phenyl]-, compound with 1,1’-sulfinylbis (1:1). It has a molecular formula C26H23FIN5O4C2H6OS with a molecular mass of 693.53. Trametinib dimethyl sulfoxide has the following chemical structure: - Trametinib dimethyl sulfoxide is a white to almost white powder. It is practically insoluble in the pH range of 2 to 8 in aqueous media. - Trametinib (trametinib) tablets are supplied as 0.5-mg, 1-mg, and 2-mg tablets for oral administration. Each 0.5-mg tablet contains 0.5635 mg trametinib dimethyl sulfoxide equivalent to 0.5 mg of trametinib non-solvated parent. Each 1-mg tablet contains 1.127 mg trametinib dimethyl sulfoxide equivalent to 1 mg of trametinib non-solvated parent. Each 2-mg tablet contains 2.254 mg trametinib dimethyl sulfoxide equivalent to 2 mg of trametinib non-solvated parent. - The inactive ingredients of Trametinib tablets are: Tablet Core: colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate (vegetable source), mannitol, microcrystalline cellulose, sodium lauryl sulfate. Coating: hypromellose, iron oxide red (2-mg tablets), iron oxide yellow (0.5-mg tablets), polyethylene glycol, polysorbate 80 (2-mg tablets), titanium dioxide. ## Pharmacodynamics - Administration of 1 mg and 2 mg trametinib to patients with BRAF V600 mutation-positive melanoma resulted in dose-dependent changes in tumor biomarkers including inhibition of phosphorylated ERK, inhibition of Ki67 (a marker of cell proliferation), and increases in p27 (a marker of apoptosis). ## Pharmacokinetics - The pharmacokinetics (PK) of trametinib were characterized following single- and repeat-oral administration in patients with solid tumors and BRAF V600 mutation-positive metastatic melanoma. - Absorption: After oral administration, the median time to achieve peak plasma concentrations (Tmax) is 1.5 hours post-dose. The mean absolute bioavailability of a single 2-mg oral dose of trametinib tablet is 72%. The increase in Cmax was dose proportional after a single dose of 0.125 to 10 mg while the increase in AUC was greater than dose proportional. After repeat doses of 0.125 to 4 mg daily, both Cmax and AUC increase proportionally with dose. Inter-subject variability in AUC and Cmax at steady state is 22% and 28%, respectively. - Administration of a single dose of trametinib with a high-fat, high-calorie meal decreased AUC by 24%, Cmax by 70%, and delayed Tmax by approximately 4 hours as compared with fasted conditions. - Distribution: Trametinib is 97.4% bound to human plasma proteins. The apparent volume of distribution (Vc/F) is 214 L. - Metabolism: Trametinib is metabolized predominantly via deacetylation alone or with mono-oxygenation or in combination with glucuronidation biotransformation pathways in vitro. Deacetylation is likely mediated by hydrolytic enzymes, such as carboxyl-esterases or amidases. - Following a single dose of -trametinib, approximately 50% of circulating radioactivity is represented as the parent compound. However, based on metabolite profiling after repeat dosing of trametinib, ≥75% of drug-related material in plasma is the parent compound. - Elimination: The estimated elimination half-life based on the population PK model is 3.9 to 4.8 days. The apparent clearance is 4.9 L/h. - Following oral administration of -trametinib, >80% of excreted radioactivity was recovered in the feces while <20% of excreted radioactivity was recovered in the urine with <0.1% of the excreted dose as parent. - Based on a population pharmacokinetic analysis, age, gender, and body weight do not have a clinically important effect on the exposure of trametinib. There are insufficient data to evaluate potential differences in the exposure of trametinib by race or ethnicity. - Hepatic Impairment: Based on a population pharmacokinetic analysis in 64 patients with mild hepatic impairment (total bilirubin ≤ULN and AST >ULN or total bilirubin >1.0 to 1.5 x ULN and any AST), mild hepatic impairment has no clinically important effect on the systemic exposure of trametinib. The pharmacokinetics of trametinib have not been studied in patients with moderate or severe hepatic impairment . - Renal Impairment: As renal excretion of trametinib is low (<20%), renal impairment is unlikely to have a clinically important effect on the exposure of trametinib. Based on a population PK analysis in 223 patients with mild renal impairment (GFR 60 to 89 mL/min/1.73 m2) and 35 patients with moderate renal impairment (GFR 30 to 59 mL/min/1.73 m2), mild and moderate renal impairment have no clinically important effects on the systemic exposure of trametinib. The pharmacokinetics of trametinib have not been studied in patients with severe renal impairment . - Pediatrics: No trials have been conducted to evaluate the pharmacokinetics of trametinib in pediatric patients. - Trametinib is not a substrate of CYP enzymes or efflux transporters human P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) in vitro. - Based on in vitro studies, trametinib is not an inhibitor of CYP450 including CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, or of transporters including human organic anion transporting polypeptide (OATP1B1, OATP1B3), P-gp, and BCRP at a clinically relevant systemic concentration of 0.04 µM. Trametinib is an inhibitor of CYP2C8 in vitro. - Trametinib is an inducer of CYP3A4 in vitro. Based on cross-study comparisons, oral administration of trametinib 2 mg once daily with everolimus (sensitive CYP3A4 substrate) 5 mg once daily, had no clinically important effect on the AUC and Cmax of everolimus. - Coadministration of trametinib 2 mg daily with dabrafenib 150 mg twice daily resulted in a 23% increase in AUC of dabrafenib, a 33% increase in AUC of desmethyl-dabrafenib, and no change in AUC of trametinib or hydroxy-dabrafenib as compared with administration of either drug alone. ## Nonclinical Toxicology - Carcinogenicity studies with trametinib have not been conducted. Trametinib was not genotoxic in studies evaluating reverse mutations in bacteria, chromosomal aberrations in mammalian cells, and micronuclei in the bone marrow of rats. - Trametinib may impair fertility in humans. In female rats given trametinib for up to 13 weeks, increased follicular cysts and decreased corpora lutea were observed at doses ≥0.016 mg/kg/day (approximately 0.3 times the human exposure at the recommended dose based on AUC). In rat and dog toxicity studies up to 13 weeks in duration, there were no treatment effects observed on male reproductive tissues # Clinical Studies - BRAF V600E or V600K Mutation-Positive Unresectable or metastatic melanoma - The safety and efficacy of Trametinib were evaluated in two clinical trials. Trial 1 was an international, multicenter, randomized (2:1), open-label, active-controlled trial in 322 patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma. Trial 2 was a multicenter, randomized (1:1:1), open-label, dose-ranging trial designed to evaluate the clinical activity and safety of Trametinib (at two different doses) in combination with dabrafenib and to compare the safety with dabrafenib as a single agent in 162 patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma. - In Trial 1, patients were not permitted to have more than one prior chemotherapy regimen for advanced or metastatic disease; prior treatment with a BRAF inhibitor or MEK inhibitor was not permitted. The primary efficacy outcome measure was progression-free survival (PFS). Patients were randomized to receive Trametinib 2 mg orally once daily (N = 214) or chemotherapy (N = 108) consisting of either dacarbazine 1,000 mg/m2 intravenously every 3 weeks or paclitaxel 175 mg/m2intravenously every 3 weeks. Treatment continued until disease progression or unacceptable toxicity. Randomization was stratified according to prior use of chemotherapy for advanced or metastatic disease (yes versus no) and lactate dehydrogenase level (normal versus greater than upper limit of normal). Tumor tissue was evaluated for BRAF mutations at a central testing site using a clinical trial assay. Tumor samples from 289 patients (196 patients treated with Trametinib and 93 chemotherapy-treated patients) were also tested retrospectively using an FDA-approved companion diagnostic test, THxID™-BRAF assay. - The median age for randomized patients was 54 years, 54% were male, >99% were white, and all patients had baseline ECOG performance status of 0 or 1. Most patients had metastatic disease (94%), were Stage M1c (64%), had elevated LDH (36%), no history of brain metastasis (97%), and received no prior chemotherapy for advanced or metastatic disease (66%). The distribution of BRAF V600 mutations was BRAF V600E (87%), V600K (12%), or both (<1%). The median durations of follow-up prior to initiation of alternative treatment were 4.9 months for patients treated with Trametinib and 3.1 months for patients treated with chemotherapy. Fifty-one (47%) patients crossed over from the chemotherapy arm at the time of disease progression to receive Trametinib . - Trial 1 demonstrated a statistically significant increase in progression-free survival in the patients treated with Trametinib . Table 7 and Figure 1 summarize the PFS results. - In supportive analyses based on independent radiologic review committee (IRRC) assessment, the PFS results were consistent with those of the primary efficacy analysis. - Trial 2 randomized (1:1:1) patients to Trametinib (at two different doses) in combination with dabrafenib compared with dabrafenib as a single agent in 162 patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma. Patients were permitted to have had one prior chemotherapy regimen and prior aldesleukin; patients with prior exposure to BRAF or MEK inhibitors were ineligible. Patients were randomized to receive Trametinib 2 mg orally once daily with dabrafenib 150 mg orally twice daily (n = 54), Trametinib 1 mg orally once daily with dabrafenib 150 mg orally twice daily (n = 54), or dabrafenib 150 mg orally twice daily (n = 54). Treatment continued until disease progression or unacceptable toxicity. Patients randomized to receive dabrafenib as a single agent were offered Trametinib 2 mg orally once daily with dabrafenib 150 mg orally twice daily at the time of investigator-assessed disease progression. The major efficacy outcome measure was investigator-assessed overall response rate (ORR). Additional efficacy outcome measures were investigator-assessed duration of response, independent radiology review committee (IRRC)-assessed ORR, and IRRC-assessed duration of response. - The median age of patients in Trial 2 was 53 years, 57% were male, >99% were white, 66% of patients had a pretreatment ECOG performance status of 0, 67% had M1c disease, 54% had a normal LDH at baseline, and 8% had a history of brain metastases. Most patients (81%) had not received prior anti-cancer therapy for unresectable or metastatic disease. All patients had tumor containing BRAF V600E or V600K mutations as determined by local laboratory or centralized testing, 85% with BRAF V600E mutations and 15% with BRAF V600K mutations. - The median duration of follow-up was 14 months. Efficacy outcomes for the arm receiving Trametinib 2 mg daily in combination with dabrafenib and the arm receiving dabrafenib as a single agent are summarized in Table 8. - The ORR results were similar in subgroups defined by BRAF mutation subtype, i.e., in the 85% of patients with V600E mutation-positive melanoma and in the 15% of patients with V600K mutation-positive melanoma. In exploratory subgroup analyses of the patients with retrospectively confirmed BRAF V600E or V600K mutation-positive melanoma using the THxID™-BRAF assay, the ORR results were also similar to the intent-to-treat analysis. - The clinical activity of Trametinib as a single agent was evaluated in a single-arm, multicenter, international trial (Trial 3) in 40 patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma who had received prior treatment with a BRAF inhibitor. All patients received Trametinib at a dose of 2 mg orally once daily until disease progression or unacceptable toxicity. - The median age was 58 years, 63% were male, all were white, 98% had baseline ECOG PS of 0 or 1, and the distribution of BRAF V600 mutations was V600E (83%), V600K (10%), and the remaining patients had multiple V600 mutations (5%), or unknown mutational status (2%). No patient in Trial 3 achieved a confirmed partial or complete response as determined by the clinical investigators. # How Supplied - 0.5-mg Tablets: Yellow, modified oval, biconvex, film-coated tablets with ‘GS’ debossed on one face and ‘TFC’ on the opposing face and are available in bottles of 30 (NDC 0173-0849-13). - 1-mg Tablets: White, round, biconvex, film-coated tablets with ‘GS’ debossed on one face and ‘LHE’ on the opposing face and are available in bottles of 30 (NDC 0173-0858-13). - 2-mg Tablets: Pink, round, biconvex, film-coated tablets with ‘GS’ debossed on one face and ‘HMJ’ on the opposing face and are available in bottles of 30 (NDC 0173-0848-13). ## Storage - Store refrigerated at 2° to 8°C (36° to 46°F). Do not freeze. Dispense in original bottle. Do not remove desiccant. Protect from moisture and light. Do not place medication in pill boxes. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Trametinib in the drug label. # Precautions with Alcohol - Alcohol-Trametinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - MEKINIST® # Look-Alike Drug Names There is limited information regarding Trametinib Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Trametinib 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 Trametinib is an kinase inhibitor that is FDA approved for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. Common adverse reactions include decreased left ventricular ejection fraction (LVEF), pneumonitis, renal failure, diarrhea, and rash. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Trametinib ® as a single agent is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test . - Trametinib, in combination with dabrafenib, is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. This indication is based on the demonstration of durable response rate . Improvement in disease-related symptoms or overall survival has not been demonstrated for Trametinib in combination with dabrafenib. - Limitation of use: Trametinib as a single agent is not indicated for treatment of patients who have received prior BRAF-inhibitor therapy - Select patients for treatment of unresectable or metastatic melanoma with Trametinib based on presence of BRAF V600E or V600K mutation in tumor specimens . - The recommended dosage regimens of Trametinib are: - 2 mg orally taken once daily as a single agent - 2 mg orally taken once daily in combination with dabrafenib 150 mg orally taken twice daily - Continue treatment until disease progression or unacceptable toxicity occurs. Take Trametinib as a single agent, or Trametinib in combination with dabrafenib, at least 1 hour before or 2 hours after a meal . Do not take a missed dose of Trametinib within 12 hours of the next dose of Trametinib . When administered in combination with dabrafenib, take the once daily dose of Trametinib at the same time each day with either the morning dose or the evening dose of dabrafenib. - For New Primary Cutaneous Malignancies: No dose modifications are required. - For New Primary Non-Cutaneous Malignancies: No dose modifications are required for Trametinib . If used in combination with dabrafenib, permanently discontinue dabrafenib in patients who develop RAS mutation-positive non-cutaneous malignancies. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Trametinib in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Trametinib in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Trametinib in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Trametinib in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Trametinib in pediatric patients. # Contraindications - None. # Warnings - Review the Full Prescribing Information for dabrafenib prior to initiation of Trametinib in combination with dabrafenib. The following serious adverse reactions of dabrafenib as a single agent, which may occur when Trametinib is used in combination with dabrafenib, are not described in the Full Prescribing Information for Trametinib : - Tumor promotion in patients with BRAF wild-type melanoma - Hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency - New primary malignancies, cutaneous and non-cutaneous, can occur when Trametinib is used in combination with dabrafenib and with dabrafenib as a single agent [refer to Full Prescribing Information for dabrafenib]. - In Trial 2, the incidence of basal cell carcinoma was increased in patients receiving Trametinib in combination with dabrafenib, with an incidence of 9% (5/55) in patients receiving Trametinib in combination with dabrafenib compared with 2% (1/53) in patients receiving dabrafenib as a single agent. The range of time to diagnosis of basal cell carcinoma was 28 to 249 days in patients receiving Trametinib in combination with dabrafenib and was 197 days for the patient receiving dabrafenib as a single agent. - Cutaneous squamous cell carcinomas (SCC), including keratoacanthoma, occurred in 7% of patients receiving Trametinib in combination with dabrafenib and 19% of patients receiving dabrafenib as a single agent. The range of time to diagnosis of cuSCC was 136 to 197 days in the combination arm and was 9 to 197 days in the arm receiving dabrafenib as a single agent. - New primary melanoma occurred in 2% (1/53) of patients receiving dabrafenib and in none of the 55 patients receiving Trametinib in combination with dabrafenib. - Perform dermatologic evaluations prior to initiation of Trametinib in combination with dabrafenib, every 2 months while on therapy, and for up to 6 months following discontinuation of the combination. No dose modifications of Trametinib or dabrafenib are recommended in patients who develop new primary cutaneous malignancies. - Based on its mechanism of action, dabrafenib may promote growth and development of malignancies with activation of RAS through mutation or other mechanisms [refer to the Full Prescribing Information for dabrafenib]. In patients receiving Trametinib in combination with dabrafenib, four cases of non-cutaneous malignancies were identified: KRAS mutation-positive pancreatic adenocarcinoma (n = 1), recurrent NRAS mutation-positive colorectal carcinoma (n = 1), head and neck carcinoma (n = 1), and glioblastoma (n = 1). Monitor patients receiving the combination closely for signs or symptoms of non-cutaneous malignancies. If used in combination with dabrafenib, no dose modification is required for Trametinib in patients who develop non-cutaneous malignancies. Permanently discontinue dabrafenib in patients who develop RAS mutation-positive non-cutaneous malignancies. - Hemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur when Trametinib is used in combination with dabrafenib. - In Trial 2, treatment with Trametinib in combination with dabrafenib resulted in an increased incidence and severity of any hemorrhagic events: 16% (9/55) of patients treated with Trametinib in combination with dabrafenib compared with 2% (1/53) of patients treated with dabrafenib as a single agent. The major hemorrhagic events of intracranial or gastric hemorrhage occurred in 5% (3/55) of patients treated with Trametinib in combination with dabrafenib compared with none of the 53 patients treated with dabrafenib as a single agent. Intracranial hemorrhage was fatal in two (4%) patients receiving the combination of Trametinib and dabrafenib. - Permanently discontinue Trametinib , and also permanently discontinue dabrafenib if administered in combination, for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve. Withhold Trametinib for up to 3 weeks for Grade 3 hemorrhagic events; if improved resume at a lower dose level. Withhold dabrafenib for Grade 3 hemorrhagic events; if improved resume at a lower dose level. - Venous thromboembolism can occur when Trametinib is used in combination with dabrafenib. - In Trial 2, treatment with Trametinib in combination with dabrafenib resulted in an increased incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE): 7% (4/55) of patients treated with Trametinib in combination with dabrafenib compared with none of the 53 patients treated with dabrafenib as a single agent. Pulmonary embolism was fatal in one (2%) patient receiving the combination of Trametinib and dabrafenib. - Advise patients to immediately seek medical care if they develop symptoms of DVT or PE, such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue Trametinib and dabrafenib for life threatening PE. Withhold Trametinib for uncomplicated DVT and PE for up to 3 weeks; if improved, Trametinib may be resumed at a lower dose level. Do not modify the dose of dabrafenib . - Cardiomyopathy can occur when Trametinib is administered as a single agent or when used in combination with dabrafenib. - In Trial 1, cardiomyopathy (defined as cardiac failure, left ventricular dysfunction, or decreased left ventricular ejection fraction [LVEF]) occurred in 7% (14/211) of patients treated with Trametinib ; no chemotherapy-treated patients in Trial 1 developed cardiomyopathy. In Trial 2, cardiomyopathy occurred in 9% (5/55) of patients treated with Trametinib in combination with dabrafenib and in none of patients treated with dabrafenib as a single agent. The median time to onset of cardiomyopathy in patients treated with Trametinib was 63 days (range: 16 to 156 days) for Trial 1 and 86 days (range: 27 to 253 days) for Trial 2. - Cardiomyopathy was identified within the first month of treatment with Trametinib in 5 of 14 patients in Trial 1 and in 2 of 5 patients in Trial 2. Development of cardiomyopathy resulted in dose reduction (7/211) and/or discontinuation (4/211) of study drug in Trial 1, and resulted in dose reduction (4/55) and/or dose interruption (1/55) in Trial 2. Cardiomyopathy resolved in 10 of 14 (71%) patients in Trial 1 and in all 5 patients in Trial 2. - Across clinical trials of Trametinib administered either as a single agent (N = 329), or in combination with dabrafenib (N = 202), 11% and 8% of patients, respectively, developed evidence of cardiomyopathy (decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF ≥10% below baseline). Five percent and 2% in single-agent and in combination trials, respectively, demonstrated a decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of ≥20% below baseline. - Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of Trametinib as a single agent and in combination with dabrafenib, one month after initiation, and then at 2- to 3-month intervals while on treatment. Withhold treatment with Trametinib for up to 4 weeks if absolute LVEF value decreases by 10% from pretreatment values and is less than the lower limit of normal. For symptomatic cardiomyopathy or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue Trametinib and withhold dabrafenib. Resume dabrafenib at the same dose upon recovery of cardiac function . - Across all clinical trials of Trametinib , the incidence of RVO was 0.2% (4/1,749). RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma. - Urgently (within 24 hours) perform ophthalmological evaluation for patient-reported loss of vision or other visual disturbances. Permanently discontinue Trametinib in patients with documented RVO. If Trametinib is used in combination with dabrafenib, do not modify dabrafenib dose . - Retinal pigment epithelial detachment (RPED) can occur when Trametinib is administered as a single agent or when used in combination with dabrafenib. - In Trial 1 and Trial 2, ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment. - In Trial 1, one patient (0.5%) receiving Trametinib developed RPED and no cases of RPED were identified in chemotherapy-treated patients. Across all clinical trials of Trametinib , the incidence of RPED was 0.8% (14/1,749). Retinal detachments were often bilateral and multifocal, occurring in the macular region of the retina. RPED led to reduction in visual acuity that resolved after a median of 11.5 days (range: 3 to 71 days) following the interruption of dosing with Trametinib , although Ocular Coherence Tomography (OCT) abnormalities persisted beyond a month in at least several cases. - In Trial 2, one patient (2%) receiving Trametinib in combination with dabrafenib developed RPED. - Perform ophthalmological evaluation at any time a patient reports visual disturbances and compare with baseline, if available. Withhold Trametinib if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume Trametinib at a lower dose level. Discontinue Trametinib if no improvement after 3 weeks. If Trametinib is used in combination with dabrafenib, do not modify the dose of dabrafenib - Uveitis and iritis can occur when Trametinib is used in combination with dabrafenib and with dabrafenib as a single agent [refer to Full Prescribing Information for dabrafenib]. - Uveitis occurred in 1% (2/202) of patients treated with Trametinib in combination with dabrafenib. - Symptomatic treatment employed in clinical trials included steroid and mydriatic ophthalmic drops. Monitor patients for visual signs and symptoms of uveitis (e.g., change in vision, photophobia, eye pain). If diagnosed, withhold dabrafenib for up to 6 weeks until uveitis/iritis resolves to Grade 0-1. If not improved, permanently discontinue dabrafenib. If Trametinib is used in combination with dabrafenib, do not modify the dose of Trametinib . - In clinical trials of Trametinib (N = 329) as a single agent, ILD or pneumonitis occurred in 2% of patients. In Trial 1, 2% (5/211) of patients treated with Trametinib developed ILD or pneumonitis; all five patients required hospitalization. The median time to first presentation of ILD or pneumonitis was 160 days (range: 60 to 172 days). - Withhold Trametinib in patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Permanently discontinue Trametinib for patients diagnosed with treatment-related ILD or pneumonitis.If Trametinib is used in combination with dabrafenib, do not modify the dose of dabrafenib . - Serious febrile reactions and fever of any severity accompanied by hypotension, rigors or chills, dehydration, or renal failure, can occur when Trametinib is used in combination with dabrafenib and with dabrafenib as a single agent [refer to Full Prescribing Information for dabrafenib]. - The incidence and severity of pyrexia are increased when Trametinib is used in combination with dabrafenib compared with dabrafenib as a single agent . - In Trial 2, the incidence of fever (serious and non-serious) was 71% (39/55) in patients treated with Trametinib in combination with dabrafenib and 26% (14/53) in patients treated with dabrafenib as a single agent. Serious febrile reactions and fever of any severity accompanied by hypotension, rigors, or chills occurred in 25% (14/55) of patients treated with Trametinib in combination with dabrafenib compared with 2% (1/53) of patients treated with dabrafenib as a single agent. Fever was complicated with chills/rigors in 51% (28/55), dehydration in 9% (5/55), renal failure in 4% (2/55), and syncope in 4% (2/55) of patients in Trial 2. In patients treated with Trametinib in combination with dabrafenib, the median time to initial onset of fever was 30 days compared with 19 days in patients treated with dabrafenib as a single agent; the median duration of fever was 6 days with the combination compared with 4 days with dabrafenib as a single agent. - Across clinical trials of Trametinib administered in combination with dabrafenib (N = 202), the incidence of pyrexia was 57% (116/202). - Withhold dabrafenib for fever of 101.3ºF or higher. Withhold Trametinib for fever higher than 104ºF. Withhold dabrafenib and Trametinib for any serious febrile reaction or fever accompanied by hypotension, rigors or chills, dehydration, or renal failure, and evaluate for signs and symptoms of infection. Refer to Table 2 for recommended dose modifications for adverse reactions . Prophylaxis with antipyretics may be required when resuming Trametinib or dabrafenib. - Serious skin toxicity can occur when Trametinib is administered as a single agent or when used in combination with dabrafenib. Serious skin toxicity can also occur with dabrafenib as a single agent[refer to Full Prescribing Information for dabrafenib]. - In Trial 1, the overall incidence of any skin toxicity, the most common of which were rash, dermatitis acneiform rash, palmar-plantar erythrodysesthesia syndrome, and erythema, was 87% in patients treated with Trametinib and 13% in chemotherapy-treated patients. Severe skin toxicity occurred in 12% of patients treated with Trametinib . Skin toxicity requiring hospitalization occurred in 6% of patients treated with Trametinib , most commonly for secondary infections of the skin requiring intravenous antibiotics or severe skin toxicity without secondary infection. In comparison, no patients treated with chemotherapy required hospitalization for severe skin toxicity or infections of the skin. The median time to onset of skin toxicity in patients treated with Trametinib was 15 days (range: 1 to 221 days) and median time to resolution of skin toxicity was 48 days (range: 1 to 282 days). Reductions in the dose of Trametinib were required in 12% and permanent discontinuation of Trametinib was required in 1% of patients with skin toxicity. - In Trial 2, the incidence of any skin toxicity was similar for patients receiving Trametinib in combination with dabrafenib (65% [36/55]) compared with patients receiving dabrafenib as a single agent (68% [36/53]). The median time to onset of skin toxicity in patients treated with Trametinib in combination with dabrafenib was 37 days (range: 1 to 225 days) and median time to resolution of skin toxicity was 33 days (range: 3 to 421 days). No patient required dose reduction or permanent discontinuation of Trametinib or dabrafenib for skin toxicity. - Across clinical trials of Trametinib administered in combination with dabrafenib (n = 202), severe skin toxicity and secondary infection of the skin requiring hospitalization occurred in 2.5% (5/202) of patients treated with Trametinib in combination with dabrafenib. - Withhold Trametinib , and dabrafenib if used in combination, for intolerable or severe skin toxicity. Trametinib and dabrafenib may be resumed at lower dose levels in patients with improvement or recovery from skin toxicity within 3 weeks . - Hyperglycemia can occur when Trametinib is used in combination with dabrafenib and with dabrafenib as a single agent. Hyperglycemia requiring an increase in the dose of, or initiation of insulin or oral hypoglycemic agent therapy occurred with dabrafenib as a single agent [refer to Full Prescribing Information for dabrafenib]. - In Trial 2, the incidence of Grade 3 hyperglycemia based on laboratory values was 5% (3/55) in patients treated with Trametinib in combination with dabrafenib compared with 2% (1/53) in patients treated with dabrafenib as a single agent. - Monitor serum glucose levels as clinically appropriate during treatment with Trametinib in combination with dabrafenib in patients with pre-existing diabetes or hyperglycemia. Advise patients to report symptoms of severe hyperglycemia. - Based on its mechanism of action, Trametinib can cause fetal harm when administered to a pregnant woman. Trametinib was embryotoxic and abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 0.3 times the human exposure at the recommended clinical dose. 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 a fetus . - Advise female patients of reproductive potential to use highly effective contraception during treatment with Trametinib and for 4 months after treatment. Advise patients to use a highly effective non-hormonal method of contraception when Trametinib is administered in combination with dabrafenib, since dabrafenib can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking Trametinib # Adverse Reactions ## Clinical Trials Experience - The following adverse reactions are discussed in greater detail in another section of the label: - New Primary Malignancies - Hemorrhage - Venous Thromboembolism - Cardiomyopathy - Ocular Toxicities - Interstitial Lung Disease - Serious Febrile Reactions - Serious Skin Toxicity - Hyperglycemia - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. - The data described in the Warnings and Precautions section and below reflect exposure to Trametinib as a single agent and in combination with dabrafenib. Trametinib as a single agent was evaluated in 329 patients including 107 (33%) exposed for greater than or equal to 6 months and 30 (9%) exposed for greater than or equal to one year. Trametinib as a single agent was studied in open-label, single-arm trials (N = 118) or in an open-label, randomized, active-controlled trial (N = 211). The median age was 54 years, 60% were male, >99% were white, and all patients had metastatic melanoma. All patients received 2 mg once-daily doses of Trametinib . The incidence of RPED and RVO are obtained from the 1,749 patients from all clinical trials with Trametinib . - The safety of Trametinib in combination with dabrafenib was evaluated in Trial 2 and other trials consisting of 202 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma who received Trametinib 2 mg orally once daily in combination with dabrafenib 150 mg orally twice daily until disease progression or unacceptable toxicity. Among these 202 patients, 68 (34%) were exposed to Trametinib and 66 (33%) were exposed to dabrafenib for greater than 6 to 12 months while 36 (18%) were exposed to Trametinib and 40 (20%) were exposed to dabrafenib for greater than one year. The median age was 54 years, 57% were male and >99% were white. - Table 3 presents adverse reactions identified from analyses of Trial 1, a randomized, open-label trial of patients with BRAF V600E or V600K mutation-positive melanoma receiving Trametinib (N = 211) 2 mg orally once daily or chemotherapy (N = 99) (either dacarbazine 1,000 mg/m2 every 3 weeks or paclitaxel 175 mg/m2 every 3 weeks) . Patients with abnormal LVEF, history of acute coronary syndrome within 6 months, or current evidence of Class II or greater congestive heart failure (New York Heart Association) were excluded from Trial 1. The median duration of treatment with Trametinib was 4.3 months. In Trial 1, 9% of patients receiving Trametinib experienced adverse reactions resulting in permanent discontinuation of trial medication. The most common adverse reactions resulting in permanent discontinuation of Trametinib were decreased left ventricular ejection fraction (LVEF), pneumonitis, renal failure, diarrhea, and rash. Adverse reactions led to dose reductions in 27% of patients treated with Trametinib . Rash and decreased LVEF were the most common reasons cited for dose reductions of Trametinib . - Table 5 presents adverse reactions from Trial 2, a multicenter, open-label, randomized trial of 162 patients with BRAF V600E or V600K mutation-positive melanoma receiving Trametinib 2 mg once daily in combination with dabrafenib 150 mg twice daily (N = 55), Trametinib 1 mg once daily in combination with dabrafenib 150 mg twice daily (N = 54), and dabrafenib as a single agent 150 mg twice daily (N = 53) . Patients with abnormal LVEF, history of acute coronary syndrome within 6 months, current evidence of Class II or greater congestive heart failure (New York Heart Association), history of RVO, or RPED, QTc interval ≥480 msec, treatment refractory hypertension, uncontrolled arrhythmias, history of pneumonitis or interstitial lung disease, or a known history of G6PD deficiency were excluded. The median duration of treatment was 10.9 months for both Trametinib (2-mg once-daily treatment group) and dabrafenib when used in combination, 10.6 months for both Trametinib (1-mg once-daily treatment group) and dabrafenib when used in combination, and 6.1 months for dabrafenib as a single agent. - In Trial 2, 13% of patients receiving Trametinib in combination with dabrafenib at the recommended dose experienced adverse reactions resulting in permanent discontinuation of trial medication(s). The most common adverse reaction resulting in permanent discontinuation was pyrexia (4%). Adverse reactions led to dose reductions in 49% and dose interruptions in 67% of patients treated with Trametinib in combination with dabrafenib. Pyrexia, chills, and nausea were the most common reasons cited for dose reductions, and pyrexia, chills, and decreased ejection fraction were the most common reasons cited for dose interruptions of Trametinib and dabrafenib when used in combination. - QT Prolongation: In Trial 2, QTcF prolongation to >500 msec occurred in 4% (2/55) of patients treated with Trametinib in combination with dabrafenib and in 2% (1/53) of patients treated with dabrafenib as a single agent. The QTcF was increased more than 60 msec from baseline in 13% (7/55) of patients treated with Trametinib in combination with dabrafenib and 2% (1/53) of patients treated with dabrafenib as a single agent. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Trametinib in the drug label. # Drug Interactions - No formal clinical trials have been conducted to evaluate human cytochrome P450 (CYP) enzyme-mediated drug interactions with trametinib . - Coadministration of Trametinib 2 mg once daily and dabrafenib 150 mg twice daily resulted in no clinically relevant pharmacokinetic drug interactions . - Refer to the Full Prescribing Information for dabrafenib for further details on the drug interaction potential of dabrafenib. Avoid concurrent administration of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 with dabrafenib. If concomitant use of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors or loss of efficacy when taking strong inducers. Concomitant use of dabrafenib with agents that are sensitive substrates of CYP3A4, CYP2C8, CYP2C9, CYP2C19, or CYP2B6 may result in loss of efficacy of these agents. Substitute for these medications or monitor patients for loss of efficacy if use of these medications is unavoidable. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D - Trametinib can cause fetal harm when administered to a pregnant woman. Trametinib was embryotoxic and abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 0.3 times the human exposure at the recommended clinical dose. 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. - In reproductive toxicity studies, administration of trametinib to rats during the period of organogenesis resulted in decreased fetal weights at doses greater than or equal to 0.031 mg/kg/day (approximately 0.3 times the human exposure based on AUC at the recommended dose). In rats, at a dose resulting in exposures 1.8-fold higher than the human exposure at the recommended dose, there was maternal toxicity and an increase in post-implantation loss. - In pregnant rabbits, administration of trametinib during the period of organogenesis resulted in decreased fetal body weight and increased incidence of variations in ossification at doses greater than or equal to 0.039 mg/kg/day (approximately 0.08 times the human exposure at the recommended dose based on AUC). In rabbits administered trametinib at 0.15 mg/kg/day (approximately 0.3 times the human exposure at the recommended dose based on AUC) there was an increase in post-implantation loss, including total loss of pregnancy, compared with control animals. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Trametinib in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Trametinib during labor and delivery. ### Nursing Mothers - It is not known whether this drug is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from Trametinib , 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 Trametinib as a single agent or in combination with dabrafenib have not been established in pediatric patients. - Adequate juvenile animal studies using trametinib have not been completed. In a repeat-dose toxicity study in juvenile rats, an increased incidence of kidney cysts and tubular deposits were noted at doses as low as 0.2 times the human exposure at the recommended adult dose of dabrafenib based on AUC. Additionally, forestomach hyperplasia, decreased bone length, and early vaginal opening were noted at doses as low as 0.8 times the human exposure at the recommended adult dose based on AUC. ### Geriatic Use - Clinical trials of Trametinib as a single agent did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In Trial 1, 49 patients (23%) were 65 years of age and older, and 9 patients (4%) were 75 years of age and older. - Across all clinical trials of Trametinib administered in combination with dabrafenib, there was an insufficient number of patients aged 65 years and over to determine whether they respond differently from younger patients. In Trial 2, 11 patients (20%) were 65 years of age and older, and 2 patients (4%) were 75 years of age and older. ### Gender There is no FDA guidance on the use of Trametinib with respect to specific gender populations. ### Race There is no FDA guidance on the use of Trametinib with respect to specific racial populations. ### Renal Impairment - No formal clinical trial has been conducted to evaluate the effect of renal impairment on the pharmacokinetics of trametinib. No dose adjustment is recommended in patients with mild or moderate renal impairment based on a population pharmacokinetic analysis . The appropriate dose of Trametinib has not been established in patients with severe renal impairment. ### Hepatic Impairment - No formal clinical trial has been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of trametinib. No dose adjustment is recommended in patients with mild hepatic impairment based on a population pharmacokinetic analysis - The appropriate dose of Trametinib has not been established in patients with moderate or severe hepatic impairment. ### Females of Reproductive Potential and Males - Females: Trametinib can cause fetal harm when administered during pregnancy. Advise female patients of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of Trametinib . When Trametinib is used in combination with dabrafenib, counsel patients to use a non-hormonal method of contraception since dabrafenib can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking Trametinib . - Females: Trametinib may impair fertility in female patients . - Males: Effects on spermatogenesis have been observed in animals treated with dabrafenib. Advise male patients of the potential risk for impaired spermatogenesis, and to seek counseling on fertility and family planning options prior to starting treatment with Trametinib in combination with dabrafenib. ### Immunocompromised Patients There is no FDA guidance one the use of Trametinib in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Trametinib in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Trametinib in the drug label. # Overdosage - There were no reported cases of overdosage with Trametinib . The highest doses of Trametinib evaluated in clinical trials were 4 mg orally once daily and 10 mg administered orally once daily on 2 consecutive days followed by 3 mg once daily. In seven patients treated on one of these two schedules, there were two cases of retinal pigment epithelial detachments for an incidence of 28%. Since trametinib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with Trametinib . # Pharmacology ## Mechanism of Action - Trametinib is a reversible inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activation and of MEK1 and MEK2 kinase activity. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation. BRAF V600E mutations result in constitutive activation of the BRAF pathway which includes MEK1 and MEK2. Trametinib inhibits BRAF V600 mutation-positive melanoma cell growth in vitro and in vivo. - Trametinib and dabrafenib target two different tyrosine kinases in the RAS/RAF/MEK/ERK pathway. Use of trametinib and dabrafenib in combination resulted in greater growth inhibition of BRAF V600 mutation-positive melanoma cell lines in vitro and prolonged inhibition of tumor growth in BRAF V600 mutation positive melanoma xenografts compared with either drug alone. ## Structure - Trametinib dimethyl sulfoxide is a kinase inhibitor. The chemical name is acetamide, N-[3-[3-cyclopropyl-5-[(2-fluoro-4- iodophenyl)amino]-3,4,6,7-tetrahydro-6,8-dimethyl- 2,4,7-trioxopyrido[4,3-d]pyrimidin-1(2H)-yl]phenyl]-, compound with 1,1’-sulfinylbis[methane] (1:1). It has a molecular formula C26H23FIN5O4•C2H6OS with a molecular mass of 693.53. Trametinib dimethyl sulfoxide has the following chemical structure: - Trametinib dimethyl sulfoxide is a white to almost white powder. It is practically insoluble in the pH range of 2 to 8 in aqueous media. - Trametinib (trametinib) tablets are supplied as 0.5-mg, 1-mg, and 2-mg tablets for oral administration. Each 0.5-mg tablet contains 0.5635 mg trametinib dimethyl sulfoxide equivalent to 0.5 mg of trametinib non-solvated parent. Each 1-mg tablet contains 1.127 mg trametinib dimethyl sulfoxide equivalent to 1 mg of trametinib non-solvated parent. Each 2-mg tablet contains 2.254 mg trametinib dimethyl sulfoxide equivalent to 2 mg of trametinib non-solvated parent. - The inactive ingredients of Trametinib tablets are: Tablet Core: colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate (vegetable source), mannitol, microcrystalline cellulose, sodium lauryl sulfate. Coating: hypromellose, iron oxide red (2-mg tablets), iron oxide yellow (0.5-mg tablets), polyethylene glycol, polysorbate 80 (2-mg tablets), titanium dioxide. ## Pharmacodynamics - Administration of 1 mg and 2 mg trametinib to patients with BRAF V600 mutation-positive melanoma resulted in dose-dependent changes in tumor biomarkers including inhibition of phosphorylated ERK, inhibition of Ki67 (a marker of cell proliferation), and increases in p27 (a marker of apoptosis). ## Pharmacokinetics - The pharmacokinetics (PK) of trametinib were characterized following single- and repeat-oral administration in patients with solid tumors and BRAF V600 mutation-positive metastatic melanoma. - Absorption: After oral administration, the median time to achieve peak plasma concentrations (Tmax) is 1.5 hours post-dose. The mean absolute bioavailability of a single 2-mg oral dose of trametinib tablet is 72%. The increase in Cmax was dose proportional after a single dose of 0.125 to 10 mg while the increase in AUC was greater than dose proportional. After repeat doses of 0.125 to 4 mg daily, both Cmax and AUC increase proportionally with dose. Inter-subject variability in AUC and Cmax at steady state is 22% and 28%, respectively. - Administration of a single dose of trametinib with a high-fat, high-calorie meal decreased AUC by 24%, Cmax by 70%, and delayed Tmax by approximately 4 hours as compared with fasted conditions. - Distribution: Trametinib is 97.4% bound to human plasma proteins. The apparent volume of distribution (Vc/F) is 214 L. - Metabolism: Trametinib is metabolized predominantly via deacetylation alone or with mono-oxygenation or in combination with glucuronidation biotransformation pathways in vitro. Deacetylation is likely mediated by hydrolytic enzymes, such as carboxyl-esterases or amidases. - Following a single dose of [14C]-trametinib, approximately 50% of circulating radioactivity is represented as the parent compound. However, based on metabolite profiling after repeat dosing of trametinib, ≥75% of drug-related material in plasma is the parent compound. - Elimination: The estimated elimination half-life based on the population PK model is 3.9 to 4.8 days. The apparent clearance is 4.9 L/h. - Following oral administration of [14C]-trametinib, >80% of excreted radioactivity was recovered in the feces while <20% of excreted radioactivity was recovered in the urine with <0.1% of the excreted dose as parent. - Based on a population pharmacokinetic analysis, age, gender, and body weight do not have a clinically important effect on the exposure of trametinib. There are insufficient data to evaluate potential differences in the exposure of trametinib by race or ethnicity. - Hepatic Impairment: Based on a population pharmacokinetic analysis in 64 patients with mild hepatic impairment (total bilirubin ≤ULN and AST >ULN or total bilirubin >1.0 to 1.5 x ULN and any AST), mild hepatic impairment has no clinically important effect on the systemic exposure of trametinib. The pharmacokinetics of trametinib have not been studied in patients with moderate or severe hepatic impairment [see Use in Specific Populations (8.7)]. - Renal Impairment: As renal excretion of trametinib is low (<20%), renal impairment is unlikely to have a clinically important effect on the exposure of trametinib. Based on a population PK analysis in 223 patients with mild renal impairment (GFR 60 to 89 mL/min/1.73 m2) and 35 patients with moderate renal impairment (GFR 30 to 59 mL/min/1.73 m2), mild and moderate renal impairment have no clinically important effects on the systemic exposure of trametinib. The pharmacokinetics of trametinib have not been studied in patients with severe renal impairment . - Pediatrics: No trials have been conducted to evaluate the pharmacokinetics of trametinib in pediatric patients. - Trametinib is not a substrate of CYP enzymes or efflux transporters human P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) in vitro. - Based on in vitro studies, trametinib is not an inhibitor of CYP450 including CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, or of transporters including human organic anion transporting polypeptide (OATP1B1, OATP1B3), P-gp, and BCRP at a clinically relevant systemic concentration of 0.04 µM. Trametinib is an inhibitor of CYP2C8 in vitro. - Trametinib is an inducer of CYP3A4 in vitro. Based on cross-study comparisons, oral administration of trametinib 2 mg once daily with everolimus (sensitive CYP3A4 substrate) 5 mg once daily, had no clinically important effect on the AUC and Cmax of everolimus. - Coadministration of trametinib 2 mg daily with dabrafenib 150 mg twice daily resulted in a 23% increase in AUC of dabrafenib, a 33% increase in AUC of desmethyl-dabrafenib, and no change in AUC of trametinib or hydroxy-dabrafenib as compared with administration of either drug alone. ## Nonclinical Toxicology - Carcinogenicity studies with trametinib have not been conducted. Trametinib was not genotoxic in studies evaluating reverse mutations in bacteria, chromosomal aberrations in mammalian cells, and micronuclei in the bone marrow of rats. - Trametinib may impair fertility in humans. In female rats given trametinib for up to 13 weeks, increased follicular cysts and decreased corpora lutea were observed at doses ≥0.016 mg/kg/day (approximately 0.3 times the human exposure at the recommended dose based on AUC). In rat and dog toxicity studies up to 13 weeks in duration, there were no treatment effects observed on male reproductive tissues # Clinical Studies - BRAF V600E or V600K Mutation-Positive Unresectable or metastatic melanoma - The safety and efficacy of Trametinib were evaluated in two clinical trials. Trial 1 was an international, multicenter, randomized (2:1), open-label, active-controlled trial in 322 patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma. Trial 2 was a multicenter, randomized (1:1:1), open-label, dose-ranging trial designed to evaluate the clinical activity and safety of Trametinib (at two different doses) in combination with dabrafenib and to compare the safety with dabrafenib as a single agent in 162 patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma. - In Trial 1, patients were not permitted to have more than one prior chemotherapy regimen for advanced or metastatic disease; prior treatment with a BRAF inhibitor or MEK inhibitor was not permitted. The primary efficacy outcome measure was progression-free survival (PFS). Patients were randomized to receive Trametinib 2 mg orally once daily (N = 214) or chemotherapy (N = 108) consisting of either dacarbazine 1,000 mg/m2 intravenously every 3 weeks or paclitaxel 175 mg/m2intravenously every 3 weeks. Treatment continued until disease progression or unacceptable toxicity. Randomization was stratified according to prior use of chemotherapy for advanced or metastatic disease (yes versus no) and lactate dehydrogenase level (normal versus greater than upper limit of normal). Tumor tissue was evaluated for BRAF mutations at a central testing site using a clinical trial assay. Tumor samples from 289 patients (196 patients treated with Trametinib and 93 chemotherapy-treated patients) were also tested retrospectively using an FDA-approved companion diagnostic test, THxID™-BRAF assay. - The median age for randomized patients was 54 years, 54% were male, >99% were white, and all patients had baseline ECOG performance status of 0 or 1. Most patients had metastatic disease (94%), were Stage M1c (64%), had elevated LDH (36%), no history of brain metastasis (97%), and received no prior chemotherapy for advanced or metastatic disease (66%). The distribution of BRAF V600 mutations was BRAF V600E (87%), V600K (12%), or both (<1%). The median durations of follow-up prior to initiation of alternative treatment were 4.9 months for patients treated with Trametinib and 3.1 months for patients treated with chemotherapy. Fifty-one (47%) patients crossed over from the chemotherapy arm at the time of disease progression to receive Trametinib . - Trial 1 demonstrated a statistically significant increase in progression-free survival in the patients treated with Trametinib . Table 7 and Figure 1 summarize the PFS results. - In supportive analyses based on independent radiologic review committee (IRRC) assessment, the PFS results were consistent with those of the primary efficacy analysis. - Trial 2 randomized (1:1:1) patients to Trametinib (at two different doses) in combination with dabrafenib compared with dabrafenib as a single agent in 162 patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma. Patients were permitted to have had one prior chemotherapy regimen and prior aldesleukin; patients with prior exposure to BRAF or MEK inhibitors were ineligible. Patients were randomized to receive Trametinib 2 mg orally once daily with dabrafenib 150 mg orally twice daily (n = 54), Trametinib 1 mg orally once daily with dabrafenib 150 mg orally twice daily (n = 54), or dabrafenib 150 mg orally twice daily (n = 54). Treatment continued until disease progression or unacceptable toxicity. Patients randomized to receive dabrafenib as a single agent were offered Trametinib 2 mg orally once daily with dabrafenib 150 mg orally twice daily at the time of investigator-assessed disease progression. The major efficacy outcome measure was investigator-assessed overall response rate (ORR). Additional efficacy outcome measures were investigator-assessed duration of response, independent radiology review committee (IRRC)-assessed ORR, and IRRC-assessed duration of response. - The median age of patients in Trial 2 was 53 years, 57% were male, >99% were white, 66% of patients had a pretreatment ECOG performance status of 0, 67% had M1c disease, 54% had a normal LDH at baseline, and 8% had a history of brain metastases. Most patients (81%) had not received prior anti-cancer therapy for unresectable or metastatic disease. All patients had tumor containing BRAF V600E or V600K mutations as determined by local laboratory or centralized testing, 85% with BRAF V600E mutations and 15% with BRAF V600K mutations. - The median duration of follow-up was 14 months. Efficacy outcomes for the arm receiving Trametinib 2 mg daily in combination with dabrafenib and the arm receiving dabrafenib as a single agent are summarized in Table 8. - The ORR results were similar in subgroups defined by BRAF mutation subtype, i.e., in the 85% of patients with V600E mutation-positive melanoma and in the 15% of patients with V600K mutation-positive melanoma. In exploratory subgroup analyses of the patients with retrospectively confirmed BRAF V600E or V600K mutation-positive melanoma using the THxID™-BRAF assay, the ORR results were also similar to the intent-to-treat analysis. - The clinical activity of Trametinib as a single agent was evaluated in a single-arm, multicenter, international trial (Trial 3) in 40 patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma who had received prior treatment with a BRAF inhibitor. All patients received Trametinib at a dose of 2 mg orally once daily until disease progression or unacceptable toxicity. - The median age was 58 years, 63% were male, all were white, 98% had baseline ECOG PS of 0 or 1, and the distribution of BRAF V600 mutations was V600E (83%), V600K (10%), and the remaining patients had multiple V600 mutations (5%), or unknown mutational status (2%). No patient in Trial 3 achieved a confirmed partial or complete response as determined by the clinical investigators. # How Supplied - 0.5-mg Tablets: Yellow, modified oval, biconvex, film-coated tablets with ‘GS’ debossed on one face and ‘TFC’ on the opposing face and are available in bottles of 30 (NDC 0173-0849-13). - 1-mg Tablets: White, round, biconvex, film-coated tablets with ‘GS’ debossed on one face and ‘LHE’ on the opposing face and are available in bottles of 30 (NDC 0173-0858-13). - 2-mg Tablets: Pink, round, biconvex, film-coated tablets with ‘GS’ debossed on one face and ‘HMJ’ on the opposing face and are available in bottles of 30 (NDC 0173-0848-13). ## Storage - Store refrigerated at 2° to 8°C (36° to 46°F). Do not freeze. Dispense in original bottle. Do not remove desiccant. Protect from moisture and light. Do not place medication in pill boxes. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Trametinib in the drug label. # Precautions with Alcohol - Alcohol-Trametinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - MEKINIST® # Look-Alike Drug Names There is limited information regarding Trametinib Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Trametinib
ee5252670fbcd311dfc21208a99d66d28e3f9962	wikidoc	Transistor	Transistor In electronics, a transistor is a semiconductor device commonly used to amplify or switch electronic signals. The transistor is the fundamental building block of computers, and all other modern electronic devices. Some transistors are packaged individually but most are found in integrated circuits. # Introduction An electrical signal can be amplified by using a device that allows a small current or voltage to control the flow of a much larger current. Transistors are the basic devices providing control of this kind. Modern transistors are divided into two main categories: bipolar junction transistors (BJTs) and field effect transistors (FETs). Applying current in BJTs and voltage in FETs between the input and common terminals increases the conductivity between the common and output terminals, thereby controlling current flow between them. The characteristics of a transistor depend on its type. The term "transistor" originally referred to the point contact type, which saw very limited commercial application, being replaced by the much more practical bipolar junction types in the early 1950s. Today's most widely used schematic symbol, like the term "transistor", originally referred to these long-obsolete devices. In analog circuits, transistors are used in amplifiers, (direct current amplifiers, audio amplifiers, radio frequency amplifiers), and linear regulated power supplies. Transistors are also used in digital circuits where they function as electronic switches, but rarely as discrete devices, almost always being incorporated in monolithic Integrated Circuits. Digital circuits include logic gates, random access memory (RAM), microprocessors, and digital signal processors (DSPs). # History The first patent for the field-effect transistor principle was filed in Canada by Austrian-Hungarian physicist Julius Edgar Lilienfeld on October 22, 1925, but Lilienfeld did not publish any research articles about his devices, and they were ignored by industry. In 1934 German physicist Dr. Oskar Heil patented another field-effect transistor. There is no direct evidence that these devices were built, but later work in the 1990s shows that one of Lilienfeld's designs worked as described and gave substantial gain. Legal papers from the Bell Labs patent show that Shockley and Pearson had built operational versions from Lilienfeld's patents, yet they never referenced this work in any of their later research papers or historical articles. On 16 December 1947, William Shockley, John Bardeen, and Walter Brattain succeeded in building the first practical point-contact transistor at Bell Labs. This work followed from their war-time efforts to produce extremely pure germanium "crystal" mixer diodes, used in radar units as a frequency mixer element in microwave radar receivers. They made a demonstration to several of their colleagues and managers at Bell Labs on the afternoon of 23 December 1947, often given as the birth date of the transistor. A parallel project on germanium diodes at Purdue University succeeded in producing the good-quality germanium semiconducting crystals that were used at Bell Labs. Early tube-based technology did not switch fast enough for this role, leading the Bell team to use solid state diodes instead. With this knowledge in hand they turned to the design of a triode, but found this was not at all easy. Bardeen eventually developed a new branch of surface physics to account for the "odd" behavior they saw, and Bardeen and Brattain eventually succeeded in building a working device. At the same time some European scientists were led by the idea of solid-state amplifiers. In August 1948 German physicists Herbert F. Mataré (1912– ) and Heinrich Welker (1912–1981), working in Aulnay-sous-Bois, France, for Compagnie des Freins et Signaux Westinghouse of Paris, applied for a patent on an amplifier based on the minority carrier injection process which they called the "transistron". Since Bell Labs did not make a public announcement of the transistor until June 1948, the transistron was considered to be independently developed. Mataré had first observed transconductance effects during the manufacture of germanium duodiodes for German radar equipment during WWII. Transistrons were commercially manufactured for the French telephone company and military, and in 1953 a solid-state radio receiver with four transistrons was demonstrated at the Düsseldorf Radio Fair. Bell Telephone Laboratories needed a generic name for the new invention: "Semiconductor Triode", "Solid Triode", "Surface States Triode", "Crystal Triode" and "Iotatron" were all considered, but "transistor," coined by John R. Pierce, won an internal ballot. The rationale for the name is described in the following extract from the company's Technical Memorandum calling for votes: Transistor. This is an abbreviated combination of the words "transconductance" or "transfer", and "varistor". The device logically belongs in the varistor family, and has the transconductance or transfer impedance of a device having gain, so that this combination is descriptive. Pierce recalled the naming somewhat differently: The way I provided the name, was to think of what the device did. And at that time, it was supposed to be the dual of the vacuum tube. The vacuum tube had transconductance, so the transistor would have 'transresistance.' And the name should fit in with the names of other devices, such as varistor and thermistor. And. . . I suggested the name 'transistor.' Over the next two decades, transistors gradually replaced the earlier vacuum tubes in most applications and later made possible many new devices such as integrated circuits and personal computers. Shockley, Bardeen and Brattain were honored with the Nobel Prize in Physics "for their researches on semiconductors and their discovery of the transistor effect". Bardeen would go on to win a second Nobel in physics, one of only two people to receive more than one in the same discipline, for his work on the exploration of superconductivity. The commercial uses of germanium transistors were limited by their sensitivity to temperature and humidity. Silicon, a semiconductor with crystal structure identical to germanium, looked promising but attempts over several years to make useful transistors were unsuccessful. In early 1954, M. Tanenbaum et al. (Jl. of Applied Physics, 26, 686 (1955)) at Bell Labs made a high performance silicon transistor using npn junctions produced by growth rate fluctuations during crystal growing. A few months later, working independently at Texas Instruments, G. Teal (unpublished) made similar devices using sequential doping. While these devices had much superior temperature and environmental properties compared to gemanium transistors, the doping processes were difficult to control. That problem was solved by Tanenbaum and Fuller (Bell Sys. Tech. Jl., 35, 1 (1956)) using gas diffusion techniques to produce npn silicon transistors. The resulting diffused base silicon transistor was the subject of the second Bell Labs symposium. The diffusion process was easy to control, quickly adopted by the semiconductor industry and was the basis for the later invention of the integrated circuit initiating the "silicon age". The first gallium-arsenide Schottky-gate field-effect transistor (MESFET) was made by Carver Mead and reported in 1966. # Importance The transistor is considered by many to be the greatest invention of the twentieth century. It is the key active component in practically all modern electronics. Its importance in today's society rests on its ability to be mass produced using a highly automated process (fabrication) that achieves astonishingly low per-transistor costs. Although several companies each produce over a billion individually-packaged (known as discrete) transistors every year the vast majority of transistors produced are in integrated circuits (often abbreviated as IC and also called microchips or simply chips) along with diodes, resistors, capacitors and other electronic components to produce complete electronic circuits. A logic gate consists of about twenty transistors whereas an advanced microprocessor, as of 2006, can use as many as 1.7 billion transistors (MOSFETs). "About 60 million transistors were built this year ... for man, woman, and child on Earth." The transistor's low cost, flexibility and reliability have made it a universal device for non-mechanical tasks, such as digital computing. Transistorized mechatronics circuits have replaced electromechanical devices for the control of appliances and machinery as well. It is often easier and cheaper to use a standard microcontroller and write a computer program to carry out a control function than to design an equivalent mechanical control function. Because of the low cost of transistors and hence digital computers, there is a trend to digitize information, such as the Internet Archive. With digital computers offering the ability to quickly find, sort and process digital information, more and more effort has been put into making information digital. As a result, today, much media data is delivered in digital form, finally being converted and presented in analog form to the user. Areas influenced by the Digital Revolution include television, radio, and newspapers. # Comparison with vacuum tubes Prior to the development of transistors, vacuum (electron) tubes (or in the UK "thermionic valves" or just "valves") were the main active components in electronic equipment. ## Advantages The key advantages that have allowed transistors to replace their vacuum tube predecessors in most applications are: - Small size and minimal weight, allowing the development of miniaturized electronic devices. - Highly automated manufacturing processes, resulting in low per-unit cost. - Lower possible operating voltages, making transistors suitable for small, battery-powered applications. - No warm-up period for cathode heaters required after power application. - Lower power dissipation and generally greater energy efficiency. - Higher reliability and greater physical ruggedness. - Extremely long life. Some transistorized devices produced more than 30 years ago are still in service. - Complementary devices available, facilitating the design of complementary-symmetry circuits, something not possible with vacuum tubes. - Though in most transistors the junctions have different doping levels and geometry, some allow bidirectional current - Ability to control very large currents, as much as several hundred amperes. - Insensitivity to mechanical shock and vibration, thus avoiding the problem of microphonics in audio applications. - More sensitive than the hot and macroscopic tubes ## Disadvantages - Silicon transistors do not operate at voltages higher than about 1 kV, SiC go to 3 kV. - The electron mobility is higher in a vacuum, so that high power, high frequency operation is easier in tubes. # Types Transistors are categorized by: - Semiconductor material : germanium, silicon, gallium arsenide, silicon carbide, etc. - Structure: BJT, JFET, IGFET (MOSFET), IGBT, "other types" - Polarity: NPN, PNP (BJTs); N-channel, P-channel (FETs) - Maximum power rating: low, medium, high - Maximum operating frequency: low, medium, high, radio frequency (RF), microwave (The maximum effective frequency of a transistor is denoted by the term f_\mathrm{T}, an abbreviation for "frequency of transition". The frequency of transition is the frequency at which the transistor yields unity gain). - Application: switch, general purpose, audio, high voltage, super-beta, matched pair - Physical packaging: through hole metal, through hole plastic, surface mount, ball grid array, power modules - Amplification factor hfe (transistor beta) Thus, a particular transistor may be described as: silicon, surface mount, BJT, NPN, low power, high frequency switch. ## Bipolar junction transistor The bipolar junction transistor (BJT) was the first type of transistor to be mass-produced. Bipolar transistors are so named because they conduct by using both majority and minority carriers. The three terminals of the BJT are named emitter, base and collector. Two p-n junctions exist inside a BJT: the base/emitter junction and base/collector junction. "The is useful in amplifiers because the currents at the emitter and collector are controllable by the relatively small base current." In an NPN transistor operating in the active region, the emitter-base junction is forward biased, and electrons are injected into the base region. Because the base is narrow, most of these electrons will diffuse into the reverse-biased base-collector junction and be swept into the collector; perhaps one-hundredth of the electrons will recombine in the base, which is the dominant mechanism in the base current. By controlling the number of electrons that can leave the base, the number of electrons entering the collector can be controlled. Unlike the FET, the BJT is a low–input-impedance device. Also, as the base–emitter voltage (V_{be}) is increased the base–emitter current and hence the collector–emitter current (I_{ce}) increase exponentially according to the Shockley diode model and the Ebers-Moll model. Because of this exponential relationship, the BJT has a higher transconductance than the FET. Bipolar transistors can be made to conduct by exposure to light, since absorption of photons in the base region generates a photocurrent that acts as a base current; the collector current is approximately beta times the photocurrent. Devices designed for this purpose have a transparent window in the package and are called phototransistors. ## Field-effect transistor The field-effect transistor (FET), sometimes called a unipolar transistor, uses either electrons (in N-channel FET) or holes (in P-channel FET) for conduction. The four terminals of the FET are named source, gate, drain, and body (substrate). On most FETs, the body is connected to the source inside the package, and this will be assumed for the following description. In FETs, the drain-to-source current flows via a conducting channel that connects the source region to the drain region. The conductivity is varied by the electric field that is produced when a voltage is applied between the gate and source terminals; hence the current flowing between the drain and source is controlled by the voltage applied between the gate and source. As the gate–source voltage (V_{gs}) is increased, the drain–source current (I_{ds}) increases exponentially for Vgs below threshold, and then at a roughly quadratic rate (I_{ds} \propto (V_{gs}-V_T)^2) (where V_T is the threshold voltage at which drain current begins) in the "space-charge-limited" region above threshold. A quadratic behavior is not observed in modern devices, for example, at the 65nm technology node. To turn on a transistor it has to be charged like a capacitor. One polarity of charge is responsible for conduction, the other serves for charge neutrality. In the BJT, both types of charge carriers come close together and so the capacitance is high, therefore only low voltages are needed to produce a given amount of charge. In a FET both types of charges are separated by the dielectric and additionally the Debye length, thus reducing the capacity and increasing the voltage needed for switching. Above zero Kelvin, the exponential curve is convoluted with the hard turn on of the BJT and the parabolic turn on of the FET. For low noise at narrow bandwidth the higher input resistance of the FET is advantageous. FETs are divided into two families: junction FET (JFET) and insulated gate FET (IGFET). The IGFET is more commonly known as metal–oxide–semiconductor FET (MOSFET), from their original construction as a layer of metal (the gate), a layer of oxide (the insulation), and a layer of semiconductor. Unlike IGFETs, the JFET gate forms a PN diode with the channel which lies between the source and drain. Functionally, this makes the N-channel JFET the solid state equivalent of the vacuum tube triode which, similarly, forms a diode between its grid and cathode. Also, both devices operate in the depletion mode, they both have a high input impedance, and they both conduct current under the control of an input voltage. Metal–semiconductor FETs (MESFETs) are JFETs in which the reverse biased PN junction is replaced by a metal–semiconductor Schottky-junction. These, and the HEMTs (high electron mobility transistors, or HFETs), in which a two-dimensional electron gas with very high carrier mobility is used for charge transport, are especially suitable for use at very high frequencies (microwave frequencies; several GHz). Unlike bipolar transistors, FETs do not inherently amplify a photocurrent. Nevertheless, there are ways to use them, especially JFETs, as light-sensitive devices, by exploiting the photocurrents in channel–gate or channel–body junctions. FETs are further divided into depletion-mode and enhancement-mode types, depending on whether the channel is turned on or off with zero gate-to-source voltage. For enhancement mode, the channel is off at zero bias, and a gate potential can "enhance" the conduction. For depletion mode, the channel is on at zero bias, and a gate potential (of the opposite polarity) can "deplete" the channel, reducing conduction. For either mode, a more positive gate voltage corresponds to a higher current for N-channel devices and a lower current for P-channel devices. Nearly all JFETs are depletion-mode as the diode junctions would forward bias and conduct if they were enhancement mode devices; most IGFETs are enhancement-mode types. ## Other transistor types - Heterojunction bipolar transistor - Alloy junction transistor - Tetrode transistor - Pentode transistor - Spacistor - Surface barrier transistor - Micro alloy transistor - Micro alloy diffused transistor - Drift-field transistor - Unijunction transistors can be used as simple pulse generators. They comprise a main body of either P-type or N-type semiconductor with ohmic contacts at each end (terminals Base1 and Base2). A junction with the opposite semiconductor type is formed at a point along the length of the body for the third terminal (Emitter). - Dual gate FETs have a single channel with two gates in cascode; a configuration that is optimized for high frequency amplifiers, mixers, and oscillators. - Darlington transistors are two BJTs connected together to provide a high current gain equal to the product of the current gains of the two transistors. - Insulated gate bipolar transistors (IGBTs) use a medium power IGFET, similarly connected to a power BJT, to give a high input impedance. Power diodes are often connected between certain terminals depending on specific use. IGBTs are particularly suitable for heavy-duty industrial applications. The Asea Brown Boveri (ABB) 5SNA2400E170100 illustrates just how far power semiconductor technology has advanced. Intended for three-phase power supplies, this device houses three NPN IGBTs in a case measuring 38 by 140 by 190 mm and weighing 1.5 kg. Each IGBT is rated at 1,700 volts and can handle 2,400 amperes. - Single-electron transistors (SET) consist of a gate island between two tunnelling junctions. The tunnelling current is controlled by a voltage applied to the gate through a capacitor. - Nanofluidic transistor Control the movement of ions through sub-microscopic, water-filled channels. Nanofluidic transistor, the basis of future chemical processors - Trigate transistors (Prototype by Intel) - Avalanche transistor - Ballistic transistor - Spin transistor Magnetically-sensitive - Thin film transistor Used in LCD display. - Floating-gate transistor Used for non-volatile storage. - Photo transistor React to light - Inverted-T field effect transistor - Ion sensitive field effect transistor To measure ion concentrations in solution. - FinFET The source/drain region forms fins on the silicon surface. - FREDFET Fast-Reverse Epitaxial Diode Field-Effect Transistor - EOSFET Electrolyte-Oxide-Semiconductor Field Effect Transistor (Neurochip) - OFET Organic Field-Effect Transistor, in which the semiconductor is an organic compound - DNAFET Deoxyribonucleic acid field-effect transistor # Semiconductor material The first BJTs were made from germanium (Ge) and some high power types still are. Silicon (Si) types currently predominate but certain advanced microwave and high performance versions now employ the compound semiconductor material gallium arsenide (GaAs) and the semiconductor alloy silicon germanium (SiGe). Single element semiconductor material (Ge and Si) is described as elemental. Rough parameters for the most common semiconductor materials used to make transistors are given in the table below; it must be noted that these parameters will vary with increase in temperature, electric field, impurity level, strain and various other factors: The junction forward voltage is the voltage applied to the emitter-base junction of a BJT in order to make the base conduct a specified current. The current increases exponentially as the junction forward voltage is increased. The values given in the table are typical for a current of 1 mA (the same values apply to semiconductor diodes). The lower the junction forward voltage the better, as this means that less power is required to "drive" the transistor. The junction forward voltage for a given current decreases with increase in temperature. For a typical silicon junction the change is approximately −2.1 mV/°C. The density of mobile carriers in the channel of a MOSFET is a function of the electric field forming the channel and of various other phenomena such as the impurity level in the channel. Some impurities, called dopants, are introduced deliberately in making a MOSFET, to control the MOSFET electrical behavior. The electron mobility and hole mobility columns show the average speed that electrons and holes diffuse through the semiconductor material with an electric field of 1 volt per meter applied across the material. In general, the higher the electron mobility the faster the transistor. The table indicates that Ge is a better material than Si in this respect. However, Ge has four major shortcomings compared to silicon and gallium arsenide: - its maximum temperature is limited - it has relatively high leakage current - it cannot withstand high voltages - it is less suitable for fabricating integrated circuits Because the electron mobility is higher than the hole mobility for all semiconductor materials, a given bipolar NPN transistor tends to be faster than an equivalent PNP transistor type. GaAs has the highest electron mobility of the three semiconductors. It is for this reason that GaAs is used in high frequency applications. A relatively recent FET development, the high electron mobility transistor (HEMT), has a heterostructure (junction between different semiconductor materials) of aluminium gallium arsenide (AlGaAs)-gallium arsenide (GaAs) which has double the electron mobility of a GaAs-metal barrier junction. Because of their high speed and low noise, HEMTs are used in satellite receivers working at frequencies around 12 GHz. Max. junction temperature values represent a cross section taken from various manufacturers' data sheets. This temperature should not be exceeded or the transistor may be damaged. Al-Si junction refers to the high-speed (aluminum-silicon) semiconductor-metal barrier diode, commonly known as a Schottky diode. This is included in the table because some silicon power IGFETs have a parasitic reverse Schottky diode formed between the source and drain as part of the fabrication process. This diode can be a nuisance, but sometimes it is used in the circuit. # Packaging Transistors come in many different packages (chip carriers) (see images). The two main categories are through-hole (or leaded), and surface-mount, also known as surface mount device (SMD). The ball grid array (BGA) is the latest surface mount package (currently only for large transistor arrays). It has solder "balls" on the underside in place of leads. Because they are smaller and have shorter interconnections, SMDs have better high frequency characteristics but lower power rating. Transistor packages are made of glass, metal, ceramic or plastic. The package often dictates the power rating and frequency characteristics. Power transistors have large packages that can be clamped to heat sinks for enhanced cooling. Additionally, most power transistors have the collector or drain physically connected to the metal can/metal plate. At the other extreme, some surface-mount microwave transistors are as small as grains of sand. Often a given transistor type is available in different packages. Transistor packages are mainly standardized, but the assignment of a transistor's functions to the terminals is not: different transistor types can assign different functions to the package's terminals. Even for the same transistor type the terminal assignment can vary (normally indicated by a suffix letter to the part number- i.e. BC212L and BC212K). # Usage For a basic guide to the operation of transistors, see How a transistor works. In the early days of transistor circuit design, the bipolar junction transistor, or BJT, was the most commonly used transistor. Even after MOSFETs became available, the BJT remained the transistor of choice for digital and analog circuits because of their ease of manufacture and speed. However, desirable properties of MOSFETs, such as their utility in low-power devices, have made them the ubiquitous choice for use in digital circuits and a very common choice for use in analog circuits. ## Switches Transistors are commonly used as electronic switches, for both high power applications including switched-mode power supplies and low power applications such as logic gates. ## Amplifiers From mobile phones to televisions, vast numbers of products include amplifiers for sound reproduction, radio transmission, and signal processing. The first discrete transistor audio amplifiers barely supplied a few hundred milliwatts, but power and audio fidelity gradually increased as better transistors became available and amplifier architecture evolved. Transistors are commonly used in modern musical instrument amplifiers, in which circuits up to a few hundred watts are common and relatively cheap. Transistors have largely replaced valves (electron tubes) in instrument amplifiers. Some musical instrument amplifier manufacturers mix transistors and vacuum tubes in the same circuit, to utilize the inherent benefits of both devices. ## Computers The "first generation" of electronic computers used vacuum tubes, which generated large amounts of heat, were bulky, and were unreliable. The development of the transistor was key to computer miniaturization and reliability. The "second generation" of computers, through the late 1950s and 1960s featured boards filled with individual transistors and magnetic memory cores. Subsequently, transistors, other components, and their necessary wiring were integrated into a single, mass-manufactured component: the integrated circuit.	Transistor In electronics, a transistor is a semiconductor device commonly used to amplify or switch electronic signals. The transistor is the fundamental building block of computers, and all other modern electronic devices. Some transistors are packaged individually but most are found in integrated circuits. # Introduction An electrical signal can be amplified by using a device that allows a small current or voltage to control the flow of a much larger current. Transistors are the basic devices providing control of this kind. Modern transistors are divided into two main categories: bipolar junction transistors (BJTs) and field effect transistors (FETs). Applying current in BJTs and voltage in FETs between the input and common terminals increases the conductivity between the common and output terminals, thereby controlling current flow between them. The characteristics of a transistor depend on its type. The term "transistor" originally referred to the point contact type, which saw very limited commercial application, being replaced by the much more practical bipolar junction types in the early 1950s. Today's most widely used schematic symbol, like the term "transistor", originally referred to these long-obsolete devices.[1] In analog circuits, transistors are used in amplifiers, (direct current amplifiers, audio amplifiers, radio frequency amplifiers), and linear regulated power supplies. Transistors are also used in digital circuits where they function as electronic switches, but rarely as discrete devices, almost always being incorporated in monolithic Integrated Circuits. Digital circuits include logic gates, random access memory (RAM), microprocessors, and digital signal processors (DSPs). # History The first patent[2] for the field-effect transistor principle was filed in Canada by Austrian-Hungarian physicist Julius Edgar Lilienfeld on October 22, 1925, but Lilienfeld did not publish any research articles about his devices, and they were ignored by industry. In 1934 German physicist Dr. Oskar Heil patented another field-effect transistor. There is no direct evidence that these devices were built, but later work in the 1990s shows that one of Lilienfeld's designs worked as described and gave substantial gain. Legal papers from the Bell Labs patent show that Shockley and Pearson had built operational versions from Lilienfeld's patents, yet they never referenced this work in any of their later research papers or historical articles.[3] On 16 December 1947, William Shockley, John Bardeen, and Walter Brattain succeeded in building the first practical point-contact transistor at Bell Labs. This work followed from their war-time efforts to produce extremely pure germanium "crystal" mixer diodes, used in radar units as a frequency mixer element in microwave radar receivers. They made a demonstration to several of their colleagues and managers at Bell Labs on the afternoon of 23 December 1947, often given as the birth date of the transistor. A parallel project on germanium diodes at Purdue University succeeded in producing the good-quality germanium semiconducting crystals that were used at Bell Labs.[4] Early tube-based technology did not switch fast enough for this role, leading the Bell team to use solid state diodes instead. With this knowledge in hand they turned to the design of a triode, but found this was not at all easy. Bardeen eventually developed a new branch of surface physics to account for the "odd" behavior they saw, and Bardeen and Brattain eventually succeeded in building a working device. At the same time some European scientists were led by the idea of solid-state amplifiers. In August 1948 German physicists Herbert F. Mataré (1912– ) and Heinrich Welker (1912–1981), working in Aulnay-sous-Bois, France, for Compagnie des Freins et Signaux Westinghouse of Paris, applied for a patent on an amplifier based on the minority carrier injection process which they called the "transistron".[5][6][7][8] Since Bell Labs did not make a public announcement of the transistor until June 1948, the transistron was considered to be independently developed. Mataré had first observed transconductance effects during the manufacture of germanium duodiodes for German radar equipment during WWII. Transistrons were commercially manufactured for the French telephone company and military, and in 1953 a solid-state radio receiver with four transistrons was demonstrated at the Düsseldorf Radio Fair. Bell Telephone Laboratories needed a generic name for the new invention: "Semiconductor Triode", "Solid Triode", "Surface States Triode", "Crystal Triode" and "Iotatron" were all considered, but "transistor," coined by John R. Pierce, won an internal ballot. The rationale for the name is described in the following extract from the company's Technical Memorandum calling for votes: Transistor. This is an abbreviated combination of the words "transconductance" or "transfer", and "varistor". The device logically belongs in the varistor family, and has the transconductance or transfer impedance of a device having gain, so that this combination is descriptive. Pierce recalled the naming somewhat differently: The way I provided the name, was to think of what the device did. And at that time, it was supposed to be the dual of the vacuum tube. The vacuum tube had transconductance, so the transistor would have 'transresistance.' And the name should fit in with the names of other devices, such as varistor and thermistor. And. . . I suggested the name 'transistor.' Over the next two decades, transistors gradually replaced the earlier vacuum tubes in most applications and later made possible many new devices such as integrated circuits and personal computers. Shockley, Bardeen and Brattain were honored with the Nobel Prize in Physics "for their researches on semiconductors and their discovery of the transistor effect". Bardeen would go on to win a second Nobel in physics, one of only two people to receive more than one in the same discipline, for his work on the exploration of superconductivity. The commercial uses of germanium transistors were limited by their sensitivity to temperature and humidity. Silicon, a semiconductor with crystal structure identical to germanium, looked promising but attempts over several years to make useful transistors were unsuccessful. In early 1954, M. Tanenbaum et al. (Jl. of Applied Physics, 26, 686 (1955)) at Bell Labs made a high performance silicon transistor using npn junctions produced by growth rate fluctuations during crystal growing. A few months later, working independently at Texas Instruments, G. Teal (unpublished) made similar devices using sequential doping. While these devices had much superior temperature and environmental properties compared to gemanium transistors, the doping processes were difficult to control. That problem was solved by Tanenbaum and Fuller (Bell Sys. Tech. Jl., 35, 1 (1956)) using gas diffusion techniques to produce npn silicon transistors. The resulting diffused base silicon transistor was the subject of the second Bell Labs symposium. The diffusion process was easy to control, quickly adopted by the semiconductor industry and was the basis for the later invention of the integrated circuit initiating the "silicon age". The first gallium-arsenide Schottky-gate field-effect transistor (MESFET) was made by Carver Mead and reported in 1966.[9] # Importance The transistor is considered by many to be the greatest invention of the twentieth century.[10] It is the key active component in practically all modern electronics. Its importance in today's society rests on its ability to be mass produced using a highly automated process (fabrication) that achieves astonishingly low per-transistor costs. Although several companies each produce over a billion individually-packaged (known as discrete) transistors every year [11], the vast majority of transistors produced are in integrated circuits (often abbreviated as IC and also called microchips or simply chips) along with diodes, resistors, capacitors and other electronic components to produce complete electronic circuits. A logic gate consists of about twenty transistors whereas an advanced microprocessor, as of 2006, can use as many as 1.7 billion transistors (MOSFETs). [12] "About 60 million transistors were built this year [2002] ... for [each] man, woman, and child on Earth." [13] The transistor's low cost, flexibility and reliability have made it a universal device for non-mechanical tasks, such as digital computing. Transistorized mechatronics circuits have replaced electromechanical devices for the control of appliances and machinery as well. It is often easier and cheaper to use a standard microcontroller and write a computer program to carry out a control function than to design an equivalent mechanical control function. Because of the low cost of transistors and hence digital computers, there is a trend to digitize information, such as the Internet Archive. With digital computers offering the ability to quickly find, sort and process digital information, more and more effort has been put into making information digital. As a result, today, much media data is delivered in digital form, finally being converted and presented in analog form to the user. Areas influenced by the Digital Revolution include television, radio, and newspapers. # Comparison with vacuum tubes Prior to the development of transistors, vacuum (electron) tubes (or in the UK "thermionic valves" or just "valves") were the main active components in electronic equipment. ## Advantages The key advantages that have allowed transistors to replace their vacuum tube predecessors in most applications are: - Small size and minimal weight, allowing the development of miniaturized electronic devices. - Highly automated manufacturing processes, resulting in low per-unit cost. - Lower possible operating voltages, making transistors suitable for small, battery-powered applications. - No warm-up period for cathode heaters required after power application. - Lower power dissipation and generally greater energy efficiency. - Higher reliability and greater physical ruggedness. - Extremely long life. Some transistorized devices produced more than 30 years ago are still in service. - Complementary devices available, facilitating the design of complementary-symmetry circuits, something not possible with vacuum tubes. - Though in most transistors the junctions have different doping levels and geometry, some allow bidirectional current - Ability to control very large currents, as much as several hundred amperes. - Insensitivity to mechanical shock and vibration, thus avoiding the problem of microphonics in audio applications. - More sensitive than the hot and macroscopic tubes ## Disadvantages - Silicon transistors do not operate at voltages higher than about 1 kV, SiC go to 3 kV. - The electron mobility is higher in a vacuum, so that high power, high frequency operation is easier in tubes. # Types Template:Float begin Template:Float end Transistors are categorized by: - Semiconductor material : germanium, silicon, gallium arsenide, silicon carbide, etc. - Structure: BJT, JFET, IGFET (MOSFET), IGBT, "other types" - Polarity: NPN, PNP (BJTs); N-channel, P-channel (FETs) - Maximum power rating: low, medium, high - Maximum operating frequency: low, medium, high, radio frequency (RF), microwave (The maximum effective frequency of a transistor is denoted by the term <math>f_\mathrm{T}</math>, an abbreviation for "frequency of transition". The frequency of transition is the frequency at which the transistor yields unity gain). - Application: switch, general purpose, audio, high voltage, super-beta, matched pair - Physical packaging: through hole metal, through hole plastic, surface mount, ball grid array, power modules - Amplification factor hfe (transistor beta)[14] Thus, a particular transistor may be described as: silicon, surface mount, BJT, NPN, low power, high frequency switch. ## Bipolar junction transistor The bipolar junction transistor (BJT) was the first type of transistor to be mass-produced. Bipolar transistors are so named because they conduct by using both majority and minority carriers. The three terminals of the BJT are named emitter, base and collector. Two p-n junctions exist inside a BJT: the base/emitter junction and base/collector junction. "The [BJT] is useful in amplifiers because the currents at the emitter and collector are controllable by the relatively small base current."[15] In an NPN transistor operating in the active region, the emitter-base junction is forward biased, and electrons are injected into the base region. Because the base is narrow, most of these electrons will diffuse into the reverse-biased base-collector junction and be swept into the collector; perhaps one-hundredth of the electrons will recombine in the base, which is the dominant mechanism in the base current. By controlling the number of electrons that can leave the base, the number of electrons entering the collector can be controlled.[15] Unlike the FET, the BJT is a low–input-impedance device. Also, as the base–emitter voltage (<math>V_{be}</math>) is increased the base–emitter current and hence the collector–emitter current (<math>I_{ce}</math>) increase exponentially according to the Shockley diode model and the Ebers-Moll model. Because of this exponential relationship, the BJT has a higher transconductance than the FET. Bipolar transistors can be made to conduct by exposure to light, since absorption of photons in the base region generates a photocurrent that acts as a base current; the collector current is approximately beta times the photocurrent. Devices designed for this purpose have a transparent window in the package and are called phototransistors. ## Field-effect transistor The field-effect transistor (FET), sometimes called a unipolar transistor, uses either electrons (in N-channel FET) or holes (in P-channel FET) for conduction. The four terminals of the FET are named source, gate, drain, and body (substrate). On most FETs, the body is connected to the source inside the package, and this will be assumed for the following description. In FETs, the drain-to-source current flows via a conducting channel that connects the source region to the drain region. The conductivity is varied by the electric field that is produced when a voltage is applied between the gate and source terminals; hence the current flowing between the drain and source is controlled by the voltage applied between the gate and source. As the gate–source voltage (<math>V_{gs}</math>) is increased, the drain–source current (<math>I_{ds}</math>) increases exponentially for Vgs below threshold, and then at a roughly quadratic rate (<math>I_{ds} \propto (V_{gs}-V_T)^2</math>) (where <math>V_T</math> is the threshold voltage at which drain current begins)[16] in the "space-charge-limited" region above threshold. A quadratic behavior is not observed in modern devices, for example, at the 65nm technology node.[17] To turn on a transistor it has to be charged like a capacitor. One polarity of charge is responsible for conduction, the other serves for charge neutrality. In the BJT, both types of charge carriers come close together and so the capacitance is high, therefore only low voltages are needed to produce a given amount of charge. In a FET both types of charges are separated by the dielectric and additionally the Debye length, thus reducing the capacity and increasing the voltage needed for switching. Above zero Kelvin, the exponential curve is convoluted with the hard turn on of the BJT and the parabolic turn on of the FET. For low noise at narrow bandwidth the higher input resistance of the FET is advantageous. FETs are divided into two families: junction FET (JFET) and insulated gate FET (IGFET). The IGFET is more commonly known as metal–oxide–semiconductor FET (MOSFET), from their original construction as a layer of metal (the gate), a layer of oxide (the insulation), and a layer of semiconductor. Unlike IGFETs, the JFET gate forms a PN diode with the channel which lies between the source and drain. Functionally, this makes the N-channel JFET the solid state equivalent of the vacuum tube triode which, similarly, forms a diode between its grid and cathode. Also, both devices operate in the depletion mode, they both have a high input impedance, and they both conduct current under the control of an input voltage. Metal–semiconductor FETs (MESFETs) are JFETs in which the reverse biased PN junction is replaced by a metal–semiconductor Schottky-junction. These, and the HEMTs (high electron mobility transistors, or HFETs), in which a two-dimensional electron gas with very high carrier mobility is used for charge transport, are especially suitable for use at very high frequencies (microwave frequencies; several GHz). Unlike bipolar transistors, FETs do not inherently amplify a photocurrent. Nevertheless, there are ways to use them, especially JFETs, as light-sensitive devices, by exploiting the photocurrents in channel–gate or channel–body junctions. FETs are further divided into depletion-mode and enhancement-mode types, depending on whether the channel is turned on or off with zero gate-to-source voltage. For enhancement mode, the channel is off at zero bias, and a gate potential can "enhance" the conduction. For depletion mode, the channel is on at zero bias, and a gate potential (of the opposite polarity) can "deplete" the channel, reducing conduction. For either mode, a more positive gate voltage corresponds to a higher current for N-channel devices and a lower current for P-channel devices. Nearly all JFETs are depletion-mode as the diode junctions would forward bias and conduct if they were enhancement mode devices; most IGFETs are enhancement-mode types. ## Other transistor types - Heterojunction bipolar transistor - Alloy junction transistor - Tetrode transistor - Pentode transistor - Spacistor - Surface barrier transistor - Micro alloy transistor - Micro alloy diffused transistor - Drift-field transistor - Unijunction transistors can be used as simple pulse generators. They comprise a main body of either P-type or N-type semiconductor with ohmic contacts at each end (terminals Base1 and Base2). A junction with the opposite semiconductor type is formed at a point along the length of the body for the third terminal (Emitter). - Dual gate FETs have a single channel with two gates in cascode; a configuration that is optimized for high frequency amplifiers, mixers, and oscillators. - Darlington transistors are two BJTs connected together to provide a high current gain equal to the product of the current gains of the two transistors. - Insulated gate bipolar transistors (IGBTs) use a medium power IGFET, similarly connected to a power BJT, to give a high input impedance. Power diodes are often connected between certain terminals depending on specific use. IGBTs are particularly suitable for heavy-duty industrial applications. The Asea Brown Boveri (ABB) 5SNA2400E170100 illustrates just how far power semiconductor technology has advanced. Intended for three-phase power supplies, this device houses three NPN IGBTs in a case measuring 38 by 140 by 190 mm and weighing 1.5 kg. Each IGBT is rated at 1,700 volts and can handle 2,400 amperes. - Single-electron transistors (SET) consist of a gate island between two tunnelling junctions. The tunnelling current is controlled by a voltage applied to the gate through a capacitor. [1][2] - Nanofluidic transistor Control the movement of ions through sub-microscopic, water-filled channels. Nanofluidic transistor, the basis of future chemical processors - Trigate transistors (Prototype by Intel) - Avalanche transistor - Ballistic transistor - Spin transistor Magnetically-sensitive - Thin film transistor Used in LCD display. - Floating-gate transistor Used for non-volatile storage. - Photo transistor React to light - Inverted-T field effect transistor - Ion sensitive field effect transistor To measure ion concentrations in solution. - FinFET The source/drain region forms fins on the silicon surface. - FREDFET Fast-Reverse Epitaxial Diode Field-Effect Transistor - EOSFET Electrolyte-Oxide-Semiconductor Field Effect Transistor (Neurochip) - OFET Organic Field-Effect Transistor, in which the semiconductor is an organic compound - DNAFET Deoxyribonucleic acid field-effect transistor # Semiconductor material The first BJTs were made from germanium (Ge) and some high power types still are. Silicon (Si) types currently predominate but certain advanced microwave and high performance versions now employ the compound semiconductor material gallium arsenide (GaAs) and the semiconductor alloy silicon germanium (SiGe). Single element semiconductor material (Ge and Si) is described as elemental. Rough parameters for the most common semiconductor materials used to make transistors are given in the table below; it must be noted that these parameters will vary with increase in temperature, electric field, impurity level, strain and various other factors: The junction forward voltage is the voltage applied to the emitter-base junction of a BJT in order to make the base conduct a specified current. The current increases exponentially as the junction forward voltage is increased. The values given in the table are typical for a current of 1 mA (the same values apply to semiconductor diodes). The lower the junction forward voltage the better, as this means that less power is required to "drive" the transistor. The junction forward voltage for a given current decreases with increase in temperature. For a typical silicon junction the change is approximately −2.1 mV/°C.[18] The density of mobile carriers in the channel of a MOSFET is a function of the electric field forming the channel and of various other phenomena such as the impurity level in the channel. Some impurities, called dopants, are introduced deliberately in making a MOSFET, to control the MOSFET electrical behavior. The electron mobility and hole mobility columns show the average speed that electrons and holes diffuse through the semiconductor material with an electric field of 1 volt per meter applied across the material. In general, the higher the electron mobility the faster the transistor. The table indicates that Ge is a better material than Si in this respect. However, Ge has four major shortcomings compared to silicon and gallium arsenide: - its maximum temperature is limited - it has relatively high leakage current - it cannot withstand high voltages - it is less suitable for fabricating integrated circuits Because the electron mobility is higher than the hole mobility for all semiconductor materials, a given bipolar NPN transistor tends to be faster than an equivalent PNP transistor type. GaAs has the highest electron mobility of the three semiconductors. It is for this reason that GaAs is used in high frequency applications. A relatively recent FET development, the high electron mobility transistor (HEMT), has a heterostructure (junction between different semiconductor materials) of aluminium gallium arsenide (AlGaAs)-gallium arsenide (GaAs) which has double the electron mobility of a GaAs-metal barrier junction. Because of their high speed and low noise, HEMTs are used in satellite receivers working at frequencies around 12 GHz. Max. junction temperature values represent a cross section taken from various manufacturers' data sheets. This temperature should not be exceeded or the transistor may be damaged. Al-Si junction refers to the high-speed (aluminum-silicon) semiconductor-metal barrier diode, commonly known as a Schottky diode. This is included in the table because some silicon power IGFETs have a parasitic reverse Schottky diode formed between the source and drain as part of the fabrication process. This diode can be a nuisance, but sometimes it is used in the circuit. # Packaging Transistors come in many different packages (chip carriers) (see images). The two main categories are through-hole (or leaded), and surface-mount, also known as surface mount device (SMD). The ball grid array (BGA) is the latest surface mount package (currently only for large transistor arrays). It has solder "balls" on the underside in place of leads. Because they are smaller and have shorter interconnections, SMDs have better high frequency characteristics but lower power rating. Transistor packages are made of glass, metal, ceramic or plastic. The package often dictates the power rating and frequency characteristics. Power transistors have large packages that can be clamped to heat sinks for enhanced cooling. Additionally, most power transistors have the collector or drain physically connected to the metal can/metal plate. At the other extreme, some surface-mount microwave transistors are as small as grains of sand. Often a given transistor type is available in different packages. Transistor packages are mainly standardized, but the assignment of a transistor's functions to the terminals is not: different transistor types can assign different functions to the package's terminals. Even for the same transistor type the terminal assignment can vary (normally indicated by a suffix letter to the part number- i.e. BC212L and BC212K). # Usage For a basic guide to the operation of transistors, see How a transistor works. In the early days of transistor circuit design, the bipolar junction transistor, or BJT, was the most commonly used transistor. Even after MOSFETs became available, the BJT remained the transistor of choice for digital and analog circuits because of their ease of manufacture and speed. However, desirable properties of MOSFETs, such as their utility in low-power devices, have made them the ubiquitous choice for use in digital circuits and a very common choice for use in analog circuits. ## Switches Transistors are commonly used as electronic switches, for both high power applications including switched-mode power supplies and low power applications such as logic gates. ## Amplifiers From mobile phones to televisions, vast numbers of products include amplifiers for sound reproduction, radio transmission, and signal processing. The first discrete transistor audio amplifiers barely supplied a few hundred milliwatts, but power and audio fidelity gradually increased as better transistors became available and amplifier architecture evolved. Transistors are commonly used in modern musical instrument amplifiers, in which circuits up to a few hundred watts are common and relatively cheap. Transistors have largely replaced valves (electron tubes) in instrument amplifiers. Some musical instrument amplifier manufacturers mix transistors and vacuum tubes in the same circuit, to utilize the inherent benefits of both devices. ## Computers The "first generation" of electronic computers used vacuum tubes, which generated large amounts of heat, were bulky, and were unreliable. The development of the transistor was key to computer miniaturization and reliability. The "second generation" of computers, through the late 1950s and 1960s featured boards filled with individual transistors and magnetic memory cores. Subsequently, transistors, other components, and their necessary wiring were integrated into a single, mass-manufactured component: the integrated circuit.	https://www.wikidoc.org/index.php/Transistor
0f87a61ff65e54d5b4425a5945d40c59cb90c105	wikidoc	Travoprost	Travoprost # 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 Travoprost is a prostaglandin analog that is FDA approved for the {{{indicationType}}} of open-angle glaucoma or ocular hypertension. Common adverse reactions include conjunctival hyperemia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - TRAVATAN Z® (travoprost ophthalmic solution) 0.004% is indicated for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension. - The recommended dosage is one drop in the affected eye(s) once daily in the evening. TRAVATAN Z® (travoprost ophthalmic solution) should not be administered more than once daily since it has been shown that more frequent administration of prostaglandin analogs may decrease the intraocular pressure lowering effect. - Reduction of the intraocular pressure starts approximately 2 hours after the first administration with maximum effect reached after 12 hours. - TRAVATAN Z® may be used concomitantly with other topical ophthalmic drug products to lower intraocular pressure. If more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes apart. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Travoprost in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Travoprost in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Travoprost in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Travoprost in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Travoprost in pediatric patients. # Contraindications - None # Warnings ### Precautions - Pigmentation - Travoprost ophthalmic solution has been reported to cause changes to pigmented tissues. The most frequently reported changes have been increased pigmentation of the iris, periorbital tissue (eyelid) and eyelashes. Pigmentation is expected to increase as long as travoprost is administered. The pigmentation change is due to increased melanin content in the melanocytes rather than to an increase in the number of melanocytes. After discontinuation of travoprost, pigmentation of the iris is likely to be permanent, while pigmentation of the periorbital tissue and eyelash changes have been reported to be reversible in some patients. Patients who receive treatment should be informed of the possibility of increased pigmentation. The long term effects of increased pigmentation are not known. - Iris color change may not be noticeable for several months to years. Typically, the brown pigmentation around the pupil spreads concentrically towards the periphery of the iris and the entire iris or parts of the iris become more brownish. Neither nevi nor freckles of the iris appear to be affected by treatment. While treatment with TRAVATAN Z® (travoprost ophthalmic solution) 0.004% can be continued in patients who develop noticeably increased iris pigmentation, these patients should be examined regularly. - Eyelash Changes - TRAVATAN Z® may gradually change eyelashes and vellus hair in the treated eye. These changes include increased length, thickness, and number of lashes. Eyelash changes are usually reversible upon discontinuation of treatment. - Intraocular Inflammation - TRAVATAN Z® should be used with caution in patients with active intraocular inflammation (e.g., uveitis) because the inflammation may be exacerbated. - Macular Edema - Macular edema, including cystoid macular edema, has been reported during treatment with travoprost ophthalmic solution. TRAVATAN Z® should be used with caution in aphakic patients, in pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors for macular edema. - Angle-closure, Inflammatory or Neovascular Glaucoma - TRAVATAN Z® has not been evaluated for the treatment of angle-closure, inflammatory or neovascular glaucoma. - Bacterial Keratitis - There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products. These containers had been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface. - Use with Contact Lenses - Contact lenses should be removed prior to instillation of TRAVATAN Z® and may be reinserted 15 minutes following its administration. # Adverse Reactions ## Clinical Trials 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 rates in the clinical studies of another drug and may not reflect the rates observed in practice. - The most common adverse reaction observed in controlled clinical studies with TRAVATAN® (travoprost ophthalmic solution) 0.004% and TRAVATAN Z® (travoprost ophthalmic solution) 0.004% was ocular hyperemia which was reported in 30 to 50% of patients. Up to 3% of patients discontinued therapy due to conjunctival hyperemia. Ocular adverse reactions reported at an incidence of 5 to 10% in these clinical studies included decreased visual acuity, eye discomfort, foreign body sensation, pain and pruritus. - Ocular adverse reactions reported at an incidence of 1 to 4% in clinical studies with TRAVATAN® or TRAVATAN Z® included abnormal vision, blepharitis, blurred vision, cataract, conjunctivitis, corneal staining, dry eye, iris discoloration, keratitis, lid margin crusting, ocular inflammation, photophobia, subconjunctival hemorrhage and tearing. - Nonocular adverse reactions reported at an incidence of 1 to 5% in these clinical studies were allergy, angina pectoris, anxiety, arthritis, back pain, bradycardia, bronchitis, chest pain, cold/flu syndrome, depression, dyspepsia, gastrointestinal disorder, headache, hypercholesterolemia, hypertension, hypotension, infection, pain, prostate disorder, sinusitis, urinary incontinence and urinary tract infections. ## Postmarketing Experience - In postmarketing use with prostaglandin analogs, periorbital and lid changes including deepening of the eyelid sulcus have been observed. # Drug Interactions There is limited information regarding Travoprost Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Teratogenic effects: Travoprost was teratogenic in rats, at an intravenous (IV) dose up to 10 mcg/kg/day (250 times the maximal recommended human ocular dose (MRHOD), evidenced by an increase in the incidence of skeletal malformations as well as external and visceral malformations, such as fused sternebrae, domed head and hydrocephaly. Travoprost was not teratogenic in rats at IV doses up to 3 mcg/kg/day (75 times the MRHOD), or in mice at subcutaneous doses up to 1 mcg/kg/day (25 times the MRHOD). Travoprost produced an increase in post-implantation losses and a decrease in fetal viability in rats at IV doses > 3 mcg/kg/day (75 times the MRHOD) and in mice at subcutaneous doses > 0.3 mcg/kg/day (7.5 times the MRHOD). - In the offspring of female rats that received travoprost subcutaneously from Day 7 of pregnancy to lactation Day 21 at doses of = 0.12 mcg/kg/day (3 times the MRHOD), the incidence of postnatal mortality was increased, and neonatal body weight gain was decreased. Neonatal development was also affected, evidenced by delayed eye opening, pinna detachment and preputial separation, and by decreased motor activity. - There are no adequate and well-controlled studies of TRAVATAN Z® (travoprost ophthalmic solution) 0.004% administration in pregnant women. Because animal reproductive studies are not always predictive of human response, TRAVATAN Z® should be administered 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 Travoprost in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Travoprost during labor and delivery. ### Nursing Mothers - A study in lactating rats demonstrated that radiolabeled travoprost and/or its metabolites were excreted in milk. It is not known whether this drug or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TRAVATAN Z® is administered to a nursing woman. ### Pediatric Use - Use in pediatric patients below the age of 16 years is not recommended because of potential safety concerns related to increased pigmentation following long-term chronic use. ### Geriatic Use - No overall clinical differences in safety or effectiveness have been observed between elderly and other adult patients. ### Gender There is no FDA guidance on the use of Travoprost with respect to specific gender populations. ### Race There is no FDA guidance on the use of Travoprost with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Travoprost in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Travoprost in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Travoprost in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Travoprost in patients who are immunocompromised. # Administration and Monitoring ### Administration - Topical ### Monitoring There is limited information regarding Monitoring of Travoprost in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Travoprost in the drug label. # Overdosage ## Chronic Overdose There is limited information regarding Chronic Overdose of Travoprost in the drug label. # Pharmacology ## Mechanism of Action - Travoprost free acid, a prostaglandin analog is a selective FP prostanoid receptor agonist which is believed to reduce intraocular pressure by increasing uveoscleral outflow. The exact mechanism of action is unknown at this time. ## Structure - Travoprost is a synthetic prostaglandin F analogue. Its chemical name is ]-7--1-butenyl]cyclopentyl]-5-heptenoic acid, 1-methylethylester. It has a molecular formula of C26H35F3O6 and a molecular weight of 500.55. The chemical structure of travoprost is: - Travoprost is a clear, colorless to slightly yellow oil that is very soluble in acetonitrile, methanol, octanol, and chloroform. It is practically insoluble in water. - TRAVATAN Z® (travoprost ophthalmic solution) 0.004% is supplied as sterile, buffered aqueous solution of travoprost with a pH of approximately 5.7 and an osmolality of approximately 290 mOsmol/kg. - TRAVATAN Z® contains Active: travoprost 0.04 mg/mL; Inactives: polyoxyl 40 hydrogenated castor oil, sofZia® (boric acid, propylene glycol, sorbitol, zinc chloride), sodium hydroxide and/or hydrochloric acid (to adjust pH) and purified water, USP. Preserved in the bottle with an ionic buffered system, sofZia®. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Travoprost in the drug label. ## Pharmacokinetics - Travoprost is absorbed through the cornea and is hydrolyzed to the active free acid. Data from four multiple dose pharmacokinetic studies (totaling 107 subjects) have shown that plasma concentrations of the free acid are below 0.01 ng/ml (the quantitation limit of the assay) in two-thirds of the subjects. In those individuals with quantifiable plasma concentrations (N=38), the mean plasma Cmax was 0.018 ± 0.007 ng/ml (ranged 0.01 to 0.052 ng/mL) and was reached within 30 minutes. From these studies, travoprost is estimated to have a plasma half-life of 45 minutes. There was no difference in plasma concentrations between Days 1 and 7, indicating steady-state was reached early and that there was no significant accumulation. - Travoprost, an isopropyl ester prodrug, is hydrolyzed by esterases in the cornea to its biologically active free acid. Systemically, travoprost free acid is metabolized to inactive metabolites via beta-oxidation of the α(carboxylic acid) chain to give the 1,2-dinor and 1,2,3,4-tetranor analogs, via oxidation of the 15-hydroxyl moiety, as well as via reduction of the 13,14 double bond. - The elimination of travoprost free acid from plasma was rapid and levels were generally below the limit of quantification within one hour after dosing. The terminal elimination half-life of travoprost free acid was estimated from fourteen subjects and ranged from 17 minutes to 86 minutes with the mean half-life of 45 minutes. Less than 2% of the topical ocular dose of travoprost was excreted in the urine within 4 hours as the travoprost free acid. ## Nonclinical Toxicology - Two-year carcinogenicity studies in mice and rats at subcutaneous doses of 10, 30, or 100 mcg/kg/day did not show any evidence of carcinogenic potential. However, at 100 mcg/kg/day, male rats were only treated for 82 weeks, and the maximum tolerated dose (MTD) was not reached in the mouse study. The high dose (100 mcg/kg) corresponds to exposure levels over 400 times the human exposure at the maximum recommended human ocular dose (MRHOD) of 0.04 mcg/kg, based on plasma active drug levels. - Travoprost was not mutagenic in the Ames test, mouse micronucleus test or rat chromosome aberration assay. A slight increase in the mutant frequency was observed in one of two mouse lymphoma assays in the presence of rat S-9 activation enzymes. - Travoprost did not affect mating or fertility indices in male or female rats at subcutaneous doses up to 10 mcg/kg/day . At 10 mcg/kg/day, the mean number of corpora lutea was reduced, and the post-implantation losses were increased. These effects were not observed at 3 mcg/kg/day (75 times the MRHOD). # Clinical Studies - In clinical studies, patients with open-angle glaucoma or ocular hypertension and baseline pressure of 25-27 mmHg who were treated with TRAVATAN® (travoprost ophthalmic solution) 0.004% or TRAVATAN Z® (travoprost ophthalmic solution) 0.004% dosed once-daily in the evening demonstrated 7-8 mmHg reductions in intraocular pressure. In subgroup analyses of these studies, mean IOP reduction in black patients was up to 1.8 mmHg greater than in non-black patients. It is not known at this time whether this difference is attributed to race or to heavily pigmented irides. - In a multi-center, randomized, controlled trial, patients with mean baseline intraocular pressure of 24-26 mmHg on TIMOPTIC- 0.5% BID who were treated with TRAVATAN® (travoprost ophthalmic solution) 0.004% dosed QD adjunctively to TIMOPTIC- 0.5% BID demonstrated 6-7 mmHg reductions in intraocular pressure. # How Supplied - TRAVATAN Z® (travoprost ophthalmic solution) 0.004% is a sterile, isotonic, buffered, preserved, aqueous solution of travoprost (0.04 mg/mL) supplied in Alcon's oval DROP-TAINER® package system. - TRAVATAN Z® is supplied as a 2.5 mL solution in a 4 mL and a 5 mL solution in a 7.5 mL natural polypropylene dispenser bottle with a natural polypropylene dropper tip and a turquoise polypropylene or high density polyethylene overcap. Tamper evidence is provided with a shrink band around the closure and neck area of the package. - 2.5 mL fill NDC 0065-0260-25 - 5 mL fill NDC 0065-0260-05 - Storage: Store at 2° - 25°C (36° - 77°F). ## Storage There is limited information regarding Travoprost Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Potential for Pigmentation - Patients should be advised about the potential for increased brown pigmentation of the iris, which may be permanent. Patients should also be informed about the possibility of eyelid skin darkening, which may be reversible after discontinuation of TRAVATAN Z® (travoprost ophthalmic solution) 0.004%. - Potential for Eyelash Changes - Patients should also be informed of the possibility of eyelash and vellus hair changes in the treated eye during treatment with TRAVATAN Z®. These changes may result in a disparity between eyes in length, thickness, pigmentation, number of eyelashes or vellus hairs, and/or direction of eyelash growth. Eyelash changes are usually reversible upon discontinuation of treatment. - Handling the Container - Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye, surrounding structures, fingers, or any other surface in order to avoid contamination of the solution by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions. - When to Seek Physician Advice - Patients should also be advised that if they develop an intercurrent ocular condition (e.g., trauma or infection), have ocular surgery, or develop any ocular reactions, particularly conjunctivitis and eyelid reactions, they should immediately seek their physician's advice concerning the continued use of TRAVATAN Z®. - Use with Contact Lenses - Contact lenses should be removed prior to instillation of TRAVATAN Z® and may be reinserted 15 minutes following its administration. - Use with Other Ophthalmic Drugs - If more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes between applications. # Precautions with Alcohol - Alcohol-Travoprost interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - TRAVATAN Z® # Look-Alike Drug Names There is limited information regarding Travoprost Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Travoprost 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 Travoprost is a prostaglandin analog that is FDA approved for the {{{indicationType}}} of open-angle glaucoma or ocular hypertension. Common adverse reactions include conjunctival hyperemia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - TRAVATAN Z® (travoprost ophthalmic solution) 0.004% is indicated for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension. - The recommended dosage is one drop in the affected eye(s) once daily in the evening. TRAVATAN Z® (travoprost ophthalmic solution) should not be administered more than once daily since it has been shown that more frequent administration of prostaglandin analogs may decrease the intraocular pressure lowering effect. - Reduction of the intraocular pressure starts approximately 2 hours after the first administration with maximum effect reached after 12 hours. - TRAVATAN Z® may be used concomitantly with other topical ophthalmic drug products to lower intraocular pressure. If more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes apart. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Travoprost in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Travoprost in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Travoprost in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Travoprost in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Travoprost in pediatric patients. # Contraindications - None # Warnings ### Precautions - Pigmentation - Travoprost ophthalmic solution has been reported to cause changes to pigmented tissues. The most frequently reported changes have been increased pigmentation of the iris, periorbital tissue (eyelid) and eyelashes. Pigmentation is expected to increase as long as travoprost is administered. The pigmentation change is due to increased melanin content in the melanocytes rather than to an increase in the number of melanocytes. After discontinuation of travoprost, pigmentation of the iris is likely to be permanent, while pigmentation of the periorbital tissue and eyelash changes have been reported to be reversible in some patients. Patients who receive treatment should be informed of the possibility of increased pigmentation. The long term effects of increased pigmentation are not known. - Iris color change may not be noticeable for several months to years. Typically, the brown pigmentation around the pupil spreads concentrically towards the periphery of the iris and the entire iris or parts of the iris become more brownish. Neither nevi nor freckles of the iris appear to be affected by treatment. While treatment with TRAVATAN Z® (travoprost ophthalmic solution) 0.004% can be continued in patients who develop noticeably increased iris pigmentation, these patients should be examined regularly. - Eyelash Changes - TRAVATAN Z® may gradually change eyelashes and vellus hair in the treated eye. These changes include increased length, thickness, and number of lashes. Eyelash changes are usually reversible upon discontinuation of treatment. - Intraocular Inflammation - TRAVATAN Z® should be used with caution in patients with active intraocular inflammation (e.g., uveitis) because the inflammation may be exacerbated. - Macular Edema - Macular edema, including cystoid macular edema, has been reported during treatment with travoprost ophthalmic solution. TRAVATAN Z® should be used with caution in aphakic patients, in pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors for macular edema. - Angle-closure, Inflammatory or Neovascular Glaucoma - TRAVATAN Z® has not been evaluated for the treatment of angle-closure, inflammatory or neovascular glaucoma. - Bacterial Keratitis - There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products. These containers had been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface. - Use with Contact Lenses - Contact lenses should be removed prior to instillation of TRAVATAN Z® and may be reinserted 15 minutes following its administration. # Adverse Reactions ## Clinical Trials 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 rates in the clinical studies of another drug and may not reflect the rates observed in practice. - The most common adverse reaction observed in controlled clinical studies with TRAVATAN® (travoprost ophthalmic solution) 0.004% and TRAVATAN Z® (travoprost ophthalmic solution) 0.004% was ocular hyperemia which was reported in 30 to 50% of patients. Up to 3% of patients discontinued therapy due to conjunctival hyperemia. Ocular adverse reactions reported at an incidence of 5 to 10% in these clinical studies included decreased visual acuity, eye discomfort, foreign body sensation, pain and pruritus. - Ocular adverse reactions reported at an incidence of 1 to 4% in clinical studies with TRAVATAN® or TRAVATAN Z® included abnormal vision, blepharitis, blurred vision, cataract, conjunctivitis, corneal staining, dry eye, iris discoloration, keratitis, lid margin crusting, ocular inflammation, photophobia, subconjunctival hemorrhage and tearing. - Nonocular adverse reactions reported at an incidence of 1 to 5% in these clinical studies were allergy, angina pectoris, anxiety, arthritis, back pain, bradycardia, bronchitis, chest pain, cold/flu syndrome, depression, dyspepsia, gastrointestinal disorder, headache, hypercholesterolemia, hypertension, hypotension, infection, pain, prostate disorder, sinusitis, urinary incontinence and urinary tract infections. ## Postmarketing Experience - In postmarketing use with prostaglandin analogs, periorbital and lid changes including deepening of the eyelid sulcus have been observed. # Drug Interactions There is limited information regarding Travoprost Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Teratogenic effects: Travoprost was teratogenic in rats, at an intravenous (IV) dose up to 10 mcg/kg/day (250 times the maximal recommended human ocular dose (MRHOD), evidenced by an increase in the incidence of skeletal malformations as well as external and visceral malformations, such as fused sternebrae, domed head and hydrocephaly. Travoprost was not teratogenic in rats at IV doses up to 3 mcg/kg/day (75 times the MRHOD), or in mice at subcutaneous doses up to 1 mcg/kg/day (25 times the MRHOD). Travoprost produced an increase in post-implantation losses and a decrease in fetal viability in rats at IV doses > 3 mcg/kg/day (75 times the MRHOD) and in mice at subcutaneous doses > 0.3 mcg/kg/day (7.5 times the MRHOD). - In the offspring of female rats that received travoprost subcutaneously from Day 7 of pregnancy to lactation Day 21 at doses of = 0.12 mcg/kg/day (3 times the MRHOD), the incidence of postnatal mortality was increased, and neonatal body weight gain was decreased. Neonatal development was also affected, evidenced by delayed eye opening, pinna detachment and preputial separation, and by decreased motor activity. - There are no adequate and well-controlled studies of TRAVATAN Z® (travoprost ophthalmic solution) 0.004% administration in pregnant women. Because animal reproductive studies are not always predictive of human response, TRAVATAN Z® should be administered 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 Travoprost in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Travoprost during labor and delivery. ### Nursing Mothers - A study in lactating rats demonstrated that radiolabeled travoprost and/or its metabolites were excreted in milk. It is not known whether this drug or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TRAVATAN Z® is administered to a nursing woman. ### Pediatric Use - Use in pediatric patients below the age of 16 years is not recommended because of potential safety concerns related to increased pigmentation following long-term chronic use. ### Geriatic Use - No overall clinical differences in safety or effectiveness have been observed between elderly and other adult patients. ### Gender There is no FDA guidance on the use of Travoprost with respect to specific gender populations. ### Race There is no FDA guidance on the use of Travoprost with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Travoprost in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Travoprost in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Travoprost in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Travoprost in patients who are immunocompromised. # Administration and Monitoring ### Administration - Topical ### Monitoring There is limited information regarding Monitoring of Travoprost in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Travoprost in the drug label. # Overdosage ## Chronic Overdose There is limited information regarding Chronic Overdose of Travoprost in the drug label. # Pharmacology ## Mechanism of Action - Travoprost free acid, a prostaglandin analog is a selective FP prostanoid receptor agonist which is believed to reduce intraocular pressure by increasing uveoscleral outflow. The exact mechanism of action is unknown at this time. ## Structure - Travoprost is a synthetic prostaglandin F analogue. Its chemical name is [1R-[1α(Z),2β(1E,3R),3α,5α]]-7-[3,5-Dihydroxy-2-[3-hydroxy-4-[3-(trifluoromethyl) phenoxy]-1-butenyl]cyclopentyl]-5-heptenoic acid, 1-methylethylester. It has a molecular formula of C26H35F3O6 and a molecular weight of 500.55. The chemical structure of travoprost is: - Travoprost is a clear, colorless to slightly yellow oil that is very soluble in acetonitrile, methanol, octanol, and chloroform. It is practically insoluble in water. - TRAVATAN Z® (travoprost ophthalmic solution) 0.004% is supplied as sterile, buffered aqueous solution of travoprost with a pH of approximately 5.7 and an osmolality of approximately 290 mOsmol/kg. - TRAVATAN Z® contains Active: travoprost 0.04 mg/mL; Inactives: polyoxyl 40 hydrogenated castor oil, sofZia® (boric acid, propylene glycol, sorbitol, zinc chloride), sodium hydroxide and/or hydrochloric acid (to adjust pH) and purified water, USP. Preserved in the bottle with an ionic buffered system, sofZia®. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Travoprost in the drug label. ## Pharmacokinetics - Travoprost is absorbed through the cornea and is hydrolyzed to the active free acid. Data from four multiple dose pharmacokinetic studies (totaling 107 subjects) have shown that plasma concentrations of the free acid are below 0.01 ng/ml (the quantitation limit of the assay) in two-thirds of the subjects. In those individuals with quantifiable plasma concentrations (N=38), the mean plasma Cmax was 0.018 ± 0.007 ng/ml (ranged 0.01 to 0.052 ng/mL) and was reached within 30 minutes. From these studies, travoprost is estimated to have a plasma half-life of 45 minutes. There was no difference in plasma concentrations between Days 1 and 7, indicating steady-state was reached early and that there was no significant accumulation. - Travoprost, an isopropyl ester prodrug, is hydrolyzed by esterases in the cornea to its biologically active free acid. Systemically, travoprost free acid is metabolized to inactive metabolites via beta-oxidation of the α(carboxylic acid) chain to give the 1,2-dinor and 1,2,3,4-tetranor analogs, via oxidation of the 15-hydroxyl moiety, as well as via reduction of the 13,14 double bond. - The elimination of travoprost free acid from plasma was rapid and levels were generally below the limit of quantification within one hour after dosing. The terminal elimination half-life of travoprost free acid was estimated from fourteen subjects and ranged from 17 minutes to 86 minutes with the mean half-life of 45 minutes. Less than 2% of the topical ocular dose of travoprost was excreted in the urine within 4 hours as the travoprost free acid. ## Nonclinical Toxicology - Two-year carcinogenicity studies in mice and rats at subcutaneous doses of 10, 30, or 100 mcg/kg/day did not show any evidence of carcinogenic potential. However, at 100 mcg/kg/day, male rats were only treated for 82 weeks, and the maximum tolerated dose (MTD) was not reached in the mouse study. The high dose (100 mcg/kg) corresponds to exposure levels over 400 times the human exposure at the maximum recommended human ocular dose (MRHOD) of 0.04 mcg/kg, based on plasma active drug levels. - Travoprost was not mutagenic in the Ames test, mouse micronucleus test or rat chromosome aberration assay. A slight increase in the mutant frequency was observed in one of two mouse lymphoma assays in the presence of rat S-9 activation enzymes. - Travoprost did not affect mating or fertility indices in male or female rats at subcutaneous doses up to 10 mcg/kg/day [250 times the maximum recommended human ocular dose of 0.04 mcg/kg/day on a mcg/kg basis (MRHOD)]. At 10 mcg/kg/day, the mean number of corpora lutea was reduced, and the post-implantation losses were increased. These effects were not observed at 3 mcg/kg/day (75 times the MRHOD). # Clinical Studies - In clinical studies, patients with open-angle glaucoma or ocular hypertension and baseline pressure of 25-27 mmHg who were treated with TRAVATAN® (travoprost ophthalmic solution) 0.004% or TRAVATAN Z® (travoprost ophthalmic solution) 0.004% dosed once-daily in the evening demonstrated 7-8 mmHg reductions in intraocular pressure. In subgroup analyses of these studies, mean IOP reduction in black patients was up to 1.8 mmHg greater than in non-black patients. It is not known at this time whether this difference is attributed to race or to heavily pigmented irides. - In a multi-center, randomized, controlled trial, patients with mean baseline intraocular pressure of 24-26 mmHg on TIMOPTIC 0.5% BID who were treated with TRAVATAN® (travoprost ophthalmic solution) 0.004% dosed QD adjunctively to TIMOPTIC* 0.5% BID demonstrated 6-7 mmHg reductions in intraocular pressure. # How Supplied - TRAVATAN Z® (travoprost ophthalmic solution) 0.004% is a sterile, isotonic, buffered, preserved, aqueous solution of travoprost (0.04 mg/mL) supplied in Alcon's oval DROP-TAINER® package system. - TRAVATAN Z® is supplied as a 2.5 mL solution in a 4 mL and a 5 mL solution in a 7.5 mL natural polypropylene dispenser bottle with a natural polypropylene dropper tip and a turquoise polypropylene or high density polyethylene overcap. Tamper evidence is provided with a shrink band around the closure and neck area of the package. - 2.5 mL fill NDC 0065-0260-25 - 5 mL fill NDC 0065-0260-05 - Storage: Store at 2° - 25°C (36° - 77°F). ## Storage There is limited information regarding Travoprost Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Potential for Pigmentation - Patients should be advised about the potential for increased brown pigmentation of the iris, which may be permanent. Patients should also be informed about the possibility of eyelid skin darkening, which may be reversible after discontinuation of TRAVATAN Z® (travoprost ophthalmic solution) 0.004%. - Potential for Eyelash Changes - Patients should also be informed of the possibility of eyelash and vellus hair changes in the treated eye during treatment with TRAVATAN Z®. These changes may result in a disparity between eyes in length, thickness, pigmentation, number of eyelashes or vellus hairs, and/or direction of eyelash growth. Eyelash changes are usually reversible upon discontinuation of treatment. - Handling the Container - Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye, surrounding structures, fingers, or any other surface in order to avoid contamination of the solution by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions. - When to Seek Physician Advice - Patients should also be advised that if they develop an intercurrent ocular condition (e.g., trauma or infection), have ocular surgery, or develop any ocular reactions, particularly conjunctivitis and eyelid reactions, they should immediately seek their physician's advice concerning the continued use of TRAVATAN Z®. - Use with Contact Lenses - Contact lenses should be removed prior to instillation of TRAVATAN Z® and may be reinserted 15 minutes following its administration. - Use with Other Ophthalmic Drugs - If more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes between applications. # Precautions with Alcohol - Alcohol-Travoprost interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - TRAVATAN Z®[1] # Look-Alike Drug Names There is limited information regarding Travoprost Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Travoprost
2c51f73fe4c55f3e501ab4aff1c6aa107f0d505f	wikidoc	Trenbolone	Trenbolone Trenbolone is a steroid used by veterinarians on livestock to increase muscle growth and appetite. To increase its effective half-life, trenbolone is not used in an unrefined form, but is rather administered as trenbolone acetate (Finaplix Gold from Valopharm USA, TREMBLONA QV75 from Quality Vet, Mexico), Trenbolone enanthate or Trenbolone cyclohexylmethylcarbonate (Parabolan from Laboratoires NEGMA until 1997). Plasma lipases then remove the ester in the bloodstream leaving the trenbolone base. # Illicit Use No trenbolone compounds have been approved by the FDA for human use, due to a lack of clinical applications and some potential negative side-effects. It is classified as a Schedule III drug under the Controlled Substances Act. However, bodybuilders have been known to use the drug illicitly in order to increase body mass more effectively than by weight training alone. A normal bodybuilding dosage can range from 200 mg/week up to 1400 mg/week. Due to the relatively short metabolic half-life of trenbolone acetate, dosages should commonly be split into injections at least once every two days. Trenbolone enanthate can be injected once a week. The 2006 book Game of Shadows alleges that baseball superstar Barry Bonds used this drug in 2001, when he set the current single-season home run record. Trenbolone acetate is often referred to as "Fina" by illicit users, because injectible trenbolone acetate is often prepared from Finaplix H pellets, an ear-implant used by cattle ranchers to maintain the weight of cattle during shipping to slaughter. Trenbolone compounds have a binding affinity for the androgen receptor three times as high as that of testosterone. Once metabolised, the drugs have the effect of increasing nitrogen uptake by muscles, leading to an increase in the rate of protein synthesis. It also has the secondary effects of stimulating appetite, reducing the amount of fat being deposited in the body, and decreasing the rate of catabolism. Trenbolone has proven popular with anabolic steroid users as it is not metabolised by aromatase or 5α-reductase into estrogenic compounds such as estradiol, or into DHT. This means that it also does not cause any water retention normally associated with highly androgenic steroidal compounds like testosterone or methandrostenolone. It is also loved by many for the dramatic strength increases commonly experienced with it. Short-term side effects include insomnia, high blood pressure, increased aggression, night sweats, and libido. However, since women will suffer virilization effects even at small doses, this drug should not be taken by a female. Urban wisdom/myth in bodybuilding culture, states that the use of the drug over extended periods of time can lead to kidney damage. The kidney toxicity has not yet been proven, and scientific evidence supporting the idea is suspiciously absent from the bodybuilding community that perpetuates this idea. The origin of this myth most likely has to do with the rust colored oxidized metabolites of trenbolone which are excreted in urine and often mistaken for blood. After Schänzer (Clin Chem 1996; 42(7): 1001-1020, Metabolism of anabolic androgenic steroids) trenbolone and 17epi-trenbolone are both excreted (in urine) as conjugates that can be hydrolyzed with beta-glucuronidase. This implies that trenbolone leaves the body as beta-glucuronides or sulfates, that means mostly non metabolized.	Trenbolone Trenbolone is a steroid used by veterinarians on livestock to increase muscle growth and appetite. To increase its effective half-life, trenbolone is not used in an unrefined form, but is rather administered as trenbolone acetate (Finaplix Gold from Valopharm USA, TREMBLONA QV75 from Quality Vet, Mexico), Trenbolone enanthate or Trenbolone cyclohexylmethylcarbonate (Parabolan from Laboratoires NEGMA until 1997). Plasma lipases then remove the ester in the bloodstream leaving the trenbolone base. # Illicit Use No trenbolone compounds have been approved by the FDA for human use,[1] due to a lack of clinical applications and some potential negative side-effects.[2] It is classified as a Schedule III drug under the Controlled Substances Act. However, bodybuilders have been known to use the drug illicitly in order to increase body mass more effectively than by weight training alone. A normal bodybuilding dosage can range from 200 mg/week up to 1400 mg/week. Due to the relatively short metabolic half-life of trenbolone acetate, dosages should commonly be split into injections at least once every two days. Trenbolone enanthate can be injected once a week. The 2006 book Game of Shadows alleges that baseball superstar Barry Bonds used this drug in 2001, when he set the current single-season home run record. Trenbolone acetate is often referred to as "Fina" by illicit users, because injectible trenbolone acetate is often prepared from Finaplix H pellets, an ear-implant used by cattle ranchers to maintain the weight of cattle during shipping to slaughter. Trenbolone compounds have a binding affinity for the androgen receptor three times as high as that of testosterone.[citation needed] Once metabolised, the drugs have the effect of increasing nitrogen uptake by muscles, leading to an increase in the rate of protein synthesis. It also has the secondary effects of stimulating appetite, reducing the amount of fat being deposited in the body, and decreasing the rate of catabolism. Trenbolone has proven popular with anabolic steroid users as it is not metabolised by aromatase or 5α-reductase into estrogenic compounds such as estradiol, or into DHT. This means that it also does not cause any water retention normally associated with highly androgenic steroidal compounds like testosterone or methandrostenolone. It is also loved by many for the dramatic strength increases commonly experienced with it. Short-term side effects include insomnia, high blood pressure, increased aggression, night sweats, and libido. However, since women will suffer virilization effects even at small doses, this drug should not be taken by a female. Urban wisdom/myth in bodybuilding culture, states that the use of the drug over extended periods of time can lead to kidney damage. The kidney toxicity has not yet been proven, and scientific evidence supporting the idea is suspiciously absent from the bodybuilding community that perpetuates this idea. The origin of this myth most likely has to do with the rust colored oxidized metabolites of trenbolone which are excreted in urine and often mistaken for blood. After Schänzer (Clin Chem 1996; 42(7): 1001-1020, Metabolism of anabolic androgenic steroids) trenbolone and 17epi-trenbolone are both excreted (in urine) as conjugates that can be hydrolyzed with beta-glucuronidase. This implies that trenbolone leaves the body as beta-glucuronides or sulfates, that means mostly non metabolized.	https://www.wikidoc.org/index.php/Trenbolone
0a09fb9bc1f874937f285d55e1c77bb0b16d6479	wikidoc	Trestolone	Trestolone Trestolone (7α-methyl-19-nortestosterone) is a synthetic androgen developed by the Population Council as a potential candidate drug for use in hormonal male contraceptive methods. In males, regular administration of sufficient quantities of trestolone induces a state of temporary infertility. Trestolone, under the brand name MENT, is an experimental contraceptive treatment and is not yet available commercially. It is currently being evaluated for safety and effectiveness in a number of scientific studies. # Mechanism of action As a derivative of the anabolic steroid hormone nandrolone, trestolone's viability as a male contraceptive is twofold. ## Inhibition of sperm production Spermatozoa are produced in the testes of males in a process called spermatogenesis. In order to render a man infertile, a hormone-based male contraceptive method must stop spermatogenesis by interrupting the release of gonadotropins from the pituitary gland. Even in low concetrations, trestolone is a potent inhibitor of the release of the gonadotropin hormones, luteinizing hormone (LH) and follicle stimulating hormone (FSH). In order for spermatogenesis to occur in the testes, both FSH and the male hormone testosterone must be present. By inhibiting release of FSH, trestolone creates an endocrine environment in which conditions for spermatogenesis are not ideal. Manufacture of sperm is further impaired by the suppression of LH, which in turn drastically cutails the production of testosterone. Sufficient regular doses of trestolone cause severe oligozoospermia or azoospermia, and therefore infertility, in most male patients. Trestolone-induced sterility has been found to be quickly reversible upon discontinuation. ## Support of secondary sex characteristics When LH release is inhibited, the amount of testosterone made in the testes declines dramatically. As a result of trestolone's gonadotropin-suppressing qualities, levels of serum testosterone fall sharply in patients. Testosterone is the primary hormone responsible for maintenance of male secondary sex characteristics. Normally, inadequate testosterone levels cause undesirable effects, such as fatigue, loss of skeletal muscle mass, reduced libido, and weight gain. However, the androgenic and anabolic properties of trestolone largely ameliorate this problem. Essentially, trestolone replaces testosterone's role as the primary male hormone in the body.	Trestolone Trestolone (7α-methyl-19-nortestosterone) is a synthetic androgen developed by the Population Council as a potential candidate drug for use in hormonal male contraceptive methods. In males, regular administration of sufficient quantities of trestolone induces a state of temporary infertility. Trestolone, under the brand name MENT, is an experimental contraceptive treatment and is not yet available commercially. It is currently being evaluated for safety and effectiveness in a number of scientific studies. # Mechanism of action As a derivative of the anabolic steroid hormone nandrolone, trestolone's viability as a male contraceptive is twofold. ## Inhibition of sperm production Spermatozoa are produced in the testes of males in a process called spermatogenesis. In order to render a man infertile, a hormone-based male contraceptive method must stop spermatogenesis by interrupting the release of gonadotropins from the pituitary gland. Even in low concetrations, trestolone is a potent inhibitor of the release of the gonadotropin hormones, luteinizing hormone (LH) and follicle stimulating hormone (FSH).[citation needed] In order for spermatogenesis to occur in the testes, both FSH and the male hormone testosterone must be present. By inhibiting release of FSH, trestolone creates an endocrine environment in which conditions for spermatogenesis are not ideal. Manufacture of sperm is further impaired by the suppression of LH, which in turn drastically cutails the production of testosterone. Sufficient regular doses of trestolone cause severe oligozoospermia or azoospermia, and therefore infertility, in most male patients.[citation needed] Trestolone-induced sterility has been found to be quickly reversible upon discontinuation.[citation needed] ## Support of secondary sex characteristics When LH release is inhibited, the amount of testosterone made in the testes declines dramatically. As a result of trestolone's gonadotropin-suppressing qualities, levels of serum testosterone fall sharply in patients. Testosterone is the primary hormone responsible for maintenance of male secondary sex characteristics. Normally, inadequate testosterone levels cause undesirable effects, such as fatigue, loss of skeletal muscle mass, reduced libido, and weight gain. However, the androgenic and anabolic properties of trestolone largely ameliorate this problem. Essentially, trestolone replaces testosterone's role as the primary male hormone in the body. # External links - MENT – project information from the Population Council	https://www.wikidoc.org/index.php/Trestolone
012a2905cebae261fb2cb7922824e94cefa399b6	wikidoc	Triage tag	Triage tag # Overview Triage Tags is a tool first responders and medical personnel use during a mass casuality incident i.e., triage. With the aide of the triage tags, the first-arriving personnel are able to effectively and efficiently distribute the limited resources and provide the necessary immediate care for the victims until more help arrives. The concept behind triage tags was first introduced by Baron Dominique Jean Larrey, a French surgeon in Napoleon’s army. Simple Triage and Rapid Treatment (START) is a strategy that the first responders and medical personnel employ to evaluate the severity of injury of each victim as quickly as possible and tag the victims in about 30-60 seconds. The triage tags are placed near the head and are used to better separate the victims so that when more help arrives, the patients are easily recognizable for the extra help to ascertain the most dire cases. # Design A triage tag is two-sided, but the actual layout of the sections vary between states and between governmental agencies. It is common nowadays to use triage tags to allow first responders to have a better handle of the victims during a triage. There is not a universal agreement in the design of a triage tag, so each state has implemented their own version to meet their needs. ## Dynamic Triage Tag Another popular Triage Tag is the Smart Tag with its unique folded design means that effective triage is quick and simple, but most importantly it allows casualties to be re-triaged without having to replace the tag. It has been adopted as the standard triage tag for New York, Connecticut, Philadelphia, Boston and Nevada. ## Standard Sections Of A Triage Tag The basic sections of a triage tag include: - The four colors of triage and they come in the form of: Black (Deceased) which entails no care needed Red (Immediate) which entails life threatening injuries Yellow (Delayed) which entails non-life threatening injuries Green: (Minor) which entails minor injuries - Black (Deceased) which entails no care needed - Red (Immediate) which entails life threatening injuries - Yellow (Delayed) which entails non-life threatening injuries - Green: (Minor) which entails minor injuries - A section informing medical personnel of the patient’s vital signs along with the treatment administered. - A section on the patient’s demographics i.e., gender, residential address, etc. and the patient’s medical history. - A section with a full pictorial view of the human body. The medical personnel indicates which parts of the body are injured. ## Categories There are three basic categories of a triage tag (from top-to-bottom): - tear off sections to label the victim properly in terms of severity of injury and to inform other medical personnel, that may arrive later, of the victim’s status. - main body for the first responders to fill out during their assessment of the patient. This portion will stay with the patient. - peel off stickers to keep a record of what transportation or treatment was provided to the victim. ## Benefits A benefit in using the triage tag, besides the fact of improving traffic flow and increasing distributed care among injured patients is during the collection of data. The fill-in slots on the triage tags do not need to be filled out all at once. Information can be obtained and added onto the triage tag throughout the triage. There are cases which a patient’s medical condition changes while still in triage, medical personnel would just tag the patient again with the updated information and label the tags sequentially. The other option is to use a tag which can be altered and where the priority can go up or down. This eliminates the need to re-tag the patient. ## Examples of Types - The military uses the MT-137 design while Maryland and New Jersey use their customized version. - The(METTAG Medical Emergency Triage Tags) was developed in the early 1970s and is widely used among the U.S. military, federal, state, and local agencies, and others. - Another example of a triage tags is the dynamic folding tag from TSG Associates based in the UK Smart Tag. This was adopted by the State of NY in 2004, the British Military in 2002, used by London Ambulance Service in the terrorist bombings of 2005 and used by the combined forces Afganistan in 2006. An older style dynamic card is the "Cruciform", used in parts of the UK including some of the North Sea oil industry and used by the Royal London Hospital during the London bombings in 2005. - New York, Philadelphia, Boston and Nevada have chosen the Smart Tag with its folded design means that effective triage is quick and simple. - The States of Connecticut and Massachusetts also mandated the Smart Tag for state wide use. - Maryland has a more detailed customized design of a triage tag - New Jersey also has a more detailed customized design - Community Emergency Response Teams carry color-coded flagging tape for triage use. # Related Chapters - Emergency Medical Technician - First responders - Health Insurance Portability and Accountability Act (HIPAA) - MSEHPA - Client confidentiality	Triage tag Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Triage Tags is a tool first responders and medical personnel use during a mass casuality incident i.e., triage. With the aide of the triage tags, the first-arriving personnel are able to effectively and efficiently distribute the limited resources and provide the necessary immediate care for the victims until more help arrives. The concept behind triage tags was first introduced by Baron Dominique Jean Larrey, a French surgeon in Napoleon’s army. Simple Triage and Rapid Treatment (START) is a strategy that the first responders and medical personnel employ to evaluate the severity of injury of each victim as quickly as possible and tag the victims in about 30-60 seconds. The triage tags are placed near the head and are used to better separate the victims so that when more help arrives, the patients are easily recognizable for the extra help to ascertain the most dire cases. # Design A triage tag is two-sided, but the actual layout of the sections vary between states and between governmental agencies. It is common nowadays to use triage tags to allow first responders to have a better handle of the victims during a triage. There is not a universal agreement in the design of a triage tag, so each state has implemented their own version to meet their needs. ## Dynamic Triage Tag Another popular Triage Tag is the Smart Tag with its unique folded design means that effective triage is quick and simple, but most importantly it allows casualties to be re-triaged without having to replace the tag. It has been adopted as the standard triage tag for New York, Connecticut, Philadelphia, Boston and Nevada. ## Standard Sections Of A Triage Tag The basic sections of a triage tag include: - The four colors of triage and they come in the form of: Black (Deceased) which entails no care needed Red (Immediate) which entails life threatening injuries Yellow (Delayed) which entails non-life threatening injuries Green: (Minor) which entails minor injuries - Black (Deceased) which entails no care needed - Red (Immediate) which entails life threatening injuries - Yellow (Delayed) which entails non-life threatening injuries - Green: (Minor) which entails minor injuries - A section informing medical personnel of the patient’s vital signs along with the treatment administered. - A section on the patient’s demographics i.e., gender, residential address, etc. and the patient’s medical history. - A section with a full pictorial view of the human body. The medical personnel indicates which parts of the body are injured. ## Categories There are three basic categories of a triage tag (from top-to-bottom): - tear off sections to label the victim properly in terms of severity of injury and to inform other medical personnel, that may arrive later, of the victim’s status. - main body for the first responders to fill out during their assessment of the patient. This portion will stay with the patient. - peel off stickers to keep a record of what transportation or treatment was provided to the victim. ## Benefits A benefit in using the triage tag, besides the fact of improving traffic flow and increasing distributed care among injured patients is during the collection of data. The fill-in slots on the triage tags do not need to be filled out all at once. Information can be obtained and added onto the triage tag throughout the triage. There are cases which a patient’s medical condition changes while still in triage, medical personnel would just tag the patient again with the updated information and label the tags sequentially. The other option is to use a tag which can be altered and where the priority can go up or down. This eliminates the need to re-tag the patient. ## Examples of Types - The military uses the MT-137 design while Maryland and New Jersey use their customized version. - The(METTAG Medical Emergency Triage Tags) was developed in the early 1970s and is widely used among the U.S. military, federal, state, and local agencies, and others. - Another example of a triage tags is the dynamic folding tag from TSG Associates based in the UK Smart Tag. This was adopted by the State of NY in 2004, the British Military in 2002, used by London Ambulance Service in the terrorist bombings of 2005 and used by the combined forces Afganistan in 2006. An older style dynamic card is the "Cruciform", used in parts of the UK including some of the North Sea oil industry and used by the Royal London Hospital during the London bombings in 2005. - New York, Philadelphia, Boston and Nevada have chosen the Smart Tag with its folded design means that effective triage is quick and simple. - The States of Connecticut and Massachusetts also mandated the Smart Tag for state wide use. - Maryland has a more detailed customized design of a triage tag - New Jersey also has a more detailed customized design - Community Emergency Response Teams carry color-coded flagging tape for triage use. # Related Chapters - Emergency Medical Technician - First responders - Health Insurance Portability and Accountability Act (HIPAA) - MSEHPA - Client confidentiality # External Links - http://www.tsgassociates.co.uk/English/Civilian/products/smart_tag.htm - http://www.state.nj.us/health/ems/documents/njdisastertag.pdf - http://www.miemss.umaryland.edu/MDTriage.pdf	https://www.wikidoc.org/index.php/Triage_tag
8af5a99ead9fad3fd2fb3b105c5493cd19e5ce19	wikidoc	Trichiasis	Trichiasis # Overview Trichiasis is a medical term for ingrown eyelashes. This can be caused by infection, inflammation, autoimmune conditions, and trauma such as burns or eyelid injury. Standard treatment involves destruction of the affected eyelashes with electrology, specialized laser, or surgery. Trichiasis in dogs is hair from the eyelid growing in the wrong direction and rubbing on the eye, causing irritation. It usually occurs at the lateral upper eyelid, especially in the English Cocker Spaniel. Trichiasis also refers to hair from a nasal fold rubbing on the eye. This type of trichiasis can be flattened by rubbing petroleum jelly onto it, but surgery is sometimes necessary for permanent correction.	Trichiasis # Overview Trichiasis is a medical term for ingrown eyelashes. This can be caused by infection, inflammation, autoimmune conditions, and trauma such as burns or eyelid injury. Standard treatment involves destruction of the affected eyelashes with electrology, specialized laser, or surgery. Trichiasis in dogs is hair from the eyelid growing in the wrong direction and rubbing on the eye, causing irritation. It usually occurs at the lateral upper eyelid, especially in the English Cocker Spaniel.[1] Trichiasis also refers to hair from a nasal fold rubbing on the eye. This type of trichiasis can be flattened by rubbing petroleum jelly onto it, but surgery is sometimes necessary for permanent correction.	https://www.wikidoc.org/index.php/Trichiasis
25fcc22ee7e53184ed1c62c17e1501d8c46f0c18	wikidoc	Trifectant	Trifectant Trifectant is a brand name for a powerful, multi-purpose disinfectant. The solution is used in many areas, including hospitals, laboratories, nursing homes, funeral homes, medical, dental and veterinary facilities, and anywhere else where control of pathogens is required. It is typically used for cleaning up hazardous spills, disinfecting surfaces, disinfecting fabrics, and soaking equipment. Trifectant has a remarkable spectrum of activity against viruses, fungi, spores and bacteria, including mycobacteria such as tuberculosis. It is also effective against SARS and Avian influenza. However, for full effectiveness it must be sprayed liberally on a surface and allowed to sit for at least two minutes before being wiped off, or items must be soaked in it for at least two minutes. # Ingredients Trifectant's ingredients are: - potassium peroxymonosulfate (21.5%) — disinfecting/cleansing agent - sulphamic acid — disinfecting/cleansing agent - malic acid — disinfecting/cleansing agent - sodium dodecyl benzene sulphonate — detergent - sodium chloride (1.5%) — disinfecting/cleansing agent - sodium hexametaphosphate — buffering agent - Amaranth dye — an indicator colour - Lemon extract — odorant The disinfecting agents and detergents work synergistically to attack pathogens. # Preparation and use It is most often sold as yellow tablets or powder which dissolve readily in water. It is intended to be mixed with water to form a 1% to 3% solution (by weight, i.e. 10g to 30g per litre). The yellow colour is useful in that in helps gauge the concentration when preparing the Trifectant, and importantly, as the Trifectant ages it discolours, making it obvious when it needs to be replaced. The prepared solution is generally stable for five to seven days. Trifectant has a faint lemon odor, but the scent is still considered unpleasant by some. It is relatively safe in terms of skin contact, but can cause eye damage and should not be used as a hand-washing liquid. When ordered in bulk, Trifectant costs about 35 US cents per litre to produce, which is comparable to most bleaches. Nevertheless, some facilities prefer to produce their own alternative disinfectants to save costs. Trifectant is a registered trademark of Antec International, a subsidiary of DuPont.	Trifectant Trifectant is a brand name for a powerful, multi-purpose disinfectant. The solution is used in many areas, including hospitals, laboratories, nursing homes, funeral homes, medical, dental and veterinary facilities, and anywhere else where control of pathogens is required. It is typically used for cleaning up hazardous spills, disinfecting surfaces, disinfecting fabrics, and soaking equipment. [1] Trifectant has a remarkable spectrum of activity against viruses, fungi, spores and bacteria, including mycobacteria such as tuberculosis. It is also effective against SARS[2] and Avian influenza. However, for full effectiveness it must be sprayed liberally on a surface and allowed to sit for at least two minutes before being wiped off, or items must be soaked in it for at least two minutes. # Ingredients Trifectant's ingredients are: - potassium peroxymonosulfate (21.5%) — disinfecting/cleansing agent - sulphamic acid — disinfecting/cleansing agent - malic acid — disinfecting/cleansing agent - sodium dodecyl benzene sulphonate — detergent - sodium chloride (1.5%) — disinfecting/cleansing agent - sodium hexametaphosphate — buffering agent - Amaranth dye — an indicator colour - Lemon extract — odorant The disinfecting agents and detergents work synergistically to attack pathogens. # Preparation and use It is most often sold as yellow tablets or powder which dissolve readily in water. It is intended to be mixed with water to form a 1% to 3% solution (by weight, i.e. 10g to 30g per litre). The yellow colour is useful in that in helps gauge the concentration when preparing the Trifectant, and importantly, as the Trifectant ages it discolours, making it obvious when it needs to be replaced. The prepared solution is generally stable for five to seven days. Trifectant has a faint lemon odor, but the scent is still considered unpleasant by some. It is relatively safe in terms of skin contact, but can cause eye damage and should not be used as a hand-washing liquid. When ordered in bulk, Trifectant costs about 35 US cents per litre to produce, which is comparable to most bleaches. Nevertheless, some facilities prefer to produce their own alternative disinfectants to save costs. Trifectant is a registered trademark of Antec International, a subsidiary of DuPont.	https://www.wikidoc.org/index.php/Trifectant
f75284253b555450daf633f6b19088dc05cd7fe1	wikidoc	Trigonitis	Trigonitis Steven C. Campbell, M.D., Ph.D. # Overview Trigonitis is a condition where inflammatory lesions form on the trigone region of the bladder. It is more common in women. The cause of trigonitis is not yet known, and there is no solid treatment as of yet. Electrocautery is sometimes used, but is generally unreliable as a treatment, and typically does not have quick results. Several drugs, such as muscle relaxants, antibiotics, antiseptics such as Urised, have varied and unreliable results. Other forms of treatment include; - urethrotomy, - cryosurgery - neurostimulation	Trigonitis Template:Search infobox Steven C. Campbell, M.D., Ph.D. # Overview Trigonitis is a condition where inflammatory lesions form on the trigone region of the bladder. It is more common in women. The cause of trigonitis is not yet known, and there is no solid treatment as of yet. Electrocautery is sometimes used, but is generally unreliable as a treatment, and typically does not have quick results. Several drugs, such as muscle relaxants, antibiotics, antiseptics such as Urised, have varied and unreliable results. Other forms of treatment include; - urethrotomy, - cryosurgery - neurostimulation # External links Medscape Link Template:Nephrology Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Trigonitis
fa7d7a57a80ffef68a6a835a65d6975bd41cc505	wikidoc	Trilostane	Trilostane # Overview Trilostane is an inhibitor of 3 β-hydroxysteroid dehydrogenase used in the treatment of Cushing's syndrome. It was withdrawn from human use in the United States market in April 1994. The drug is available in the United Kingdom for use in humans under the brand name Modrenal and is used for treatment of Cushing's disease and for breast cancer treatment. It was approved in the United States in 2008 for the treatment of Cushing's disease (hyperadrenocorticism) in dogs under the brand name Vetoryl. It was available by prescription in the UK under the Vetoryl brand name for some time before it was approved in the US. The drug is also used to treat the skin disorder Alopecia X in dogs. It is also the first drug approved to treat both pituitary- and adrenal-dependent Cushing's in dogs. This prescription drug works by stopping the production of cortisol in the adrenal glands. In studies of the drug, the most common side effects were vomiting, lack of energy, diarrhea, and weight loss. Trilostane should not be given to a dog that: - has kidney or liver disease; - takes certain medications used to treat heart disease; - is pregnant, nursing or intended for breeding The safety and effectiveness of trilostane were shown in several studies. Success was measured by improvements in both blood test results and physical symptoms (increased appetite and activity level, and decreased panting, thirst and urination). Only one other drug, Anipryl (veterinary brand name) selegiline, is FDA-approved to treat Cushing's disease in dogs, but only to treat uncomplicated, pituitary-dependent Cushing's. The only previous treatment for the disease was the use of Mitotane (brand name Lysodren) off-label. It has been used as a progesterone inhibitor. A number of compounding pharmacies in the US sell the product. Since the US approval of Vetoryl in December 2008, compounding pharmacies are no longer able to use a bulk drug product for compounding purposes, but must prepare the compounded drug from Vetoryl. It is a 3β-hydroxysteroid dehydrogenase inhibitor. # Chemistry The compound is prepared from testosterone in a four-step synthesis.	Trilostane Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Trilostane is an inhibitor of 3 β-hydroxysteroid dehydrogenase used in the treatment of Cushing's syndrome.[1][2] It was withdrawn from human use in the United States market in April 1994.[3][4] The drug is available in the United Kingdom for use in humans under the brand name Modrenal and is used for treatment of Cushing's disease and for breast cancer treatment.[5][6][7] It was approved in the United States in 2008 for the treatment of Cushing's disease (hyperadrenocorticism) in dogs under the brand name Vetoryl.[8] It was available by prescription in the UK under the Vetoryl brand name for some time before it was approved in the US.[9] The drug is also used to treat the skin disorder Alopecia X in dogs.[3][10][11] It is also the first drug approved to treat both pituitary- and adrenal-dependent Cushing's in dogs. This prescription drug works by stopping the production of cortisol in the adrenal glands.[12][13] In studies of the drug, the most common side effects were vomiting, lack of energy, diarrhea, and weight loss. Trilostane should not be given to a dog that: - has kidney or liver disease;[9][14] - takes certain medications used to treat heart disease;[citation needed] - is pregnant, nursing or intended for breeding [9][14] The safety and effectiveness of trilostane were shown in several studies. Success was measured by improvements in both blood test results and physical symptoms (increased appetite and activity level, and decreased panting, thirst and urination).[7][15] Only one other drug, Anipryl (veterinary brand name) selegiline, is FDA-approved to treat Cushing's disease in dogs, but only to treat uncomplicated, pituitary-dependent Cushing's.[16] The only previous treatment for the disease was the use of Mitotane (brand name Lysodren) off-label.[15][17] It has been used as a progesterone inhibitor.[18] A number of compounding pharmacies in the US sell the product. Since the US approval of Vetoryl in December 2008,[8] compounding pharmacies are no longer able to use a bulk drug product for compounding purposes, but must prepare the compounded drug from Vetoryl.[19] It is a 3β-hydroxysteroid dehydrogenase inhibitor.[20] # Chemistry The compound is prepared from testosterone in a four-step synthesis.	https://www.wikidoc.org/index.php/Trilostane
69831f802ade39ce273713d0e06ff800595ea632	wikidoc	Trisomy 22	Trisomy 22 # Overview Trisomy 22 is a chromosomal disorder in which there are three copies of chromosome 22 rather than two. It is a frequent cause of spontaneous abortion during the first trimester of pregnancy. Progression to the second trimester and livebirth are rare. This disorder is found in individuals with an extra copy or a variation of chromosome 22 in some or all cells of their body. There are many kinds of disorders associated with Trisomy 22: Emanuel Syndrome is named after the genetic contributions made by researcher Dr. Beverly Emanuel. This condition is assigned to individuals born with an unbalanced 11/22 translocation. That is, when a fragment of chromosome 11 is moved, or translocated to chromosome 22. 22q11 Deletion Syndrome is a rare condition which occurs in approximately 1 in 4000 births. This condition is identified when a band in the q11.2 section of the arm of chromosome 22 is missing or deleted. This condition has several different names, The 22q11.2 Deletion Syndrome, Velocardiofacial syndrome, DiGeorge Syndrome, Conotruncal Anomaly Face syndrome, Opitz G/BBB Syndrome, Cayler Cardiofacial Syndrome.The effects of this disorder are different in each individual but similarities exist such as heart defects, immune system problems, a distinctive facial appearance, learning challenges, cleft palate, hearing loss, kidney problems, hypocalcemia, and sometimes psychiatric issues. 22q11 microduplication syndrome is the opposite of the 22q11 deletion syndrome, in this condition, a band of q.11.2 section of chromosome 22 is duplicated. Individuals carrying this deficiency are relatively “normal” as in they don’t possess any major birth defects or major medical illnesses. This microduplication is more common than the deletion; this might be due to the milder phenotype of the individuals. Phelan-McDermid Syndrome / 22q13 Deletion Syndrome is a condition caused by the deletion of the tip of the q arm on chromosome 22. Most individuals with this disorder experience cognitive delays as well as low muscle tone and sleeping, eating and behavioural issues. Chromosome Ring 22 is a rare disorder caused by the break and re-join of both ends of chromosome 22, forming a ring. The effects on the individual with this disorder are dependent on the amount of genetic information lost during the break/re-join. Major characteristics for this disorder are mental retardation, muscle weakness and lack of coordination. Cat Eye Syndrome / Schmid Fraccaro Syndrome is a condition caused by a partial trisomy or tetrasomy in chromosome 22. A small extra chromosome is found, made up of the top half of chromosome 22 and a portion of the q arm at the q11.2 break. This chromosome can be found three or four times. This syndrome is referred as “Cat Eye” due to the eye appearance of reported affected individuals who have coloboma of the iris; however, this feature is only seen in about half of the cases. Mosaic trisomy 22 is a disorder in which an extra chromosome 22 is found only in some cells of the body. The severity of each case is determined by the number of cells with this extra copy. Some characteristics of individuals with this condition are cardiac abnormalities, growth retardation, mental delay, etc.. Complete Trisomy 22 is in contrast with Mosaic trisomy 22; this disorder is characterized by an extra copy of chromosome 22 which is found in each cell of the body of the affected individual. These cases are very rare, and most of the affected individuals die before birth or shortly after.	Trisomy 22 Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Trisomy 22 is a chromosomal disorder in which there are three copies of chromosome 22 rather than two. It is a frequent cause of spontaneous abortion during the first trimester of pregnancy. Progression to the second trimester and livebirth are rare. This disorder is found in individuals with an extra copy or a variation of chromosome 22 in some or all cells of their body. There are many kinds of disorders associated with Trisomy 22: Emanuel Syndrome [1] is named after the genetic contributions made by researcher Dr. Beverly Emanuel. This condition is assigned to individuals born with an unbalanced 11/22 translocation. That is, when a fragment of chromosome 11 is moved, or translocated to chromosome 22. 22q11 Deletion Syndrome [2] is a rare condition which occurs in approximately 1 in 4000 births. This condition is identified when a band in the q11.2 section of the arm of chromosome 22 is missing or deleted. This condition has several different names, The 22q11.2 Deletion Syndrome, Velocardiofacial syndrome, DiGeorge Syndrome, Conotruncal Anomaly Face syndrome, Opitz G/BBB Syndrome, Cayler Cardiofacial Syndrome.The effects of this disorder are different in each individual but similarities exist such as heart defects, immune system problems, a distinctive facial appearance, learning challenges, cleft palate, hearing loss, kidney problems, hypocalcemia, and sometimes psychiatric issues. 22q11 microduplication syndrome[3] is the opposite of the 22q11 deletion syndrome, in this condition, a band of q.11.2 section of chromosome 22 is duplicated. Individuals carrying this deficiency are relatively “normal” as in they don’t possess any major birth defects or major medical illnesses. This microduplication is more common than the deletion; this might be due to the milder phenotype of the individuals. Phelan-McDermid Syndrome / 22q13 Deletion Syndrome[4] is a condition caused by the deletion of the tip of the q arm on chromosome 22. Most individuals with this disorder experience cognitive delays as well as low muscle tone and sleeping, eating and behavioural issues. Chromosome Ring 22[5] is a rare disorder caused by the break and re-join of both ends of chromosome 22, forming a ring. The effects on the individual with this disorder are dependent on the amount of genetic information lost during the break/re-join. Major characteristics for this disorder are mental retardation, muscle weakness and lack of coordination. Cat Eye Syndrome / Schmid Fraccaro Syndrome[6] is a condition caused by a partial trisomy or tetrasomy in chromosome 22. A small extra chromosome is found, made up of the top half of chromosome 22 and a portion of the q arm at the q11.2 break. This chromosome can be found three or four times. This syndrome is referred as “Cat Eye” due to the eye appearance of reported affected individuals who have coloboma of the iris; however, this feature is only seen in about half of the cases. Mosaic trisomy 22[7] is a disorder in which an extra chromosome 22 is found only in some cells of the body. The severity of each case is determined by the number of cells with this extra copy. Some characteristics of individuals with this condition are cardiac abnormalities, growth retardation, mental delay, etc.. Complete Trisomy 22[8] is in contrast with Mosaic trisomy 22; this disorder is characterized by an extra copy of chromosome 22 which is found in each cell of the body of the affected individual. These cases are very rare, and most of the affected individuals die before birth or shortly after.	https://www.wikidoc.org/index.php/Trisomy_22
b028f649572c9fe6d7c91a17f82130fbe4350869	wikidoc	Tsetse fly	Tsetse fly Tsetse (pronounced /ts/e-/ts/e, teet-SEE, or set-see) are large biting flies from Africa which live by feeding on the blood of vertebrate animals. Tsetse include all the species in the genus Glossina, which are generally placed in their own family, Glossinidae. Tsetse have been extensively studied because they are biological vectors of the African trypanosomiases, deadly diseases which include sleeping sickness in people and nagana in cattle. Tsetse are crudely similar to other large flies, such as the housefly, but can be distinguished by four characteristics of their anatomy, two of which are easy to observe. Tsetse fold their wings completely when they are resting so that one wing rests directly on top of the other over their abdomen. Tsetse also have a long proboscis which extends directly forward and is attached by a distinct bulb to the bottom of their head. Tsetse have existed in the modern morphological form for at least 34 million years since fossil tsetse have been recovered from the Florissant Fossil Beds in Colorado. # Biology The biology of tsetse is relatively well understood. Tsetse have been extensively studied because of their medical, veterinary, and economic importance, because the flies can be raised in a laboratory, and because the flies are relatively large, facilitating their analysis. Entomologists have discovered a great deal about tsetse morphology, anatomy, development, and metabolism. ## Morphology Tsetse can be seen as independent individuals in two forms: as third instar larva, as adults. Tsetse first become separate from their mothers during the third larval instar, during which they have the typical appearance of maggots. However, this life stage is short, lasting at most a few hours, and is almost never observed outside of the laboratory. Tsetse next become puparia—small, hard shelled, oblongs with two distinctive, small, dark lobes at one end. Tsetse puparia are under 1.0 cm long. Within the puparial shell, tsetse complete the last two larval instars and the pupal stage. Tsetse then emerge as adult flies. Tsetse adults are relatively large flies, with lengths of ½–1½ cm , and have a recognizable shape or bauplan so they can usually be distinguished without trouble from other flies. Tsetse have large heads, distinctly separated eyes, and unusual antennae. The tsetse thorax is quite large, while the abdomen is wide rather than elongated and shorter than the wings. Four characteristics definitively separate adult tsetse from other kinds of flies: ## Anatomy Like all other insects, tsetse flies have an adult body comprising three visibly distinct parts: the head, the thorax and the abdomen. The head has large eyes, distinctly separated on each side, and a distinct, forward-pointing proboscis attached underneath by a large bulb. The thorax is large, made of three fused segments. Three pairs of legs are attached to the thorax, as are two wings and two halteres. The abdomen is short but wide and changes dramatically in volume during feeding. The internal anatomy of tsetse is fairly typical of the insects. The crop is large enough to accommodate a huge increase in size during the bloodmeal since tsetse can take a bloodmeal weighing as much as themselves. The reproductive tract of adult females includes a uterus which can become large enough to hold the third instar larva at the end of each pregnancy. Most tsetse flies are physically very tough indeed. Houseflies are easily killed with a fly-swatter but it takes a great deal of effort to crush a tsetse fly. ## Life cycle Tsetse have an unusual life cycle which may be due to the richness of their food source. Female tsetse only fertilize one egg at a time and retain each egg within their uterus to have the offspring develop internally during the first larval stages, a strategy called adenotrophic viviparity. During this time, the female feeds the developing offspring with a milky substance which is secreted by a modified gland in the uterus. In the third larval stage, the tsetse larva finally leave the uterus and begin their independent life. However, the newly independent tsetse larva simply crawls into the ground, forms a hard outer shell called the puparial case in which it completes its morphological transformation into an adult fly. This lifestage has a variable duration, generally twenty to thirty days, and the larva must rely on stored resources during this time. The importance of the richness of blood to this development can be seen since all tsetse development prior to the emergence from the puparial case as a full adult occurs without feeding based only on nutritional resources provided by the female parent. The female must obtain enough energy for her needs, for the needs of her developing offspring, and to store the resources which her offspring will require until it emerges as an adult. Technically these insects undergo the standard development process of insects which comprises oocyte formation, ovulation and fertilization, development of the egg, five larval stages, a pupal stage, and the emergence and maturation of the adult. ## Metabolism Tsetse metabolism consists of ingesting vertebrate blood, which is called hematophagy, and digesting this blood to obtain energy and biomass. Tsetse have specialized cells that contain cells of Wigglesworthia glossinidia brevipalpis, the bacterial endosymbionts that it requires for survival. An unusual aspect of tsetse metabolism is the particular pathway which tsetse use for flight which seems to be responsible for the extremely high energy output and elevated flying speeds which tsetse can achieve. Most insects, such as honey bees, consume sugar predominantly for metabolic energy. Tsetse, instead, use a pathway which involves the conversion of the amino acids proline and alanine. The result of this pathway is that tsetse can create large amounts of ATP but can only sustain this metabolic output for short durations. Tsetse therefore fly at very high speeds (they are known to be able to follow a car moving at thirty miles an hour) but can only sustain their flight for short durations of around thirty seconds. ## General biology Tsetse has three distinct symbionts. The primary symbiont is Wigglesworthia within bacteriocyte, the secondary symbiont is Sodalis intercellularly or intracellularly, and the third is some kind of Wolbachia. The tsetse Glossina palpalis is also a vector and host of Hepatozoon petti, a parasitic Sporozoa of the nile crocodile. # Systematics Tsetse include up to thirty four species and sub-species depending on the particular classification used. Tsetse are sufficiently different in appearance and behavior to have been placed in their own distinct branch of the flies. This placement is controversial. The science of systematics is currently struggling to reconcile the traditional form of biological classification with the modern understanding of genomic evolution and speciation. The controversy surrounding the placement of tsetse is therefore likely to continue into the future. All current classifications place all the tsetse species in a single genus named Glossina. Most classifications place this genus as the sole member of the family Glossinidae. The Glossinidae are generally placed within the superfamily Hippoboscoidea, which contains other hematophagous families. This superfamily is in the subsection Calyptratae which includes the housefly and the blowfly due to the similarity of their developmental biology. This infraorder in turn, is part of the sub-order Brachycera, the stubby flies with reduced antenna. ## Species The tsetse genus is generally split into three different groups of species based on a combination of distributional, behavioral, and morphological characteristics. The genus includes : # Trypanosomiasis Tsetse are biological vectors of trypanosomes meaning that tsetse, in the process of feeding, acquire and then transmit small, single-celled organisms called trypanosomes from infected vertebrate hosts to uninfected animals. Some tsetse transmitted trypanosome species cause trypanosomiasis, an infectious disease. In humans, tsetse transmitted trypanosomiasis is called sleeping sickness. In animals, tsetse vectored trypanosomiases include nagana, souma, and surra according to the animal infected and the trypanosome species involved, although the usage is not strict and nagana is occasionally used for any form of animal trypanosomiasis. Trypanosomes are animal parasites, specifically protozoa of the genus Trypanosoma. These organisms are approximately the size of red blood cells. Different species of trypanosomes infect different hosts as can be seen in the table attached to this section. Trypanosomes range widely in their effects on the vertebrate hosts. Some species, such as Trypanosoma theileri, do not seem to cause any health problems except perhaps in animals which are already quite sick . Some strains are much more virulent. Tsetse seem to be unaffected by the infection of trypanosomes but it is entirely possible that the parasites alter tsetse behavior or have other effects which improve the chances of transmission and survival. These trypanosomes have become highly evolved and developed a life cycle which requires periods in both the vertebrate and tsetse hosts. Tsetse transmit trypanosomes in two ways, mechanical and biological transmission. - Mechanical transmission involves the direct transmission of the same individual trypanosomes taken from an infected host into an uninfected host. The name mechanical reflects the similarity of this mode of transmission to the transmission which could be caused mechanically with a syringe. Mechanical transmission requires that tsetse feed on an infected host and acquire trypanosomes in the bloodmeal, and then, within in a relatively short period, for tsetse to feed on an uninfected host and regurgitate some of the infected blood from the first bloodmeal into the tissue of the uninfected animal. This type of transmission occurs most frequently when tsetse are interrupted during a bloodmeal and attempt to satiate themselves with another meal. Other flies, such as horse-flies, also can cause mechanical transmission of trypanosomes . - Biological transmission requires a period of incubation of the trypanosomes within the tsetse host. The term biological is used because trypanosomes must reproduce through several generations inside the tsetse host during the period of incubation, which requires extreme adaptation of the trypanosomes to their tsetse host. In this mode of transmission, trypanosomes reproduce through several generations, changing in morphology at certain periods. This mode of transmission also includes the sexual phase of the trypanosomes. Tsetse are believed to be more likely to become infected by trypanosomes during their first few bloodmeals. Tsetse infected by trypanosomes are thought to remain infected for the remainder of their lives. Because of the adaptations required for biological transmission, trypanosomes which are transmitted biologically by tsetse cannot be transmitted in this manner by other insects. The relative importance of these two modes of transmission for the propagation of tsetse-vectored trypanosomiases is not yet well understood. However, since the sexual phase of the trypanosome lifecycle occurs within the tsetse host, biological transmission is a required step in the life cycle of the tsetse vectored trypanosomes. The cycle of biological transmission of trypanosomiasis involves two phases, one inside the tsetse host and the other inside the vertebrate host. Trypanosomes are not passed between a pregnant tsetse and her offspring so all newly emerged tsetse adults are free of infection. An uninfected fly which feeds upon an infected vertebrate animal may acquire trypanosomes in its proboscis or gut. These trypanosomes, depending on the species, may remain in place, move to a different part of the digestive tract, or migrate through the tsetse body into the salivary glands. When an infected tsetse bites a susceptible host, the fly may regurgitate part of a previous bloodmeal which contains trypanosomes or may inject trypanosomes contained within its saliva. It is believed that the inoculation must contain a minimum of 300 to 450 individual trypanosomes to be successful, and may contain up to 40,000 individuals . The trypanosomes are injected into vertebrate muscle tissue but make their way, first into the lymphatic system, then into the bloodstream, and eventually into the brain. The disease causes the swelling of the lymph glands, emaciation of the body, and eventually leads to death. Uninfected tsetse may bite the infected animal prior to its death and acquire the disease, thereby closing the transmission cycle. The tsetse vectored trypanosomiases affect various vertebrate species including humans, antelopes, bovine cattle, camels, horses, sheep, goats, and pigs. These diseases are caused by several different trypanosome species which may also survive in wild animals such as crocodiles and monitor lizards. The diseases have different distributions across the African continent and are therefore transmitted by different species of tsetse. The following table summarizes this information : ## Human trypanosomiasis Human African trypanosomiasis, also called sleeping sickness, is caused by trypanosomes of the Trypanosoma brucei species. This disease is invariably fatal unless treated but can almost always be cured with current medicines, if the disease is diagnosed early enough. Sleeping sickness begins with a tsetse bite leading to an inoculation in the sub-cutaneous tissue. The infection moves into the lymphatic system leading to a characteristic swelling of the lymph glands which is called Winterbottoms's sign. The infection progresses into the blood stream and eventually crosses into the central nervous system and invades the brain leading to extreme lethargy and eventually to death. The Trypanosoma brucei species, which causes the disease, has often been subdivided into three sub-genera which were identified based either on the vertebrate hosts which the strain could infect or on the virulence of the disease in humans. The trypanosomes infectious to animals and not to humans were named Trypanosoma brucei brucei. The strains which infected humans were divided into two sub-species based on their different virulences: Trypanosoma brucei gambiense was thought to have a slower onset and Trypanosoma brucei rhodesiense refers to strains with a more rapid, virulent onset. This characterization has always been problematic but was the best that could be done given the knowledge of the time and the tools available for identification. A recent molecular study using restriction fragment length polymorphism analysis suggests that the three sub-genera are polyphyletic , so the elucidation of the strains of T. brucei infective to humans will require a more complex explanation. Other forms of human trypanosomiasis also exist but are not transmitted by tsetse. The most notable is American trypanosomiasis, known as Chagas disease, which occurs in South America, caused by Trypanosoma cruzi, and transmitted by certain species of the Reduviidae, members of the Hemiptera. ## Animal trypanosomiasis Animal trypanosomiasis, also called nagana when it occurs in bovine cattle or horses or sura when it occurs in domestic pigs, is caused by several trypanosome species. These diseases reduce the growth rate, milk productivity, and strength of farm animals, generally leading to the eventually death of the infected animals. Certain species of cattle are called trypanotolerant because they can survive and grow even when infected with trypanosomes although they also have lower productivity rates when infected. The course of the disease in animals is similar to the course of sleeping sickness in humans. Trypanosoma congolense and Trypanosoma vivax are the two most important species infecting bovine cattle in sub-saharan Africa. Trypanosoma simiae causes a virulent disease in swine. Other forms of animal trypanosomiasis are also known from other areas of the globe, caused by different species of trypanosomes and transmitted without the intervention of the tsetse fly. Tsetse vector ranges mostly in the central part of Africa. # Control Tsetse control has been undertaken in order to reduce the incidence of the diseases which the flies transmit. Two alternative strategies have been used in the attempts to reduce the African trypanosomiases. One tactic is primarily medical or veterinary and targets the disease directly using monitoring, prophylaxis, treatment, and surveillance to reduce the number of organisms which carry the disease. The second strategy is generally entomological and intends to disrupt the cycle of transmission by reducing the number of flies. The idea of tsetse control implies a change in the relationship between people and these insects. Prior to the twentieth century, people in Africa had largely adapted to the presence of tsetse. Human settlement patterns and agricultural practices had adapted to the presence of the fly. For example, in Ethiopia draft powered farming was restricted to the highland areas where the flies were absent whereas lowland areas where tsetse are present were more sparsely populated by people living a nomadic, less agriculturally intensive lifestyle. Tsetse control is a response to changing conditions. Tsetse control has been proposed as a way of reducing the incidence of the disease in the populations living in tsetse regions, of allowing the expansion of human settlement and agriculture into new areas, and of helping people previously relocated either in forced transfers or due to migration. Tsetse control efforts have been undertaken throughout the African continent but long-term, sustainable control has rarely been achieved. Tsetse control efforts invariably are tied to the complex problems of poverty, heath, politics, and violence which have proved such a disaster for the African people. The reduction of fly numbers has generally been attempted with two different aims, either eradication which intends to completely eliminate tsetse from the area or control which aims simply to reduce the numbers. Eradication is an idea which has often been imagined, has repeatedly been attempted, and is still proposed but many reasons suggest that control is a safer, cheaper, more realistic, and sustainable approach. Eradication refers to the successful killing of every tsetse either in a region or, under more grandiose proposals, from the entire African continent. Local eradication efforts have repeatedly been undertaken and have achieved temporary success only to fail in the long term because tsetse were able to re-invade (Zanzibar). All of the economic, ecological, political, and environmental justifications for eradication have been called into question. The economic justification for eradication offsets the immense costs of the eradication campaign against the medical and veterinary benefits which are considered to accrue in perpetuity. However, eradication campaigns may have unintended social consequences, as a successful campaign may open up lands for agriculture which have previously been populated by nomadic hunters, resulting in the displacement of the original population with its attendant consequences. ## Control techniques Many techniques have been used to reduce tsetse populations with earlier crude methods being replaced in more recent times by methods which are cheaper, more directed, and ecologically better considered. ### Slaughter of wild animals One early technique involved the slaughter of all the wild animals on which tsetse fed. For example, the island of Principé off the west coast of Africa, was entirely cleared of feral pigs in the 1930s which led to the extirpation of the fly. While the fly eventually re-invaded in the 1950s, the new population of tsetse was free from the disease. ### Land clearing Another early technique involved the complete removal of any brush or woody vegetation from an area. Tsetse tend to rest on the trunks of trees so the removal of woody vegetation made the area inhospitable to the flies. However, the technique has not been widely used and has been abandoned in more recent times. Preventing the regrowth of woody vegetation requires continuous clearing efforts which is only practicable where large human populations are present. The clearing of woody vegetation has come to be seen as an environmental problem more than a benefit. ### Pesticide campaigns Pesticides have been used to control tsetse starting initially during the early part of the twentieth century in localized efforts using the inorganic metal based pesticides, expanding after the Second World war into massive aerial and ground based campaigns using the early organic pesticides such as DDT, and continuing with the targeted use of pour-ons in which advanced organic pesticides are applied directly to the backs of cattle. ### Trapping Tsetse populations can be monitored and effectively controlled using simple, inexpensive traps. These often use electric blue cloth, since this colour attracts the flies. Early traps mimicked the form of cattle but this seems unnecessary and recent traps are simple sheets or have a biconical form. The traps can kill by channeling the flies into a collection chamber or by exposing the flies to insecticide sprayed on the cloth. The use of chemicals as attractants to lure tsetse to the traps has been studied extensively in the late 20th century, but this has mostly been of interest to scientists rather than as an economically reasonable solution. The attractants studied have been those which might be used by tsetse to find their food, like carbon dioxide and acetone, which are given off in the animals' breath and distributed downwind to form an 'odour plume'. Synthetic versions of these chemicals can be used to create artificial odour plumes. A cheaper approach is to place some cattle urine in a half gourd near the trap. For large trapping efforts, the use of additional traps is generally cheaper than the use of expensive artificial attractants. A special trapping method is applied in Ethiopia, where the BioFarm Consortium (ICIPE, BioVision Foundation, BEA, Helvetas, DLCO-EA, Praxis Ethiopia) applies the traps in a sustainable agriculture and rural development context (SARD). The traps are just the entry point, followed by improved farming, human health and marketing inputs. This method is in the final stage of testing (as per 2006). ### Releases of irradiated males The sterile insect technique has been used to reduce tsetse populations. This technique involves the rearing of large numbers of tsetse, separation of the males, irradiation of these flies with large doses of gamma rays to make them sterile and then release into to the wild. Since females only mate a few times in their life, generally only once, any mating with a sterile male will prevent that female from giving birth to any offspring. The Sterile Insect Technique has recently been used on Zanzibar, an island off the coast of East Africa. Like other eradication efforts, early indications are that the fly numbers have been decimated with the fly possibly extirpated (locally eradicated) from the island. A number of traps are in place to monitor the island and repress any resurgence. Additionally, using the parasite refractory strains is another method to control the tsetse, that means providing the blood meal containing the trypanocide before releasing the sterilised males. Also we can consider to use the cytoplasmic incompatibility (CI) strategy to control the population of tsetse. With the development of genetic engineering, the releasing of engineered parasite refractory counterparts is another strategy to control the population of tsetse. # Etymology The word 'tsetse' comes from Tswana, a language of southern Africa, and, in that language, the word means fly. Recently 'tsetse' without the 'fly' has become more common in English, particularly in the scientific and development communities. The pronunuciation of the word differs in different regions. Many African languages have an ejective ts sound and so a common pronunciation of the word involves two identical syllables both having this ts sound and a shorter sound of the vowel, as ts-eh-ts-eh. The British pronunciation of the word uses two different sounds for the two different syllables, generally tee-tsee. In Zimbabwe, it is generally pronounced tseh-tsee.	Tsetse fly Tsetse (pronounced /ts/e-/ts/e, teet-SEE, or set-see) are large biting flies from Africa which live by feeding on the blood of vertebrate animals. Tsetse include all the species in the genus Glossina, which are generally placed in their own family, Glossinidae. Tsetse have been extensively studied because they are biological vectors of the African trypanosomiases, deadly diseases which include sleeping sickness in people and nagana in cattle. Tsetse are crudely similar to other large flies, such as the housefly, but can be distinguished by four characteristics of their anatomy, two of which are easy to observe. Tsetse fold their wings completely when they are resting so that one wing rests directly on top of the other over their abdomen. Tsetse also have a long proboscis which extends directly forward and is attached by a distinct bulb to the bottom of their head. Tsetse have existed in the modern morphological form for at least 34 million years since fossil tsetse have been recovered from the Florissant Fossil Beds in Colorado[1]. # Biology The biology of tsetse is relatively well understood. Tsetse have been extensively studied because of their medical, veterinary, and economic importance, because the flies can be raised in a laboratory, and because the flies are relatively large, facilitating their analysis. Entomologists have discovered a great deal about tsetse morphology, anatomy, development, and metabolism. ## Morphology Tsetse can be seen as independent individuals in two forms: as third instar larva, as adults. Tsetse first become separate from their mothers during the third larval instar, during which they have the typical appearance of maggots. However, this life stage is short, lasting at most a few hours, and is almost never observed outside of the laboratory. Tsetse next become puparia—small, hard shelled, oblongs with two distinctive, small, dark lobes at one end. Tsetse puparia are under 1.0 cm long[2]. Within the puparial shell, tsetse complete the last two larval instars and the pupal stage. Tsetse then emerge as adult flies. Tsetse adults are relatively large flies, with lengths of ½–1½ cm [2], and have a recognizable shape or bauplan so they can usually be distinguished without trouble from other flies. Tsetse have large heads, distinctly separated eyes, and unusual antennae. The tsetse thorax is quite large, while the abdomen is wide rather than elongated and shorter than the wings. Four characteristics definitively separate adult tsetse from other kinds of flies: ## Anatomy Like all other insects, tsetse flies have an adult body comprising three visibly distinct parts: the head, the thorax and the abdomen. The head has large eyes, distinctly separated on each side, and a distinct, forward-pointing proboscis attached underneath by a large bulb. The thorax is large, made of three fused segments. Three pairs of legs are attached to the thorax, as are two wings and two halteres. The abdomen is short but wide and changes dramatically in volume during feeding. The internal anatomy of tsetse is fairly typical of the insects. The crop is large enough to accommodate a huge increase in size during the bloodmeal since tsetse can take a bloodmeal weighing as much as themselves. The reproductive tract of adult females includes a uterus which can become large enough to hold the third instar larva at the end of each pregnancy. Most tsetse flies are physically very tough indeed. Houseflies are easily killed with a fly-swatter but it takes a great deal of effort to crush a tsetse fly. ## Life cycle Tsetse have an unusual life cycle which may be due to the richness of their food source. Female tsetse only fertilize one egg at a time and retain each egg within their uterus to have the offspring develop internally during the first larval stages, a strategy called adenotrophic viviparity. During this time, the female feeds the developing offspring with a milky substance which is secreted by a modified gland in the uterus. In the third larval stage, the tsetse larva finally leave the uterus and begin their independent life. However, the newly independent tsetse larva simply crawls into the ground, forms a hard outer shell called the puparial case in which it completes its morphological transformation into an adult fly. This lifestage has a variable duration, generally twenty to thirty days, and the larva must rely on stored resources during this time. The importance of the richness of blood to this development can be seen since all tsetse development prior to the emergence from the puparial case as a full adult occurs without feeding based only on nutritional resources provided by the female parent. The female must obtain enough energy for her needs, for the needs of her developing offspring, and to store the resources which her offspring will require until it emerges as an adult. Technically these insects undergo the standard development process of insects which comprises oocyte formation, ovulation and fertilization, development of the egg, five larval stages, a pupal stage, and the emergence and maturation of the adult. ## Metabolism Tsetse metabolism consists of ingesting vertebrate blood, which is called hematophagy, and digesting this blood to obtain energy and biomass. Tsetse have specialized cells that contain cells of Wigglesworthia glossinidia brevipalpis, the bacterial endosymbionts that it requires for survival[3]. An unusual aspect of tsetse metabolism is the particular pathway which tsetse use for flight which seems to be responsible for the extremely high energy output and elevated flying speeds which tsetse can achieve. Most insects, such as honey bees, consume sugar predominantly for metabolic energy. Tsetse, instead, use a pathway which involves the conversion of the amino acids proline and alanine. The result of this pathway is that tsetse can create large amounts of ATP but can only sustain this metabolic output for short durations. Tsetse therefore fly at very high speeds (they are known to be able to follow a car moving at thirty miles an hour) but can only sustain their flight for short durations of around thirty seconds. ## General biology Tsetse has three distinct symbionts. The primary symbiont is Wigglesworthia within bacteriocyte, the secondary symbiont is Sodalis intercellularly or intracellularly, and the third is some kind of Wolbachia. The tsetse Glossina palpalis is also a vector and host of Hepatozoon petti, a parasitic Sporozoa of the nile crocodile. # Systematics Tsetse include up to thirty four species and sub-species depending on the particular classification used. Tsetse are sufficiently different in appearance and behavior to have been placed in their own distinct branch of the flies. This placement is controversial. The science of systematics is currently struggling to reconcile the traditional form of biological classification with the modern understanding of genomic evolution and speciation. The controversy surrounding the placement of tsetse is therefore likely to continue into the future. All current classifications place all the tsetse species in a single genus named Glossina. Most classifications place this genus as the sole member of the family Glossinidae. The Glossinidae are generally placed within the superfamily Hippoboscoidea, which contains other hematophagous families. This superfamily is in the subsection Calyptratae which includes the housefly and the blowfly due to the similarity of their developmental biology. This infraorder in turn, is part of the sub-order Brachycera, the stubby flies with reduced antenna. ## Species The tsetse genus is generally split into three different groups of species based on a combination of distributional, behavioral, and morphological characteristics. The genus includes [4][5]: # Trypanosomiasis Tsetse are biological vectors of trypanosomes meaning that tsetse, in the process of feeding, acquire and then transmit small, single-celled organisms called trypanosomes from infected vertebrate hosts to uninfected animals. Some tsetse transmitted trypanosome species cause trypanosomiasis, an infectious disease. In humans, tsetse transmitted trypanosomiasis is called sleeping sickness. In animals, tsetse vectored trypanosomiases include nagana, souma, and surra according to the animal infected and the trypanosome species involved, although the usage is not strict and nagana is occasionally used for any form of animal trypanosomiasis. Trypanosomes are animal parasites, specifically protozoa of the genus Trypanosoma. These organisms are approximately the size of red blood cells. Different species of trypanosomes infect different hosts as can be seen in the table attached to this section. Trypanosomes range widely in their effects on the vertebrate hosts. Some species, such as Trypanosoma theileri, do not seem to cause any health problems except perhaps in animals which are already quite sick [7]. Some strains are much more virulent. Tsetse seem to be unaffected by the infection of trypanosomes but it is entirely possible that the parasites alter tsetse behavior or have other effects which improve the chances of transmission and survival. These trypanosomes have become highly evolved and developed a life cycle which requires periods in both the vertebrate and tsetse hosts. Tsetse transmit trypanosomes in two ways, mechanical and biological transmission. - Mechanical transmission involves the direct transmission of the same individual trypanosomes taken from an infected host into an uninfected host. The name mechanical reflects the similarity of this mode of transmission to the transmission which could be caused mechanically with a syringe. Mechanical transmission requires that tsetse feed on an infected host and acquire trypanosomes in the bloodmeal, and then, within in a relatively short period, for tsetse to feed on an uninfected host and regurgitate some of the infected blood from the first bloodmeal into the tissue of the uninfected animal. This type of transmission occurs most frequently when tsetse are interrupted during a bloodmeal and attempt to satiate themselves with another meal. Other flies, such as horse-flies, also can cause mechanical transmission of trypanosomes [8]. - Biological transmission requires a period of incubation of the trypanosomes within the tsetse host. The term biological is used because trypanosomes must reproduce through several generations inside the tsetse host during the period of incubation, which requires extreme adaptation of the trypanosomes to their tsetse host. In this mode of transmission, trypanosomes reproduce through several generations, changing in morphology at certain periods. This mode of transmission also includes the sexual phase of the trypanosomes. Tsetse are believed to be more likely to become infected by trypanosomes during their first few bloodmeals. Tsetse infected by trypanosomes are thought to remain infected for the remainder of their lives. Because of the adaptations required for biological transmission, trypanosomes which are transmitted biologically by tsetse cannot be transmitted in this manner by other insects. The relative importance of these two modes of transmission for the propagation of tsetse-vectored trypanosomiases is not yet well understood. However, since the sexual phase of the trypanosome lifecycle occurs within the tsetse host, biological transmission is a required step in the life cycle of the tsetse vectored trypanosomes. The cycle of biological transmission of trypanosomiasis involves two phases, one inside the tsetse host and the other inside the vertebrate host. Trypanosomes are not passed between a pregnant tsetse and her offspring so all newly emerged tsetse adults are free of infection. An uninfected fly which feeds upon an infected vertebrate animal may acquire trypanosomes in its proboscis or gut. These trypanosomes, depending on the species, may remain in place, move to a different part of the digestive tract, or migrate through the tsetse body into the salivary glands. When an infected tsetse bites a susceptible host, the fly may regurgitate part of a previous bloodmeal which contains trypanosomes or may inject trypanosomes contained within its saliva. It is believed that the inoculation must contain a minimum of 300 to 450 individual trypanosomes to be successful, and may contain up to 40,000 individuals [7]. The trypanosomes are injected into vertebrate muscle tissue but make their way, first into the lymphatic system, then into the bloodstream, and eventually into the brain. The disease causes the swelling of the lymph glands, emaciation of the body, and eventually leads to death. Uninfected tsetse may bite the infected animal prior to its death and acquire the disease, thereby closing the transmission cycle. The tsetse vectored trypanosomiases affect various vertebrate species including humans, antelopes, bovine cattle, camels, horses, sheep, goats, and pigs. These diseases are caused by several different trypanosome species which may also survive in wild animals such as crocodiles and monitor lizards. The diseases have different distributions across the African continent and are therefore transmitted by different species of tsetse. The following table summarizes this information [7][9]: ## Human trypanosomiasis Human African trypanosomiasis, also called sleeping sickness, is caused by trypanosomes of the Trypanosoma brucei species. This disease is invariably fatal unless treated but can almost always be cured with current medicines, if the disease is diagnosed early enough. Sleeping sickness begins with a tsetse bite leading to an inoculation in the sub-cutaneous tissue. The infection moves into the lymphatic system leading to a characteristic swelling of the lymph glands which is called Winterbottoms's sign[1]. The infection progresses into the blood stream and eventually crosses into the central nervous system and invades the brain leading to extreme lethargy and eventually to death. The Trypanosoma brucei species, which causes the disease, has often been subdivided into three sub-genera which were identified based either on the vertebrate hosts which the strain could infect or on the virulence of the disease in humans. The trypanosomes infectious to animals and not to humans were named Trypanosoma brucei brucei. The strains which infected humans were divided into two sub-species based on their different virulences: Trypanosoma brucei gambiense was thought to have a slower onset and Trypanosoma brucei rhodesiense refers to strains with a more rapid, virulent onset. This characterization has always been problematic but was the best that could be done given the knowledge of the time and the tools available for identification. A recent molecular study using restriction fragment length polymorphism analysis suggests that the three sub-genera are polyphyletic [10], so the elucidation of the strains of T. brucei infective to humans will require a more complex explanation. Other forms of human trypanosomiasis also exist but are not transmitted by tsetse. The most notable is American trypanosomiasis, known as Chagas disease, which occurs in South America, caused by Trypanosoma cruzi, and transmitted by certain species of the Reduviidae, members of the Hemiptera. ## Animal trypanosomiasis Animal trypanosomiasis, also called nagana when it occurs in bovine cattle or horses or sura when it occurs in domestic pigs, is caused by several trypanosome species. These diseases reduce the growth rate, milk productivity, and strength of farm animals, generally leading to the eventually death of the infected animals. Certain species of cattle are called trypanotolerant because they can survive and grow even when infected with trypanosomes although they also have lower productivity rates when infected. The course of the disease in animals is similar to the course of sleeping sickness in humans. Trypanosoma congolense and Trypanosoma vivax are the two most important species infecting bovine cattle in sub-saharan Africa. Trypanosoma simiae causes a virulent disease in swine. Other forms of animal trypanosomiasis are also known from other areas of the globe, caused by different species of trypanosomes and transmitted without the intervention of the tsetse fly. Tsetse vector ranges mostly in the central part of Africa. # Control Template:Wikify Tsetse control has been undertaken in order to reduce the incidence of the diseases which the flies transmit. Two alternative strategies have been used in the attempts to reduce the African trypanosomiases. One tactic is primarily medical or veterinary and targets the disease directly using monitoring, prophylaxis, treatment, and surveillance to reduce the number of organisms which carry the disease. The second strategy is generally entomological and intends to disrupt the cycle of transmission by reducing the number of flies. The idea of tsetse control implies a change in the relationship between people and these insects. Prior to the twentieth century, people in Africa had largely adapted to the presence of tsetse. Human settlement patterns and agricultural practices had adapted to the presence of the fly. For example, in Ethiopia draft powered farming was restricted to the highland areas where the flies were absent whereas lowland areas where tsetse are present were more sparsely populated by people living a nomadic, less agriculturally intensive lifestyle. Tsetse control is a response to changing conditions. Tsetse control has been proposed as a way of reducing the incidence of the disease in the populations living in tsetse regions, of allowing the expansion of human settlement and agriculture into new areas, and of helping people previously relocated either in forced transfers or due to migration. Tsetse control efforts have been undertaken throughout the African continent but long-term, sustainable control has rarely been achieved. Tsetse control efforts invariably are tied to the complex problems of poverty, heath, politics, and violence which have proved such a disaster for the African people. The reduction of fly numbers has generally been attempted with two different aims, either eradication which intends to completely eliminate tsetse from the area or control which aims simply to reduce the numbers. Eradication is an idea which has often been imagined, has repeatedly been attempted, and is still proposed but many reasons suggest that control is a safer, cheaper, more realistic, and sustainable approach. Eradication refers to the successful killing of every tsetse either in a region or, under more grandiose proposals, from the entire African continent. Local eradication efforts have repeatedly been undertaken and have achieved temporary success only to fail in the long term because tsetse were able to re-invade (Zanzibar). All of the economic, ecological, political, and environmental justifications for eradication have been called into question. The economic justification for eradication offsets the immense costs of the eradication campaign against the medical and veterinary benefits which are considered to accrue in perpetuity. However, eradication campaigns may have unintended social consequences, as a successful campaign may open up lands for agriculture which have previously been populated by nomadic hunters, resulting in the displacement of the original population with its attendant consequences. ## Control techniques Many techniques have been used to reduce tsetse populations with earlier crude methods being replaced in more recent times by methods which are cheaper, more directed, and ecologically better considered. ### Slaughter of wild animals One early technique involved the slaughter of all the wild animals on which tsetse fed. For example, the island of Principé off the west coast of Africa, was entirely cleared of feral pigs in the 1930s which led to the extirpation of the fly. While the fly eventually re-invaded in the 1950s, the new population of tsetse was free from the disease. ### Land clearing Another early technique involved the complete removal of any brush or woody vegetation from an area. Tsetse tend to rest on the trunks of trees so the removal of woody vegetation made the area inhospitable to the flies. However, the technique has not been widely used and has been abandoned in more recent times. Preventing the regrowth of woody vegetation requires continuous clearing efforts which is only practicable where large human populations are present. The clearing of woody vegetation has come to be seen as an environmental problem more than a benefit. ### Pesticide campaigns Pesticides have been used to control tsetse starting initially during the early part of the twentieth century in localized efforts using the inorganic metal based pesticides, expanding after the Second World war into massive aerial and ground based campaigns using the early organic pesticides such as DDT, and continuing with the targeted use of pour-ons in which advanced organic pesticides are applied directly to the backs of cattle. ### Trapping Tsetse populations can be monitored and effectively controlled using simple, inexpensive traps. These often use electric blue cloth, since this colour attracts the flies. Early traps mimicked the form of cattle but this seems unnecessary and recent traps are simple sheets or have a biconical form. The traps can kill by channeling the flies into a collection chamber or by exposing the flies to insecticide sprayed on the cloth. The use of chemicals as attractants to lure tsetse to the traps has been studied extensively in the late 20th century, but this has mostly been of interest to scientists rather than as an economically reasonable solution. The attractants studied have been those which might be used by tsetse to find their food, like carbon dioxide and acetone, which are given off in the animals' breath and distributed downwind to form an 'odour plume'. Synthetic versions of these chemicals can be used to create artificial odour plumes. A cheaper approach is to place some cattle urine in a half gourd near the trap. For large trapping efforts, the use of additional traps is generally cheaper than the use of expensive artificial attractants. A special trapping method is applied in Ethiopia, where the BioFarm Consortium (ICIPE, BioVision Foundation, BEA, Helvetas, DLCO-EA, Praxis Ethiopia) applies the traps in a sustainable agriculture and rural development context (SARD). The traps are just the entry point, followed by improved farming, human health and marketing inputs. This method is in the final stage of testing (as per 2006). ### Releases of irradiated males The sterile insect technique has been used to reduce tsetse populations. This technique involves the rearing of large numbers of tsetse, separation of the males, irradiation of these flies with large doses of gamma rays to make them sterile and then release into to the wild. Since females only mate a few times in their life, generally only once, any mating with a sterile male will prevent that female from giving birth to any offspring. The Sterile Insect Technique has recently been used on Zanzibar, an island off the coast of East Africa. Like other eradication efforts, early indications are that the fly numbers have been decimated with the fly possibly extirpated (locally eradicated) from the island. A number of traps are in place to monitor the island and repress any resurgence. Additionally, using the parasite refractory strains is another method to control the tsetse, that means providing the blood meal containing the trypanocide before releasing the sterilised males. Also we can consider to use the cytoplasmic incompatibility (CI) strategy to control the population of tsetse. With the development of genetic engineering, the releasing of engineered parasite refractory counterparts is another strategy to control the population of tsetse. # Etymology The word 'tsetse' comes from Tswana, a language of southern Africa, and, in that language, the word means fly[11]. Recently 'tsetse' without the 'fly' has become more common in English, particularly in the scientific and development communities. The pronunuciation of the word differs in different regions. Many African languages have an ejective ts sound and so a common pronunciation of the word involves two identical syllables both having this ts sound and a shorter sound of the vowel, as ts-eh-ts-eh. The British pronunciation of the word uses two different sounds for the two different syllables, generally tee-tsee. In Zimbabwe, it is generally pronounced tseh-tsee.	https://www.wikidoc.org/index.php/Tsetse_fly
2474ca5e55e865cf8cc0433fcd46bd686096ab5c	wikidoc	Turbulence	Turbulence In fluid dynamics, turbulence or turbulent flow is a fluid regime characterized by chaotic, stochastic property changes. This includes low momentum diffusion, high momentum convection, and rapid variation of pressure and velocity in space and time. Flow that is not turbulent is called laminar flow. The (dimensionless) Reynolds number characterizes whether flow conditions lead to laminar or turbulent flow; e.g. for pipe flow, a Reynolds number above about 4000 (A Reynolds number between 2100 and 4000 is known as transitional flow) will be turbulent. At very low speeds the flow is laminar, i.e., the flow is smooth (though it may involve vortices on a large scale). As the speed increases, at some point the transition is made to turbulent flow. In turbulent flow, unsteady vortices appear on many scales and interact with each other. Drag due to boundary layer skin friction increases. The structure and location of boundary layer separation often changes, sometimes resulting in a reduction of overall drag. Because laminar-turbulent transition is governed by Reynolds number, the same transition occurs if the size of the object is gradually increased, or the viscosity of the fluid is decreased, or if the density of the fluid is increased. Turbulence causes the formation of eddies of many different length scales. Most of the kinetic energy of the turbulent motion is contained in the large scale structures. The energy "cascades" from these large scale structures to smaller scale structures by an inertial and essentially inviscid mechanism. This process continues, creating smaller and smaller structures which produces a hierarchy of eddies. Eventually this process creates structures that are small enough that molecular diffusion becomes important and viscous dissipation of energy finally takes place. The scale at which this happens is the Kolmogorov length scale. In two dimensional turbulence (as can be approximated in the atmosphere or ocean), energy actually flows to larger scales. This is referred to as the inverse energy cascade and is characterized by a k^{-(5/3)} in the power spectrum. This is the main reason why large scale weather features such as hurricanes occur. Turbulent diffusion is usually described by a turbulent diffusion coefficient. This turbulent diffusion coefficient is defined in a phenomenological sense, by analogy with the molecular diffusivities, but it does not have a true physical meaning, being dependent on the flow conditions, and not a property of the fluid, itself. In addition, the turbulent diffusivity concept assumes a constitutive relation between a turbulent flux and the gradient of a mean variable similar to the relation between flux and gradient that exists for molecular transport. In the best case, this assumption is only an approximation. Nevertheless, the turbulent diffusivity is the simplest approach for quantitative analysis of turbulent flows, and many models have been postulated to calculate it. For instance, in large bodies of water like oceans this coefficient can be found using Richardson's four-third power law and is governed by the random walk principle. In rivers and large ocean currents, the diffusion coefficient is given by variations of Elder's formula. When designing piping systems, turbulent flow requires a higher input of energy from a pump (or fan) than laminar flow. However, for applications such as heat exchangers and reaction vessels, turbulent flow is essential for good heat transfer and mixing. While it is possible to find some particular solutions of the Navier-Stokes equations governing fluid motion, all such solutions are unstable at large Reynolds numbers. Sensitive dependence on the initial and boundary conditions makes fluid flow irregular both in time and in space so that a statistical description is needed. Russian mathematician Andrey Kolmogorov proposed the first statistical theory of turbulence, based on the aforementioned notion of the energy cascade (an idea originally introduced by Richardson) and the concept of self-similarity. As a result, the Kolmogorov microscales were named after him. It is now known that the self-similarity is broken so the statistical description is presently modified . Still, the complete description of turbulence remains one of the unsolved problems in physics. According to an apocryphal story Werner Heisenberg was asked what he would ask God, given the opportunity. His reply was: "When I meet God, I am going to ask him two questions: Why relativity? And why turbulence? I really believe he will have an answer for the first." A similar witticism has been attributed to Horace Lamb (who had published a noted text book on Hydrodynamics)—his choice being quantum mechanics (instead of relativity) and turbulence. Lamb was quoted as saying in a speech to the British Association for the Advancement of Science, "I am an old man now, and when I die and go to heaven there are two matters on which I hope for enlightenment. One is quantum electrodynamics, and the other is the turbulent motion of fluids. And about the former I am rather optimistic." # Examples of turbulence - Smoke rising from a cigarette. For the first few centimeters, the flow remains laminar, and then becomes unstable and turbulent as the rising hot air accelerates upwards. Similarly, the dispersion of pollutants in the atmosphere is governed by turbulent processes. - Flow over a golf ball. (This can be best understood by considering the golf ball to be stationary, with air flowing over it.) If the golf ball were smooth, the boundary layer flow over the front of the sphere would be laminar at typical conditions. However, the boundary layer would separate early, as the pressure gradient switched from favorable (pressure decreasing in the flow direction) to unfavorable (pressure increasing in the flow direction), creating a large region of low pressure behind the ball that creates high form drag. To prevent this from happening, the surface is dimpled to perturb the boundary layer and promote transition to turbulence. This results in higher skin friction, but moves the point of boundary layer separation further along, resulting in lower form drag and lower overall drag. - The mixing of warm and cold air in the atmosphere by wind, which causes clear-air turbulence experienced during airplane flight, as well as poor astronomical seeing (the blurring of images seen through the atmosphere.) - Most of the terrestrial atmospheric circulation - The oceanic and atmospheric mixed layers and intense oceanic currents. - The flow conditions in many industrial equipment (such as pipes, ducts, precipitators, gas scrubbers, etc.) and machines (for instance, internal combustion engines and gas turbines). - The external flow over all kind of vehicles such as cars, airplanes, ships and submarines. - The motions of matter in stellar atmospheres. - A jet exhausting from a nozzle into a quiescent fluid. As the flow emerges into this external fluid, shear layers originating at the lips of the nozzle are created. These layers separate the fast moving jet from the external fluid, and at a certain critical Reynolds number they become unstable and break down to turbulence. - Race cars unable to follow each other through fast corners due to turbulence created by the leading car causing understeer. - In windy conditions, trucks that are on the motorway gets buffeted by their wake. - Round bridge supports under water. In the summer when the river is flowing slowly the water goes smoothly around the support legs. In the winter the flow is faster, so a higher Reynolds Number, so the flow may start off laminar but is quickly separated from the leg and becomes turbulent. # Kolmogorov 1941 Theory The Richardson's notion of turbulence was that a turbulent flow is composed by "eddies" of different sizes. The sizes define a characteristic length scale for the eddies, which are also characterized by velocity scales and time scales (turnover time) dependent on the length scale. The large eddies are unstable and eventually break up originating smaller eddies, and the kinetic energy of the initial large eddy is divided into the smaller eddies that stemmed from it. These smaller eddies undergo the same process, giving rise to even smaller eddies which inherit the energy of their predecessor eddy, and so on. In this way, the energy is passed down from the large scales of the motion to smaller scales until reaching a sufficiently small length scale such that the viscosity of the fluid can effectively dissipate the kinetic energy into internal energy. In his original theory of 1941, Kolmogorov postulated that for very high Reynolds number, the small scale turbulent motions are statistically isotropic (i.e. no preferential spatial direction could be discerned). In general, the large scales of a flow are not isotropic, since they are determined by the particular geometrical features of the boundaries (the size characterizing the large scales will be denoted as L). Kolmogorov's idea was that in the Richardson's energy cascade this geometrical and directional information is lost, while the scale is reduced, so that the statistics of the small scales has a universal character: they are the same for all turbulent flows when the Reynolds number is sufficiently high. Thus, Kolmogorov introduced a second hypothesis: for very high Reynolds numbers the statistics of small scales are universally and uniquely determined by the viscosity (\nu) and the rate of energy dissipation (\varepsilon). With only these two parameters, the unique length that can be formed by dimensional analysis is \eta = (\frac{\nu^3}{\varepsilon})^{1/4}. This is today known as the Kolmogorov length scale (see Kolmogorov microscales). A turbulent flow is characterized by a hierarchy of scales through which the energy cascade takes place. Dissipation of kinetic energy takes place at scales of the order of Kolmogorov length \eta, while the input of energy into the cascade comes from the decay of the large scales, of order L. These two scales at the extremes of the cascade can differ by several orders of magnitude at high Reynolds numbers. In between there is a range of scales (each one with its own characteristic length r) that has formed at the expense of the energy of the large ones. These scales, are very large compared with the Kolmogorov length, but still very small compared with the large scale of the flow (i.e. \eta \ll r \ll L). Since eddies in this range are much larger than the dissipative eddies that exist at Kolmogorov scales, kinetic energy is essentially not dissipated in this range, and it is merely transferred to smaller scales until viscous effects become important as the order of the Kolmogorov scale is approached. Within this range inertial effects are still much larger than viscous effects, and it is possible to assume that viscosity does not play a role in their internal dynamics (for this reason this range is called "inertial range"). Hence, a third hypothesis of Kolmogorov was that at very high Reynolds number the statistics of scales in the range \eta \ll r \ll L are universally and uniquely determined by the scale r and the rate of energy dissipation \varepsilon. The way in which the kinetic energy is distributed over the multiplicity of scales is a fundamental characterization of a turbulent flow. For homogeneous turbulence (i.e., statistically invariant under translations of the reference frame) this is usually done by means of the energy spectrum function E(k), where k is the modulus of the wavenumber vector corresponding to some harmonics in a Fourier representation of the flow velocity field u(x): \mathbf{u}(\mathbf{x}) = \iiint_{\mathbb{R}^3} \widehat{\mathbf{u}}(\mathbf{k})e^{i \mathbf{k \cdot x}} \mathrm{d}^3\mathbf{k}, where û(k) is the Fourier transform of the velocity field. Thus, E(k)dk represents the contribution to the kinetic energy from all the Fourier modes with k < \|k\| < k + dk, and therefore, \mathrm{Total\,\, kinetic\,\, energy} = \int_{0}^{\infty}E(k)\mathrm{d}k. The wavenumber k corresponding to length scale r is k=2\pi/r. Therefore, by dimensional analysis, the only possible form for the energy spectrum function according with the third Kolmogorov's hypothesis is E(k) = C \varepsilon^{2/3} k^{-5/3} , where C would be a universal constant. This is one of the most famous results of Kolmogorov 1941 theory, and considerable experimental evidence has accumulated that supports it. In spite of this success, Kolmogorov theory is at present under revision. This theory implicitly assumes that the turbulence is statistically self-similar at different scales. This essentially means that the statistics are scale-invariant in the inertial range. A usual way of studying turbulent velocity fields is by means of velocity increments: \delta \mathbf{u}(r) = \mathbf{u}(\mathbf{x} + \mathbf{r}) - \mathbf{u}(\mathbf{x}), that is, the difference in velocity between points separated by a vector r (since the turbulence is assumed isotropic, the velocity increment depends only on the modulus of r). Velocity increments are useful because they emphasize the effects of scales of the order of the separation r when statistics are computed. The statistical scale-invariance implies that the scaling of velocity increments should occur with a unique scaling exponent \beta, so that when r is scaled by a factor \lambda, \delta \mathbf{u}(\lambda r) should have the same statistical distribution than \lambda^{\beta}\delta \mathbf{u}(r), with \beta independent of the scale r. From this fact, and other results of Kolmogorov 1941 theory, it follows that the statistical moments of the velocity increments (known as structure functions in turbulence) should scale as \langle ^n \rangle = C_n \varepsilon^{n/3} r^{n/3}, where the brackets denote the statistical average, and the C_n would be universal constants. There is considerable evidence that turbulent flows deviate from this behavior. The scaling exponents deviate from the n/3 value predicted by the theory, becoming a non-linear function of the order n of the structure function. The universality of the constants have also been questioned. For low orders the discrepancy with the Kolmogorov n/3 value is very small, which explain the success of Kolmogorov theory in regards to low order statistical moments. In particular, it can be shown that when the energy spectrum follows a power law E(k) \propto k^{-p}, with 1 , the second order structure function has also a power law, with the form \langle ^2 \rangle \propto r^{p-1} . Since the experimental values obtained for the second order structure function only deviate slightly from the 2/3 value predicted by Kolmogorov theory, the value for p is very near to 5/3 (differences are about 2%). Thus the "Kolmogorov -5/3 spectrum" is generally observed in turbulence. However, for high order structure functions the difference with the Kolmogorov scaling is significant, and the breakdown of the statistical self-similarity is clear. This behavior, and the lack of universality of the C_n constants, are related with the phenomenon of intermittency in turbulence. This is an important area of research in this field, and a major goal of the modern theory of turbulence is to understand what is really universal in the inertial range.	Turbulence In fluid dynamics, turbulence or turbulent flow is a fluid regime characterized by chaotic, stochastic property changes. This includes low momentum diffusion, high momentum convection, and rapid variation of pressure and velocity in space and time. Flow that is not turbulent is called laminar flow. The (dimensionless) Reynolds number characterizes whether flow conditions lead to laminar or turbulent flow; e.g. for pipe flow, a Reynolds number above about 4000 (A Reynolds number between 2100 and 4000 is known as transitional flow) will be turbulent. At very low speeds the flow is laminar, i.e., the flow is smooth (though it may involve vortices on a large scale). As the speed increases, at some point the transition is made to turbulent flow. In turbulent flow, unsteady vortices appear on many scales and interact with each other. Drag due to boundary layer skin friction increases. The structure and location of boundary layer separation often changes, sometimes resulting in a reduction of overall drag. Because laminar-turbulent transition is governed by Reynolds number, the same transition occurs if the size of the object is gradually increased, or the viscosity of the fluid is decreased, or if the density of the fluid is increased. Turbulence causes the formation of eddies of many different length scales. Most of the kinetic energy of the turbulent motion is contained in the large scale structures. The energy "cascades" from these large scale structures to smaller scale structures by an inertial and essentially inviscid mechanism. This process continues, creating smaller and smaller structures which produces a hierarchy of eddies. Eventually this process creates structures that are small enough that molecular diffusion becomes important and viscous dissipation of energy finally takes place. The scale at which this happens is the Kolmogorov length scale. In two dimensional turbulence (as can be approximated in the atmosphere or ocean), energy actually flows to larger scales. This is referred to as the inverse energy cascade and is characterized by a <math>k^{-(5/3)}</math> in the power spectrum. This is the main reason why large scale weather features such as hurricanes occur. Turbulent diffusion is usually described by a turbulent diffusion coefficient. This turbulent diffusion coefficient is defined in a phenomenological sense, by analogy with the molecular diffusivities, but it does not have a true physical meaning, being dependent on the flow conditions, and not a property of the fluid, itself. In addition, the turbulent diffusivity concept assumes a constitutive relation between a turbulent flux and the gradient of a mean variable similar to the relation between flux and gradient that exists for molecular transport. In the best case, this assumption is only an approximation. Nevertheless, the turbulent diffusivity is the simplest approach for quantitative analysis of turbulent flows, and many models have been postulated to calculate it. For instance, in large bodies of water like oceans this coefficient can be found using Richardson's four-third power law and is governed by the random walk principle. In rivers and large ocean currents, the diffusion coefficient is given by variations of Elder's formula. When designing piping systems, turbulent flow requires a higher input of energy from a pump (or fan) than laminar flow. However, for applications such as heat exchangers and reaction vessels, turbulent flow is essential for good heat transfer and mixing. While it is possible to find some particular solutions of the Navier-Stokes equations governing fluid motion, all such solutions are unstable at large Reynolds numbers. Sensitive dependence on the initial and boundary conditions makes fluid flow irregular both in time and in space so that a statistical description is needed. Russian mathematician Andrey Kolmogorov proposed the first statistical theory of turbulence, based on the aforementioned notion of the energy cascade (an idea originally introduced by Richardson) and the concept of self-similarity. As a result, the Kolmogorov microscales were named after him. It is now known that the self-similarity is broken so the statistical description is presently modified [1]. Still, the complete description of turbulence remains one of the unsolved problems in physics. According to an apocryphal story Werner Heisenberg was asked what he would ask God, given the opportunity. His reply was: "When I meet God, I am going to ask him two questions: Why relativity? And why turbulence? I really believe he will have an answer for the first."[2] A similar witticism has been attributed to Horace Lamb (who had published a noted text book on Hydrodynamics)—his choice being quantum mechanics (instead of relativity) and turbulence. Lamb was quoted as saying in a speech to the British Association for the Advancement of Science, "I am an old man now, and when I die and go to heaven there are two matters on which I hope for enlightenment. One is quantum electrodynamics, and the other is the turbulent motion of fluids. And about the former I am rather optimistic."[3] ## Examples of turbulence - Smoke rising from a cigarette. For the first few centimeters, the flow remains laminar, and then becomes unstable and turbulent as the rising hot air accelerates upwards. Similarly, the dispersion of pollutants in the atmosphere is governed by turbulent processes. - Flow over a golf ball. (This can be best understood by considering the golf ball to be stationary, with air flowing over it.) If the golf ball were smooth, the boundary layer flow over the front of the sphere would be laminar at typical conditions. However, the boundary layer would separate early, as the pressure gradient switched from favorable (pressure decreasing in the flow direction) to unfavorable (pressure increasing in the flow direction), creating a large region of low pressure behind the ball that creates high form drag. To prevent this from happening, the surface is dimpled to perturb the boundary layer and promote transition to turbulence. This results in higher skin friction, but moves the point of boundary layer separation further along, resulting in lower form drag and lower overall drag. - The mixing of warm and cold air in the atmosphere by wind, which causes clear-air turbulence experienced during airplane flight, as well as poor astronomical seeing (the blurring of images seen through the atmosphere.) - Most of the terrestrial atmospheric circulation - The oceanic and atmospheric mixed layers and intense oceanic currents. - The flow conditions in many industrial equipment (such as pipes, ducts, precipitators, gas scrubbers, etc.) and machines (for instance, internal combustion engines and gas turbines). - The external flow over all kind of vehicles such as cars, airplanes, ships and submarines. - The motions of matter in stellar atmospheres. - A jet exhausting from a nozzle into a quiescent fluid. As the flow emerges into this external fluid, shear layers originating at the lips of the nozzle are created. These layers separate the fast moving jet from the external fluid, and at a certain critical Reynolds number they become unstable and break down to turbulence. Template:Unsolved - Race cars unable to follow each other through fast corners due to turbulence created by the leading car causing understeer. - In windy conditions, trucks that are on the motorway gets buffeted by their wake. - Round bridge supports under water. In the summer when the river is flowing slowly the water goes smoothly around the support legs. In the winter the flow is faster, so a higher Reynolds Number, so the flow may start off laminar but is quickly separated from the leg and becomes turbulent. ## Kolmogorov 1941 Theory The Richardson's notion of turbulence was that a turbulent flow is composed by "eddies" of different sizes. The sizes define a characteristic length scale for the eddies, which are also characterized by velocity scales and time scales (turnover time) dependent on the length scale. The large eddies are unstable and eventually break up originating smaller eddies, and the kinetic energy of the initial large eddy is divided into the smaller eddies that stemmed from it. These smaller eddies undergo the same process, giving rise to even smaller eddies which inherit the energy of their predecessor eddy, and so on. In this way, the energy is passed down from the large scales of the motion to smaller scales until reaching a sufficiently small length scale such that the viscosity of the fluid can effectively dissipate the kinetic energy into internal energy. In his original theory of 1941, Kolmogorov postulated that for very high Reynolds number, the small scale turbulent motions are statistically isotropic (i.e. no preferential spatial direction could be discerned). In general, the large scales of a flow are not isotropic, since they are determined by the particular geometrical features of the boundaries (the size characterizing the large scales will be denoted as L). Kolmogorov's idea was that in the Richardson's energy cascade this geometrical and directional information is lost, while the scale is reduced, so that the statistics of the small scales has a universal character: they are the same for all turbulent flows when the Reynolds number is sufficiently high. Thus, Kolmogorov introduced a second hypothesis: for very high Reynolds numbers the statistics of small scales are universally and uniquely determined by the viscosity (<math>\nu</math>) and the rate of energy dissipation (<math>\varepsilon</math>). With only these two parameters, the unique length that can be formed by dimensional analysis is <math>\eta = (\frac{\nu^3}{\varepsilon})^{1/4}</math>. This is today known as the Kolmogorov length scale (see Kolmogorov microscales). A turbulent flow is characterized by a hierarchy of scales through which the energy cascade takes place. Dissipation of kinetic energy takes place at scales of the order of Kolmogorov length <math>\eta</math>, while the input of energy into the cascade comes from the decay of the large scales, of order L. These two scales at the extremes of the cascade can differ by several orders of magnitude at high Reynolds numbers. In between there is a range of scales (each one with its own characteristic length r) that has formed at the expense of the energy of the large ones. These scales, are very large compared with the Kolmogorov length, but still very small compared with the large scale of the flow (i.e. <math>\eta \ll r \ll L</math>). Since eddies in this range are much larger than the dissipative eddies that exist at Kolmogorov scales, kinetic energy is essentially not dissipated in this range, and it is merely transferred to smaller scales until viscous effects become important as the order of the Kolmogorov scale is approached. Within this range inertial effects are still much larger than viscous effects, and it is possible to assume that viscosity does not play a role in their internal dynamics (for this reason this range is called "inertial range"). Hence, a third hypothesis of Kolmogorov was that at very high Reynolds number the statistics of scales in the range <math>\eta \ll r \ll L</math> are universally and uniquely determined by the scale r and the rate of energy dissipation <math>\varepsilon</math>. The way in which the kinetic energy is distributed over the multiplicity of scales is a fundamental characterization of a turbulent flow. For homogeneous turbulence (i.e., statistically invariant under translations of the reference frame) this is usually done by means of the energy spectrum function <math>E(k)</math>, where k is the modulus of the wavenumber vector corresponding to some harmonics in a Fourier representation of the flow velocity field u(x): <math>\mathbf{u}(\mathbf{x}) = \iiint_{\mathbb{R}^3} \widehat{\mathbf{u}}(\mathbf{k})e^{i \mathbf{k \cdot x}} \mathrm{d}^3\mathbf{k}</math>, where û(k) is the Fourier transform of the velocity field. Thus, E(k)dk represents the contribution to the kinetic energy from all the Fourier modes with k < \|k\| < k + dk, and therefore, <math>\mathrm{Total\,\, kinetic\,\, energy} = \int_{0}^{\infty}E(k)\mathrm{d}k</math>. The wavenumber k corresponding to length scale r is <math>k=2\pi/r</math>. Therefore, by dimensional analysis, the only possible form for the energy spectrum function according with the third Kolmogorov's hypothesis is <math>E(k) = C \varepsilon^{2/3} k^{-5/3} </math>, where C would be a universal constant. This is one of the most famous results of Kolmogorov 1941 theory, and considerable experimental evidence has accumulated that supports it[4]. In spite of this success, Kolmogorov theory is at present under revision. This theory implicitly assumes that the turbulence is statistically self-similar at different scales. This essentially means that the statistics are scale-invariant in the inertial range. A usual way of studying turbulent velocity fields is by means of velocity increments: <math>\delta \mathbf{u}(r) = \mathbf{u}(\mathbf{x} + \mathbf{r}) - \mathbf{u}(\mathbf{x})</math>, that is, the difference in velocity between points separated by a vector r (since the turbulence is assumed isotropic, the velocity increment depends only on the modulus of r). Velocity increments are useful because they emphasize the effects of scales of the order of the separation r when statistics are computed. The statistical scale-invariance implies that the scaling of velocity increments should occur with a unique scaling exponent <math>\beta</math>, so that when r is scaled by a factor <math>\lambda</math>, <math>\delta \mathbf{u}(\lambda r)</math> should have the same statistical distribution than <math>\lambda^{\beta}\delta \mathbf{u}(r)</math>, with <math>\beta</math> independent of the scale r. From this fact, and other results of Kolmogorov 1941 theory, it follows that the statistical moments of the velocity increments (known as structure functions in turbulence) should scale as <math>\langle [\delta \mathbf{u}(r)]^n \rangle = C_n \varepsilon^{n/3} r^{n/3}</math>, where the brackets denote the statistical average, and the <math>C_n</math> would be universal constants. There is considerable evidence that turbulent flows deviate from this behavior. The scaling exponents deviate from the n/3 value predicted by the theory, becoming a non-linear function of the order n of the structure function. The universality of the constants have also been questioned. For low orders the discrepancy with the Kolmogorov n/3 value is very small, which explain the success of Kolmogorov theory in regards to low order statistical moments. In particular, it can be shown that when the energy spectrum follows a power law <math>E(k) \propto k^{-p}</math>, with <math>1 < p < 3</math>, the second order structure function has also a power law, with the form <math>\langle [\delta \mathbf{u}(r)]^2 \rangle \propto r^{p-1} </math>. Since the experimental values obtained for the second order structure function only deviate slightly from the 2/3 value predicted by Kolmogorov theory, the value for p is very near to 5/3 (differences are about 2%[5]). Thus the "Kolmogorov -5/3 spectrum" is generally observed in turbulence. However, for high order structure functions the difference with the Kolmogorov scaling is significant, and the breakdown of the statistical self-similarity is clear. This behavior, and the lack of universality of the <math>C_n</math> constants, are related with the phenomenon of intermittency in turbulence. This is an important area of research in this field, and a major goal of the modern theory of turbulence is to understand what is really universal in the inertial range.	https://www.wikidoc.org/index.php/Turbulence
a191beae054502edc1d74788dd88098377dbdfd0	wikidoc	Turpentine	Turpentine Turpentine (also called spirit of turpentine, oil of turpentine, wood turpentine, gum turpentine) is a fluid obtained by the distillation of resin obtained from trees, mainly pine trees. It is composed of terpenes, mainly the monoterpenes alpha-pinene and beta-pinene. It has a potent odor similar to that of nail polish remover. It is sometimes known colloquially as turps, but this more often refers to turpentine substitute (or mineral turpentine). The word turpentine is formed (via French and Latin) from the Greek word terebinthine, the name of a species of tree, the terebinth tree, from whose sap the spirit was originally distilled. # Production One of the earliest sources was the terebinth or turpentine tree (Pistacia terebinthus), a Mediterranean tree related to the pistachio. Important pines for turpentine production include: - Maritime Pine Pinus pinaster - Aleppo Pine Pinus halepensis - Masson's Pine Pinus massoniana - Sumatran Pine Pinus merkusii - Longleaf Pine Pinus palustris - Loblolly Pine Pinus taeda - Ponderosa Pine Pinus ponderosa # Industrial uses The two primary uses of turpentine in industry are as a solvent and as a source of materials for organic synthesis. As a solvent, turpentine is used for thinning oil-based paints, for producing varnishes, and as a raw material for the chemical industry. Its industrial use as a solvent in industrialized nations has largely been replaced by the much cheaper turpentine substitutes distilled from crude oil. Canada balsam, also called Canada turpentine or balsam of fir, is a turpentine which is made from the resin of the balsam fir. Venice turpentine is produced from the Western Larch Larix occidentalis. Turpentine is also used as a source of raw materials in the synthesis of fragrant chemical compounds. Commercially used camphor, linalool, alpha-terpineol, and geraniol are all usually produced from alpha-pinene and beta-pinene, which are two of the chief chemical components of turpentine. These pinenes are separated and purified by distillation. The mixture of diterpenes and triterpenes that is left as residue after turpentine distillation is sold as rosin. Turpentine is also added to many cleaning and sanitary products due to its antiseptic properties and its "clean scent". # Medicinal uses Turpentine has been used medically since ancient times. - Applied externally to the affected areas, turpentine is a highly effective treatment for lice. - Turpentine can be mixed with animal fat as a primitive chest rub for nasal and throat ailments. Many modern chest rubs still contain some turpentine (e.g., Vicks). - Internal administration of turpentine is no longer common today, though it was once the preferred means of treating intestinal parasites due to its antiseptic and diuretic properties. - Drinking turpentine is extremely dangerous and can be life threatening. In addition, drinking turpentine is not an effective way to induce an abortion # Hazards Turpentine is an organic solvent, and thus poses many of the same hazards as do other such substances. Being "natural" does not make it less harmful than artificial solvents. Its vapor can burn the skin and eyes, damage the lungs and respiratory system, as well as the central nervous system when inhaled, and cause renal failure when ingested, among other things. It is highly flammable.	Turpentine Template:Chembox new Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] Turpentine (also called spirit of turpentine, oil of turpentine, wood turpentine, gum turpentine) is a fluid obtained by the distillation of resin obtained from trees, mainly pine trees. It is composed of terpenes, mainly the monoterpenes alpha-pinene and beta-pinene. It has a potent odor similar to that of nail polish remover. It is sometimes known colloquially as turps, but this more often refers to turpentine substitute (or mineral turpentine). The word turpentine is formed (via French and Latin) from the Greek word terebinthine, the name of a species of tree, the terebinth tree, from whose sap the spirit was originally distilled.[1] # Production One of the earliest sources was the terebinth or turpentine tree (Pistacia terebinthus), a Mediterranean tree related to the pistachio. Important pines for turpentine production include: - Maritime Pine Pinus pinaster - Aleppo Pine Pinus halepensis - Masson's Pine Pinus massoniana - Sumatran Pine Pinus merkusii - Longleaf Pine Pinus palustris - Loblolly Pine Pinus taeda - Ponderosa Pine Pinus ponderosa # Industrial uses The two primary uses of turpentine in industry are as a solvent and as a source of materials for organic synthesis. As a solvent, turpentine is used for thinning oil-based paints, for producing varnishes, and as a raw material for the chemical industry. Its industrial use as a solvent in industrialized nations has largely been replaced by the much cheaper turpentine substitutes distilled from crude oil. Canada balsam, also called Canada turpentine or balsam of fir, is a turpentine which is made from the resin of the balsam fir. Venice turpentine is produced from the Western Larch Larix occidentalis. Turpentine is also used as a source of raw materials in the synthesis of fragrant chemical compounds. Commercially used camphor, linalool, alpha-terpineol, and geraniol are all usually produced from alpha-pinene and beta-pinene, which are two of the chief chemical components of turpentine. These pinenes are separated and purified by distillation. The mixture of diterpenes and triterpenes that is left as residue after turpentine distillation is sold as rosin. Turpentine is also added to many cleaning and sanitary products due to its antiseptic properties and its "clean scent". # Medicinal uses Turpentine has been used medically since ancient times. - Applied externally to the affected areas, turpentine is a highly effective treatment for lice. - Turpentine can be mixed with animal fat as a primitive chest rub for nasal and throat ailments. Many modern chest rubs still contain some turpentine (e.g., Vicks). - Internal administration of turpentine is no longer common today, though it was once the preferred means of treating intestinal parasites due to its antiseptic and diuretic properties. - Drinking turpentine is extremely dangerous and can be life threatening. In addition, drinking turpentine is not an effective way to induce an abortion[2] # Hazards Turpentine is an organic solvent, and thus poses many of the same hazards as do other such substances. Being "natural" does not make it less harmful than artificial solvents. Its vapor can burn the skin and eyes, damage the lungs and respiratory system, as well as the central nervous system when inhaled, and cause renal failure when ingested, among other things. It is highly flammable.	https://www.wikidoc.org/index.php/Turpentine
59e74c7aef86fd9a26d3ac22b0f311a73f3de345	wikidoc	Turritella	Turritella Turritella is a genus of gastropod in the family Turritellidae with highly coiled shells in a pronounced, elongated cone. The shells are quite frequently found as fossils, and the carbonate stone made from large quantities of Turritella shells is often referred to as "Turritella limestone", or, if silicified, "Turritella agate". Both varieties of this stone are commonly sold as polished cabochons. Turritella species originated in the Cretaceous and span to the present day. # Palaeontological locations - The Turritellenplatte of Ermingen (near Ulm) is situated in the northern part of the North Alpine Foreland Basin (NAFB) and is famous for its plenty of gastropod shells of Turritella turris (BASTEROT) within sediments. The fauna of this gastropod-rich sandstone reflects mainly near-coastal and shallow marine conditions. Petrographical and palaeontological data allow a correlation of Turritellenplatte of Ermingen with lower Ottnangian (Lower Miocene). Sr-isotope composition of shark teeth suggests an age of about 18,5 Ma for the Turritellenplatte of Ermingen. References: - ↑ J. Baier, K.-H. Schmitt & R. Mick: Notizen zur untermiozänen Hai- und Rochenfauna der Erminger Turritellenplatte (Mittlere Schwäbische Alb, SW-Deutschland). - Jahresbericht Mitt. oberrhein. geol. Ver., N.F. 86, 361-371; Stuttgart, 2004 Template:ISSN - ↑ J. Baier: Ein Beitrag zur Erminger Turritellenplatte (Mittlere Schwäbische Alb, SW-Deutschland). - Jahresbericht Mitt. oberrhein. geol. Ver., N.F. 90; Stuttgart, 2008. Template:ISSN - # Weblinks - Selachian fauna of Turritellenplatte: Abstract of Baier et al. 2004	Turritella Turritella is a genus of gastropod in the family Turritellidae with highly coiled shells in a pronounced, elongated cone. The shells are quite frequently found as fossils, and the carbonate stone made from large quantities of Turritella shells is often referred to as "Turritella limestone", or, if silicified, "Turritella agate". Both varieties of this stone are commonly sold as polished cabochons. Turritella species originated in the Cretaceous and span to the present day. # Palaeontological locations - The Turritellenplatte of Ermingen (near Ulm) is situated in the northern part of the North Alpine Foreland Basin (NAFB) and is famous for its plenty of gastropod shells of Turritella turris (BASTEROT) within sediments. The fauna of this gastropod-rich sandstone reflects mainly near-coastal and shallow marine conditions.[1] Petrographical and palaeontological data allow a correlation of Turritellenplatte of Ermingen with lower Ottnangian (Lower Miocene). Sr-isotope composition of shark teeth suggests an age of about 18,5 Ma for the Turritellenplatte of Ermingen.[2] References: - ↑ J. Baier, K.-H. Schmitt & R. Mick: Notizen zur untermiozänen Hai- und Rochenfauna der Erminger Turritellenplatte (Mittlere Schwäbische Alb, SW-Deutschland). - Jahresbericht Mitt. oberrhein. geol. Ver., N.F. 86, 361-371; Stuttgart, 2004 Template:ISSN - ↑ J. Baier: Ein Beitrag zur Erminger Turritellenplatte (Mittlere Schwäbische Alb, SW-Deutschland). - Jahresbericht Mitt. oberrhein. geol. Ver., N.F. 90; Stuttgart, 2008. Template:ISSN - [in press] # Weblinks - Selachian fauna of Turritellenplatte: Abstract of Baier et al. 2004	https://www.wikidoc.org/index.php/Turritella
e5674c2e96340d02a5d6cf944fd697b4aa6c484f	wikidoc	Twin study	Twin study Twin studies are one of a family of designs in behavior genetics which aid the study of individual differences by highlighting the role of environmental and genetic causes on behavior. Twins are invaluable for studying these important questions because they disentangle the sharing of genes and environments. If we observe that children in a family are more similar than might be expected by chance, this may reflect shared environmental influences common to members of family —class, parenting styles, education etc.— but they will also reflect shared genes, inherited from parents. The twin design compares the similarity of identical twins who share 100% of their genes, to that of dizygotic or fraternal twins, who share only 50% of their genes. By studying many hundreds of families of twins, researchers can then understand more about the role of genetic effects, and the effects of shared and unique environment effects. Modern twin studies have shown that almost all traits are in part influenced by genetic differences, with some characteristics showing a strong influence (e.g., height), others an intermediate level (i.e. IQ) and some more complex heritabilities, with evidence for different genes affecting different elements of the trait - for instance Autism. ## History While twins have been of interest to scholars since early civilization, such as the early physician Hippocrates (5th c. BCE), who attributed similar diseases in twins to shared material circumstances, and the stoic philosopher Posidonius (1rst c. BCE), who attributed such similarities to shared astrological sex circumstances, the modern history of the twin study derives from Sir Francis Galton's pioneering use of twins to study the role of genes and environment on human development and behavior. # Methods The power of twin designs arises from the fact that twins may be either monozygotic (MZ: developing from a single fertilized egg and therefore sharing all of their genes) – or dizygotic (DZ: developing from two fertilized eggs and therefore sharing on average 50% of their genes, the same level of genetic similarity as found in non-twin siblings). These known differences in genetic similarity, together with a testable assumption of equal environments for MZ and DZ twins (Bouchard & Propping, 1993) creates the basis for the twin design for exploring the effects of genetic and environmental variance on a phenotype (Neale & Cardon, 1992). The basic logic of the twin study can be understood with very little mathematics beyond an understanding of correlation and the concept of variance. Like all behavior genetic research, the classic twin study begins from assessing the variance of a behavior (called a phenotype by geneticists) in a large group, and attempts to estimate how much of this is due to genetic effects (heritability), how much appears to be due to shared environmental effects, and how much is due to unique environmental effects - events occurring to one twin but not another. Typically these three components are called A (additive genetics) C (common environment) and E (unique environment). the so-called ACE Model. It is also possible to examine non-additive genetics effects (often denoted D for dominance (see below for more complex twin designs). Given the ACE model, researchers can determine what proportion of variance in a trait is heritable, versus the proportions which are due to shared environment or unshared environment. While nearly all research is carried out using SEM programs such as the freeware Mx, the essential logic of the twin design is as follows: MZ twins raised in a family share both 100% of their genes, and all of the shared environment. All differences between them in this framework are unique. The correlation we observe between MZ twins provides an estimate of A+C. DZ twins have a common shared environment, and share 50% of their genes: so the correlation between DZ twins is a direct estimate of 1/2A + C. rMZ = A+C rDZ = .5A+C These two equations allow us to derive A C and E: A = 2(rmz- rdz) C = rmz-A E= 1-rmz Where rmz and rdz are simply the correlations of the trait in MZ and DZ twins respectively. Twice difference between MZ and DZ twins gives us A: the additive genetic effect. C is simply the MZ correlation - our estimate of A, and E is estimated directly by how much the MZ twin correlation deviates from 1. (Jinks & Fulker, 1970; Plomin, DeFries , McClearn, & McGuffin, 2001). ### Modern Modeling Beginning in the 1970s, research transitioned to explicitly modeling the values of A, C, and E within a maximum likelihood framework (Martin & Eaves, 1977). While computationally much more complex, benefits of this approach are manifold, and modeling tools such as Mx (Neale, Boker, Xie, & Maes, 2002) have made the new techniques relatively accessible. ## Assumptions Equal environments. It can be seen from the modelling above, that the main assumption of the twin study is that of equal environments. At an intuitive level, this seems reasonable - why would parents note that two children shared their hair and eye color, and then contrive to make their IQs identical? Indeed, how could they? This assumption, however, has been directly tested. An interesting case occurs where parents believe their twins to be non-identical when in fact they are genetically MZ. Studies of a range of psychological traits indicate that these children remain as concordant as MZs raised by parents who treated them as identical (Kendler, Neale, Kessler, Heath, & Eaves, 1993). ## Measured similarity: A direct test of assumptions in twin designs A particularly powerful technique for testing the twin method has recently been reported by Visscher et al. Instead of using twins, this group took advantage of the fact that while siblings on average share 50% of their genes, the actual gene-sharing for individual sibling pairs varies around this value, essentially creating a continuum of genetic similarity or "twinness" within families. Estimates of heritability based on direct estimates of gene sharing confirm those from the twin method, providing support for the assumptions of the method in the domains of cognition, personality, and psychopathology. ## Extended twin designs and more complex genetic models The basic or classical twin-design contains only MZ and DZ twins raised in their biological family. This represents only a sub-set of the possible genetic and environmental relationships. It is fair to say, therefore, that the heritability estimates from twin designs represent a first step in understanding the genetics of behavior. The variance partitioning of the twin study into additive genetic, shared, and unshared environment is a first approximation to a complete analysis taking into account gene-environment covariance and interaction, as well as other non-additive effects on behavior. The revolution in molecular genetics has provided more effective tools for describing the genome, and many researchers are pursuing molecular genetics in order to directly assess the influence of alleles and environments on traits. An initial limitation of the twin design is that is does not afford an opportunity to consider both Shared Environment and Non-additive genetic effects simultaneously. This limit can be addressed by including additional siblings to the design. A second limitation is that GE correlation is not detectable as a distinct effect. Addressing this limit requires incorporating adoption models, or children-of-twins designs, to assess family influences uncorrelated with shared genetic effects. # Criticism The Twin Method has been subject to criticism from Statistical Genetics, Statistics and Psychology, with some argueing that conclusions reached via this method are ambiguous or meaningless. Core elements of these criticisms and their rejoinders are listed below: ## Criticisms of Statistical Methods It has been argued that that the Statistical underpinnings of twin research are invalid. Such statistical critiques argue that heritability estimates used for most twin studies rest on restrictive assumptions which are usually not tested, and if they are, are often found to be violated by the data. For example, Peter Schonemann has criticized methods for estimating heritability developed in the 1970s. He has also argued that the heritability estimate from a twin study may reflect factors other than shared genes. Using the statistical models published in Loehlin and Nichols (1976), the narrow heritability’s of HR of responses to the question “did you have your back rubbed” has been shown to work out to .92 heritable for males and .21 heritable for females, and the question “Did you wear sunglasses after dark?” is 130% heritable for males and 103% for females In the days before the computer, statisticians were forced to use methods which were computationally tractable, at the cost of known limitations. Since the 1980s these approximate statistical methods have been discarded: Modern twin methods based on Structural Equation Modeling are not subject to the limitations and heritability estimates such as those noted above are impossible. Critically, the newer methods allow for explicit testing of the role of different pathways and incorporation and testing of complex effects. ## Sampling: Twins as representative members of the population The results of twin studies cannot be automatically generalised beyond the population in which they have been derived. It is therefore important to understand the particular sample studied, and the nature of twins themselves. Twins are not a random sample of the population, and they differ in their developmental environment. In this sense they are not representative For example: Dizygotic (DZ) twin births are affected by many factors. Some women frequently produce more than one egg at each menstrual period and, therefore, are more likely to have twins. This tendency may run in the family either in the mother's or father's side of the family, and often runs through both. Women over the age of 35 are more likely to produce two eggs. Women who have three or more children are also likely to have dizygotic twins. Artificial induction of ovulation and in vitro fertilization-embryo replacement can also give rise to DZ and MZ twins Twins differ very little from non-twin siblings. Measured studies on the personality and intelligence of twins suggest that they have scores on these traits very similar to those of non-twins (for instance Deary et al. 2006). ## Observational nature of twin studies For very obvious reasons, studies of twins are with almost no exceptions observational. This contrasts with, for instance, studies in plants or in animal breeding where the effects of experimentally randomized genotypes and environment combinations are measured. In human studies, we observe rather than control the exposure of individuals to different environments. The observational study and it inherent confounding of causes is common in psychology. Twin studies are in part motivated by an attempt to take advantage of the random assortment of genes between members of a family to help understand these correlations. This, while the twin study tells us only how genes and families affect behavior within the observed range of environments, and with the caveat that often genes and environments will covary, this argued to be a considerable advance over the alternative: which is no knowledge of the different roles of genes and families whatsoever. # Advanced Methodology ## Interactions The effects of genes depend on the environment they are in. Possible complex genetic effects include GE interactions, in which the effects of a gene allele differ across different environments. Simple examples would include situations where a gene multiples the effect of an environment (in this case the slope of response to an environment would differ between genotypes). A second effect is "GE correlation", in which certain allelles occur more frequently than others in certain environments. If a gene causes a person to enjoy reading, then children with this allele are likely to be raised in households with books in them (due to GE correlation: one or both of their parents has the allele and therefore both accumulates a book collection and passes on the book-reading allele). Such effects can be assessed by measuring the purported environmental correlate (in this case books in the home) directly. Often the role of environment seems maximal very early in life, and decreases rapidly after compulsory education begins. This is observed for instance in reading (Byrne etal 2006) as well as intelligence (Deary et al, 2006). This is an example of a GAge effect and allows an examination of both GE correlations due to parental environments (these are broken up with time), and of G*E correlations caused by individuals actively seeking certain environments (Plomin et al., 1987). ## Continuous variable or Correlational studies While concordance studies compare traits which are either present or absent in each twin, correlational studies compare the agreement in continuously varying traits across twins. # Terminology Pairwise concordance Probandwise concordance ## Pairwise concordance For a group of twins, pairwise concordance is defined as C/(C+D), where C is the number of concordant pairs and D is the number of discordant pairs. For example, a group of 10 twins have been pre-selected to have one affected member (of the pair). During the course of the study four other previously non-affected members become affected, giving a pairwise concordance of 4/(4+6) or 4/10 or 40%. ## Probandwise concordance For a group of twins in which at least one member of each pair is affected, probandwise concordance is a measure of the proportion of twins who have the illness who have an affected twin and can be calculated with the formula of 2C/(2C+D), in which C is the number of concordant pairs and D is the number of discordant pairs. For example, consider a group of 10 twins that have been pre-selected to have one affected member. During the course of the study, four other previously non-affected members become affected, giving a probandwise concordance of 8/(8+6) or 8/14 or 57%. # Further reading - Textbook, software, and example scripts for twin research - Jang, K.L., McCrae, R.R., Angleitner, A. Riemann, R. & Livesley, W.J. (1998). Heritability of facet-level traits in a cross-cultural twin sample: support for a hierarchical model of personality. Journal of Personality and Social Psychology 74:1556-1565. - Plomin, DeFries, McClearn & McGuffin (2000). Behavioral Genetics: A Primer 4th edition. W.H.Freeman & Co Ltd. - Nancy L. Segal (2005) Indivisible by Two: Lives of Extraordinary Twins. New York, Harvard University Press. ### Critical Accounts - Peter Schonemann (1997). Models and muddles of heritability. Genetica, 99, 97-108: - Peter Schonemann and Roberta D. Schonemann (1994). Environmental versus genetic models for Osborne’s personality data on identical and fraternal twins. CPC, 1994, 13 (2), 141-167 - Kamin, L. J. (1974). The Science and Politics of I.Q. Potomac, MD: Lawrence Erlbaum Associates. - Kempthorne O. (1997). Heritability: uses and abuses. Genetica, Volume 99, Numbers 2-3, 1997 , pp. 109-112(4) - Joseph, J. (2003). The Gene Illusion: Genetic Research in Psychiatry and Psychology Under the Microscope. PCCS Books. - Christiane Capron, Adrian R. Vetta, Michel Duyme and Atam Vetta (1999). Misconceptions of biometrical IQists. Cahiers de Psychologie Cognitive/Current Psychology of Cognition 1999, 18 (2), 115-160 - Horwitz AV, Videon TM, Schmitz MF, Davis D. Rethinking twins and environments: possible social sources for assumed genetic influences in twin research. J Health Soc Behav. 2003 Jun;44(2):111-129. And in reply to this article see: - Freese J and Powell B Tilting at Twindmills: rethinking sociological responses to behavioral genetics. J Health Soc Behav. 2003 Jun;44(2):130-135.	Twin study Twin studies are one of a family of designs in behavior genetics which aid the study of individual differences by highlighting the role of environmental and genetic causes on behavior. Twins are invaluable for studying these important questions because they disentangle the sharing of genes and environments. If we observe that children in a family are more similar than might be expected by chance, this may reflect shared environmental influences common to members of family —class, parenting styles, education etc.— but they will also reflect shared genes, inherited from parents. The twin design compares the similarity of identical twins who share 100% of their genes, to that of dizygotic or fraternal twins, who share only 50% of their genes. By studying many hundreds of families of twins, researchers can then understand more about the role of genetic effects, and the effects of shared and unique environment effects. Modern twin studies have shown that almost all traits are in part influenced by genetic differences, with some characteristics showing a strong influence (e.g., height), others an intermediate level (i.e. IQ) and some more complex heritabilities, with evidence for different genes affecting different elements of the trait - for instance Autism. ## History While twins have been of interest to scholars since early civilization, such as the early physician Hippocrates (5th c. BCE), who attributed similar diseases in twins to shared material circumstances, and the stoic philosopher Posidonius (1rst c. BCE), who attributed such similarities to shared astrological sex circumstances, the modern history of the twin study derives from Sir Francis Galton's pioneering use of twins to study the role of genes and environment on human development and behavior. # Methods The power of twin designs arises from the fact that twins may be either monozygotic (MZ: developing from a single fertilized egg and therefore sharing all of their genes) – or dizygotic (DZ: developing from two fertilized eggs and therefore sharing on average 50% of their genes, the same level of genetic similarity as found in non-twin siblings). These known differences in genetic similarity, together with a testable assumption of equal environments for MZ and DZ twins (Bouchard & Propping, 1993) creates the basis for the twin design for exploring the effects of genetic and environmental variance on a phenotype (Neale & Cardon, 1992). The basic logic of the twin study can be understood with very little mathematics beyond an understanding of correlation and the concept of variance. Like all behavior genetic research, the classic twin study begins from assessing the variance of a behavior (called a phenotype by geneticists) in a large group, and attempts to estimate how much of this is due to genetic effects (heritability), how much appears to be due to shared environmental effects, and how much is due to unique environmental effects - events occurring to one twin but not another. Typically these three components are called A (additive genetics) C (common environment) and E (unique environment). the so-called ACE Model. It is also possible to examine non-additive genetics effects (often denoted D for dominance (see below for more complex twin designs). Given the ACE model, researchers can determine what proportion of variance in a trait is heritable, versus the proportions which are due to shared environment or unshared environment. While nearly all research is carried out using SEM programs such as the freeware Mx, the essential logic of the twin design is as follows: MZ twins raised in a family share both 100% of their genes, and all of the shared environment. All differences between them in this framework are unique. The correlation we observe between MZ twins provides an estimate of A+C. DZ twins have a common shared environment, and share 50% of their genes: so the correlation between DZ twins is a direct estimate of 1/2A + C. rMZ = A+C rDZ = .5A+C These two equations allow us to derive A C and E: A = 2(rmz- rdz) C = rmz-A E= 1-rmz Where rmz and rdz are simply the correlations of the trait in MZ and DZ twins respectively. Twice difference between MZ and DZ twins gives us A: the additive genetic effect. C is simply the MZ correlation - our estimate of A, and E is estimated directly by how much the MZ twin correlation deviates from 1. (Jinks & Fulker, 1970; Plomin, DeFries , McClearn, & McGuffin, 2001). ### Modern Modeling Beginning in the 1970s, research transitioned to explicitly modeling the values of A, C, and E within a maximum likelihood framework (Martin & Eaves, 1977). While computationally much more complex, benefits of this approach are manifold, and modeling tools such as Mx (Neale, Boker, Xie, & Maes, 2002) have made the new techniques relatively accessible. ## Assumptions Equal environments. It can be seen from the modelling above, that the main assumption of the twin study is that of equal environments. At an intuitive level, this seems reasonable - why would parents note that two children shared their hair and eye color, and then contrive to make their IQs identical? Indeed, how could they? This assumption, however, has been directly tested. An interesting case occurs where parents believe their twins to be non-identical when in fact they are genetically MZ. Studies of a range of psychological traits indicate that these children remain as concordant as MZs raised by parents who treated them as identical (Kendler, Neale, Kessler, Heath, & Eaves, 1993). ## Measured similarity: A direct test of assumptions in twin designs A particularly powerful technique for testing the twin method has recently been reported by Visscher et al. Instead of using twins, this group took advantage of the fact that while siblings on average share 50% of their genes, the actual gene-sharing for individual sibling pairs varies around this value, essentially creating a continuum of genetic similarity or "twinness" within families. Estimates of heritability based on direct estimates of gene sharing confirm those from the twin method, providing support for the assumptions of the method in the domains of cognition, personality, and psychopathology. ## Extended twin designs and more complex genetic models The basic or classical twin-design contains only MZ and DZ twins raised in their biological family. This represents only a sub-set of the possible genetic and environmental relationships. It is fair to say, therefore, that the heritability estimates from twin designs represent a first step in understanding the genetics of behavior. The variance partitioning of the twin study into additive genetic, shared, and unshared environment is a first approximation to a complete analysis taking into account gene-environment covariance and interaction, as well as other non-additive effects on behavior. The revolution in molecular genetics has provided more effective tools for describing the genome, and many researchers are pursuing molecular genetics in order to directly assess the influence of alleles and environments on traits. An initial limitation of the twin design is that is does not afford an opportunity to consider both Shared Environment and Non-additive genetic effects simultaneously. This limit can be addressed by including additional siblings to the design. A second limitation is that GE correlation is not detectable as a distinct effect. Addressing this limit requires incorporating adoption models, or children-of-twins designs, to assess family influences uncorrelated with shared genetic effects. # Criticism The Twin Method has been subject to criticism from Statistical Genetics, Statistics and Psychology, with some argueing that conclusions reached via this method are ambiguous or meaningless. Core elements of these criticisms and their rejoinders are listed below: ## Criticisms of Statistical Methods It has been argued that that the Statistical underpinnings of twin research are invalid. Such statistical critiques argue that heritability estimates used for most twin studies rest on restrictive assumptions which are usually not tested, and if they are, are often found to be violated by the data. For example, Peter Schonemann has criticized methods for estimating heritability developed in the 1970s. He has also argued that the heritability estimate from a twin study may reflect factors other than shared genes. Using the statistical models published in Loehlin and Nichols (1976)[1], the narrow heritability’s of HR of responses to the question “did you have your back rubbed” has been shown to work out to .92 heritable for males and .21 heritable for females, and the question “Did you wear sunglasses after dark?” is 130% heritable for males and 103% for females [2] [3] In the days before the computer, statisticians were forced to use methods which were computationally tractable, at the cost of known limitations. Since the 1980s these approximate statistical methods have been discarded: Modern twin methods based on Structural Equation Modeling are not subject to the limitations and heritability estimates such as those noted above are impossible. Critically, the newer methods allow for explicit testing of the role of different pathways and incorporation and testing of complex effects. ## Sampling: Twins as representative members of the population The results of twin studies cannot be automatically generalised beyond the population in which they have been derived. It is therefore important to understand the particular sample studied, and the nature of twins themselves. Twins are not a random sample of the population, and they differ in their developmental environment. In this sense they are not representative [4] For example: Dizygotic (DZ) twin births are affected by many factors. Some women frequently produce more than one egg at each menstrual period and, therefore, are more likely to have twins. This tendency may run in the family either in the mother's or father's side of the family, and often runs through both. Women over the age of 35 are more likely to produce two eggs. Women who have three or more children are also likely to have dizygotic twins. Artificial induction of ovulation and in vitro fertilization-embryo replacement can also give rise to DZ and MZ twins [5] [6] [7][8] [9] [10]. Twins differ very little from non-twin siblings. Measured studies on the personality and intelligence of twins suggest that they have scores on these traits very similar to those of non-twins (for instance Deary et al. 2006). ## Observational nature of twin studies For very obvious reasons, studies of twins are with almost no exceptions observational. This contrasts with, for instance, studies in plants or in animal breeding where the effects of experimentally randomized genotypes and environment combinations are measured. In human studies, we observe rather than control the exposure of individuals to different environments. [11] [12] [13] [14] The observational study and it inherent confounding of causes is common in psychology. Twin studies are in part motivated by an attempt to take advantage of the random assortment of genes between members of a family to help understand these correlations. This, while the twin study tells us only how genes and families affect behavior within the observed range of environments, and with the caveat that often genes and environments will covary, this argued to be a considerable advance over the alternative: which is no knowledge of the different roles of genes and families whatsoever. # Advanced Methodology ## Interactions The effects of genes depend on the environment they are in. Possible complex genetic effects include GE interactions, in which the effects of a gene allele differ across different environments. Simple examples would include situations where a gene multiples the effect of an environment (in this case the slope of response to an environment would differ between genotypes). A second effect is "GE correlation", in which certain allelles occur more frequently than others in certain environments. If a gene causes a person to enjoy reading, then children with this allele are likely to be raised in households with books in them (due to GE correlation: one or both of their parents has the allele and therefore both accumulates a book collection and passes on the book-reading allele). Such effects can be assessed by measuring the purported environmental correlate (in this case books in the home) directly. Often the role of environment seems maximal very early in life, and decreases rapidly after compulsory education begins. This is observed for instance in reading (Byrne etal 2006) as well as intelligence (Deary et al, 2006). This is an example of a GAge effect and allows an examination of both GE correlations due to parental environments (these are broken up with time), and of G*E correlations caused by individuals actively seeking certain environments (Plomin et al., 1987). ## Continuous variable or Correlational studies While concordance studies compare traits which are either present or absent in each twin, correlational studies compare the agreement in continuously varying traits across twins. # Terminology Pairwise concordance Probandwise concordance ## Pairwise concordance For a group of twins, pairwise concordance is defined as C/(C+D), where C is the number of concordant pairs and D is the number of discordant pairs. For example, a group of 10 twins have been pre-selected to have one affected member (of the pair). During the course of the study four other previously non-affected members become affected, giving a pairwise concordance of 4/(4+6) or 4/10 or 40%. ## Probandwise concordance For a group of twins in which at least one member of each pair is affected, probandwise concordance is a measure of the proportion of twins who have the illness who have an affected twin and can be calculated with the formula of 2C/(2C+D), in which C is the number of concordant pairs and D is the number of discordant pairs. For example, consider a group of 10 twins that have been pre-selected to have one affected member. During the course of the study, four other previously non-affected members become affected, giving a probandwise concordance of 8/(8+6) or 8/14 or 57%. # Further reading - Textbook, software, and example scripts for twin research - Jang, K.L., McCrae, R.R., Angleitner, A. Riemann, R. & Livesley, W.J. (1998). Heritability of facet-level traits in a cross-cultural twin sample: support for a hierarchical model of personality. Journal of Personality and Social Psychology 74:1556-1565. - Plomin, DeFries, McClearn & McGuffin (2000). Behavioral Genetics: A Primer 4th edition. W.H.Freeman & Co Ltd. - Nancy L. Segal (2005) Indivisible by Two: Lives of Extraordinary Twins. New York, Harvard University Press. ### Critical Accounts - Peter Schonemann (1997). Models and muddles of heritability. Genetica, 99, 97-108: [1] - Peter Schonemann and Roberta D. Schonemann (1994). Environmental versus genetic models for Osborne’s personality data on identical and fraternal twins. CPC, 1994, 13 (2), 141-167 [2] - Kamin, L. J. (1974). The Science and Politics of I.Q. Potomac, MD: Lawrence Erlbaum Associates. - Kempthorne O. (1997). Heritability: uses and abuses. Genetica, Volume 99, Numbers 2-3, 1997 , pp. 109-112(4) - Joseph, J. (2003). The Gene Illusion: Genetic Research in Psychiatry and Psychology Under the Microscope. PCCS Books. - Christiane Capron, Adrian R. Vetta, Michel Duyme and Atam Vetta (1999). Misconceptions of biometrical IQists. Cahiers de Psychologie Cognitive/Current Psychology of Cognition 1999, 18 (2), 115-160 - Horwitz AV, Videon TM, Schmitz MF, Davis D. Rethinking twins and environments: possible social sources for assumed genetic influences in twin research. J Health Soc Behav. 2003 Jun;44(2):111-129. And in reply to this article see: - Freese J and Powell B Tilting at Twindmills: rethinking sociological responses to behavioral genetics. J Health Soc Behav. 2003 Jun;44(2):130-135.	https://www.wikidoc.org/index.php/Twin_studies
f6e05b960652f17898fc6f747f37d490edf93e79	wikidoc	Tylenol PM	Tylenol PM Tylenol PM is the trademark for a mixture of paracetamol (acetaminophen) and diphenhydramine, distributed by Johnson & Johnson. It is marketed as a combined analgesic and sedative, or more simply, pain reliever and sleep aid, intended to treat occasional headaches and minor aches and pains with accompanying sleeplessness. It is listed as non-habit forming. Acetaminophen alone is sold as simply Tylenol, while diphenhydramine alone is marketed as Simply Sleep, and as Benadryl. Diphenhydramine is an anti-histamine and is also the active ingredient in Benadryl(allergies) and Benylin which is used in cough and cold therapy as an anti-cough (anti-tussive) with the drying effect of the anti-histamine. The drowsiness is caused by the anti-histamine. # Cheese Tylenol PM, along with black tar heroin, is a main ingredient in Cheese, a relatively new drug that has become widespread among young teenagers in the Dallas, Texas area. Recently, some stores in the Dallas area have pulled Tylenol PM from their shelves . This is because store managers believed that the people producing the 'Cheese' were shoplifting the Tylenol PM.	Tylenol PM Tylenol PM is the trademark for a mixture of paracetamol (acetaminophen) and diphenhydramine, distributed by Johnson & Johnson. It is marketed as a combined analgesic and sedative, or more simply, pain reliever and sleep aid, intended to treat occasional headaches and minor aches and pains with accompanying sleeplessness. It is listed as non-habit forming. Acetaminophen alone is sold as simply Tylenol, while diphenhydramine alone is marketed as Simply Sleep, and as Benadryl. Diphenhydramine is an anti-histamine and is also the active ingredient in Benadryl(allergies) and Benylin which is used in cough and cold therapy as an anti-cough (anti-tussive) with the drying effect of the anti-histamine. The drowsiness is caused by the anti-histamine. # Cheese Tylenol PM, along with black tar heroin, is a main ingredient in Cheese, a relatively new drug that has become widespread among young teenagers in the Dallas, Texas area. Recently, some stores in the Dallas area have pulled Tylenol PM from their shelves [1]. This is because store managers believed that the people producing the 'Cheese' were shoplifting the Tylenol PM. Template:Pharma-stub	https://www.wikidoc.org/index.php/Tylenol_PM
19db8b0413659397cf18acf135ba5755aa38f41e	wikidoc	Tyrocidine	Tyrocidine Tyrocidine is a class of naturally occurring antibiotics produced by some strains of Bacillus brevis. Tyrocidines A, B, and C are cyclic decapeptides. The biosynthesis of tyrocidine involves three enzymes. Parts of its sequence are identical to gramicidin S. Tyrocidine and gramicidin are the constituents of tyrothricin, which was originally isolated by René Dubos in 1939, and was the first commercially produced antibiotic. It is used as a topical application; toxicity prevents systemic use. Dubos's discovery helped revive interest in research on penicillin. Tyrocidine kills bacteria by interacting with their cytoplasmic membrane and causing leakage of their intracellular content. It also affects intracellular membranes such as those of mitochondria.	Tyrocidine Tyrocidine is a class of naturally occurring antibiotics produced by some strains of Bacillus brevis. Tyrocidines A, B, and C are cyclic decapeptides. The biosynthesis of tyrocidine involves three enzymes. Parts of its sequence are identical to gramicidin S. Tyrocidine and gramicidin are the constituents of tyrothricin, which was originally isolated by René Dubos in 1939, and was the first commercially produced antibiotic. It is used as a topical application; toxicity prevents systemic use. Dubos's discovery helped revive interest in research on penicillin. Tyrocidine kills bacteria by interacting with their cytoplasmic membrane and causing leakage of their intracellular content. It also affects intracellular membranes such as those of mitochondria. # External links - Tyrocidine at the US National Library of Medicine Medical Subject Headings (MeSH) Template:WH Template:WS	https://www.wikidoc.org/index.php/Tyrocidine
f7a2d62e0692ea481cc9c68b1c2308ba47b6058c	wikidoc	Tyrosinase	Tyrosinase Tyrosinase is an oxidase that is the rate-limiting enzyme for controlling the production of melanin. The enzyme is mainly involved in two distinct reactions of melanin synthesis; firstly, the hydroxylation of a monophenol and secondly, the conversion of an o-diphenol to the corresponding o-quinone. o-Quinone undergoes several reactions to eventually form melanin. Tyrosinase is a copper-containing enzyme present in plant and animal tissues that catalyzes the production of melanin and other pigments from tyrosine by oxidation, as in the blackening of a peeled or sliced potato exposed to air. It is found inside melanosomes which are synthesised in the skin melanocytes. In humans, the tyrosinase enzyme is encoded by the TYR gene. # Significance ## Clinical significance A mutation in the tyrosinase gene resulting in impaired tyrosinase production leads to type I oculocutaneous albinism, a hereditary disorder that affects one in every 20,000 people. Tyrosinase activity is very important. If uncontrolled during the synthesis of melanin, it results in increased melanin synthesis. Decreasing tyrosinase activity has been targeted for the betterment or prevention of conditions related to the hyperpigmentation of the skin, such as melasma and age spots. Several polyphenols, including flavonoids or stilbenoid, substrate analogues, free radical scavengers, and copper chelators, have been known to inhibit tyrosinase. Henceforth, the medical and cosmetic industries are focusing research on tyrosinase inhibitors to treat skin disorders. ## Significance in food industry In food industry, tyrosinase inhibition is desired as tyrosinase catalyzes the oxidation of phenolic compounds found in fruits and vegetables into quinones, which gives an undesirable taste and color and also decreases the availability of certain essential amino acids as well as the digestibility of the products. As such, highly effective tyrosinase inhibitors are also needed in agriculture and the food industry. Well known tyrosinase inhibitors include kojic acid, tropolone, coumarins, vanillic acid, vanillin, and vanillic alcohol. ## Significance in insects Tyrosinase has a wide range of functions in insects, including wound healing, sclerotization, melanin synthesis and parasite encapsulation. As a result, it is an important enzyme as it is the defensive mechanism of insects. Some insecticides are aimed to inhibit tyrosinase. # Catalyzed reaction Tyrosinase carries out the oxidation of phenols such as tyrosine and dopamine using dioxygen (O2). In the presence of catechol, benzoquinone is formed (see reaction below). Hydrogens removed from catechol combine with oxygen to form water. The substrate specificity becomes dramatically restricted in mammalian tyrosinase which uses only L-form of tyrosine or DOPA as substrates, and has restricted requirement for L-DOPA as cofactor. # Structure Tyrosinases have been isolated and studied from a wide variety of plant, animal, and fungal species. Tyrosinases from different species are diverse in terms of their structural properties, tissue distribution, and cellular location. No common tyrosinase protein structure occurring across all species has been found. The enzymes found in plant, animal, and fungal tissue frequently differ with respect to their primary structure, size, glycosylation pattern, and activation characteristics. However, all tyrosinases have in common a binuclear, type 3 copper centre within their active sites. Here, two copper atoms are each coordinated with three histidine residues. ## Human tyrosinase Human tyrosinase is a single membrane-spanning transmembrane protein. In humans, tyrosinase is sorted into melanosomes and the catalytically active domain of the protein resides within melanosomes. Only a small, enzymatically inessential part of the protein extends into the cytoplasm of the melanocyte. As opposed to fungal tyrosinase, human tyrosinase is a membrane-bound glycoprotein and has 13% carbohydrate content. The derived TYR allele (rs2733832) is associated with lighter skin pigmentation in human populations. It is most common in Europe, but is also found at lower, moderate frequencies in Central Asia, the Middle East, North Africa, and among the San and Mbuti Pygmies. ## Active site The two copper atoms within the active site of tyrosinase enzymes interact with dioxygen to form a highly reactive chemical intermediate that then oxidizes the substrate. The activity of tyrosinase is similar to catechol oxidase, a related class of copper oxidase. Tyrosinases and catechol oxidases are collectively termed polyphenol oxidases. # Gene regulation The gene for tyrosinase is regulated by the microphthalmia-associated transcription factor (MITF).	Tyrosinase Tyrosinase is an oxidase that is the rate-limiting enzyme for controlling the production of melanin. The enzyme is mainly involved in two distinct reactions of melanin synthesis; firstly, the hydroxylation of a monophenol and secondly, the conversion of an o-diphenol to the corresponding o-quinone. o-Quinone undergoes several reactions to eventually form melanin.[1] Tyrosinase is a copper-containing enzyme present in plant and animal tissues that catalyzes the production of melanin and other pigments from tyrosine by oxidation, as in the blackening of a peeled or sliced potato exposed to air.[2] It is found inside melanosomes which are synthesised in the skin melanocytes. In humans, the tyrosinase enzyme is encoded by the TYR gene.[3] # Significance ## Clinical significance A mutation in the tyrosinase gene resulting in impaired tyrosinase production leads to type I oculocutaneous albinism, a hereditary disorder that affects one in every 20,000 people.[4] Tyrosinase activity is very important. If uncontrolled during the synthesis of melanin, it results in increased melanin synthesis. Decreasing tyrosinase activity has been targeted for the betterment or prevention of conditions related to the hyperpigmentation of the skin, such as melasma and age spots.[5] Several polyphenols, including flavonoids or stilbenoid, substrate analogues, free radical scavengers, and copper chelators, have been known to inhibit tyrosinase.[6] Henceforth, the medical and cosmetic industries are focusing research on tyrosinase inhibitors to treat skin disorders.[1] ## Significance in food industry In food industry, tyrosinase inhibition is desired as tyrosinase catalyzes the oxidation of phenolic compounds found in fruits and vegetables into quinones, which gives an undesirable taste and color and also decreases the availability of certain essential amino acids as well as the digestibility of the products. As such, highly effective tyrosinase inhibitors are also needed in agriculture and the food industry.[7] Well known tyrosinase inhibitors include kojic acid,[8] tropolone,[9] coumarins,[10] vanillic acid, vanillin, and vanillic alcohol.[11] ## Significance in insects Tyrosinase has a wide range of functions in insects, including wound healing, sclerotization, melanin synthesis and parasite encapsulation. As a result, it is an important enzyme as it is the defensive mechanism of insects. Some insecticides are aimed to inhibit tyrosinase.[7] # Catalyzed reaction Tyrosinase carries out the oxidation of phenols such as tyrosine and dopamine using dioxygen (O2). In the presence of catechol, benzoquinone is formed (see reaction below). Hydrogens removed from catechol combine with oxygen to form water. The substrate specificity becomes dramatically restricted in mammalian tyrosinase which uses only L-form of tyrosine or DOPA as substrates, and has restricted requirement for L-DOPA as cofactor.[12] # Structure Tyrosinases have been isolated and studied from a wide variety of plant, animal, and fungal species. Tyrosinases from different species are diverse in terms of their structural properties, tissue distribution, and cellular location.[13] No common tyrosinase protein structure occurring across all species has been found.[14] The enzymes found in plant, animal, and fungal tissue frequently differ with respect to their primary structure, size, glycosylation pattern, and activation characteristics. However, all tyrosinases have in common a binuclear, type 3 copper centre within their active sites. Here, two copper atoms are each coordinated with three histidine residues. ## Human tyrosinase Human tyrosinase is a single membrane-spanning transmembrane protein.[15] In humans, tyrosinase is sorted into melanosomes[16] and the catalytically active domain of the protein resides within melanosomes. Only a small, enzymatically inessential part of the protein extends into the cytoplasm of the melanocyte. As opposed to fungal tyrosinase, human tyrosinase is a membrane-bound glycoprotein and has 13% carbohydrate content.[7] The derived TYR allele (rs2733832) is associated with lighter skin pigmentation in human populations. It is most common in Europe, but is also found at lower, moderate frequencies in Central Asia, the Middle East, North Africa, and among the San and Mbuti Pygmies.[17] ## Active site The two copper atoms within the active site of tyrosinase enzymes interact with dioxygen to form a highly reactive chemical intermediate that then oxidizes the substrate. The activity of tyrosinase is similar to catechol oxidase, a related class of copper oxidase. Tyrosinases and catechol oxidases are collectively termed polyphenol oxidases. # Gene regulation The gene for tyrosinase is regulated by the microphthalmia-associated transcription factor (MITF).[19][20]	https://www.wikidoc.org/index.php/Tyrosinase
ae3b356e97b0924b7ba441a12501fa900c52ed99	wikidoc	UTY (gene)	UTY (gene) Histone demethylase UTY is an enzyme that in humans is encoded by the UTY gene. This gene encodes a protein containing tetratricopeptide repeats which are thought to be involved in protein-protein interactions. This protein is a minor histocompatibility antigen which may induce graft rejection of male stem cell grafts. Alternative splicing results in multiple transcript variants encoding different isoforms. # Interactions UTY (gene) has been shown to interact with TLE1, and WDR90	UTY (gene) Histone demethylase UTY is an enzyme that in humans is encoded by the UTY gene.[1][2][3] This gene encodes a protein containing tetratricopeptide repeats which are thought to be involved in protein-protein interactions. This protein is a minor histocompatibility antigen which may induce graft rejection of male stem cell grafts. Alternative splicing results in multiple transcript variants encoding different isoforms.[3] # Interactions UTY (gene) has been shown to interact with TLE1,[4] and WDR90[5]	https://www.wikidoc.org/index.php/UTY_(gene)
0e2ca5c2aa0f20813c0d67829a394a8c90f4962a	wikidoc	Ultrasound	Ultrasound # Overview Ultrasound is cyclic sound pressure with a frequency greater than the upper limit of human hearing. Although this limit varies from person to person, it is approximately 20 kilohertz (20,000 hertz) in healthy, young adults and thus, 20 kHz serves as a useful lower limit in describing ultrasound. Ultrasound is manually produced in many different fields, typically to penetrate a medium and measure the reflection signature or supply focused energy. The reflection signature can reveal details about the inner structure of the medium. The most well known application of this technique is its use in sonography to produce pictures of fetuses in the human womb. There are a vast number of other applications as well. # Ability to hear ultrasound The upper frequency limit in humans (approximately 20 kHz) is caused by the middle ear, which acts as a low-pass filter. If ultrasound is fed directly into the skull bone and reaches the cochlea without passing through the middle ear, much higher frequencies can be heard. This effect is discussed in ultrasonic hearing. Carefully-designed scientific studies have been performed and confirmed what they call the hypersonic effect - that even without consciously hearing it, high-frequency sound can have a measurable effect on the mind. It is a fact in psychoacoustics that children can hear some high-pitched sounds that older adults cannot hear, because in humans the upper limit pitch of hearing tends to become lower with age. A cell phone company has used this to create ring signals supposedly only able to be heard by younger humans; but many older people claim to be able to hear it, which is likely given the considerable variation of age-related deterioration in the upper hearing threshold. Some animals – such as dogs, cats, dolphins, bats, and mice have an upper frequency limit that is greater than that of the human ear and thus can hear ultrasound. # Diagnostic sonography Medical sonography (ultrasonography) is an ultrasound-based diagnostic medical imaging technique used to visualize muscles, tendons, and many internal organs, their size, structure and any pathological lesions with real time tomographic images. It is also used to visualize a fetus during routine and emergency prenatal care. Ultrasound scans are performed by medical health care professionals called sonographers. Obstetric sonography is commonly used during pregnancy. Ultrasound has been used to image the human body for at least 50 years. It is one of the most widely used diagnostic tools in modern medicine. The technology is relatively inexpensive and portable, especially when compared with modalities such as magnetic resonance imaging(MRI) and computed tomography (CT). As currently applied in the medical environment, ultrasound poses no known risks to the patient. Sonography is generally described as a "safe test" because it does not use ionizing radiation, which imposes hazards, such as cancer production and chromosome breakage. However, ultrasonic energy has two potential physiological effects: it enhances inflammatory response; and it can heat soft tissue. Ultrasound energy produces a mechanical pressure wave through soft tissue. This pressure wave may cause microscopic bubbles in living tissues, and distortion of the cell membrane, influencing ion fluxes and intracellular activity. When ultrasound enters the body, it causes molecular friction and heats the tissues slightly. This effect is very minor as normal tissue perfusion dissipates heat. With high intensity, it can also cause small pockets of gas in body fluids or tissues to expand and contract/collapse in a phenomenon called cavitation (this is not known to occur at diagnostic power levels used by modern diagnostic ultrasound units). The long-term effects of tissue heating and cavitation are not known. There are several studies that indicate the harmful side effects on animal fetuses associated with the use of sonography on pregnant mammals. A noteworthy study in 2006 suggests exposure to ultrasound can affect fetal brain development in mice. This misplacement of brain cells during their development is linked to disorders ranging "from mental retardation and childhood epilepsy to developmental dyslexia, autism spectrum disorders and schizophrenia, the researchers said. There is no link made yet between the test results on animals, such as mice, and the possible outcome to humans. Widespread clinical use of diagnostic ultrasound testing on humans has not been done for ethical reasons. The possibility exists that biological effects may be identified in the future, currently most doctors feel that based on available information the benefits to patients outweigh the risks. Obstetric ultrasound can be used to identify many conditions that would be harmful to the mother and the baby. For this reason many health care professionals consider that the risk of leaving these conditions undiagnosed is much greater than the very small risk, if any, associated with undergoing the scan. According to Cochrane review, routine ultrasound in early pregnancy (less than 24 weeks) appears to enable better gestational age assessment, earlier detection of multiple pregnancies and earlier detection of clinically unsuspected fetal malformation at a time when termination of pregnancy is possible. Sonography is used routinely in obstetric appointments during pregnancy, but the FDA discourages its use for non-medical purposes such as fetal keepsake videos and photos, even though it is the same technology used in hospitals. Obstetric ultrasound is primarily used to: - Date the pregnancy (gestational age) - Confirm fetal viability - Determine location of fetus, intrauterine vs ectopic - Check the location of the placenta in relation to the cervix - Check for the number of fetuses (multiple pregnancy) - Check for major physical abnormalities. - Assess fetal growth (for evidence of intrauterine growth restriction (IUGR)) - Check for fetal movement and heartbeat. - Determine the sex of the baby Unfortunately, results are occasionally wrong, producing a false positive (the Cochrane Collaboration is a relevant effort to improve the reliability of health care trials). False detection may result in patients being warned of birth defects when no such defect exists. Sex determination is only accurate after 12 weeks gestation . When balancing risk and reward, there are recommendations to avoid the use of routine ultrasound for low risk pregnancies . In many countries ultrasound is used routinely in the management of all pregnancies. According to European Committee of Medical Ultrasound Safety (ECMUS) "Ultrasonic examinations should only be performed by competent personnel who are trained and updated in safety matters. Ultrasound produces heating, pressure changes and mechanical disturbances in tissue. Diagnostic levels of ultrasound can produce temperature rises that are hazardous to sensitive organs and the embryo/fetus. Biological effects of non-thermal origin have been reported in animals but, to date, no such effects have been demonstrated in humans, except when a microbubble contrast agent is present." A study on rodent fetus brains that are exposed to ultrasound showed signs of damage. Speculation on human fetuses can be in a range of no significant complications to a variety of mental and brain disorders. The study shows that rodent brain cells failed to grow to their proper position and remained scattered in incorrect parts of the brain. The conditions of this experiment are different from typical fetal scanning because of the long dwell times. . Care should be taken to use low power settings and avoid pulsed wave scanning of the fetal brain unless specifically indicated in high risk pregnancies. It should be noted that obstetrics is not the only use of ultrasound. Soft tissue imaging of many other parts of the body is conducted with ultrasound. Other scans routinely conducted are cardiac, renal, liver and gallbladder (hepatic). Other common applications include musculo-skeletal imaging of muscles, ligaments and tendons, ophthalmic ultrasound (eye) scans and superficial structures such as testicle, thyroid, salivary glands and lymph nodes. Because of the real time nature of ultrasound, it is often used to guide interventional procedures such as fine needle aspiration FNA or biopsy of masses for cytology or histology testing in the breast, thyroid, liver, kidney, lymph nodes, muscles and joints. Ultrasound scanners using pulsed wave and colour Doppler are used to visualize arteries and veins. Figures released for the period 2005-2006 by UK Government (Department of Health) show that non-obstetric ultrasound examinations contributed to more than 65% of the total number of ultrasound scans conducted. # Biomedical ultrasonic applications Ultrasound also has therapeutic applications, which can be highly beneficial when used with dosage precautions: - According to RadiologyInfo , ultrasounds are useful in the detection of Pelvic abnormalities and can involve techniques known as abdominal (transabdominal) ultrasound, vaginal (transvaginal or endovaginal) ultrasound in women, and also rectal (transrectal) ultrasound in men. - Treating benign and malignant tumors and other disorders, via a process known as Focused Ultrasound Surgery (FUS) or HIFU, High Intensity Focused Ultrasound. These procedures generally use lower frequencies than medical diagnostic ultrasound (from 250 kHz to 2000 kHz), but significantly higher time-averaged intensities. The treatment is often guided by MRI, as in Magnetic Resonance guided Focused Ultrasound. - Therapeutic ultrasound, a technique that uses more powerful ultrasound sources to generate local heating in biological tissue, e.g. in occupational therapy, physical therapy and cancer treatment. - Delivering chemotherapy to brain cancer cells and various drugs to other tissues, via a process known as Acoustic Targeted Drug Delivery These procedures generally use high frequency ultrasound (from 1 MHz to 10 MHz) and a range of intensities from 0-20 watts/cm2. The acoustic energy is focused on the tissue of interest to agitate its matrix and make it more permeable to therapeutic drugs. Enhanced drug uptake using Acoustic Targeted Drug Delivery - Cleaning teeth in dental hygiene. - Focused ultrasound sources may be used for cataract treatment by phacoemulsification. - Additional physiological effects of low-intensity ultrasound have recently been discovered, e.g. the ability to stimulate bone-growth and its potential to disrupt the blood-brain barrier for drug delivery. - Ultrasound is used in UAL (ultrasound-assisted lipectomy), or liposuction. - Doppler ultrasound is being tested for use in aiding tissue plasminogen activator treatment in stroke sufferers. This procedure is called Ultrasound-Enhanced Systemic Thrombolysis. - Low intensity pulsed ultrasound is used for therapeutic tooth and bone regeneration. - Ultrasound can also be used for elastography. This can be useful in medical diagnoses, as elasticity can discern healthy from unhealthy tissue for specific organs/growths. In some cases unhealthy tissue may have a lower system Q, meaning that the system acts more like a large heavy spring as compared to higher values of system Q (healthy tissue) that respond to higher forcing frequencies. Ultrasonic elastography is different from conventional ultrasound, as a transceiver (pair) and a transmitter are used instead of only a transceiver. One transducer (a single element {or array of elements} acts as both the transmitter and receiver to image the region of interest over time. The extra transmitter is a very low frequency transmitter, and perturbs the system so the unhealthy tissue oscillates at a low frequency and the healthy tissue does not. The transceiver, which operates at a high frequency (typically MHz) then measures the displacement of the unhealthy tissue (oscillating at a much lower frequency). The movement of the slowly oscillating tissue is used to determine the elasticity of the material, which can then be used to distinguish healthy tissue from the unhealthy tissue. - Ultrasound has been shown to act synergistically with antibiotics in bacterial cell killing. - Ultrasound has been postulated to allow thicker eukaryotic cell tissue cultures by promoting nutrient penetration.Scientific Article - Ultrasound in the low MHz range in the form of standing waves is an emerging tool for contactless separation, concentration and manipulation of microparticles and biological cells. The basis is the acoustic radiation force, a non-linear effect which causes particles to be attracted to either the nodes or anti-nodes of the standing wave depending on the acoustic contrast factor, which is a function of the sound velocities and densities of the particle and of the medium in which the particle is immersed.	Ultrasound Editor(s)-in-Chief: C. Michael Gibson, M.S.,M.D. [2] Phone:617-632-7753; Casey Glass, M.D. [3] # Overview Ultrasound is cyclic sound pressure with a frequency greater than the upper limit of human hearing. Although this limit varies from person to person, it is approximately 20 kilohertz (20,000 hertz) in healthy, young adults and thus, 20 kHz serves as a useful lower limit in describing ultrasound. Ultrasound is manually produced in many different fields, typically to penetrate a medium and measure the reflection signature or supply focused energy. The reflection signature can reveal details about the inner structure of the medium. The most well known application of this technique is its use in sonography to produce pictures of fetuses in the human womb. There are a vast number of other applications as well. # Ability to hear ultrasound The upper frequency limit in humans (approximately 20 kHz) is caused by the middle ear, which acts as a low-pass filter. If ultrasound is fed directly into the skull bone and reaches the cochlea without passing through the middle ear, much higher frequencies can be heard. This effect is discussed in ultrasonic hearing. Carefully-designed scientific studies have been performed and confirmed what they call the hypersonic effect - that even without consciously hearing it, high-frequency sound can have a measurable effect on the mind. It is a fact in psychoacoustics that children can hear some high-pitched sounds that older adults cannot hear, because in humans the upper limit pitch of hearing tends to become lower with age.[1] [2] A cell phone company has used this to create ring signals supposedly only able to be heard by younger humans[3]; but many older people claim to be able to hear it, which is likely given the considerable variation of age-related deterioration in the upper hearing threshold. Some animals – such as dogs, cats, dolphins, bats, and mice have an upper frequency limit that is greater than that of the human ear and thus can hear ultrasound. # Diagnostic sonography Medical sonography (ultrasonography) is an ultrasound-based diagnostic medical imaging technique used to visualize muscles, tendons, and many internal organs, their size, structure and any pathological lesions with real time tomographic images. It is also used to visualize a fetus during routine and emergency prenatal care. Ultrasound scans are performed by medical health care professionals called sonographers. Obstetric sonography is commonly used during pregnancy. Ultrasound has been used to image the human body for at least 50 years. It is one of the most widely used diagnostic tools in modern medicine. The technology is relatively inexpensive and portable, especially when compared with modalities such as magnetic resonance imaging(MRI) and computed tomography (CT). As currently applied in the medical environment, ultrasound poses no known risks to the patient.[4] Sonography is generally described as a "safe test" because it does not use ionizing radiation, which imposes hazards, such as cancer production and chromosome breakage. However, ultrasonic energy has two potential physiological effects: it enhances inflammatory response; and it can heat soft tissue.[5] Ultrasound energy produces a mechanical pressure wave through soft tissue. This pressure wave may cause microscopic bubbles in living tissues, and distortion of the cell membrane, influencing ion fluxes and intracellular activity. When ultrasound enters the body, it causes molecular friction and heats the tissues slightly. This effect is very minor as normal tissue perfusion dissipates heat. With high intensity, it can also cause small pockets of gas in body fluids or tissues to expand and contract/collapse in a phenomenon called cavitation (this is not known to occur at diagnostic power levels used by modern diagnostic ultrasound units). The long-term effects of tissue heating and cavitation are not known.[6] There are several studies that indicate the harmful side effects on animal fetuses associated with the use of sonography on pregnant mammals. A noteworthy study in 2006 suggests exposure to ultrasound can affect fetal brain development in mice. This misplacement of brain cells during their development is linked to disorders ranging "from mental retardation and childhood epilepsy to developmental dyslexia, autism spectrum disorders and schizophrenia, the researchers said. [7] There is no link made yet between the test results on animals, such as mice, and the possible outcome to humans. Widespread clinical use of diagnostic ultrasound testing on humans has not been done for ethical reasons. The possibility exists that biological effects may be identified in the future, currently most doctors feel that based on available information the benefits to patients outweigh the risks.[8] Obstetric ultrasound can be used to identify many conditions that would be harmful to the mother and the baby. For this reason many health care professionals consider that the risk of leaving these conditions undiagnosed is much greater than the very small risk, if any, associated with undergoing the scan. According to Cochrane review, routine ultrasound in early pregnancy (less than 24 weeks) appears to enable better gestational age assessment, earlier detection of multiple pregnancies and earlier detection of clinically unsuspected fetal malformation at a time when termination of pregnancy is possible.[9] Sonography is used routinely in obstetric appointments during pregnancy, but the FDA discourages its use for non-medical purposes such as fetal keepsake videos and photos, even though it is the same technology used in hospitals. Obstetric ultrasound is primarily used to: - Date the pregnancy (gestational age) - Confirm fetal viability - Determine location of fetus, intrauterine vs ectopic - Check the location of the placenta in relation to the cervix - Check for the number of fetuses (multiple pregnancy) - Check for major physical abnormalities. - Assess fetal growth (for evidence of intrauterine growth restriction (IUGR)) - Check for fetal movement and heartbeat. - Determine the sex of the baby Unfortunately, results are occasionally wrong, producing a false positive (the Cochrane Collaboration is a relevant effort to improve the reliability of health care trials). False detection may result in patients being warned of birth defects when no such defect exists. Sex determination is only accurate after 12 weeks gestation [Ultrasound in Obstetrics and Gynecology 1999]. When balancing risk and reward, there are recommendations to avoid the use of routine ultrasound for low risk pregnancies [ACOG]. In many countries ultrasound is used routinely in the management of all pregnancies. According to European Committee of Medical Ultrasound Safety (ECMUS) "Ultrasonic examinations should only be performed by competent personnel who are trained and updated in safety matters. Ultrasound produces heating, pressure changes and mechanical disturbances in tissue. Diagnostic levels of ultrasound can produce temperature rises that are hazardous to sensitive organs and the embryo/fetus. Biological effects of non-thermal origin have been reported in animals but, to date, no such effects have been demonstrated in humans, except when a microbubble contrast agent is present."[10] A study on rodent fetus brains that are exposed to ultrasound showed signs of damage. Speculation on human fetuses can be in a range of no significant complications to a variety of mental and brain disorders. The study shows that rodent brain cells failed to grow to their proper position and remained scattered in incorrect parts of the brain. The conditions of this experiment are different from typical fetal scanning because of the long dwell times. [National Institute of Neurological Disorders; Proceedings of the National Academy of Sciences]. Care should be taken to use low power settings and avoid pulsed wave scanning of the fetal brain unless specifically indicated in high risk pregnancies. It should be noted that obstetrics is not the only use of ultrasound. Soft tissue imaging of many other parts of the body is conducted with ultrasound. Other scans routinely conducted are cardiac, renal, liver and gallbladder (hepatic). Other common applications include musculo-skeletal imaging of muscles, ligaments and tendons, ophthalmic ultrasound (eye) scans and superficial structures such as testicle, thyroid, salivary glands and lymph nodes. Because of the real time nature of ultrasound, it is often used to guide interventional procedures such as fine needle aspiration FNA or biopsy of masses for cytology or histology testing in the breast, thyroid, liver, kidney, lymph nodes, muscles and joints. Ultrasound scanners using pulsed wave and colour Doppler are used to visualize arteries and veins. Figures released for the period 2005-2006 by UK Government (Department of Health) show that non-obstetric ultrasound examinations contributed to more than 65% of the total number of ultrasound scans conducted. # Biomedical ultrasonic applications Ultrasound also has therapeutic applications, which can be highly beneficial when used with dosage precautions:[11] - According to RadiologyInfo [12], ultrasounds are useful in the detection of Pelvic abnormalities and can involve techniques known as abdominal (transabdominal) ultrasound, vaginal (transvaginal or endovaginal) ultrasound in women, and also rectal (transrectal) ultrasound in men. - Treating benign and malignant tumors and other disorders, via a process known as Focused Ultrasound Surgery (FUS) or HIFU, High Intensity Focused Ultrasound. These procedures generally use lower frequencies than medical diagnostic ultrasound (from 250 kHz to 2000 kHz), but significantly higher time-averaged intensities. The treatment is often guided by MRI, as in Magnetic Resonance guided Focused Ultrasound. - Therapeutic ultrasound, a technique that uses more powerful ultrasound sources to generate local heating in biological tissue, e.g. in occupational therapy, physical therapy and cancer treatment. - Delivering chemotherapy to brain cancer cells and various drugs to other tissues, via a process known as Acoustic Targeted Drug Delivery [13] These procedures generally use high frequency ultrasound (from 1 MHz to 10 MHz) and a range of intensities from 0-20 watts/cm2. The acoustic energy is focused on the tissue of interest to agitate its matrix and make it more permeable to therapeutic drugs.[14][15] Enhanced drug uptake using Acoustic Targeted Drug Delivery - Cleaning teeth in dental hygiene. - Focused ultrasound sources may be used for cataract treatment by phacoemulsification. - Additional physiological effects of low-intensity ultrasound have recently been discovered, e.g. the ability to stimulate bone-growth and its potential to disrupt the blood-brain barrier for drug delivery. - Ultrasound is used in UAL (ultrasound-assisted lipectomy), or liposuction. - Doppler ultrasound is being tested for use in aiding tissue plasminogen activator treatment in stroke sufferers. This procedure is called Ultrasound-Enhanced Systemic Thrombolysis. - Low intensity pulsed ultrasound is used for therapeutic tooth and bone regeneration. - Ultrasound can also be used for elastography. This can be useful in medical diagnoses, as elasticity can discern healthy from unhealthy tissue for specific organs/growths. In some cases unhealthy tissue may have a lower system Q, meaning that the system acts more like a large heavy spring as compared to higher values of system Q (healthy tissue) that respond to higher forcing frequencies. Ultrasonic elastography is different from conventional ultrasound, as a transceiver (pair) and a transmitter are used instead of only a transceiver. One transducer (a single element {or array of elements} acts as both the transmitter and receiver to image the region of interest over time. The extra transmitter is a very low frequency transmitter, and perturbs the system so the unhealthy tissue oscillates at a low frequency and the healthy tissue does not. The transceiver, which operates at a high frequency (typically MHz) then measures the displacement of the unhealthy tissue (oscillating at a much lower frequency). The movement of the slowly oscillating tissue is used to determine the elasticity of the material, which can then be used to distinguish healthy tissue from the unhealthy tissue. - Ultrasound has been shown to act synergistically with antibiotics in bacterial cell killing.[16] - Ultrasound has been postulated to allow thicker eukaryotic cell tissue cultures by promoting nutrient penetration.Scientific Article - Ultrasound in the low MHz range in the form of standing waves is an emerging tool for contactless separation, concentration and manipulation of microparticles and biological cells. The basis is the acoustic radiation force, a non-linear effect which causes particles to be attracted to either the nodes or anti-nodes of the standing wave depending on the acoustic contrast factor, which is a function of the sound velocities and densities of the particle and of the medium in which the particle is immersed.	https://www.wikidoc.org/index.php/Ultrasound
dba6d58638d2775c818a8a0bd1e1b684430f71c8	wikidoc	Unblinding	Unblinding # Overview Blinding is the best way to investigate a new drug or any type of new intervention in clinical research, especially, if related to a placebo-controlled trial. However, sometimes blinding is challenging and when it becomes not possible and bias is more difficult to prevent. # Unblinding sponsors In a trial, the word “sponsor” can be designated as an individual, company, institution or organization which takes responsibility for the initiation, management, and/or financing of a clinical trial . The main sponsors of clinical trials are pharmaceutical and biotechnology companies. Blinding (sometimes called masking) refers to keeping key persons, such as participants, health care providers, and sponsors, unaware of the treatment administered or interventions after inclusion of participants into the study ;. In general, sponsors are unblinded after the completion of the research trial. Unblinding the sponsors during the study process would introduce false estimates to the study, since the sponsor would be aware of the results and the level of treatment while the trial is ongoing. In other words, the sponsor will have access to which group is taking the medication and to the results, therefore the unblinded sponsor is able to modify the course of the trial. # Unblinding participants After the completion of the research trial, each participant will be required to return to a consult to be unblinded. This option allows them to know what medication they were taking during the trial. Usually, unblinding of participants during conduct of a clinical trial is not allowed unless there are compelling severe adverse effects . # Risks of unblinding - Biasing the protocol, since it would appears more interesting to continue the trial (falsifying data/results for patients known to receive a given treatment, in hopes of making the treatment look better); - Changes of protocol by scientific developments (new tests, approval of new products, announcement of results of other trials); - Changes of protocol by financial considerations, production problems, enrollment problems and missing data) ; - Unavoidable bias by changing an endpoint; - Adversity in interpreting the results; - Change statistical methodology during trial based on trends seen so far; - Hard to prove bias did not enter study; - Adversity in interpreting the results; - Unavoidable bias by changing an endpoint. ## Bias Bias is a systematic error that causes false estimates , which affects the measure in a constant way; for instance, studying the effectiveness of a new drug for any type of disease, where the pharmacokinetic properties, such as absorption, distribution, metabolism, and excretion of the drug are critically influenced by the route of administration makes blinding not feasible leading to biases and, consequently, jeopardizing the results. # Who can be unblinded? - Study Treatment Manufacturer ; - Pharmacist; - Medical Monitors (in case of patient having a serious safety issue); - Data Safety Monitoring Board (DSMB); - Statisticians who generated the randomization schedule used by pharmacists/manufacturers. # Summary In summary, all clinical trials should be double-blinded and sponsor/study personnel should be blinded even if is an “open label” trial.	Unblinding Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor-In-Chief: Marcelo R. Zacarkim, M.D. [2] # Overview Blinding is the best way to investigate a new drug or any type of new intervention in clinical research, especially, if related to a placebo-controlled trial. However, sometimes blinding is challenging and when it becomes not possible and bias is more difficult to prevent. # Unblinding sponsors In a trial, the word “sponsor” can be designated as an individual, company, institution or organization which takes responsibility for the initiation, management, and/or financing of a clinical trial [1]. The main sponsors of clinical trials are pharmaceutical and biotechnology companies. Blinding (sometimes called masking) refers to keeping key persons, such as participants, health care providers, and sponsors, unaware of the treatment administered or interventions after inclusion of participants into the study [2][3][4];. In general, sponsors are unblinded after the completion of the research trial. Unblinding the sponsors during the study process would introduce false estimates to the study, since the sponsor would be aware of the results and the level of treatment while the trial is ongoing. In other words, the sponsor will have access to which group is taking the medication and to the results, therefore the unblinded sponsor is able to modify the course of the trial. # Unblinding participants After the completion of the research trial, each participant will be required to return to a consult to be unblinded. This option allows them to know what medication they were taking during the trial. Usually, unblinding of participants during conduct of a clinical trial is not allowed unless there are compelling severe adverse effects [1]. # Risks of unblinding - Biasing the protocol, since it would appears more interesting to continue the trial (falsifying data/results for patients known to receive a given treatment, in hopes of making the treatment look better)[5]; - Changes of protocol by scientific developments (new tests, approval of new products, announcement of results of other trials); - Changes of protocol by financial considerations, production problems, enrollment problems and missing data) [3]; - Unavoidable bias by changing an endpoint; - Adversity in interpreting the results; - Change statistical methodology during trial based on trends seen so far; - Hard to prove bias did not enter study; - Adversity in interpreting the results; - Unavoidable bias by changing an endpoint. ## Bias Bias is a systematic error that causes false estimates [6], which affects the measure in a constant way; for instance, studying the effectiveness of a new drug for any type of disease, where the pharmacokinetic properties, such as absorption, distribution, metabolism, and excretion of the drug are critically influenced by the route of administration makes blinding not feasible leading to biases and, consequently, jeopardizing the results. # Who can be unblinded? - Study Treatment Manufacturer [4]; - Pharmacist; - Medical Monitors (in case of patient having a serious safety issue)[1]; - Data Safety Monitoring Board (DSMB); - Statisticians who generated the randomization schedule used by pharmacists/manufacturers. # Summary In summary, all clinical trials should be double-blinded and sponsor/study personnel should be blinded even if is an “open label” trial.	https://www.wikidoc.org/index.php/Unblinding
e87cbb54e7daeb306b6927b8c5270716ceb83e8c	wikidoc	Upper limb	Upper limb # Overview In human anatomy, the upper limb (also upper extremity) refers to what in common English is known as the arm, that is, the region of the shoulder to the fingertips. It includes the entire limb, and thus, is not synonymous with the term upper arm. ## General structures The upper limb includes the following structures: - Shoulder - Arm (proper) - in anatomy, the region between the shoulder and the elbow - Elbow - Forearm - Wrist - Hand Note that anatomists use the term arm to denote only the region between the shoulder and the elbow. This is in contrast to the proper English definition. Anatomists also use the term leg to refer to the region between the knee and the ankle. This, however, is the proper and traditional usage of the word, even though popular modern usage tends to include the thigh and foot in the definition. ## Bones The following bones are considered to be part of the upper limb: - Clavicle - the only bone that directly articulates with the trunk - Scapula - Humerus - Radius - Ulna - Carpal bones - Metacarpals - Phalanges	Upper limb Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview In human anatomy, the upper limb (also upper extremity) refers to what in common English is known as the arm, that is, the region of the shoulder to the fingertips. It includes the entire limb, and thus, is not synonymous with the term upper arm. ## General structures The upper limb includes the following structures: - Shoulder - Arm (proper) - in anatomy, the region between the shoulder and the elbow - Elbow - Forearm - Wrist - Hand Note that anatomists use the term arm to denote only the region between the shoulder and the elbow. This is in contrast to the proper English definition. Anatomists also use the term leg to refer to the region between the knee and the ankle. This, however, is the proper and traditional usage of the word, even though popular modern usage tends to include the thigh and foot in the definition. ## Bones The following bones are considered to be part of the upper limb: - Clavicle - the only bone that directly articulates with the trunk - Scapula - Humerus - Radius - Ulna - Carpal bones - Metacarpals - Phalanges	https://www.wikidoc.org/index.php/Upper_extremities
05ad73cf17509255dc70a42ce9143249a332690a	wikidoc	Vaginismus	Vaginismus # Overview Vaginismus (the German equivalent of the word Vaginism) is a condition which affects a woman's ability to engage in any form of vaginal penetration, including sexual penetration, insertion of tampons, and the penetration involved in gynecological examinations. This is the result of a conditioned reflex of the pubococcygeus muscle, which is sometimes referred to as the 'PC muscle'. The reflex causes the muscles in the vagina to tense suddenly, which makes any kind of vaginal penetration -- including sexual penetration -- either painful or impossible. A vaginismic woman does not consciously control the spasm. The vaginismic reflex can be compared to the response of the eye shutting when an object comes towards it. The severity of vaginismus varies from woman to woman. # Experience of vaginismus The conditioned reflex can create a vicious circle for vaginismic women. One example: if a teenage female learns that the first time she engages in penetrative sex that it will be painful, she may develop vaginismus because she expects pain. If she then attempts to engage in penetrative sex, the muscle spasm will make penetrative sex painful. This and each further attempt at sexual penetration confirms her fear of pain and may worsen the condition. Naturally, penetration may be extremely painful without vaginismus or psychological prerequisite as well. ## Primary vaginismus Primary vaginismus occurs when a woman has never been able to have penetrative sex or achieve any kind of vaginal penetration. It is commonly discovered in teenagers and women in their early twenties, as this is when many young women in the Western world will initially attempt to use tampons, have penetrative sex, or undergo a pap smear. Women who have vaginismus may not be aware of their condition until they attempt vaginal penetration. It may be confusing for a woman to discover she has vaginismus. She may believe that vaginal penetration should be naturally easy, or she may be unaware as to the reason for her condition. Some of the things that may cause primary vaginismus are: - sexual abuse - having been taught that sex is immoral or vulgar - the fear of pain associated with penetration, particularly that of breaking the hymen upon the first attempt at sexual penetration ## Secondary vaginismus Secondary vaginismus occurs when a woman who has previously been able to achieve penetration develops vaginismus. This may be due to physical causes such as a yeast infection or trauma during childbirth, or it may be due to psychological causes. The treatment for secondary vaginismus is the same as for primary vaginismus, although, in these cases, previous experience with successful penetration can assist in a more rapid resolution of the condition. # Treatment There are a variety of factors that can contribute to vaginismus. These may be psychological or physiological, and the treatment required can depend on the reason that the woman has developed the condition. As each case is different, an individualized approach to treatment is useful. The condition will not necessarily become more severe if left untreated, unless the woman is continuing to attempt penetration, despite feeling pain. Some women may choose to refrain from seeking treatment for their condition. According to the Cochrane Collaboration review of the scientific literature, "In spite of encouraging results reported from uncontrolled case series there is very limited evidence from controlled trials concerning the effectiveness of treatments for vaginismus. Further trials are needed to compare therapies with waiting list control and with other therapies." Although few controlled trials have been carried out, many serious scientific studies have tested and proved the efficacy of the treatment of vaginismus. In all cases where the systematic desensitization method was used, success rates were close to 90-95% and even 100%. For an example of one of these studies, see Nasab, M., & Farnoosh, Z., or for a basic review, see Reissing's literature review. (links below) ## Psychological treatment According to Ward and Ogden's qualitative study on the experience of vaginismus for women (1994), the three highest ranked causes for vaginismus are usually fear of painful sex, strict religious upbringing where sex was viewed as wrong or not discussed, and early childhood traumatic experiences (not necessarily sexual in nature). It is important to address the psychological aspects of the problem as well as the actual muscle spasm. A woman may choose to address the issue on her own terms, or she may avail the help of a therapist. Many people -- even some professionals -- are not aware of the emotional difficulties associated with vaginismus, which can include low self-esteem, fears, and depression. Women with this condition may wish to seek an understanding professional who has previous experience with women who experience vaginismus. A therapist who has a positive attitude towards sex and the human body may be beneficial. ## Physical treatment Physical treatment of the internal spasms may include sensate focus exercises, exploring the vagina through touch, and desensitization with vaginal dilators. Dilating involves inserting objects, usually phallic in shape, into the vagina. In treating the spasms through dilation, the objects used gradually increase in size as the woman progresses. Medical dilators may be obtained online, though they may be expensive. # Sexuality If a woman suspects she has vaginismus, sexual penetration is likely to remain painful or impossible until her vaginismus is addressed. Women with vaginismus may be able to engage in other sexual activities, as long as penetration is avoided. Sexual partners of vaginismic women may come to believe that vaginismic women do not want to engage in penetrative sex at all, though this may not be true. Many vaginismic women do wish to engage in penetrative sex, but are deterred by the pain and emotional distress that comes with each attempt. ## Masturbation Women with vaginismus may not realize that most women who do not have vaginismus usually do experience pain or discomfort if they attempt sexual penetration without prior sexual arousal. Most women acknowledge sexual arousal as integral to painless sexual penetration so self-exploration of the vaginal area through masturbation can be beneficial in addressing vaginismus. One of the problems that can come with vaginismus is that a woman may be fearful to engage in sexual activity, due to the fear of pain with any kind of vaginal penetration. Solo masturbation, with or without penetration, can alleviate this fear, as well as the psychological pressure to 'perform' sexually or become aroused quickly, with a partner. Despite popular belief, orgasm need not be the goal of masturbation. The reason may be to simply increase comfort with the genital area, to explore various sensations through genital and clitoral touch, and to become aware of those sensations which are relaxing and pleasurable. Sexual arousal causes changes in the shape and color of the vulva, as well as in the vaginal lubrication produced. As a woman becomes more aware of her individual sexual response, she can learn which sensations are best for bringing her to a state of arousal. She will then be better equipped to teach her partner(s) which sensations feel best for her. ## Emotional experiences A wide range of emotions may surface during masturbation and other forms of genital exploration. Some women have negative associations with their genitals, including fears that their genitals are dirty, smelly, oddly shaped, or ugly. These associations can lead to negative emotions arising during any kind of sexual expression, including masturbation, and these emotions can take time to process. Especially in the case of a vaginismic woman, feelings of shame, inadequacy or of being 'defective' can be deeply troubling. Relaxation, patience and self-acceptance are vital to a pleasurable experience. The process of addressing vaginismus requires time, patience, and a focused personal intention to heal. In almost all cases it can be successfully treated.	Vaginismus For patient information, click here Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] # Overview Vaginismus (the German equivalent of the word Vaginism) is a condition which affects a woman's ability to engage in any form of vaginal penetration, including sexual penetration, insertion of tampons, and the penetration involved in gynecological examinations. This is the result of a conditioned reflex of the pubococcygeus muscle, which is sometimes referred to as the 'PC muscle'. The reflex causes the muscles in the vagina to tense suddenly, which makes any kind of vaginal penetration -- including sexual penetration -- either painful or impossible. A vaginismic woman does not consciously control the spasm. The vaginismic reflex can be compared to the response of the eye shutting when an object comes towards it. The severity of vaginismus varies from woman to woman. # Experience of vaginismus The conditioned reflex can create a vicious circle for vaginismic women. One example: if a teenage female learns that the first time she engages in penetrative sex that it will be painful, she may develop vaginismus because she expects pain. If she then attempts to engage in penetrative sex, the muscle spasm will make penetrative sex painful. This and each further attempt at sexual penetration confirms her fear of pain and may worsen the condition. Naturally, penetration may be extremely painful without vaginismus or psychological prerequisite as well. ## Primary vaginismus Primary vaginismus occurs when a woman has never been able to have penetrative sex or achieve any kind of vaginal penetration. It is commonly discovered in teenagers and women in their early twenties, as this is when many young women in the Western world will initially attempt to use tampons, have penetrative sex, or undergo a pap smear. Women who have vaginismus may not be aware of their condition until they attempt vaginal penetration. It may be confusing for a woman to discover she has vaginismus. She may believe that vaginal penetration should be naturally easy, or she may be unaware as to the reason for her condition. Some of the things that may cause primary vaginismus are: - sexual abuse - having been taught that sex is immoral or vulgar - the fear of pain associated with penetration, particularly that of breaking the hymen upon the first attempt at sexual penetration ## Secondary vaginismus Secondary vaginismus occurs when a woman who has previously been able to achieve penetration develops vaginismus. This may be due to physical causes such as a yeast infection or trauma during childbirth, or it may be due to psychological causes. The treatment for secondary vaginismus is the same as for primary vaginismus, although, in these cases, previous experience with successful penetration can assist in a more rapid resolution of the condition. # Treatment There are a variety of factors that can contribute to vaginismus. These may be psychological or physiological, and the treatment required can depend on the reason that the woman has developed the condition. As each case is different, an individualized approach to treatment is useful. The condition will not necessarily become more severe if left untreated, unless the woman is continuing to attempt penetration, despite feeling pain. Some women may choose to refrain from seeking treatment for their condition. According to the Cochrane Collaboration review of the scientific literature, "In spite of encouraging results reported from uncontrolled case series there is very limited evidence from controlled trials concerning the effectiveness of treatments for vaginismus. Further trials are needed to compare therapies with waiting list control and with other therapies." [1] Although few controlled trials have been carried out, many serious scientific studies have tested and proved the efficacy of the treatment of vaginismus. In all cases where the systematic desensitization method was used, success rates were close to 90-95% and even 100%. For an example of one of these studies, see Nasab, M., & Farnoosh, Z., or for a basic review, see Reissing's literature review. (links below) ## Psychological treatment According to Ward and Ogden's qualitative study on the experience of vaginismus for women (1994), the three highest ranked causes for vaginismus are usually fear of painful sex, strict religious upbringing where sex was viewed as wrong or not discussed, and early childhood traumatic experiences (not necessarily sexual in nature). It is important to address the psychological aspects of the problem as well as the actual muscle spasm. A woman may choose to address the issue on her own terms, or she may avail the help of a therapist. Many people -- even some professionals -- are not aware of the emotional difficulties associated with vaginismus, which can include low self-esteem, fears, and depression. Women with this condition may wish to seek an understanding professional who has previous experience with women who experience vaginismus. A therapist who has a positive attitude towards sex and the human body may be beneficial. ## Physical treatment Physical treatment of the internal spasms may include sensate focus exercises, exploring the vagina through touch, and desensitization with vaginal dilators. Dilating involves inserting objects, usually phallic in shape, into the vagina. In treating the spasms through dilation, the objects used gradually increase in size as the woman progresses. Medical dilators may be obtained online, though they may be expensive. # Sexuality If a woman suspects she has vaginismus, sexual penetration is likely to remain painful or impossible until her vaginismus is addressed. Women with vaginismus may be able to engage in other sexual activities, as long as penetration is avoided. Sexual partners of vaginismic women may come to believe that vaginismic women do not want to engage in penetrative sex at all, though this may not be true. Many vaginismic women do wish to engage in penetrative sex, but are deterred by the pain and emotional distress that comes with each attempt. ## Masturbation Women with vaginismus may not realize that most women who do not have vaginismus usually do experience pain or discomfort if they attempt sexual penetration without prior sexual arousal. Most women acknowledge sexual arousal as integral to painless sexual penetration so self-exploration of the vaginal area through masturbation can be beneficial in addressing vaginismus. One of the problems that can come with vaginismus is that a woman may be fearful to engage in sexual activity, due to the fear of pain with any kind of vaginal penetration. Solo masturbation, with or without penetration, can alleviate this fear, as well as the psychological pressure to 'perform' sexually or become aroused quickly, with a partner. Despite popular belief, orgasm need not be the goal of masturbation. The reason may be to simply increase comfort with the genital area, to explore various sensations through genital and clitoral touch, and to become aware of those sensations which are relaxing and pleasurable. Sexual arousal causes changes in the shape and color of the vulva, as well as in the vaginal lubrication produced. As a woman becomes more aware of her individual sexual response, she can learn which sensations are best for bringing her to a state of arousal. She will then be better equipped to teach her partner(s) which sensations feel best for her. ## Emotional experiences A wide range of emotions may surface during masturbation and other forms of genital exploration. Some women have negative associations with their genitals, including fears that their genitals are dirty, smelly, oddly shaped, or ugly. These associations can lead to negative emotions arising during any kind of sexual expression, including masturbation, and these emotions can take time to process. Especially in the case of a vaginismic woman, feelings of shame, inadequacy or of being 'defective' can be deeply troubling. Relaxation, patience and self-acceptance are vital to a pleasurable experience. The process of addressing vaginismus requires time, patience, and a focused personal intention to heal. In almost all cases it can be successfully treated.	https://www.wikidoc.org/index.php/Vaginismus
be3e24c44b98001b9abece07807de7c4b6b1be8e	wikidoc	Valpromide	Valpromide # Overview Valpromide (marketed as Depamide by Sanofi-Aventis) is a carboxamide derivative of valproic acid used in the treatment of epilepsy and some affective disorders. It is rapidly metabolised (80%) to valproic acid (another anticonvulsant) but has anticonvulsant properties itself. It may produce more stable plasma levels than valproic acid or sodium valproate and may be more effective at preventing febrile seizures. However, it is over one hundred times more potent as an inhibitor of liver microsomal epoxide hydrolase. This makes it incompatible with carbamazepine and can affect the ability of the body to remove other toxins. Valpromide is no safer during pregnancy than valproic acid. Valpromide is formed through the reaction of valproic acid and ammonia via an intermediate acid chloride. In pure form, valpromide is a white crystalline powder and has melting point 125–126 °C. It is practically insoluble in water but soluble in hot water. It is available on the market in some European countries.	Valpromide Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Valpromide (marketed as Depamide by Sanofi-Aventis) is a carboxamide derivative of valproic acid used in the treatment of epilepsy and some affective disorders. It is rapidly metabolised (80%) to valproic acid (another anticonvulsant) but has anticonvulsant properties itself. It may produce more stable plasma levels than valproic acid or sodium valproate and may be more effective at preventing febrile seizures. However, it is over one hundred times more potent as an inhibitor of liver microsomal epoxide hydrolase. This makes it incompatible with carbamazepine and can affect the ability of the body to remove other toxins. Valpromide is no safer during pregnancy than valproic acid. Valpromide is formed through the reaction of valproic acid and ammonia via an intermediate acid chloride. In pure form, valpromide is a white crystalline powder and has melting point 125–126 °C. It is practically insoluble in water but soluble in hot water. It is available on the market in some European countries.	https://www.wikidoc.org/index.php/Valpromide
a32f12452ce13bd0ff2113feaa76c10eb366bf40	wikidoc	Valrubicin	Valrubicin # 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 Valrubicin is an anti neoplastic that is FDA approved for the treatment of BCG-refractory carcinoma in situ (CIS) of the urinary bladder in patients for whom immediate cystectomy would be associated with unacceptable morbidity or mortality.. Common adverse reactions include abdominal pain, nausea, myalgia, asthenia, headache, bladder pain, cystitis, dysuria, hematuria, incontinence, increased frequency of urination, pain in urethra, burning sensation, malaise. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - VALSTAR is indicated for intravesical therapy of BCG-refractory carcinoma in situ (CIS) of the urinary bladder in patients for whom immediate cystectomy would be associated with unacceptable morbidity or mortality. - Valrubicin is recommended at a dose of 800 mg administered intravesically once a week for six weeks. Administration should be delayed at least two weeks after transurethral resection and/or fulguration. For each instillation, four 5 mL vials (200 mg valrubicin/5 mL vial) should be allowed to warm slowly to room temperature, but should not be heated. Twenty milliliters of valrubicin should then be withdrawn from the four vials and diluted with 55 mL 0.9% Sodium Chloride Injection, USP providing 75 mL of a diluted valrubicin solution. - A urethral catheter should then be inserted into the patients bladder under aseptic conditions, the bladder drained, and the diluted 75 mL valrubicin solution instilled slowly via gravity flow over a period of several minutes. - The catheter should then be withdrawn. The patient should retain the drug for two hours before voiding. At the end of two hours, all patients should void. (Some patients will be unable to retain the drug for the full two hours.) Patients should be instructed to maintain adequate hydration following treatment. - Patients receiving valrubicin for refractory carcinoma in situ must be monitored closely for disease recurrence or progression. Recommended evaluations include cystoscopy, biopsy, and urine cytology every 3 months. - Administration Precautions: As recommended with other cytotoxic agents, caution should be exercised in handling and preparing the solution of valrubicin. Contact toxicity, common and severe with other anthracyclines, is not typical with valrubicin and, when observed, has been mild. Skin reactions may occur with accidental exposure. The use of goggles, gloves, and protective gowns is recommended during preparation and administration of the drug. Irritation of the eye has also been reported with accidental exposure. If this happens, the eye should be flushed with water immediately and thoroughly. Procedures for proper handling and disposal of anticancer drugs should be used.¹-⁴ Spills should be cleaned up withundiluted chlorine bleach. - Valrubicin sterile solution contains polyoxyl castor oil, which has been known to cause leaching of di(2-ethylhexyl) phthalate (DEHP) a hepatotoxic plasticizer, from polyvinyl chloride (PVC) bags and intravenous tubing. valrubicin solutions should be prepared and stored in glass, polypropylene, or polyolefin containers and tubing. It is recommended that non-DEHP containing administration sets, such as those that are polyethylene-lined, be used. - Preparation for Administration: valrubicin Sterile Solution for Intravesical Instillation is a clear red solution. It should be visually inspected for particulate matter and discoloration prior to administration. At temperatures below 4°C, polyoxyl castor oil may begin to form a waxy precipitate. If this happens, the vial should be warmed in the hand until the solution is clear. If particulate matter is still seen, valrubicin should not be administered. - Stability: Unopened vials of valrubicin are stable until the date indicated on the package when stored under refrigerated conditions at 2°-8°C (36°-46°F). Vials should not be heated. valrubicin diluted in 0.9% Sodium Chloride Injection, USP for administration is stable for 12 hours at temperatures up to 25°C (77°F). Since compatibility data are not available, valrubicin should not be mixed with other drugs. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Valrubicin in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Valrubicin in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Valrubicin in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Valrubicin in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Valrubicin in pediatric patients. # Contraindications - VALSTAR is contraindicated in patients with known hypersensitivity to anthracyclines or polyoxyl castor oil. Patients with concurrent urinary tract infections should not receive valrubicin. valrubicin should not be administered to patients with a small bladder capacity, i.e., unable to tolerate a 75 mL instillation. # Warnings - Valrubicin is contraindicated in patients with known hypersensitivity to anthracyclines or polyoxyl castor oil. Patients with concurrent urinary tract infections should not receive valrubicin. VALSTAR should not be administered to patients with a small bladder capacity, i.e., unable to tolerate a 75 mL instillation. # Adverse Reactions ## Clinical Trials Experience - Approximately 84% of patients who received intravesical valrubicin in clinical studies experienced local adverse events, but approximately half of the patients reported irritable bladder symptoms prior to treatment. The local adverse reactions associated with valrubicin usually occur during or shortly after instillation and resolve within 1 to 7 days after the instillate is removed from the bladder. - TABLE 1 displays the frequency of the local adverse experiences at baseline and during treatment among 170 patients who received 800 mg doses of VALSTAR® (valrubicin) Sterile Solution for Intravesical Instillation in a multiple-cycle treatment regimen. Only 7 of 143 patients who were scheduled to receive six doses failed to receive all of the planned doses because of the occurrence of local bladder symptoms. ## Postmarketing Experience - Digestive System: Tenesmus. - Metabolic and Nutritional: Nonprotein nitrogen increased. - Skin and Appendages: Pruritus. - Special Senses: Taste loss. - Urogenital System: Local skin irritation, poor urine flow, and urethritis. - Inadvertent paravenous extravasation of VALSTAR was not associated with skin ulceration or necrosis. # Drug Interactions There is limited information regarding Valrubicin Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Valrubicin can cause fetal harm if a pregnant woman is exposed to the drug systemically. Such exposure could occur after perforation of the urinary bladder during valrubicin therapy. Daily intravenous doses of 12 mg/kg (about one sixth of the recommended human intravesical dose on a mg/m2 basis) given to rats during fetal development caused fetal malformations. A dose of 24 mg/kg (about one third the recommended human intravesical dose on a mg/m2 basis) caused numerous, severe alterations in the skull and skeleton of the developing fetuses. This dose also caused an increase in fetal resorptions and a decrease in viable fetuses. Thus, valrubicin is embryo-toxic and teratogenic. There are no preclinical studies of the effects of intra-vesical valrubicin on fetal development and no adequate and well controlled studies of valrubicin in pregnant women. If valrubicin is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. It should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women who might become pregnant should be advised to avoid doing so during therapy with VALSTAR. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Valrubicin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Valrubicin during labor and delivery. ### Nursing Mothers - It is not known whether VALSTAR is excreted in human milk. Nevertheless, the drug is highly lipophilic and any exposure of infants to VALSTAR could pose serious health risks. Women should discontinue nursing before the initiation of VALSTAR therapy. ### Pediatric Use There is no FDA guidance on the use of Valrubicin with respect to pediatric patients. ### Geriatic Use - Because carcinoma in situ of the bladder generally occurs in older individuals, 85% of the patients enrolled in the clinical studies of VALSTAR were more than 60 years of age (49% of the patients were more than 70 years of age). In the primary efficacy studies, the mean age of the population was 69.5 years. There are no specific precautions regarding use of VALSTAR in geriatric patients who are otherwise in good health. ### Gender There is no FDA guidance on the use of Valrubicin with respect to specific gender populations. ### Race There is no FDA guidance on the use of Valrubicin with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Valrubicin in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Valrubicin in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Valrubicin in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Valrubicin in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral - Intravenous ### Monitoring - If VALSTAR is administered when bladder rupture or perforation is suspected, weekly monitoring of complete blood counts should be performed for 3 weeks. - Patients receiving VALSTAR for refractory carcinoma in situ must be monitored closely for disease recurrence or progression. # IV Compatibility There is limited information regarding IV Compatibility of Valrubicin in the drug label. # Overdosage There is limited information regarding Valrubicin overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology There is limited information regarding Valrubicin Pharmacology in the drug label. ## Mechanism of Action - Valrubicin is an anthracycline that affects a variety of interrelated biological functions, most of which involve nucleic acid metabolism. It readily penetrates into cells, where it inhibits the incorporation of nucleosides into nucleic acids, causes extensive chromosomal damage, and arrests cell cycle in G2. Although valrubicin does not bind strongly to DNA, a principal mechanism of its action, mediated by valrubicin metabolites, is interference with the normal DNA breaking-resealing action of DNA topoisomerase II. ## Structure There is limited information regarding Valrubicin Structure in the drug label. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Valrubicin in the drug label. ## Pharmacokinetics - Pharmacokinetics after Intravesical Administration of VALSTAR: When 800 mg VALSTAR was administered intravesically to patients with carcinoma in situ, VALSTAR penetrated into the bladder wall. The mean total anthracycline concentration measured in bladder tissue exceeded the levels causing 90% cytotoxicity to human bladder cells cultured in vitro. During the two-hour dose-retention period, the metabolism of VALSTAR to its major metabolites N-trifluoroacetyladriamycin and N-trifluoroacetyladriamycinol was negligible. After retention, the drug was almost completely excreted by voiding the instillate. Mean percent recovery of VALSTAR, N-trifluoroacetyladriamycin, and total anthracyclines in 14 urine samples from six patients was 98.6%, 0.4%, and 99.0% of the total administered drug, respectively. During the two-hour dose-retention period, only nanogram quantities of VALSTAR were absorbed into the plasma. VALSTAR metabolites N-trifluoroacetyladriamycin and N-trifluoroacetyladriamycinol were measured in blood. - Total systemic exposure to anthracyclines during and after intravesical administration of VALSTAR is dependent upon the condition of the bladder wall. The mean AUC0-6 hours (total anthracyclines exposure) for an intravesical dose of 900 mg of VALSTAR administered 2 weeks after transurethral resection of bladder tumors (n=6) was 78 nmol/Lhr. In patients receiving 800 mg of VALSTAR 5 to 51 minutes after typical (n=8) and extensive (n=5) transurethral resection of bladder tumors (TURBs), the mean AUC0-6 hours values for total anthracyclines were 409 and 788 nmol/Lhr, respectively. The AUC0-6 hours total exposure to anthracyclines was 18,382 nmol/Lhr in one patient who experienced a perforated bladder following a transurethral resection that occurred 5 minutes before administration of an intravesical dose of 800 mg of VALSTAR. Administration of a comparable intravenous dose of VALSTAR (600 mg/m2; n=2) as a 24-hour infusion resulted in an AUC0-6 hours for total anthracyclines of 11,975 nmol/Lhr. These results are shown in FIGURE 2. - The patient with a perforated bladder who received 800 mg of VALSTAR intravesically developed severe leukopenia and neutropenia approximately two weeks after drug administration. Systemic hematologic toxicity from VALSTAR was not seen after an intravesical dose of 800 mg of VALSTAR unless perforation of the urinary bladder occurred. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Valrubicin in the drug label. # Clinical Studies - VALSTAR has been administered intravesically to a total of 230 patients with transitional cell carcinoma of the bladder, including 205 patients who received multiple weekly doses ranging from 200 to 900 mg. One hundred seventy-nine of the 205 patients received the approved dose and schedule of 800 mg weekly for multiple weeks. - In the 90 study patients with BCG-refractory carcinoma in situ (CIS), 70% had received at least 2 courses of BCG and 30% had received one course of BCG and at least one additional course of treatment with another agent(s) - e.g., mitomycin, thiotepa, or interferon. VALSTAR was administered beginning at least two weeks after transurethral resection and/or fulguration. After intravesical administration of VALSTAR, 16 patients (18%) had a complete response documented by bladder biopsies and cytology at 6 months following initiation of therapy. Median duration of response from start of treatment varied according to the method of analysis (13.5 months if measured to last bladder biopsy without tumor and 21 months if measured until time of documented recurrence). A retrospective analysis in the 16 patients with complete response to VALSTAR demonstrated that time to recurrence of their disease after treatment with VALSTAR was longer than time to recurrence after previous courses of intravesical therapy. - Of the 90 patients with BCG-refractory CIS, 11% (10 patients) developed metastatic or deeply-invasive bladder cancer during follow-up; four of these patients, none who underwent cystectomy, died with metastatic bladder cancer and six were found to have developed stage progression to deeply-invasive disease (T3), with lymph node involvement in one patient, at the time of cystectomy. It is difficult to ascertain to what extent the development of advanced bladder cancer in these patients was due to the delay in cystectomy required to receive treatment with VALSTAR (3 months was the time of follow-up to determine response), as cystectomy was often delayed or was never performed despite failure of treatment with VALSTAR. In the 10 patients documented to have invasive bladder cancer or metastatic disease, the delay between the time of treatment failure (when cystectomy should have been performed) and cystectomy or documentation of advanced bladder cancer was a median of 17.5 months. # How Supplied - VALSTAR Sterile Solution for Intravesical Instillation is a clear red solution in polyoxyl castor oil/dehydrated alcohol, USP, containing 40 mg valrubicin per mL. VALSTAR Sterile Solution for Intravesical Instillation is available in single-use, clear glass vials, individually packaged in the following sizes: ## Storage - Store vials under refrigeration at 2°-8°C (36°-46°F) in the carton. DO NOT FREEZE. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Valrubicin in the drug label. # Precautions with Alcohol - Alcohol-Valrubicin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - VALSTAR® # Look-Alike Drug Names There is limited information regarding Valrubicin Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Valrubicin 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 Valrubicin is an anti neoplastic that is FDA approved for the treatment of BCG-refractory carcinoma in situ (CIS) of the urinary bladder in patients for whom immediate cystectomy would be associated with unacceptable morbidity or mortality.. Common adverse reactions include abdominal pain, nausea, myalgia, asthenia, headache, bladder pain, cystitis, dysuria, hematuria, incontinence, increased frequency of urination, pain in urethra, burning sensation, malaise. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - VALSTAR is indicated for intravesical therapy of BCG-refractory carcinoma in situ (CIS) of the urinary bladder in patients for whom immediate cystectomy would be associated with unacceptable morbidity or mortality. - Valrubicin is recommended at a dose of 800 mg administered intravesically once a week for six weeks. Administration should be delayed at least two weeks after transurethral resection and/or fulguration. For each instillation, four 5 mL vials (200 mg valrubicin/5 mL vial) should be allowed to warm slowly to room temperature, but should not be heated. Twenty milliliters of valrubicin should then be withdrawn from the four vials and diluted with 55 mL 0.9% Sodium Chloride Injection, USP providing 75 mL of a diluted valrubicin solution. * A urethral catheter should then be inserted into the patients bladder under aseptic conditions, the bladder drained, and the diluted 75 mL valrubicin solution instilled slowly via gravity flow over a period of several minutes. * The catheter should then be withdrawn. The patient should retain the drug for two hours before voiding. At the end of two hours, all patients should void. (Some patients will be unable to retain the drug for the full two hours.) Patients should be instructed to maintain adequate hydration following treatment. - Patients receiving valrubicin for refractory carcinoma in situ must be monitored closely for disease recurrence or progression. Recommended evaluations include cystoscopy, biopsy, and urine cytology every 3 months. - Administration Precautions: As recommended with other cytotoxic agents, caution should be exercised in handling and preparing the solution of valrubicin. Contact toxicity, common and severe with other anthracyclines, is not typical with valrubicin and, when observed, has been mild. Skin reactions may occur with accidental exposure. The use of goggles, gloves, and protective gowns is recommended during preparation and administration of the drug. Irritation of the eye has also been reported with accidental exposure. If this happens, the eye should be flushed with water immediately and thoroughly. Procedures for proper handling and disposal of anticancer drugs should be used.¹-⁴ Spills should be cleaned up withundiluted chlorine bleach. - Valrubicin sterile solution contains polyoxyl castor oil, which has been known to cause leaching of di(2-ethylhexyl) phthalate (DEHP) a hepatotoxic plasticizer, from polyvinyl chloride (PVC) bags and intravenous tubing. valrubicin solutions should be prepared and stored in glass, polypropylene, or polyolefin containers and tubing. It is recommended that non-DEHP containing administration sets, such as those that are polyethylene-lined, be used. - Preparation for Administration: valrubicin Sterile Solution for Intravesical Instillation is a clear red solution. It should be visually inspected for particulate matter and discoloration prior to administration. At temperatures below 4°C, polyoxyl castor oil may begin to form a waxy precipitate. If this happens, the vial should be warmed in the hand until the solution is clear. If particulate matter is still seen, valrubicin should not be administered. - Stability: Unopened vials of valrubicin are stable until the date indicated on the package when stored under refrigerated conditions at 2°-8°C (36°-46°F). Vials should not be heated. valrubicin diluted in 0.9% Sodium Chloride Injection, USP for administration is stable for 12 hours at temperatures up to 25°C (77°F). Since compatibility data are not available, valrubicin should not be mixed with other drugs. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Valrubicin in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Valrubicin in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Valrubicin in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Valrubicin in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Valrubicin in pediatric patients. # Contraindications - VALSTAR is contraindicated in patients with known hypersensitivity to anthracyclines or polyoxyl castor oil. Patients with concurrent urinary tract infections should not receive valrubicin. valrubicin should not be administered to patients with a small bladder capacity, i.e., unable to tolerate a 75 mL instillation. # Warnings - Valrubicin is contraindicated in patients with known hypersensitivity to anthracyclines or polyoxyl castor oil. Patients with concurrent urinary tract infections should not receive valrubicin. VALSTAR should not be administered to patients with a small bladder capacity, i.e., unable to tolerate a 75 mL instillation. # Adverse Reactions ## Clinical Trials Experience - Approximately 84% of patients who received intravesical valrubicin in clinical studies experienced local adverse events, but approximately half of the patients reported irritable bladder symptoms prior to treatment. The local adverse reactions associated with valrubicin usually occur during or shortly after instillation and resolve within 1 to 7 days after the instillate is removed from the bladder. - TABLE 1 displays the frequency of the local adverse experiences at baseline and during treatment among 170 patients who received 800 mg doses of VALSTAR® (valrubicin) Sterile Solution for Intravesical Instillation in a multiple-cycle treatment regimen. Only 7 of 143 patients who were scheduled to receive six doses failed to receive all of the planned doses because of the occurrence of local bladder symptoms. ## Postmarketing Experience - Digestive System: Tenesmus. - Metabolic and Nutritional: Nonprotein nitrogen increased. - Skin and Appendages: Pruritus. - Special Senses: Taste loss. - Urogenital System: Local skin irritation, poor urine flow, and urethritis. - Inadvertent paravenous extravasation of VALSTAR was not associated with skin ulceration or necrosis. # Drug Interactions There is limited information regarding Valrubicin Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Valrubicin can cause fetal harm if a pregnant woman is exposed to the drug systemically. Such exposure could occur after perforation of the urinary bladder during valrubicin therapy. Daily intravenous doses of 12 mg/kg (about one sixth of the recommended human intravesical dose on a mg/m2 basis) given to rats during fetal development caused fetal malformations. A dose of 24 mg/kg (about one third the recommended human intravesical dose on a mg/m2 basis) caused numerous, severe alterations in the skull and skeleton of the developing fetuses. This dose also caused an increase in fetal resorptions and a decrease in viable fetuses. Thus, valrubicin is embryo-toxic and teratogenic. There are no preclinical studies of the effects of intra-vesical valrubicin on fetal development and no adequate and well controlled studies of valrubicin in pregnant women. If valrubicin is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. It should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women who might become pregnant should be advised to avoid doing so during therapy with VALSTAR. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Valrubicin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Valrubicin during labor and delivery. ### Nursing Mothers - It is not known whether VALSTAR is excreted in human milk. Nevertheless, the drug is highly lipophilic and any exposure of infants to VALSTAR could pose serious health risks. Women should discontinue nursing before the initiation of VALSTAR therapy. ### Pediatric Use There is no FDA guidance on the use of Valrubicin with respect to pediatric patients. ### Geriatic Use - Because carcinoma in situ of the bladder generally occurs in older individuals, 85% of the patients enrolled in the clinical studies of VALSTAR were more than 60 years of age (49% of the patients were more than 70 years of age). In the primary efficacy studies, the mean age of the population was 69.5 years. There are no specific precautions regarding use of VALSTAR in geriatric patients who are otherwise in good health. ### Gender There is no FDA guidance on the use of Valrubicin with respect to specific gender populations. ### Race There is no FDA guidance on the use of Valrubicin with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Valrubicin in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Valrubicin in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Valrubicin in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Valrubicin in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral - Intravenous ### Monitoring - If VALSTAR is administered when bladder rupture or perforation is suspected, weekly monitoring of complete blood counts should be performed for 3 weeks. - Patients receiving VALSTAR for refractory carcinoma in situ must be monitored closely for disease recurrence or progression. # IV Compatibility There is limited information regarding IV Compatibility of Valrubicin in the drug label. # Overdosage There is limited information regarding Valrubicin overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology There is limited information regarding Valrubicin Pharmacology in the drug label. ## Mechanism of Action - Valrubicin is an anthracycline that affects a variety of interrelated biological functions, most of which involve nucleic acid metabolism. It readily penetrates into cells, where it inhibits the incorporation of nucleosides into nucleic acids, causes extensive chromosomal damage, and arrests cell cycle in G2. Although valrubicin does not bind strongly to DNA, a principal mechanism of its action, mediated by valrubicin metabolites, is interference with the normal DNA breaking-resealing action of DNA topoisomerase II. ## Structure There is limited information regarding Valrubicin Structure in the drug label. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Valrubicin in the drug label. ## Pharmacokinetics - Pharmacokinetics after Intravesical Administration of VALSTAR: When 800 mg VALSTAR was administered intravesically to patients with carcinoma in situ, VALSTAR penetrated into the bladder wall. The mean total anthracycline concentration measured in bladder tissue exceeded the levels causing 90% cytotoxicity to human bladder cells cultured in vitro. During the two-hour dose-retention period, the metabolism of VALSTAR to its major metabolites N-trifluoroacetyladriamycin and N-trifluoroacetyladriamycinol was negligible. After retention, the drug was almost completely excreted by voiding the instillate. Mean percent recovery of VALSTAR, N-trifluoroacetyladriamycin, and total anthracyclines in 14 urine samples from six patients was 98.6%, 0.4%, and 99.0% of the total administered drug, respectively. During the two-hour dose-retention period, only nanogram quantities of VALSTAR were absorbed into the plasma. VALSTAR metabolites N-trifluoroacetyladriamycin and N-trifluoroacetyladriamycinol were measured in blood. - Total systemic exposure to anthracyclines during and after intravesical administration of VALSTAR is dependent upon the condition of the bladder wall. The mean AUC0-6 hours (total anthracyclines exposure) for an intravesical dose of 900 mg of VALSTAR administered 2 weeks after transurethral resection of bladder tumors (n=6) was 78 nmol/L•hr. In patients receiving 800 mg of VALSTAR 5 to 51 minutes after typical (n=8) and extensive (n=5) transurethral resection of bladder tumors (TURBs), the mean AUC0-6 hours values for total anthracyclines were 409 and 788 nmol/L•hr, respectively. The AUC0-6 hours total exposure to anthracyclines was 18,382 nmol/L•hr in one patient who experienced a perforated bladder following a transurethral resection that occurred 5 minutes before administration of an intravesical dose of 800 mg of VALSTAR. Administration of a comparable intravenous dose of VALSTAR (600 mg/m2; n=2) as a 24-hour infusion resulted in an AUC0-6 hours for total anthracyclines of 11,975 nmol/L•hr. These results are shown in FIGURE 2. - The patient with a perforated bladder who received 800 mg of VALSTAR intravesically developed severe leukopenia and neutropenia approximately two weeks after drug administration. Systemic hematologic toxicity from VALSTAR was not seen after an intravesical dose of 800 mg of VALSTAR unless perforation of the urinary bladder occurred. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Valrubicin in the drug label. # Clinical Studies - VALSTAR has been administered intravesically to a total of 230 patients with transitional cell carcinoma of the bladder, including 205 patients who received multiple weekly doses ranging from 200 to 900 mg. One hundred seventy-nine of the 205 patients received the approved dose and schedule of 800 mg weekly for multiple weeks. - In the 90 study patients with BCG-refractory carcinoma in situ (CIS), 70% had received at least 2 courses of BCG and 30% had received one course of BCG and at least one additional course of treatment with another agent(s) - e.g., mitomycin, thiotepa, or interferon. VALSTAR was administered beginning at least two weeks after transurethral resection and/or fulguration. After intravesical administration of VALSTAR, 16 patients (18%) had a complete response documented by bladder biopsies and cytology at 6 months following initiation of therapy. Median duration of response from start of treatment varied according to the method of analysis (13.5 months if measured to last bladder biopsy without tumor and 21 months if measured until time of documented recurrence). A retrospective analysis in the 16 patients with complete response to VALSTAR demonstrated that time to recurrence of their disease after treatment with VALSTAR was longer than time to recurrence after previous courses of intravesical therapy. - Of the 90 patients with BCG-refractory CIS, 11% (10 patients) developed metastatic or deeply-invasive bladder cancer during follow-up; four of these patients, none who underwent cystectomy, died with metastatic bladder cancer and six were found to have developed stage progression to deeply-invasive disease (T3), with lymph node involvement in one patient, at the time of cystectomy. It is difficult to ascertain to what extent the development of advanced bladder cancer in these patients was due to the delay in cystectomy required to receive treatment with VALSTAR (3 months was the time of follow-up to determine response), as cystectomy was often delayed or was never performed despite failure of treatment with VALSTAR. In the 10 patients documented to have invasive bladder cancer or metastatic disease, the delay between the time of treatment failure (when cystectomy should have been performed) and cystectomy or documentation of advanced bladder cancer was a median of 17.5 months. # How Supplied - VALSTAR Sterile Solution for Intravesical Instillation is a clear red solution in polyoxyl castor oil/dehydrated alcohol, USP, containing 40 mg valrubicin per mL. VALSTAR Sterile Solution for Intravesical Instillation is available in single-use, clear glass vials, individually packaged in the following sizes: ## Storage - Store vials under refrigeration at 2°-8°C (36°-46°F) in the carton. DO NOT FREEZE. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Valrubicin in the drug label. # Precautions with Alcohol - Alcohol-Valrubicin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - VALSTAR®[1] # Look-Alike Drug Names There is limited information regarding Valrubicin Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Valrubicin
5a95f036cb58076deb5230f1f551f1e2cb15f80c	wikidoc	Vandetanib	Vandetanib # 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 Vandetanib is an tyrosine kinase inhibitor that is FDA approved for the treatment of symptomatic or progressive medullary thyroid cancer. Common adverse reactions include diarrhea, nausea, fatigue, rash, headache, abdominal pain, dyspepsia, hypocalcemia, cough, depression. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) # Indications Medullary Thyroid Cancer (MTC) - Vandetanib is indicated for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease. - Use of vandetanib in patients with indolent, asymptomatic or slowly progressing disease should be carefully considered because of the treatment related risks of vandetanib. # Dosage - The recommended daily dose is 300 mg of vandetanib taken orally. Vandetanib treatment should be continued until patients are no longer benefiting from treatment or an unacceptable toxicity occurs. - Vandetanib may be taken with or without food. - If a patient misses a dose, the missed dose should not be taken if it is less than 12 hours before the next dose. For Patients who have Difficulty Swallowing Solids - Vandetanib tablets should not be crushed. If vandetanib tablets cannot be taken whole, the tablets can be dispersed in a glass containing 2 ounces of non-carbonated water and stirred for approximately 10 minutes until the tablet is dispersed (will not completely dissolve). No other liquids should be used. The dispersion should be swallowed immediately. To ensure the full dose is received, any residues in the glass should be mixed again with an additional 4 ounces of non-carbonated water and swallowed. - The dispersion can also be administered through nasogastric or gastrostomy tubes. - Direct contact of crushed tablets with the skin or mucous membranes should be avoided. If such contact occurs, wash thoroughly. Avoid exposure to crushed tablets. Dosage Adjustment - In the event of corrected QT interval, Fridericia (QTcF) greater than 500 ms, interrupt dosing until QTcF returns to less than 450 ms, then resume at a reduced dose. - For CTCAE (Common Terminology Criteria for Adverse Events) grade 3 or greater toxicity, interrupt dosing until toxicity resolves or improves to CTCAE grade 1, and then resume at a reduced dose. - Because of the 19-day half-life, adverse reactions including a prolonged QT interval may not resolve quickly. Monitor appropriately. - The 300-mg daily dose can be reduced to 200 mg (two 100-mg tablets) and then to 100 mg for CTCAE grade 3 or greater toxicities. Elderly - No adjustment in starting dose is required for patients over 65 years of age. There are limited data for patients over the age of 75. Concomitant Strong CYP3A4 Inducers - Avoid the concomitant use of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital). Patients should also avoid taking St. John’s Wort. Patients With Renal Impairment - The starting dose should be reduced to 200 mg in patients with moderate (creatinine clearance ≥30 to <50 mL/min) and severe (creatinine clearance <30 mL/min) renal impairment. Patients with Hepatic Impairment - Single dose pharmacokinetic data from volunteers with hepatic impairment receiving 800 mg suggest that there were no differences in pharmacokinetics compared to patients with normal hepatic function. There are limited data in patients with liver impairment (serum bilirubin greater than 1.5 times the upper limit of normal). Vandetanib is not recommended for use in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment, as safety and efficacy have not been established. DOSAGE FORMS & STRENGTHS - Vandetanib 100-mg tablets are white, round, biconvex, film-coated, and intagliated with ‘Z 100‘ on one side and plain on the reverse side. - Vandetanib 300-mg tablets are white, oval, biconvex, film-coated, and intagliated with ‘Z 300’ on one side and plain on the reverse side. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Vandetanib in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Vandetanib in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Vandetanib 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 Vandetanib in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Vandetanib in pediatric patients. # Contraindications - Do not use in patients with congenital long QT syndrome. # Warnings Prolongation and Torsades de Pointes - Vandetanib can prolong the QT interval in a concentration-dependent manner. Torsades de pointes, ventricular tachycardia and sudden deaths have been reported in patients administered vandetanib. - Vandetanib treatment should not be started in patients whose QTcF interval is greater than 450 ms. Vandetanib should not be given to patients who have a history of torsades de pointes, congenital long QT syndrome, bradyarrhythmias or uncompensated heart failure. Vandetanib has not been studied in patients with ventricular arrhythmias or recent myocardial infarction. Vandetanib exposure is increased in patients with impaired renal function. The starting dose should be reduced to 200 mg in patients with moderate to severe renal impairment and QT interval should be monitored closely. - An ECG and levels of serum potassium, calcium, magnesium and TSH should be obtained at baseline, at 2-4 weeks and 8-12 weeks after starting treatment with vandetanib and every 3 months thereafter. Electrolytes and ECGs may require more frequent monitoring in case of diarrhea. Following any dose reduction for QT prolongation, or any dose interruptions greater than 2 weeks, QT assessments should be conducted as described above. Serum potassium levels should be maintained at 4 mEq/L or higher (within normal range) and serum magnesium and serum calcium should be kept within normal range to reduce the risk of electrocardiogram QT prolongation. - Avoid using vandetanib with drugs known to prolong the electrocardiogram QT interval. If such drugs are given to patients already receiving vandetanib and no alternative therapy exists, ECG monitoring of the QT interval should be performed more frequently. - Patients who develop a QTcF greater than 500 ms should stop taking vandetanib until QTcF returns to less than 450 ms. Dosing of vandetanib can be resumed at a reduced dose. Skin Reactions and Stevens-Johnson Syndrome - Severe skin reactions (including Stevens-Johnson syndrome), some leading to death, have been reported with vandetanib. Treatment of severe skin reactions has included systemic corticosteroids and permanent discontinuation of vandetanib. Mild to moderate skin reactions may manifest as rash, acne, dry skin, dermatitis, pruritis and other skin reactions (including photosensitivity reactions and palmar-plantar erythrodysesthesia syndrome). Mild to moderate skin reactions have been treated with topical and systemic corticosteroids, oral antihistamines, and topical and systemic antibiotics. If CTCAE grade 3 or greater skin reactions occur, vandetanib treatment should be stopped until improved. Upon improvement, consideration should be given to continuing treatment at a reduced dose or permanent discontinuation of vandetanib. - Photosensitivity reactions are increased with vandetanib. Patients should be advised to wear sunscreen and protective clothing when exposed to the sun. Due to the long half-life of vandetanib, protective clothing and sunscreen should continue for 4 months after discontinuation of treatment. Interstitial Lung Disease - Interstitial Lung Disease (ILD) or pneumonitis has been observed with vandetanib and deaths have been reported. Consider a diagnosis of ILD in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations. Advise patients to report promptly any new or worsening respiratory symptoms. - Patients who develop radiological changes suggestive of ILD and have few or no symptoms may continue vandetanib therapy with close monitoring at the discretion of the treating physician. - If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of corticosteroids and antibiotics may be indicated. - For cases where symptoms of ILD are severe, discontinue vandetanib therapy and the use of corticosteroids and antibiotics may be indicated until clinical symptoms resolve. Even upon resolution of severe ILD, permanent discontinuation of vandetanib should be considered. Ischemic Cerebrovascular Events - Ischemic cerebrovascular events have been observed with vandetanib and some cases have been fatal. In the randomized medullary thyroid cancer (MTC) study, ischemic cerebrovascular events were observed more frequently with vandetanib compared to placebo (1.3% compared to 0%) and no deaths were reported. The safety of resumption of vandetanib therapy after resolution of an ischemic cerebrovascular event has not been studied. Discontinue vandetanib in patients who experience a severe ischemic cerebrovascular event. Hemorrhage - Serious hemorrhagic events, which in some cases were fatal, have been observed with vandetanib. There were no fatal bleeding events in the randomized MTC study. Three patients died of fatal bleeding events while on vandetanib therapy in clinical studies. Do not administer vandetanib to patients with recent history of hemoptysis of ≥ 1/2 teaspoon of red blood. Discontinue vandetanib in patients with severe hemorrhage. Heart Failure - Heart failure has been observed with vandetanib and some cases have been fatal. Discontinuation of vandetanib may be necessary in patients with heart failure. Heart failure may not be reversible upon stopping vandetanib. Monitor for signs and symptoms of heart failure. Diarrhea - Diarrhea was observed in patients who received vandetanib. Routine anti-diarrheal agents are recommended. Diarrhea may cause electrolyte imbalances. Since QT prolongation is seen with vandetanib, serum electrolytes and ECGs should be carefully monitored in patients with diarrhea.If severe diarrhea develops, vandetanib treatment should be stopped until diarrhea improves. Upon improvement, treatment with vandetanib should be resumed at a reduced dose. Hypothyroidism - In the randomized MTC study where 90% of the patients enrolled had prior thyroidectomy, increases in the dose of the thyroid replacement therapy were required in 49% of the patients randomized to vandetanib compared to 17% of the patients randomized to placebo. Thyroid-stimulating hormone (TSH) should be obtained at baseline, at 2 to 4 weeks and 8 to 12 weeks after starting treatment with vandetanib and every 3 months thereafter. If signs or symptoms of hypothyroidism occur, thyroid hormone levels should be examined and thyroid replacement therapy should be adjusted accordingly. Hypertension - Hypertension, including hypertensive crisis, has been observed with vandetanib. All patients should be monitored for hypertension and it should be controlled as appropriate. Dose reduction or interruption may be necessary. If high blood pressure cannot be controlled, vandetanib should not be restarted. Reversible posterior leukoencephalopathy syndrome - Reversible posterior leukoencephalopathy syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by an MRI of the brain, has been observed with vandetanib. This syndrome should be considered in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. In clinical studies, three of four patients who developed RPLS while taking vandetanib, including one pediatric patient, also had hypertension. Discontinuation of vandetanib treatment in patients with RPLS should be considered. Drug Interactions - The administration of vandetanib with agents that are strong CYP3A4 inducers should be avoided. - The administration of vandetanib with anti-arrhythmic drugs (including, but not limited to amiodarone, disopyramide, procainamide, sotalol, dofetilide) and other drugs that may prolong the QT interval (including but not limited to cloroquine, clarithromycin, dolasetron, granisetron, haloperidol, methadone, moxifloxacin, and pimozide) should be avoided. Renal Impairment - Vandetanib exposure is increased in patients with impaired renal function. The starting dose should be reduced to 200 mg in patients with moderate to severe renal impairment and QT interval should be monitored closely. There is no information available for patients with end-stage renal disease requiring dialysis. Hepatic Impairment - Vandetanib is not recommended for use in patients with moderate and severe hepatic impairment, as safety and efficacy have not been established. Use in Pregnancy - Vandetanib can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies in pregnant women using vandetanib. In nonclinical studies in rats, vandetanib was embryotoxic, fetotoxic, and teratogenic, at exposures equivalent to or lower than those expected at the recommended human dose of 300 mg/day. As expected from its pharmacological actions, vandetanib has shown significant effects on all stages of female reproduction in rats. - 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 childbearing potential should be advised to avoid becoming pregnant during treatment with vandetanib. Women should be advised that they must use effective contraception to prevent pregnancy during treatment and for at least four months following the last dose of vandetanib. Vandetanib REMS (Risk Evaluation and Mitigation Strategy) Program - Because of the risk of QT prolongation, torsades de pointes, and sudden death, vandetanib is available only through a restricted distribution program called Vandetanib REMS Program. Only prescribers and pharmacies certified with the program are able to prescribe and dispense vandetanib. - An overview of the requirements for prescribers and pharmacies is included below. - To be certified, prescribers must review the educational materials, agree to comply with the REMS requirements and enroll in the program. - To be certified, pharmacies that dispense vandetanib must enroll in the program, train their pharmacy staff to verify that each prescription is written by a certified prescriber before dispensing to a patient, and agree to comply with the REMS requirements. - To learn about the specific REMS requirements and to enroll in the Vandetanib REMS Program call 1-800-236-9933 or visit www.vandetanibrems.com. # Adverse Reactions ## Clinical Trials Experience - The most commonly reported adverse drug reactions (>20%) have been diarrhea, rash, acne, nausea, hypertension, headache, fatigue, decreased appetite, and abdominal pain. The most common laboratory abnormalities (>20%) were decreased calcium, increased ALT, and decreased glucose. - 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. Clinical Studies Experience - Patients with unresectable locally advanced or metastatic medullary thyroid cancer were treated with vandetanib 300 mg (n=231) or Placebo (n= 99). Patients with investigator-determined progression or patients who continued treatment after the data cut-off could receive open label vandetanib. The following adverse reactions have been reported - Adverse reactions resulting in death in patients receiving vandetanib (N=5) were respiratory failure, respiratory arrest, aspiration pneumonia, cardiac failure with arrhythmia, and sepsis. Adverse reactions resulting in death in patients receiving placebo were gastrointestinal hemorrhage (1%) and gastroenteritis (1%). In addition there was one sudden death and one death from cardiopulmonary arrest, in patients receiving vandetanib after data cut-off. Causes of discontinuation in vandetanib-treated patients in >1 patient included asthenia, fatigue, rash, arthralgia, diarrhea, hypertension, prolonged QT interval, increase in creatinine and pyrexia. Serious adverse events in vandetanib-treated patients in >2% of patients included diarrhea, pneumonia, and hypertension. Clinically important uncommon adverse drug reactions in patients who received vandetanib versus patients who received placebo included pancreatitis (0.4% vs. 0%) and heart failure (0.9% vs. 0%). In the integrated summary of safety database, the most common cause of death in patients who received vandetanib was pneumonia. - The incidence of Grade 1-2 bleeding events was 14% in patients receiving vandetanib compared with 7% on placebo in the randomized portion of the medullary thyroid cancer (MTC) study. The incidence was similar in the 300 mg monotherapy safety program with a 13% incidence. - Blurred vision was more common in patients who received vandetanib versus patients who received placebo for medullary thyroid cancer (9% vs. 1%, respectively). Scheduled slit lamp examinations have revealed corneal opacities (vortex keratopathies) in treated patients, which can lead to halos and decreased visual acuity. It is unknown if this will improve after discontinuation. Ophthalmologic examination, including slit lamp, is recommended in patients who report visual changes. If a patient has blurred vision, do not drive or operate machinery. - Table 2 provides the frequency and severity of laboratory abnormalities reported for patients with medullary thyroid cancer receiving randomized treatment with vandetanib or placebo. - Alanine aminotransferase elevations occurred in 51% of patients on vandetanib in the randomized medullary thyroid cancer (MTC) study. Grade 3-4 ALT elevations were seen in 2% of patients and no patients had a concomitant increase in bilirubin. Elevations in ALT have resulted in temporary discontinuation of vandetanib. However, 16 of 22 patients with a grade 2 elevation in ALT continued 300 mg vandetanib. Seven patients who continued vandetanib had a normal ALT within 6 months. In the protocol, ALT was monitored every 3 months and more frequently as indicated. ## Postmarketing Experience There is limited information regarding Vandetanib Postmarketing Experience in the drug label. # Drug Interactions CYP3A4 Inducers - Drugs that are CYP3A4 inducers can alter vandetanib plasma concentrations. The concomitant use of known strong CYP3A4 inducers should be avoided while receiving vandetanib therapy. St. John’s Wort may decrease vandetanib exposure unpredictably and should be avoided. CYP3A4 Inhibitors - In healthy subjects, no clinically significant interaction was shown between vandetanib and the potent CYP3A4 inhibitor, itraconazole. Drugs that Prolong the QT Interval - The administration of vandetanib with agents that may prolong the QT interval should be avoided. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Pregnancy Category D. - Vandetanib can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of vandetanib in pregnant women. Vandetanib is embryotoxic, fetotoxic, and teratogenic to rats, at exposures equivalent to or lower than those expected at the recommended human dose of 300 mg/day. When vandetanib was administered to female rats prior to mating and through the first week of pregnancy, there were increases in pre-implantation loss and post-implantation loss resulting in a significant reduction in the number of live embryos. This dose administered to rats during organogenesis, caused an increase in post-implantation loss including embryofetal death. Vandetanib caused total litter loss when administered at a dose of 25 mg/kg/day during organogenesis until expected parturition. When administered during organogenesis, vandetanib doses of 1, 10 and 25 mg/kg/day (approximately 0.03, 0.4, and 1.0 times respectively, the Cmax in patients with cancer at the recommended human dose) caused malformations of the heart vessels and delayed ossification of the skull, vertebrae and sternum, indicating delayed fetal development. A no effect level for these malformations was not identified in this study. In a rat pre- and post-natal development study, at doses producing maternal toxicity (1 and 10 mg/kg/day) during gestation and/or lactation, vandetanib, decreased pup survival, and/or reduced post-natal pup growth. Reduced post-natal pup growth was associated with a delay in physical development. - 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 childbearing potential should be advised to avoid pregnancy while taking vandetanib and for at least four months following the last dose of vandetanib. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Vandetanib in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Vandetanib during labor and delivery. ### Nursing Mothers - In nonclinical studies, vandetanib was excreted in rat milk and found in plasma of pups following dosing to lactating rats. Vandetanib transfer in breast milk resulted in relatively constant exposure in pups due to the long half-life of the drug. It is not known whether this drug 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 from vandetanib, 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 - Safety and efficacy of vandetanib in pediatric patients have not been established. ### Geriatic Use - In total, 18% of medullary thyroid cancer patients treated with vandetanib were age 65 years or older, and 3% were 75 years and older. No overall differences in safety and efficacy were observed between elderly and younger patients. No adjustment in starting dose is required for patients over 65 years of age. There are limited data for patients over the age of 75 years. ### Gender There is no FDA guidance on the use of Vandetanib with respect to specific gender populations. ### Race There is no FDA guidance on the use of Vandetanib with respect to specific racial populations. ### Renal Impairment - The pharmacokinetics of vandetanib were evaluated after a single dose of 800 mg in subjects with mild (n = 6), moderate (n = 8), and severe (n = 6) renal impairment and normal (n = 10) renal function. Subjects with mild renal impairment had comparable mean AUC and clearance values to those with normal renal function. In subjects with moderate and severe renal impairment, the average AUC of vandetanib increased by 39% and 41%, respectively, compared to patients with normal renal function. - The starting dose should be reduced to 200 mg in patients with moderate and severe renal impairment. ### Hepatic Impairment - The pharmacokinetics of vandetanib were evaluated after a single dose of 800 mg in subjects with mild (n = 8), moderate (n = 7), and severe (n = 6) hepatic impairment and normal hepatic function (n = 5). Subjects with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment had comparable mean AUC and clearance values to those with normal hepatic function. - There are limited data in patients with liver impairment (serum bilirubin greater than 1.5 times the upper limit of normal). Vandetanib is not recommended for use in patients with moderate and severe hepatic impairment, as safety and efficacy have not been established. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Vandetanib in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Vandetanib in patients who are immunocompromised. # Administration and Monitoring ### Administration - ORAL ### Monitoring There is limited information regarding Vandetanib Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Vandetanib and IV administrations. # Overdosage - There is no specific treatment in the event of overdose with vandetanib and possible symptoms of overdose have not been established. Because of the 19-day half-life, adverse reactions may not resolve quickly. In phase 1 clinical trials, a limited number of patients were treated with daily doses of up to 600 mg and healthy volunteers with daily doses up to 1200 mg. An increase in the frequency and severity of some adverse reactions, like rash, diarrhea and hypertension, was observed at multiple doses at and above 300 mg in healthy volunteer studies and in patients. In addition the possibility of QTc prolongation and Torsades de pointes should be considered. - Adverse reactions associated with overdose are to be treated symptomatically; in particular, severe diarrhea must be managed appropriately. In the event of an overdose, further doses of vandetanib must be interrupted, and appropriate measures taken to assure that an adverse event has not occurred, i.e., ECG within 24 hours to determine QTc prolongation. # Pharmacology ## Mechanism of Action - Vandetanib is a tyrosine kinase inhibitor. In vitro studies have shown that vandetanib inhibits the activity of tyrosine kinases including members of the epidermal growth factor receptor (EGFR) family, vascular endothelial cell growth factor (VEGF) receptors, rearranged during transfection (RET), protein tyrosine kinase 6 (BRK), TIE2, members of the EPH receptors kinase family, and members of the Src family of tyrosine kinases. Vandetanib inhibits endothelial cell migration, proliferation, survival and new blood vessel formation in in vitro models of angiogenesis. Vandetanib inhibits EGFR-dependent cell survival in vitro. In addition, vandetanib inhibits epidermal growth factor (EGF)-stimulated receptor tyrosine kinase phosphorylation in tumor cells and endothelial cells and VEGF-stimulated tyrosine kinase phosphorylation in endothelial cells. - In vivo vandetanib administration reduced tumor cell-induced angiogenesis, tumor vessel permeability, and inhibited tumor growth and metastasis in mouse models of cancer. - There is no evidence of a relationship between RET mutations and efficacy with vandetanib. ## Structure - Vandetanib tablets for daily oral administration are available in two dosage strengths, 100 mg and 300 mg, containing 100 mg and 300 mg of vandetanib, respectively. The tablet cores contain the following inactive ingredients: Tablet core: calcium hydrogen phosphate dihydrate, microcrystalline cellulose, crospovidone, povidone, and magnesium stearate. The tablet film-coat contains the following inactive ingredients: hypromellose 2910, macrogol 300, and titanium dioxide E171. - Vandetanib is chemically described as N-(4-bromo-2-fluorophenyl)-6-methoxy-7- methoxy]quinazolin-4-amine. - The structural and molecular formulas are: Vandetanib has a molecular weight of 475.36. Vandetanib exhibits pH-dependent solubility, with increased solubility at lower pH. Vandetanib is practically insoluble in water with a value of 0.008 mg/mL at 25°C (77°F ). ## Pharmacodynamics There is limited information regarding Vandetanib Pharmacodynamics in the drug label. ## Pharmacokinetics - A population pharmacokinetic analysis of vandetanib was conducted in 231 patients with MTC following oral administration of 300 mg daily doses. The pharmacokinetics of vandetanib at the 300 mg dose in MTC patients are characterized by a mean clearance of approximately 13.2 L/h, a mean volume of distribution of approximately 7450 L, and a median plasma half-life of 19 days. Absorption - Following oral administration of vandetanib, absorption is slow with peak plasma concentrations typically achieved at a median of 6 hours, range 4-10 hours, after dosing. Vandetanib accumulates approximately 8-fold on multiple dosing with steady state achieved from approximately 3 months. - Exposure to vandetanib is unaffected by food. Distribution - Vandetanib binds to human serum albumin and α1-acid-glycoprotein with in vitro protein binding being approximately 90%. In ex vivo plasma samples from colorectal cancer patients at steady state exposure after 300 mg once daily, the mean percentage protein binding was 93.7% (range 92.2 to 95.7%). Metabolism - Following oral dosing of 14C-vandetanib, unchanged vandentanib and metabolites vandetanib N-oxide and N-desmethyl vandetanib were detected in plasma, urine and feces. A glucuronide conjugate was seen as a minor metabolite in excreta only. N-desmethyl-vandetanib is primarily produced by CYP3A4 and vandetanib-N-oxide by flavin–containing monooxygenase enzymes FMO1 and FMO3. N-desmethyl-vandetanib and vandetanib-N-oxide circulate at concentrations of approximately 7-17.1% and 1.4-2.2%, respectively, of those of vandetanib. Excretion - Within a 21-day collection period after a single dose of 14C-vandetanib, approximately 69% was recovered with 44% in feces and 25% in urine. Excretion of the dose was slow and further excretion beyond 21 days would be expected based on the plasma half-life. - Vandetanib was not a substrate of hOCT2 expressed in HEK293 cells. Vandetanib inhibits the uptake of the selective OCT2 marker substrate 14C-creatinine by HEK-OCT2 cells, with a mean IC50 of approximately 2.1 μg/mL. This is higher than vandetanib plasma concentrations (approximately 0.81 μg/mL) observed after multiple dosing at 300 mg. Inhibition of renal excretion of creatinine by vandetanib provides an explanation for increases in plasma creatinine seen in human subjects receiving vandetanib. Special Populations Effects of Age and Gender - In a population pharmacokinetic evaluation in cancer patients, no relationship was apparent between oral clearance and patient age or gender. Ethnicity - Based on a cross-study comparison in a limited number of patients, Japanese (N=3) and Chinese (N=7) patients had on average exposures that were higher than Caucasian (N=7) patients receiving the same dose. Pediatric - The pharmacokinetics of vandetanib have not been evaluated in pediatric patients. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility - Carcinogenicity studies have not been conducted with vandetanib. - Vandetanib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using human lymphocytes or in the in vivo rat micronucleus assay. - Based on nonclinical findings, male and female fertility may be impaired by treatment with vandetanib. In a fertility study in male rats, vandetanib had no effect on copulation or fertility rate when undosed females were mated with males administered 1, 5, or 20 mg/kg/day of vandetanib (approximately 0.03, 0.22, or 0.40 times, respectively, the AUC in patients with cancer at the recommended human dose of 300 mg/day). There was a slight decrease in the number of live embryos at 20 mg/kg/day and an increase in preimplantation loss at >5 mg/kg/day. In a female fertility study, there was a trend towards increased estrus cycle irregularity, a slight reduction in pregnancy incidence and an increase in implantation loss. In a repeat-dose toxicity study in rats, there was a decrease in the number of corpora lutea in the ovaries of rats administered 75 mg/kg/day vandetanib (approximately 1.8 times the AUC in patients with cancer at the recommended human dose) for 1 month. Animal Pharmacology and/or Toxicology - In an animal model of wound-healing, mice dosed with vandetanib had reduced skin-breaking strength compared with controls. This suggests that vandetanib slows but does not prevent wound healing. The appropriate interval between discontinuation of vandetanib and subsequent elective surgery required to avoid the risks of impaired wound healing has not been determined. - Nodular masses were observed in a 6-month toxicology study in rats during treatment with ≥5 mg/kg/day vandetanib (approximately 0.22 or 0.40 times, respectively, the AUC in patients with cancer at the recommended human dose of 300 mg/day). Masses were palpable during clinical assessments as early as week 13, were observed in multiple organs, and were associated with hemorrhagic or inflammatory findings. # Clinical Studies - A double-blind, placebo-controlled study randomized patients with unresectable locally advanced or metastatic medullary thyroid cancer to vandetanib 300 mg (n=231) versus Placebo (n=100). - The primary objective was demonstration of improvement in progression-free survival (PFS) with vandetanib compared to placebo. Other endpoints included evaluation of overall survival and overall objective response rate (ORR). Centralized, independent blinded review of the imaging data was used in the assessment of PFS and ORR. Upon objective disease progression based on the investigator’s assessment, patients were discontinued from blinded study treatment and given the option to receive open-label vandetanib. Nineteen percent (44/231) of the patients initially randomized to vandetanib opted to receive open-label vandetanib after disease progression, and 58% (58/100) of the patients initially randomized to placebo opted to receive open-label vandetanib after disease progression. - The result of the PFS analysis, based on the central review RECIST assessment, showed a statistically significant improvement in PFS for patients randomized to vandetanib (Hazard Ratio (HR) = 0.35; 95% Confidence Interval (CI) = 0.24-0.53; p<0.0001). Analyses in the subgroups of patients who were symptomatic or had progressed within 6 months prior to their enrollment showed similar PFS results (HR = 0.31 95% CI: 0.19, 0.53 for symptomatic patients; HR = 0.41 95% CI: 0.25, 0.66 for patients who had progressed within 6 months prior to enrollment). - At the time of the primary analysis of PFS, 15% of the patients had died and there was no significant difference in overall survival between the two treatment groups. The overall objective response rate (ORR) for patients randomized to vandetanib was 44% compared to 1% for patients randomized to placebo. All objective responses were partial responses. # How Supplied - 100 mg Tablets Available in bottles containing 30 tablets (NDC 0310–7810–30). - 300 mg Tablets Available in bottles containing 30 tablets (NDC 0310–7830–30). ## Storage - Vandetanib tablets should be stored at 25°C (77°F); excursions permitted to 15oC – 30oC (59oF – 86oF) . # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information QT Interval - Vandetanib can prolong the QT interval in a concentration-dependent manner. Torsades de pointes, ventricular tachycardia and sudden death have been reported in patients administered vandetanib. Patients should be advised that their electrolytes and the electrical activity of their heartbeat (via an ECG) should be monitored regularly during treatment with vandetanib. Rash - Patients taking vandetanib should be told they may be more susceptible to sunburn and to use appropriate sun protection (e.g., sunscreen and/or clothing) while taking vandetanib and for at least 4 months after drug discontinuation. Patients should consult their physician promptly if they develop a skin rash. Interstitial lung disease - Patients should be told to contact their physician promptly if they develop sudden onset or worsening of breathlessness, persistent cough or fever. Diarrhea - Patients should be informed that they may experience diarrhea while taking vandetanib. Patients should also be advised to use standard anti-diarrheal medications and to seek medical attention if their diarrhea becomes persistent or severe. Patients with diarrhea should contact their physician to have their electrolytes monitored. Reversible Posterior Leukoencephalopathy Syndrome - Patients should be told to contact their physician promptly if they experience seizures, headaches, visual disturbances, confusion or difficulty thinking. Pregnancy and Nursing - Patients of childbearing potential must be told to use effective contraception during therapy and for at least four months following their last dose of vandetanib. - Breast-feeding mothers are advised to discontinue nursing while receiving vandetanib therapy. Drug Handling - Vandetanib tablets should not be crushed. Direct contact of crushed tablets with the skin or mucous membranes should be avoided. # Precautions with Alcohol Alcohol-Vandetanib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - VANDETANIB ® # Look-Alike Drug Names There is limited information regarding Vandetanib Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Vandetanib Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, 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 Vandetanib is an tyrosine kinase inhibitor that is FDA approved for the treatment of symptomatic or progressive medullary thyroid cancer. Common adverse reactions include diarrhea, nausea, fatigue, rash, headache, abdominal pain, dyspepsia, hypocalcemia, cough, depression. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) # Indications Medullary Thyroid Cancer (MTC) - Vandetanib is indicated for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease. - Use of vandetanib in patients with indolent, asymptomatic or slowly progressing disease should be carefully considered because of the treatment related risks of vandetanib. # Dosage - The recommended daily dose is 300 mg of vandetanib taken orally. Vandetanib treatment should be continued until patients are no longer benefiting from treatment or an unacceptable toxicity occurs. - Vandetanib may be taken with or without food. - If a patient misses a dose, the missed dose should not be taken if it is less than 12 hours before the next dose. For Patients who have Difficulty Swallowing Solids - Vandetanib tablets should not be crushed. If vandetanib tablets cannot be taken whole, the tablets can be dispersed in a glass containing 2 ounces of non-carbonated water and stirred for approximately 10 minutes until the tablet is dispersed (will not completely dissolve). No other liquids should be used. The dispersion should be swallowed immediately. To ensure the full dose is received, any residues in the glass should be mixed again with an additional 4 ounces of non-carbonated water and swallowed. - The dispersion can also be administered through nasogastric or gastrostomy tubes. - Direct contact of crushed tablets with the skin or mucous membranes should be avoided. If such contact occurs, wash thoroughly. Avoid exposure to crushed tablets. Dosage Adjustment - In the event of corrected QT interval, Fridericia (QTcF) greater than 500 ms, interrupt dosing until QTcF returns to less than 450 ms, then resume at a reduced dose. - For CTCAE (Common Terminology Criteria for Adverse Events) grade 3 or greater toxicity, interrupt dosing until toxicity resolves or improves to CTCAE grade 1, and then resume at a reduced dose. - Because of the 19-day half-life, adverse reactions including a prolonged QT interval may not resolve quickly. Monitor appropriately. - The 300-mg daily dose can be reduced to 200 mg (two 100-mg tablets) and then to 100 mg for CTCAE grade 3 or greater toxicities. Elderly - No adjustment in starting dose is required for patients over 65 years of age. There are limited data for patients over the age of 75. Concomitant Strong CYP3A4 Inducers - Avoid the concomitant use of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital). Patients should also avoid taking St. John’s Wort. Patients With Renal Impairment - The starting dose should be reduced to 200 mg in patients with moderate (creatinine clearance ≥30 to <50 mL/min) and severe (creatinine clearance <30 mL/min) renal impairment. Patients with Hepatic Impairment - Single dose pharmacokinetic data from volunteers with hepatic impairment receiving 800 mg suggest that there were no differences in pharmacokinetics compared to patients with normal hepatic function. There are limited data in patients with liver impairment (serum bilirubin greater than 1.5 times the upper limit of normal). Vandetanib is not recommended for use in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment, as safety and efficacy have not been established. DOSAGE FORMS & STRENGTHS - Vandetanib 100-mg tablets are white, round, biconvex, film-coated, and intagliated with ‘Z 100‘ on one side and plain on the reverse side. - Vandetanib 300-mg tablets are white, oval, biconvex, film-coated, and intagliated with ‘Z 300’ on one side and plain on the reverse side. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Vandetanib in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Vandetanib in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Vandetanib 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 Vandetanib in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Vandetanib in pediatric patients. # Contraindications - Do not use in patients with congenital long QT syndrome. # Warnings Prolongation and Torsades de Pointes - Vandetanib can prolong the QT interval in a concentration-dependent manner. Torsades de pointes, ventricular tachycardia and sudden deaths have been reported in patients administered vandetanib. - Vandetanib treatment should not be started in patients whose QTcF interval is greater than 450 ms. Vandetanib should not be given to patients who have a history of torsades de pointes, congenital long QT syndrome, bradyarrhythmias or uncompensated heart failure. Vandetanib has not been studied in patients with ventricular arrhythmias or recent myocardial infarction. Vandetanib exposure is increased in patients with impaired renal function. The starting dose should be reduced to 200 mg in patients with moderate to severe renal impairment and QT interval should be monitored closely. - An ECG and levels of serum potassium, calcium, magnesium and TSH should be obtained at baseline, at 2-4 weeks and 8-12 weeks after starting treatment with vandetanib and every 3 months thereafter. Electrolytes and ECGs may require more frequent monitoring in case of diarrhea. Following any dose reduction for QT prolongation, or any dose interruptions greater than 2 weeks, QT assessments should be conducted as described above. Serum potassium levels should be maintained at 4 mEq/L or higher (within normal range) and serum magnesium and serum calcium should be kept within normal range to reduce the risk of electrocardiogram QT prolongation. - Avoid using vandetanib with drugs known to prolong the electrocardiogram QT interval. If such drugs are given to patients already receiving vandetanib and no alternative therapy exists, ECG monitoring of the QT interval should be performed more frequently. - Patients who develop a QTcF greater than 500 ms should stop taking vandetanib until QTcF returns to less than 450 ms. Dosing of vandetanib can be resumed at a reduced dose. Skin Reactions and Stevens-Johnson Syndrome - Severe skin reactions (including Stevens-Johnson syndrome), some leading to death, have been reported with vandetanib. Treatment of severe skin reactions has included systemic corticosteroids and permanent discontinuation of vandetanib. Mild to moderate skin reactions may manifest as rash, acne, dry skin, dermatitis, pruritis and other skin reactions (including photosensitivity reactions and palmar-plantar erythrodysesthesia syndrome). Mild to moderate skin reactions have been treated with topical and systemic corticosteroids, oral antihistamines, and topical and systemic antibiotics. If CTCAE grade 3 or greater skin reactions occur, vandetanib treatment should be stopped until improved. Upon improvement, consideration should be given to continuing treatment at a reduced dose or permanent discontinuation of vandetanib. - Photosensitivity reactions are increased with vandetanib. Patients should be advised to wear sunscreen and protective clothing when exposed to the sun. Due to the long half-life of vandetanib, protective clothing and sunscreen should continue for 4 months after discontinuation of treatment. Interstitial Lung Disease - Interstitial Lung Disease (ILD) or pneumonitis has been observed with vandetanib and deaths have been reported. Consider a diagnosis of ILD in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations. Advise patients to report promptly any new or worsening respiratory symptoms. - Patients who develop radiological changes suggestive of ILD and have few or no symptoms may continue vandetanib therapy with close monitoring at the discretion of the treating physician. - If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of corticosteroids and antibiotics may be indicated. - For cases where symptoms of ILD are severe, discontinue vandetanib therapy and the use of corticosteroids and antibiotics may be indicated until clinical symptoms resolve. Even upon resolution of severe ILD, permanent discontinuation of vandetanib should be considered. Ischemic Cerebrovascular Events - Ischemic cerebrovascular events have been observed with vandetanib and some cases have been fatal. In the randomized medullary thyroid cancer (MTC) study, ischemic cerebrovascular events were observed more frequently with vandetanib compared to placebo (1.3% compared to 0%) and no deaths were reported. The safety of resumption of vandetanib therapy after resolution of an ischemic cerebrovascular event has not been studied. Discontinue vandetanib in patients who experience a severe ischemic cerebrovascular event. Hemorrhage - Serious hemorrhagic events, which in some cases were fatal, have been observed with vandetanib. There were no fatal bleeding events in the randomized MTC study. Three patients died of fatal bleeding events while on vandetanib therapy in clinical studies. Do not administer vandetanib to patients with recent history of hemoptysis of ≥ 1/2 teaspoon of red blood. Discontinue vandetanib in patients with severe hemorrhage. Heart Failure - Heart failure has been observed with vandetanib and some cases have been fatal. Discontinuation of vandetanib may be necessary in patients with heart failure. Heart failure may not be reversible upon stopping vandetanib. Monitor for signs and symptoms of heart failure. Diarrhea - Diarrhea was observed in patients who received vandetanib. Routine anti-diarrheal agents are recommended. Diarrhea may cause electrolyte imbalances. Since QT prolongation is seen with vandetanib, serum electrolytes and ECGs should be carefully monitored in patients with diarrhea.If severe diarrhea develops, vandetanib treatment should be stopped until diarrhea improves. Upon improvement, treatment with vandetanib should be resumed at a reduced dose. Hypothyroidism - In the randomized MTC study where 90% of the patients enrolled had prior thyroidectomy, increases in the dose of the thyroid replacement therapy were required in 49% of the patients randomized to vandetanib compared to 17% of the patients randomized to placebo. Thyroid-stimulating hormone (TSH) should be obtained at baseline, at 2 to 4 weeks and 8 to 12 weeks after starting treatment with vandetanib and every 3 months thereafter. If signs or symptoms of hypothyroidism occur, thyroid hormone levels should be examined and thyroid replacement therapy should be adjusted accordingly. Hypertension - Hypertension, including hypertensive crisis, has been observed with vandetanib. All patients should be monitored for hypertension and it should be controlled as appropriate. Dose reduction or interruption may be necessary. If high blood pressure cannot be controlled, vandetanib should not be restarted. Reversible posterior leukoencephalopathy syndrome - Reversible posterior leukoencephalopathy syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by an MRI of the brain, has been observed with vandetanib. This syndrome should be considered in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. In clinical studies, three of four patients who developed RPLS while taking vandetanib, including one pediatric patient, also had hypertension. Discontinuation of vandetanib treatment in patients with RPLS should be considered. Drug Interactions - The administration of vandetanib with agents that are strong CYP3A4 inducers should be avoided. - The administration of vandetanib with anti-arrhythmic drugs (including, but not limited to amiodarone, disopyramide, procainamide, sotalol, dofetilide) and other drugs that may prolong the QT interval (including but not limited to cloroquine, clarithromycin, dolasetron, granisetron, haloperidol, methadone, moxifloxacin, and pimozide) should be avoided. Renal Impairment - Vandetanib exposure is increased in patients with impaired renal function. The starting dose should be reduced to 200 mg in patients with moderate to severe renal impairment and QT interval should be monitored closely. There is no information available for patients with end-stage renal disease requiring dialysis. Hepatic Impairment - Vandetanib is not recommended for use in patients with moderate and severe hepatic impairment, as safety and efficacy have not been established. Use in Pregnancy - Vandetanib can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies in pregnant women using vandetanib. In nonclinical studies in rats, vandetanib was embryotoxic, fetotoxic, and teratogenic, at exposures equivalent to or lower than those expected at the recommended human dose of 300 mg/day. As expected from its pharmacological actions, vandetanib has shown significant effects on all stages of female reproduction in rats. - 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 childbearing potential should be advised to avoid becoming pregnant during treatment with vandetanib. Women should be advised that they must use effective contraception to prevent pregnancy during treatment and for at least four months following the last dose of vandetanib. Vandetanib REMS (Risk Evaluation and Mitigation Strategy) Program - Because of the risk of QT prolongation, torsades de pointes, and sudden death, vandetanib is available only through a restricted distribution program called Vandetanib REMS Program. Only prescribers and pharmacies certified with the program are able to prescribe and dispense vandetanib. - An overview of the requirements for prescribers and pharmacies is included below. - To be certified, prescribers must review the educational materials, agree to comply with the REMS requirements and enroll in the program. - To be certified, pharmacies that dispense vandetanib must enroll in the program, train their pharmacy staff to verify that each prescription is written by a certified prescriber before dispensing to a patient, and agree to comply with the REMS requirements. - To learn about the specific REMS requirements and to enroll in the Vandetanib REMS Program call 1-800-236-9933 or visit www.vandetanibrems.com. # Adverse Reactions ## Clinical Trials Experience - The most commonly reported adverse drug reactions (>20%) have been diarrhea, rash, acne, nausea, hypertension, headache, fatigue, decreased appetite, and abdominal pain. The most common laboratory abnormalities (>20%) were decreased calcium, increased ALT, and decreased glucose. - 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. Clinical Studies Experience - Patients with unresectable locally advanced or metastatic medullary thyroid cancer were treated with vandetanib 300 mg (n=231) or Placebo (n= 99). Patients with investigator-determined progression or patients who continued treatment after the data cut-off could receive open label vandetanib. The following adverse reactions have been reported - Adverse reactions resulting in death in patients receiving vandetanib (N=5) were respiratory failure, respiratory arrest, aspiration pneumonia, cardiac failure with arrhythmia, and sepsis. Adverse reactions resulting in death in patients receiving placebo were gastrointestinal hemorrhage (1%) and gastroenteritis (1%). In addition there was one sudden death and one death from cardiopulmonary arrest, in patients receiving vandetanib after data cut-off. Causes of discontinuation in vandetanib-treated patients in >1 patient included asthenia, fatigue, rash, arthralgia, diarrhea, hypertension, prolonged QT interval, increase in creatinine and pyrexia. Serious adverse events in vandetanib-treated patients in >2% of patients included diarrhea, pneumonia, and hypertension. Clinically important uncommon adverse drug reactions in patients who received vandetanib versus patients who received placebo included pancreatitis (0.4% vs. 0%) and heart failure (0.9% vs. 0%). In the integrated summary of safety database, the most common cause of death in patients who received vandetanib was pneumonia. - The incidence of Grade 1-2 bleeding events was 14% in patients receiving vandetanib compared with 7% on placebo in the randomized portion of the medullary thyroid cancer (MTC) study. The incidence was similar in the 300 mg monotherapy safety program with a 13% incidence. - Blurred vision was more common in patients who received vandetanib versus patients who received placebo for medullary thyroid cancer (9% vs. 1%, respectively). Scheduled slit lamp examinations have revealed corneal opacities (vortex keratopathies) in treated patients, which can lead to halos and decreased visual acuity. It is unknown if this will improve after discontinuation. Ophthalmologic examination, including slit lamp, is recommended in patients who report visual changes. If a patient has blurred vision, do not drive or operate machinery. - Table 2 provides the frequency and severity of laboratory abnormalities reported for patients with medullary thyroid cancer receiving randomized treatment with vandetanib or placebo. - Alanine aminotransferase elevations occurred in 51% of patients on vandetanib in the randomized medullary thyroid cancer (MTC) study. Grade 3-4 ALT elevations were seen in 2% of patients and no patients had a concomitant increase in bilirubin. Elevations in ALT have resulted in temporary discontinuation of vandetanib. However, 16 of 22 patients with a grade 2 elevation in ALT continued 300 mg vandetanib. Seven patients who continued vandetanib had a normal ALT within 6 months. In the protocol, ALT was monitored every 3 months and more frequently as indicated. ## Postmarketing Experience There is limited information regarding Vandetanib Postmarketing Experience in the drug label. # Drug Interactions CYP3A4 Inducers - Drugs that are CYP3A4 inducers can alter vandetanib plasma concentrations. The concomitant use of known strong CYP3A4 inducers should be avoided while receiving vandetanib therapy. St. John’s Wort may decrease vandetanib exposure unpredictably and should be avoided. CYP3A4 Inhibitors - In healthy subjects, no clinically significant interaction was shown between vandetanib and the potent CYP3A4 inhibitor, itraconazole. Drugs that Prolong the QT Interval - The administration of vandetanib with agents that may prolong the QT interval should be avoided. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Pregnancy Category D. - Vandetanib can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of vandetanib in pregnant women. Vandetanib is embryotoxic, fetotoxic, and teratogenic to rats, at exposures equivalent to or lower than those expected at the recommended human dose of 300 mg/day. When vandetanib was administered to female rats prior to mating and through the first week of pregnancy, there were increases in pre-implantation loss and post-implantation loss resulting in a significant reduction in the number of live embryos. This dose administered to rats during organogenesis, caused an increase in post-implantation loss including embryofetal death. Vandetanib caused total litter loss when administered at a dose of 25 mg/kg/day during organogenesis until expected parturition. When administered during organogenesis, vandetanib doses of 1, 10 and 25 mg/kg/day (approximately 0.03, 0.4, and 1.0 times respectively, the Cmax in patients with cancer at the recommended human dose) caused malformations of the heart vessels and delayed ossification of the skull, vertebrae and sternum, indicating delayed fetal development. A no effect level for these malformations was not identified in this study. In a rat pre- and post-natal development study, at doses producing maternal toxicity (1 and 10 mg/kg/day) during gestation and/or lactation, vandetanib, decreased pup survival, and/or reduced post-natal pup growth. Reduced post-natal pup growth was associated with a delay in physical development. - 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 childbearing potential should be advised to avoid pregnancy while taking vandetanib and for at least four months following the last dose of vandetanib. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Vandetanib in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Vandetanib during labor and delivery. ### Nursing Mothers - In nonclinical studies, vandetanib was excreted in rat milk and found in plasma of pups following dosing to lactating rats. Vandetanib transfer in breast milk resulted in relatively constant exposure in pups due to the long half-life of the drug. It is not known whether this drug 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 from vandetanib, 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 - Safety and efficacy of vandetanib in pediatric patients have not been established. ### Geriatic Use - In total, 18% of medullary thyroid cancer patients treated with vandetanib were age 65 years or older, and 3% were 75 years and older. No overall differences in safety and efficacy were observed between elderly and younger patients. No adjustment in starting dose is required for patients over 65 years of age. There are limited data for patients over the age of 75 years. ### Gender There is no FDA guidance on the use of Vandetanib with respect to specific gender populations. ### Race There is no FDA guidance on the use of Vandetanib with respect to specific racial populations. ### Renal Impairment - The pharmacokinetics of vandetanib were evaluated after a single dose of 800 mg in subjects with mild (n = 6), moderate (n = 8), and severe (n = 6) renal impairment and normal (n = 10) renal function. Subjects with mild renal impairment had comparable mean AUC and clearance values to those with normal renal function. In subjects with moderate and severe renal impairment, the average AUC of vandetanib increased by 39% and 41%, respectively, compared to patients with normal renal function. - The starting dose should be reduced to 200 mg in patients with moderate and severe renal impairment. ### Hepatic Impairment - The pharmacokinetics of vandetanib were evaluated after a single dose of 800 mg in subjects with mild (n = 8), moderate (n = 7), and severe (n = 6) hepatic impairment and normal hepatic function (n = 5). Subjects with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment had comparable mean AUC and clearance values to those with normal hepatic function. - There are limited data in patients with liver impairment (serum bilirubin greater than 1.5 times the upper limit of normal). Vandetanib is not recommended for use in patients with moderate and severe hepatic impairment, as safety and efficacy have not been established. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Vandetanib in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Vandetanib in patients who are immunocompromised. # Administration and Monitoring ### Administration - ORAL ### Monitoring There is limited information regarding Vandetanib Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Vandetanib and IV administrations. # Overdosage - There is no specific treatment in the event of overdose with vandetanib and possible symptoms of overdose have not been established. Because of the 19-day half-life, adverse reactions may not resolve quickly. In phase 1 clinical trials, a limited number of patients were treated with daily doses of up to 600 mg and healthy volunteers with daily doses up to 1200 mg. An increase in the frequency and severity of some adverse reactions, like rash, diarrhea and hypertension, was observed at multiple doses at and above 300 mg in healthy volunteer studies and in patients. In addition the possibility of QTc prolongation and Torsades de pointes should be considered. - Adverse reactions associated with overdose are to be treated symptomatically; in particular, severe diarrhea must be managed appropriately. In the event of an overdose, further doses of vandetanib must be interrupted, and appropriate measures taken to assure that an adverse event has not occurred, i.e., ECG within 24 hours to determine QTc prolongation. # Pharmacology ## Mechanism of Action - Vandetanib is a tyrosine kinase inhibitor. In vitro studies have shown that vandetanib inhibits the activity of tyrosine kinases including members of the epidermal growth factor receptor (EGFR) family, vascular endothelial cell growth factor (VEGF) receptors, rearranged during transfection (RET), protein tyrosine kinase 6 (BRK), TIE2, members of the EPH receptors kinase family, and members of the Src family of tyrosine kinases. Vandetanib inhibits endothelial cell migration, proliferation, survival and new blood vessel formation in in vitro models of angiogenesis. Vandetanib inhibits EGFR-dependent cell survival in vitro. In addition, vandetanib inhibits epidermal growth factor (EGF)-stimulated receptor tyrosine kinase phosphorylation in tumor cells and endothelial cells and VEGF-stimulated tyrosine kinase phosphorylation in endothelial cells. - In vivo vandetanib administration reduced tumor cell-induced angiogenesis, tumor vessel permeability, and inhibited tumor growth and metastasis in mouse models of cancer. - There is no evidence of a relationship between RET mutations and efficacy with vandetanib. ## Structure - Vandetanib tablets for daily oral administration are available in two dosage strengths, 100 mg and 300 mg, containing 100 mg and 300 mg of vandetanib, respectively. The tablet cores contain the following inactive ingredients: Tablet core: calcium hydrogen phosphate dihydrate, microcrystalline cellulose, crospovidone, povidone, and magnesium stearate. The tablet film-coat contains the following inactive ingredients: hypromellose 2910, macrogol 300, and titanium dioxide E171. - Vandetanib is chemically described as N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)] methoxy]quinazolin-4-amine. - The structural and molecular formulas are: Vandetanib has a molecular weight of 475.36. Vandetanib exhibits pH-dependent solubility, with increased solubility at lower pH. Vandetanib is practically insoluble in water with a value of 0.008 mg/mL at 25°C (77°F ). ## Pharmacodynamics There is limited information regarding Vandetanib Pharmacodynamics in the drug label. ## Pharmacokinetics - A population pharmacokinetic analysis of vandetanib was conducted in 231 patients with MTC following oral administration of 300 mg daily doses. The pharmacokinetics of vandetanib at the 300 mg dose in MTC patients are characterized by a mean clearance of approximately 13.2 L/h, a mean volume of distribution of approximately 7450 L, and a median plasma half-life of 19 days. Absorption - Following oral administration of vandetanib, absorption is slow with peak plasma concentrations typically achieved at a median of 6 hours, range 4-10 hours, after dosing. Vandetanib accumulates approximately 8-fold on multiple dosing with steady state achieved from approximately 3 months. - Exposure to vandetanib is unaffected by food. Distribution - Vandetanib binds to human serum albumin and α1-acid-glycoprotein with in vitro protein binding being approximately 90%. In ex vivo plasma samples from colorectal cancer patients at steady state exposure after 300 mg once daily, the mean percentage protein binding was 93.7% (range 92.2 to 95.7%). Metabolism - Following oral dosing of 14C-vandetanib, unchanged vandentanib and metabolites vandetanib N-oxide and N-desmethyl vandetanib were detected in plasma, urine and feces. A glucuronide conjugate was seen as a minor metabolite in excreta only. N-desmethyl-vandetanib is primarily produced by CYP3A4 and vandetanib-N-oxide by flavin–containing monooxygenase enzymes FMO1 and FMO3. N-desmethyl-vandetanib and vandetanib-N-oxide circulate at concentrations of approximately 7-17.1% and 1.4-2.2%, respectively, of those of vandetanib. Excretion - Within a 21-day collection period after a single dose of 14C-vandetanib, approximately 69% was recovered with 44% in feces and 25% in urine. Excretion of the dose was slow and further excretion beyond 21 days would be expected based on the plasma half-life. - Vandetanib was not a substrate of hOCT2 expressed in HEK293 cells. Vandetanib inhibits the uptake of the selective OCT2 marker substrate 14C-creatinine by HEK-OCT2 cells, with a mean IC50 of approximately 2.1 μg/mL. This is higher than vandetanib plasma concentrations (approximately 0.81 μg/mL) observed after multiple dosing at 300 mg. Inhibition of renal excretion of creatinine by vandetanib provides an explanation for increases in plasma creatinine seen in human subjects receiving vandetanib. Special Populations Effects of Age and Gender - In a population pharmacokinetic evaluation in cancer patients, no relationship was apparent between oral clearance and patient age or gender. Ethnicity - Based on a cross-study comparison in a limited number of patients, Japanese (N=3) and Chinese (N=7) patients had on average exposures that were higher than Caucasian (N=7) patients receiving the same dose. Pediatric - The pharmacokinetics of vandetanib have not been evaluated in pediatric patients. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility - Carcinogenicity studies have not been conducted with vandetanib. - Vandetanib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using human lymphocytes or in the in vivo rat micronucleus assay. - Based on nonclinical findings, male and female fertility may be impaired by treatment with vandetanib. In a fertility study in male rats, vandetanib had no effect on copulation or fertility rate when undosed females were mated with males administered 1, 5, or 20 mg/kg/day of vandetanib (approximately 0.03, 0.22, or 0.40 times, respectively, the AUC in patients with cancer at the recommended human dose of 300 mg/day). There was a slight decrease in the number of live embryos at 20 mg/kg/day and an increase in preimplantation loss at >5 mg/kg/day. In a female fertility study, there was a trend towards increased estrus cycle irregularity, a slight reduction in pregnancy incidence and an increase in implantation loss. In a repeat-dose toxicity study in rats, there was a decrease in the number of corpora lutea in the ovaries of rats administered 75 mg/kg/day vandetanib (approximately 1.8 times the AUC in patients with cancer at the recommended human dose) for 1 month. Animal Pharmacology and/or Toxicology - In an animal model of wound-healing, mice dosed with vandetanib had reduced skin-breaking strength compared with controls. This suggests that vandetanib slows but does not prevent wound healing. The appropriate interval between discontinuation of vandetanib and subsequent elective surgery required to avoid the risks of impaired wound healing has not been determined. - Nodular masses were observed in a 6-month toxicology study in rats during treatment with ≥5 mg/kg/day vandetanib (approximately 0.22 or 0.40 times, respectively, the AUC in patients with cancer at the recommended human dose of 300 mg/day). Masses were palpable during clinical assessments as early as week 13, were observed in multiple organs, and were associated with hemorrhagic or inflammatory findings. # Clinical Studies - A double-blind, placebo-controlled study randomized patients with unresectable locally advanced or metastatic medullary thyroid cancer to vandetanib 300 mg (n=231) versus Placebo (n=100). - The primary objective was demonstration of improvement in progression-free survival (PFS) with vandetanib compared to placebo. Other endpoints included evaluation of overall survival and overall objective response rate (ORR). Centralized, independent blinded review of the imaging data was used in the assessment of PFS and ORR. Upon objective disease progression based on the investigator’s assessment, patients were discontinued from blinded study treatment and given the option to receive open-label vandetanib. Nineteen percent (44/231) of the patients initially randomized to vandetanib opted to receive open-label vandetanib after disease progression, and 58% (58/100) of the patients initially randomized to placebo opted to receive open-label vandetanib after disease progression. - The result of the PFS analysis, based on the central review RECIST assessment, showed a statistically significant improvement in PFS for patients randomized to vandetanib (Hazard Ratio (HR) = 0.35; 95% Confidence Interval (CI) = 0.24-0.53; p<0.0001). Analyses in the subgroups of patients who were symptomatic or had progressed within 6 months prior to their enrollment showed similar PFS results (HR = 0.31 95% CI: 0.19, 0.53 for symptomatic patients; HR = 0.41 95% CI: 0.25, 0.66 for patients who had progressed within 6 months prior to enrollment). - At the time of the primary analysis of PFS, 15% of the patients had died and there was no significant difference in overall survival between the two treatment groups. The overall objective response rate (ORR) for patients randomized to vandetanib was 44% compared to 1% for patients randomized to placebo. All objective responses were partial responses. # How Supplied - 100 mg Tablets Available in bottles containing 30 tablets (NDC 0310–7810–30). - 300 mg Tablets Available in bottles containing 30 tablets (NDC 0310–7830–30). ## Storage - Vandetanib tablets should be stored at 25°C (77°F); excursions permitted to 15oC – 30oC (59oF – 86oF) [See USP controlled room temperature]. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information QT Interval - Vandetanib can prolong the QT interval in a concentration-dependent manner. Torsades de pointes, ventricular tachycardia and sudden death have been reported in patients administered vandetanib. Patients should be advised that their electrolytes and the electrical activity of their heartbeat (via an ECG) should be monitored regularly during treatment with vandetanib. Rash - Patients taking vandetanib should be told they may be more susceptible to sunburn and to use appropriate sun protection (e.g., sunscreen and/or clothing) while taking vandetanib and for at least 4 months after drug discontinuation. Patients should consult their physician promptly if they develop a skin rash. Interstitial lung disease - Patients should be told to contact their physician promptly if they develop sudden onset or worsening of breathlessness, persistent cough or fever. Diarrhea - Patients should be informed that they may experience diarrhea while taking vandetanib. Patients should also be advised to use standard anti-diarrheal medications and to seek medical attention if their diarrhea becomes persistent or severe. Patients with diarrhea should contact their physician to have their electrolytes monitored. Reversible Posterior Leukoencephalopathy Syndrome - Patients should be told to contact their physician promptly if they experience seizures, headaches, visual disturbances, confusion or difficulty thinking. Pregnancy and Nursing - Patients of childbearing potential must be told to use effective contraception during therapy and for at least four months following their last dose of vandetanib. - Breast-feeding mothers are advised to discontinue nursing while receiving vandetanib therapy. Drug Handling - Vandetanib tablets should not be crushed. Direct contact of crushed tablets with the skin or mucous membranes should be avoided. # Precautions with Alcohol Alcohol-Vandetanib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - VANDETANIB ®[1] # Look-Alike Drug Names There is limited information regarding Vandetanib Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Vandetanib
86f2c8410331357e7d72926d8f73975384c5832a	wikidoc	Venetoclax	Venetoclax # 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 Venetoclax is a BCL-2 inhibitor that is FDA approved for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion, as detected by an FDA approved test, who have received at least one prior therapy. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. Common adverse reactions include neutropenia, diarrhea, nausea, anemia, upper respiratory tract infection, thrombocytopenia, and fatigue (≥20%). # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Select patients for the treatment of relapsed or refractory CLL with Venetoclax based on the presence of 17p deletions in blood specimens. Patients without 17p deletion at diagnosis should be retested at relapse because acquisition of 17p deletion can occur. Venetoclax should be taken orally once daily until disease progression or unacceptable toxicity is observed. Assess patient-specific factors for level of risk of tumor lysis syndrome (TLS) and provide prophylactic hydration and anti-hyperuricemics to patients prior to first dose of Venetoclax to reduce risk of TLS. Administer the Venetoclax dose according to a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg as shown in Table 1. The 5-week ramp-up dosing schedule is designed to gradually reduce tumor burden (debulk) and decrease the risk of TLS. Once the ramp-up phase is completed, the 400 mg dose is achieved using 100 mg tablets. - Table 1: Dosing Schedule for Ramp-Up Phase Instruct patients to take Venetoclax tablets with a meal and water at approximately the same time each day. Venetoclax tablets should be swallowed whole and not chewed, crushed, or broken prior to swallowing. Venetoclax can cause rapid reduction in tumor and thus poses a risk for TLS in the initial 5-week ramp-up phase. Changes in blood chemistries consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the first dose of Venetoclax and at each dose increase. The risk of TLS is a continuum based on multiple factors, including tumor burden and comorbidities. Perform tumor burden assessments, including radiographic evaluation (e.g., CT scan), assess blood chemistry (potassium, uric acid, phosphorus, calcium, and creatinine) in all patients and correct pre-existing abnormalities prior to initiation of treatment with Venetoclax. Reduced renal function (creatinine clearance <80 mL/min) further increases the risk. The risk may decrease as tumor burden decreases. Table 2 below describes the recommended TLS prophylaxis and monitoring during Venetoclax treatment based on tumor burden determination from clinical trial data. - Table 2: Recommended TLS Prophylaxis Based on Tumor Burden From Clinical Trial Data (consider all patient co-morbidities before final determination of prophylaxis and monitoring schedule) Interrupt dosing or reduce dose for toxicities. See Table 3 for dose modifications for hematologic and other toxicities related to Venetoclax, and Table 4 for dose. For patients who have had a dosing interruption greater than 1 week during the first 5 weeks of ramp-up phase or greater than 2 weeks when at the daily dose of 400 mg, reassess for risk of TLS to determine if reinitiation with a reduced dose is necessary (e.g., all or some levels of the dose ramp-up schedule). - Table 3: Recommended Dose Modifications for Toxicities (a) - Table 4: Dose Modification for Toxicity During Venetoclax Treatment Concomitant use of Venetoclax with strong CYP3A inhibitors at initiation and during ramp-up phase is contraindicated. Concomitant use of Venetoclax with strong CYP3A inhibitors increases Venetoclax exposure (i.e., Cmax and AUC) and may increase the risk for TLS at initiation and during ramp-up phase. For patients who have completed the ramp-up phase and are on a steady daily dose of Venetoclax, reduce the Venetoclax dose by at least 75% when strong CYP3A inhibitors must be used concomitantly. Avoid concomitant use of Venetoclax with moderate CYP3A inhibitors or P-gp inhibitors. Consider alternative treatments. If a moderate CYP3A inhibitor or a P-gp inhibitor must be used, reduce the Venetoclax dose by at least 50%. Monitor these patients more closely for signs of toxicities. Resume the Venetoclax dose that was used prior to initiating the CYP3A inhibitor or P-gp inhibitor 2 to 3 days after discontinuation of the inhibitor. The recommendations for managing drug-drug interactions are summarized in Table 5. - Table 5: Management of Potential Venetoclax Interactions with CYP3A and P-gp Inhibitors If the patient misses a dose of Venetoclax within 8 hours of the time it is usually taken, the patient should take the missed dose as soon as possible and resume the normal daily dosing schedule. If a patient misses a dose by more than 8 hours, the patient should not take the missed dose and should resume the usual dosing schedule the next day. If the patient vomits following dosing, no additional dose should be taken that day. The next prescribed dose should be taken at the usual time. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Venetoclax in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Venetoclax in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and effectiveness have not been established in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Venetoclax in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Venetoclax in pediatric patients. # Contraindications Concomitant use of Venetoclax with strong CYP3A inhibitors at initiation and during ramp-up phase is contraindicated. # Warnings Tumor lysis syndrome, including fatal events and renal failure requiring dialysis, has occurred in previously treated CLL patients with high tumor burden when treated with Venetoclax. Venetoclax can cause rapid reduction in tumor and thus poses a risk for TLS in the initial 5-week ramp-up phase. Changes in blood chemistries consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the first dose of Venetoclax and at each dose increase. The risk of TLS is a continuum based on multiple factors, including tumor burden (see Table 2) and comorbidities. Reduced renal function (CrCl <80 mL/min) further increases the risk. Patients should be assessed for risk and should receive appropriate prophylaxis for TLS, including hydration and anti-hyperuricemics. Monitor blood chemistries and manage abnormalities promptly. Interrupt dosing if needed. Employ more intensive measures (intravenous hydration, frequent monitoring, hospitalization) as overall risk increases. Concomitant use of Venetoclax with strong or moderate CYP3A inhibitors and P-gp inhibitors increases venetoclax exposure, may increase the risk of TLS at initiation and during ramp-up phase and may require Venetoclax dose adjustment. Grade 3 or 4 neutropenia occurred in 41% (98/240) of patients treated with Venetoclax. Monitor complete blood counts throughout the treatment period. Interrupt dosing or reduce dose for severe neutropenia. Consider supportive measures including antimicrobials for signs of infection and use of growth factors (e.g., G-CSF). Do not administer live attenuated vaccines prior to, during, or after treatment with Venetoclax until B-cell recovery occurs. The safety and efficacy of immunization with live attenuated vaccines during or following Venetoclax therapy have not been studied. Advise patients that vaccinations may be less effective. Based on its mechanism of action and findings in animals, Venetoclax may cause embryo-fetal harm when administered to a pregnant woman. In an embryo-fetal study conducted in mice, administration of Venetoclax to pregnant animals at exposures equivalent to that observed in patients at the recommended dose of 400 mg daily resulted in post-implantation loss and decreased fetal weight. There are no adequate and well-controlled studies in pregnant woman using Venetoclax. Advise females of reproductive potential to avoid pregnancy during treatment. If Venetoclax is used during pregnancy or if the patient becomes pregnant while taking Venetoclax, the patient should be apprised of the potential hazard to the fetus. # Adverse Reactions ## Clinical Trials Experience The following adverse drug reactions are discussed in greater detail in other sections of the label: - Tumor Lysis Syndrome - Neutropenia Because clinical trials are conducted under widely variable conditions, adverse event rates observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of another drug and may not reflect the rates observed in practice. The safety of single agent Venetoclax at the 400 mg recommended daily dose following a dose ramp-up schedule is based on pooled data of 240 patients with previously treated CLL from two phase 2 trials and one phase 1 trial. In the pooled dataset, the median age was 66 years (range: 29 to 85 years), 95% were white, and 69% were male. The median number of prior therapies was 3 (range: 1 to 12). The median duration of treatment with Venetoclax at the time of data analysis was approximately 10.3 months (range: 0 to 34.1 months). Approximately 46% of patients received Venetoclax for more than 48 weeks. The most common adverse reactions (≥20%) of any grade were neutropenia, diarrhea, nausea, anemia, upper respiratory tract infection, thrombocytopenia, and fatigue. Serious adverse reactions were reported in 43.8% of patients. The most frequent serious adverse reactions (≥2%) were pneumonia, febrile neutropenia, pyrexia, autoimmune hemolytic anemia (AIHA), anemia, and TLS. Discontinuations due to adverse reactions occurred in 8.3% of patients. The most frequent adverse reactions leading to drug discontinuation were thrombocytopenia and AIHA. Dosage adjustments due to adverse reactions occurred in 9.6% of patients. The most frequent adverse reactions leading to dose adjustments were neutropenia, febrile neutropenia, and thrombocytopenia. Adverse reactions reported in 3 trials of patients with previously treated CLL using single agent Venetoclax are presented in Table 6. - Table 6: Adverse Reactions Reported in ≥10% (Any Grade) or ≥5% (Grade 3 or 4) of Patients with CLL ### Tumor Lysis Syndrome Tumor lysis syndrome is an important identified risk when initiating Venetoclax. In the initial Phase 1 dose-finding trials, which had shorter (2-3 week) ramp-up phase and higher starting dose, the incidence of TLS was 12% (9/77; 4 laboratory TLS, 5 clinical TLS), including 2 fatal events and 3 events of acute renal failure, 1 requiring dialysis. The risk of TLS was reduced after revision of the dosing regimen and modification to prophylaxis and monitoring measures. In Venetoclax clinical trials, patients with any measurable lymph node ≥10 cm or those with both an ALC ≥25 x 109/L and any measurable lymph node ≥5 cm were hospitalized to enable more intensive hydration and monitoring for the first day of dosing at 20 mg and 50 mg during the ramp-up phase. In 66 patients with CLL starting with a daily dose of 20 mg and increasing over 5 weeks to a daily dose of 400 mg, the rate of TLS was 6%. All events either met laboratory TLS criteria (laboratory abnormalities that met ≥2 of the following within 24 hours of each other: potassium >6 mmol/L, uric acid >476 µmol/L, calcium 1.5 mmol/L); or were reported as TLS events. The events occurred in patients who had a lymph node(s) ≥5 cm or ALC ≥25 x 109/L. No TLS with clinical consequences such as acute renal failure, cardiac arrhythmias or sudden death and/or seizures was observed in these patients. All patients had CrCl ≥50 mL/min. Laboratory abnormalities relevant to TLS observed in 66 patients with CLL who followed the dose ramp-up schedule and TLS prophylaxis measures are presented in Table 7. - Table 7: Adverse Reactions of TLS and Relevant Laboratory Abnormalities Reported in Patients with CLL ## Postmarketing Experience There is limited information regarding Venetoclax Postmarketing Experience in the drug label. # Drug Interactions Venetoclax is predominantly metabolized by CYP3A4/5. - Strong CYP3A Inhibitors Concomitant use of Venetoclax with strong CYP3A inhibitors (e.g., ketoconazole, conivaptan, clarithromycin, indinavir, itraconazole, lopinavir, ritonavir, telaprevir, posaconazole and voriconazole) at initiation and during ramp-up phase is contraindicated. For patients who have completed the ramp-up phase and are on a steady daily dose of Venetoclax, reduce the Venetoclax dose by at least 75% when used concomitantly with strong CYP3A inhibitors. Resume the Venetoclax dose that was used prior to initiating the CYP3A inhibitor 2 to 3 days after discontinuation of the inhibitor. Co-administration of ketoconazole increased Venetoclax Cmax by 2.3-fold and AUC∞ by 6.4-fold. - Moderate CYP3A Inhibitors and P-gp Inhibitors Avoid concomitant use of moderate CYP3A inhibitors (e.g., erythromycin, ciprofloxacin, diltiazem, dronedarone, fluconazole, verapamil) or P-gp inhibitors (e.g., amiodarone, azithromycin, captopril, carvedilol, cyclosporine, felodipine, quercetin, quinidine, ranolazine, ticagrelor) with Venetoclax. Consider alternative treatments. If a moderate CYP3A inhibitor or a P-gp inhibitor must be used, reduce the Venetoclax dose by at least 50%. Monitor patients more closely for signs of Venetoclax toxicities. Resume the Venetoclax dose that was used prior to initiating the CYP3A inhibitor or P-gp inhibitor 2 to 3 days after discontinuation of the inhibitor. Avoid grapefruit products, Seville oranges, and starfruit during treatment with Venetoclax, as they contain inhibitors of CYP3A. Co-administration of a single dose of rifampin, a P-gp inhibitor, increased Venetoclax Cmax by 106% and AUC∞ by 78%. - CYP3A Inducers Avoid concomitant use of Venetoclax with strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s wort) or moderate CYP3A inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin). Consider alternative treatments with less CYP3A induction. Co-administration of multiple doses of rifampin, a strong CYP3A inducer, decreased Venetoclax Cmax by 42% and AUC∞ by 71%. - Warfarin In a drug-drug interaction study in healthy subjects, administration of a single dose of Venetoclax with warfarin resulted in an 18% to 28% increase in Cmax and AUC∞ of R-warfarin and S-warfarin. Because Venetoclax was not dosed to steady state, it is recommended that the international normalized ratio (INR) be monitored closely in patients receiving warfarin. - P-gp substrates In vitro data suggest Venetoclax has inhibition potential on P-gp substrates at therapeutic dose levels in the gut. Therefore, co-administration of narrow therapeutic index P-gp substrates (e.g., digoxin, everolimus, and sirolimus) with Venetoclax should be avoided. If a narrow therapeutic index P-gp substrate must be used, it should be taken at least 6 hours before Venetoclax. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Risk Summary There are no available human data on the use of Venetoclax in pregnant women. Based on toxicity observed in mice, Venetoclax may cause fetal harm when administered to pregnant women. In mice, Venetoclax was fetotoxic at exposures 1.2 times the human clinical exposure based on AUC at the recommended human dose of 400 mg daily. If Venetoclax is used during pregnancy or if the patient becomes pregnant while taking Venetoclax, the patient should be apprised of the potential risk to a fetus. The background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. - Data - Animal Data In embryo-fetal development studies, Venetoclax was administered to pregnant mice and rabbits during the period of organogenesis. In mice, Venetoclax was associated with increased post-implantation loss and decreased fetal body weight at 150 mg/kg/day (maternal exposures approximately 1.2 times the human AUC exposure at the recommended dose of 400 mg daily). No teratogenicity was observed in either the mouse or the rabbit. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Venetoclax in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Venetoclax during labor and delivery. ### Nursing Mothers There are no data on the presence of Venetoclax in human milk, the effects of Venetoclax on the breastfed child, or the effects of Venetoclax on milk production. Because many drugs are excreted in human milk and because the potential for serious adverse reactions in breastfed infants from Venetoclax is unknown, advise nursing women to discontinue breastfeeding during treatment with Venetoclax. ### Pediatric Use Safety and effectiveness have not been established in pediatric patients. ### Geriatic Use Of the 106 patients with previously treated CLL with 17p deletion who were evaluated for efficacy, 57% were ≥65 years of age and 17% were ≥75 years of age. Of the 240 patients with previously treated CLL evaluated for safety from 3 open-label trials, 58% were ≥65 years of age and 17% were ≥75 years of age. No overall differences in safety and effectiveness were observed between older and younger patients. ### Gender There is no FDA guidance on the use of Venetoclax with respect to specific gender populations. ### Race There is no FDA guidance on the use of Venetoclax with respect to specific racial populations. ### Renal Impairment Patients with reduced renal function (CrCl <80 mL/min) are at increased risk of TLS. These patients may require more intensive prophylaxis and monitoring to reduce the risk of TLS when initiating treatment with Venetoclax. No specific clinical trials have been conducted in subjects with renal impairment. Less than 0.1% of radioactive Venetoclax dose was detected in urine. No dose adjustment is needed for patients with mild or moderate renal impairment (CrCl ≥30 mL/min) based on results of the population pharmacokinetic analysis. A recommended dose has not been determined for patients with severe renal impairment (CrCl <30 mL/min) or patients on dialysis. ### Hepatic Impairment No specific clinical trials have been conducted in subjects with hepatic impairment, however human mass balance study showed that Venetoclax undergoes hepatic elimination. Although no dose adjustment is recommended in patients with mild or moderate hepatic impairment based on results of the population pharmacokinetic analysis, a trend for increased adverse events was observed in patients with moderate hepatic impairment; monitor these patients more closely for signs of toxicity during the initiation and dose ramp-up phase. A recommended dose has not been determined for patients with severe hepatic impairment. ### Females of Reproductive Potential and Males Venetoclax may cause fetal harm. - Pregnancy Testing Females of reproductive potential should undergo pregnancy testing before initiation of Venetoclax. - Contraception Advise females of reproductive potential to use effective contraception during treatment with Venetoclax and for at least 30 days after the last dose. - Infertility Based on findings in animals, male fertility may be compromised by treatment with Venetoclax. ### Immunocompromised Patients There is no FDA guidance one the use of Venetoclax in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Venetoclax Administration in the drug label. ### Monitoring There is limited information regarding Venetoclax Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Venetoclax and IV administrations. # Overdosage There is no specific antidote for Venetoclax. For patients who experience overdose, closely monitor and provide appropriate supportive treatment; during ramp-up phase interrupt Venetoclax and monitor carefully for signs and symptoms of TLS along with other toxicities. Based on Venetoclax large volume of distribution and extensive protein binding, dialysis is unlikely to result in significant removal of Venetoclax. # Pharmacology ## Mechanism of Action Venetoclax is a selective and orally small-molecule inhibitor of BCL-2, an anti-apoptotic protein. Overexpression of BCL-2 has been demonstrated in CLL cells where it mediates tumor cell survival and has been associated with resistance to chemotherapeutics. Venetoclax helps restore the process of apoptosis by binding directly to the BCL-2 protein, displacing pro-apoptotic proteins like BIM, triggering mitochondrial outer membrane permeabilization and the activation of caspases. In nonclinical studies, Venetoclax has demonstrated cytotoxic activity in tumor cells that overexpress BCL-2. ## Structure There is limited information regarding Venetoclax Structure in the drug label. ## Pharmacodynamics - Cardiac Electrophysiology The effect of multiple doses of Venetoclax up to 1200 mg once daily on the QTc interval was evaluated in an open-label, single-arm study in 176 patients with previously treated hematologic malignancies. Venetoclax had no large effect on QTc interval (i.e., > 20 ms) and there was no relationship between Venetoclax exposure and change in QTc interval. ## Pharmacokinetics Following multiple oral administrations under fed conditions, maximum plasma concentration of Venetoclax was reached 5-8 hours after dose. Venetoclax steady state AUC increased proportionally over the dose range of 150-800 mg. Under low-fat meal conditions, Venetoclax mean (± standard deviation) steady state Cmax was 2.1 ± 1.1 μg/mL and AUC(0-24) was 32.8 ± 16.9 μgh/mL at the 400 mg once daily dose. - Food Effect Administration with a low-fat meal increased Venetoclax exposure by approximately 3.4-fold and administration with a high-fat meal increased Venetoclax exposure by 5.1- to 5.3-fold compared to fasting conditions. Venetoclax should be administered with a meal. Venetoclax is highly bound to human plasma protein with unbound fraction in plasma <0.01 across a concentration range of 1-30 µM (0.87-26 µg/mL). The mean blood-to-plasma ratio was 0.57. The population estimate for apparent volume of distribution (Vdss/F) of Venetoclax ranged from 256-321 L in patients. The population estimate for the terminal elimination half-life of Venetoclax was approximately 26 hours. The pharmacokinetics of Venetoclax does not change over time. - Metabolism In vitro studies demonstrated that Venetoclax is predominantly metabolized by CYP3A4/5. M27 was identified as a major metabolite in plasma with an inhibitory activity against BCL-2 that is at least 58-fold lower than Venetoclax in vitro. - Excretion After single oral administration of 200 mg radiolabeled -Venetoclax dose to healthy subjects, >99.9% of the dose was recovered in feces and <0.1% of the dose was excreted in urine within 9 days, indicating that hepatic elimination is responsible for the clearance of Venetoclax from the systemic circulation. Unchanged Venetoclax accounted for 20.8% of the administered radioactive dose excreted in feces. - Age, Race, Sex, and Weight Based on population pharmacokinetic analyses, age, race, sex, and weight do not have a clinically meaningful effect on Venetoclax clearance. - Renal Impairment Based on a population pharmacokinetic analysis that included 211 subjects with mild renal impairment (CrCl ≥60 and <90 mL/min, calculated by Cockcroft-Gault equation), 83 subjects with moderate renal impairment (CrCl ≥30 and <60 mL/min) and 210 subjects with normal renal function (CrCl ≥90 mL/min), Venetoclax exposures in subjects with mild or moderate renal impairment are similar to those with normal renal function. The pharmacokinetics of Venetoclax has not been studied in subjects with severe renal impairment (CrCl <30 mL/min) or subjects on dialysis. - Hepatic Impairment Based on a population pharmacokinetic analysis that included 69 subjects with mild hepatic impairment, 7 subjects with moderate hepatic impairment and 429 subjects with normal hepatic function, Venetoclax exposures are similar in subjects with mild and moderate hepatic impairment and normal hepatic function. The NCI Organ Dysfunction Working Group criteria for hepatic impairment were used in the analysis. Mild hepatic impairment was defined as normal total bilirubin and aspartate transaminase (AST) > upper limit of normal (ULN) or total bilirubin >1.0 to 1.5 times ULN, moderate hepatic impairment as total bilirubin >1.5 to 3.0 times ULN, and severe hepatic impairment as total bilirubin >3.0 times ULN. The pharmacokinetics of Venetoclax has not been studied in subjects with severe hepatic impairment. - Ketoconazole Co-administration of 400 mg once daily ketoconazole, a strong CYP3A, P-gp and BCRP inhibitor, for 7 days in 11 previously treated NHL patients increased Venetoclax Cmax by 2.3-fold and AUC∞ by 6.4-fold. - Rifampin multiple doses Co-administration of 600 mg once daily rifampin, a strong CYP3A inducer, for 13 days in 10 healthy subjects decreased Venetoclax Cmax by 42% and AUC∞ by 71%. - Rifampin single dose Co-administration of a 600 mg single dose of rifampin, an OATP1B1/1B3 and P-gp inhibitor, in 11 healthy subjects increased Venetoclax Cmax by 106% and AUC∞ by 78%. - Gastric Acid Reducing Agents Based on population pharmacokinetic analysis, gastric acid reducing agents (e.g., proton pump inhibitors, H2-receptor antagonists, antacids) do not affect Venetoclax bioavailability. - Warfarin In a drug-drug interaction study in three healthy subjects, administration of a single 400 mg dose of Venetoclax with 5 mg warfarin resulted in 18% to 28% increase in Cmax and AUC∞ of R-warfarin and S-warfarin. In vitro studies indicated that Venetoclax is not an inhibitor or inducer of CYP1A2, CYP2B6, CYP2C19, CYP2D6, or CYP3A4 at clinically relevant concentrations. Venetoclax is a weak inhibitor of CYP2C8, CYP2C9, and UGT1A1 in vitro, but it is not predicted to cause clinically relevant inhibition due to high plasma protein binding. Venetoclax is not an inhibitor of UGT1A4, UGT1A6, UGT1A9, or UGT2B7. Venetoclax is a P-gp and BCRP substrate as well as a P-gp and BCRP inhibitor and weak OATP1B1 inhibitor in vitro. To avoid a potential interaction in the gastrointestinal tract, co-administration of narrow therapeutic index P-gp substrates such as digoxin with Venetoclax should be avoided. If a narrow therapeutic index P-gp substrate must be used, it should be taken at least 6 hours before Venetoclax. Venetoclax is not expected to inhibit OATP1B3, OCT1, OCT2, OAT1, OAT3, MATE1, or MATE2K at clinically relevant concentrations. ## Nonclinical Toxicology Carcinogenicity studies have not been conducted with Venetoclax . Venetoclax was not mutagenic in an in vitro bacterial mutagenicity (Ames) assay, did not induce numerical or structural aberrations in an in vitro chromosome aberration assay using human peripheral blood lymphocytes, and was not clastogenic in an in vivo mouse bone marrow micronucleus assay at doses up to 835 mg/kg. The M27 metabolite was negative for genotoxic activity in in vitro Ames and chromosome aberration assays. Fertility and early embryonic development studies were conducted in male and female mice. These studies evaluate mating, fertilization, and embryonic development through implantation. There were no effects of Venetoclax on estrus cycles, mating, fertility, corpora lutea, uterine implants or live embryos per litter at dosages up to 600 mg/kg/day. However, a risk to human male fertility exists based on testicular toxicity (germ cell loss) observed in dogs at exposures as low as 0.5 times the human AUC exposure at the recommend dose. In dogs, Venetoclax caused single-cell necrosis in various tissues, including the gallbladder, exocrine pancreas, and stomach with no evidence of disruption of tissue integrity or organ dysfunction; these findings were minimal to mild in magnitude. Following a 4-week dosing period and subsequent 4-week recovery period, minimal single-cell necrosis was still present in some tissues and reversibility has not been assessed following longer periods of dosing or recovery. In addition, after approximately 3 months of daily dosing in dogs, Venetoclax caused progressive white discoloration of the hair coat, due to loss of melanin pigment. # Clinical Studies The efficacy of Venetoclax was established in an open-label, single-arm, multicenter clinical trial of 106 patients with CLL with 17p deletion who had received at least one prior therapy. In the study, 17p deletion was confirmed in peripheral blood specimens from patients using Vysis CLL FISH Probe Kit, which is FDA approved for selection of patients for Venetoclax treatment. Patients received Venetoclax via a weekly ramp-up schedule starting at 20 mg and ramping to 50 mg, 100 mg, 200 mg and finally 400 mg once daily. Patients continued to receive 400 mg of Venetoclax orally once daily until disease progression or unacceptable toxicity. The efficacy of Venetoclax was evaluated by overall response rate (ORR) as assessed by an Independent Review Committee (IRC) using the International Workshop for Chronic Lymphocytic Leukemia (IWCLL) updated National Cancer Institute-sponsored Working Group (NCI-WG) guidelines (2008). Table 8 summarizes the baseline demographic and disease characteristics of the study population. - Table 8: Baseline Patient Characteristics The median time on treatment at the time of evaluation was 12.1 months (range: 0 to 21.5 months). Efficacy results are shown in Table 9. - Table 9: Efficacy Results for Patients with Previously Treated CLL with 17p Deletion by IRC The median time to first response was 0.8 months (range: 0.1 to 8.1 months). Median duration of response (DOR) has not been reached with approximately 12 months median follow-up. The DOR ranged from 2.9 to 19.0+ months. Minimal residual disease (MRD) was evaluated in peripheral blood and bone marrow for patients who achieved CR or CRi, following treatment with Venetoclax. Three percent (3/106) were MRD negative in the peripheral blood and bone marrow (less than one CLL cell per 104 leukocytes). # How Supplied Venetoclax is dispensed as follows: - Venetoclax 10 mg film-coated tablets are round, biconvex shaped, pale yellow debossed with “V” on one side and “10” on the other side. - Venetoclax 50 mg film-coated tablets are oblong, biconvex shaped, beige debossed with “V” on one side and “50” on the other side. - Venetoclax 100 mg film-coated tablets are oblong, biconvex shaped, pale yellow debossed with “V” on one side and “100” on the other side. ## Storage Store at or below 86°F (30°C). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Advise the patient to read the FDA-approved patient labeling. - Tumor Lysis Syndrome Advise patients of the potential risk of TLS, particularly at treatment initiation and during ramp-up phase, and to immediately report any signs and symptoms associated with this event (fever, chills, nausea, vomiting, confusion, shortness of breath, seizure, irregular heartbeat, dark or cloudy urine, unusual tiredness, muscle pain, and/or joint discomfort) to their doctor for evaluation. Advise patients to be adequately hydrated every day when taking Venetoclax to reduce the risk of TLS. The recommended volume is 6 to 8 glasses (approximately 56 ounces total) of water each day. Patients should drink water starting 2 days before and on the day of the first dose, and every time the dose is increased. Advise patients of the importance of keeping scheduled appointments for blood work or other laboratory tests. Advise patients that it may be necessary to take Venetoclax in the presence of a doctor to allow monitoring for TLS. - Neutropenia Advise patients to contact their doctor immediately if they develop a fever or any signs of infection. Advise patients of the need for periodic monitoring of blood counts. - Drug Interactions Advise patients to avoid consuming grapefruit products, Seville oranges, or starfruit during treatment with Venetoclax. Advise patients that Venetoclax may interact with some drugs; therefore, advise patients to inform their doctor of the use of any prescription medication, over-the-counter drugs, vitamins and herbal products. - Immunizations Advise patients to avoid vaccination with live vaccines because they may not be safe or effective during treatment with Venetoclax. - Pregnancy and Lactation Advise women of the potential risk to the fetus and to avoid pregnancy during treatment with Venetoclax. Advise female patients of reproductive potential to use effective contraception during therapy and for at least 30 days after completing of therapy. Advise females to contact their doctor if they become pregnant, or if pregnancy is suspected, during treatment with Venetoclax. Also advise patients not to breastfeed while taking Venetoclax. - Male Infertility Advise patients of the possibility of infertility and possible use of sperm banking for males of reproductive potential. Instructions for Taking Venetoclax - Advise patients to take Venetoclax exactly as prescribed and not to change their dose or to stop taking Venetoclax unless they are told to do so by their doctor. Advise patients to take Venetoclax orally once daily, at approximately the same time each day, according to their doctor's instructions and that the tablets should be swallowed whole with a meal and water without being chewed, crushed, or broken. - Advise patients to keep Venetoclax in the original packaging during the first 4 weeks of treatment, and not to transfer the tablets to a different container. - Advise patients that if a dose of Venetoclax is missed by less than 8 hours, to take the missed dose right away and take the next dose as usual. If a dose of Venetoclax is missed by more than 8 hours, advise patients to wait and take the next dose at the usual time. - Advise patients not to take any additional dose that day if they vomit after taking Venetoclax, and to take the next dose at the usual time the following day. # Precautions with Alcohol Alcohol-Venetoclax interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names VENCLEXTA™ # Look-Alike Drug Names There is limited information regarding Venetoclax Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Venetoclax Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Martin Nino, 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 Venetoclax is a BCL-2 inhibitor that is FDA approved for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion, as detected by an FDA approved test, who have received at least one prior therapy. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. Common adverse reactions include neutropenia, diarrhea, nausea, anemia, upper respiratory tract infection, thrombocytopenia, and fatigue (≥20%). # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Select patients for the treatment of relapsed or refractory CLL with Venetoclax based on the presence of 17p deletions in blood specimens. Patients without 17p deletion at diagnosis should be retested at relapse because acquisition of 17p deletion can occur. Venetoclax should be taken orally once daily until disease progression or unacceptable toxicity is observed. Assess patient-specific factors for level of risk of tumor lysis syndrome (TLS) and provide prophylactic hydration and anti-hyperuricemics to patients prior to first dose of Venetoclax to reduce risk of TLS. Administer the Venetoclax dose according to a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg as shown in Table 1. The 5-week ramp-up dosing schedule is designed to gradually reduce tumor burden (debulk) and decrease the risk of TLS. Once the ramp-up phase is completed, the 400 mg dose is achieved using 100 mg tablets. - Table 1: Dosing Schedule for Ramp-Up Phase Instruct patients to take Venetoclax tablets with a meal and water at approximately the same time each day. Venetoclax tablets should be swallowed whole and not chewed, crushed, or broken prior to swallowing. Venetoclax can cause rapid reduction in tumor and thus poses a risk for TLS in the initial 5-week ramp-up phase. Changes in blood chemistries consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the first dose of Venetoclax and at each dose increase. The risk of TLS is a continuum based on multiple factors, including tumor burden and comorbidities. Perform tumor burden assessments, including radiographic evaluation (e.g., CT scan), assess blood chemistry (potassium, uric acid, phosphorus, calcium, and creatinine) in all patients and correct pre-existing abnormalities prior to initiation of treatment with Venetoclax. Reduced renal function (creatinine clearance [CrCl] <80 mL/min) further increases the risk. The risk may decrease as tumor burden decreases. Table 2 below describes the recommended TLS prophylaxis and monitoring during Venetoclax treatment based on tumor burden determination from clinical trial data. - Table 2: Recommended TLS Prophylaxis Based on Tumor Burden From Clinical Trial Data (consider all patient co-morbidities before final determination of prophylaxis and monitoring schedule) Interrupt dosing or reduce dose for toxicities. See Table 3 for dose modifications for hematologic and other toxicities related to Venetoclax, and Table 4 for dose. For patients who have had a dosing interruption greater than 1 week during the first 5 weeks of ramp-up phase or greater than 2 weeks when at the daily dose of 400 mg, reassess for risk of TLS to determine if reinitiation with a reduced dose is necessary (e.g., all or some levels of the dose ramp-up schedule). - Table 3: Recommended Dose Modifications for Toxicities (a) - Table 4: Dose Modification for Toxicity During Venetoclax Treatment Concomitant use of Venetoclax with strong CYP3A inhibitors at initiation and during ramp-up phase is contraindicated. Concomitant use of Venetoclax with strong CYP3A inhibitors increases Venetoclax exposure (i.e., Cmax and AUC) and may increase the risk for TLS at initiation and during ramp-up phase. For patients who have completed the ramp-up phase and are on a steady daily dose of Venetoclax, reduce the Venetoclax dose by at least 75% when strong CYP3A inhibitors must be used concomitantly. Avoid concomitant use of Venetoclax with moderate CYP3A inhibitors or P-gp inhibitors. Consider alternative treatments. If a moderate CYP3A inhibitor or a P-gp inhibitor must be used, reduce the Venetoclax dose by at least 50%. Monitor these patients more closely for signs of toxicities. Resume the Venetoclax dose that was used prior to initiating the CYP3A inhibitor or P-gp inhibitor 2 to 3 days after discontinuation of the inhibitor. The recommendations for managing drug-drug interactions are summarized in Table 5. - Table 5: Management of Potential Venetoclax Interactions with CYP3A and P-gp Inhibitors If the patient misses a dose of Venetoclax within 8 hours of the time it is usually taken, the patient should take the missed dose as soon as possible and resume the normal daily dosing schedule. If a patient misses a dose by more than 8 hours, the patient should not take the missed dose and should resume the usual dosing schedule the next day. If the patient vomits following dosing, no additional dose should be taken that day. The next prescribed dose should be taken at the usual time. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Venetoclax in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Venetoclax in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and effectiveness have not been established in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Venetoclax in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Venetoclax in pediatric patients. # Contraindications Concomitant use of Venetoclax with strong CYP3A inhibitors at initiation and during ramp-up phase is contraindicated. # Warnings Tumor lysis syndrome, including fatal events and renal failure requiring dialysis, has occurred in previously treated CLL patients with high tumor burden when treated with Venetoclax. Venetoclax can cause rapid reduction in tumor and thus poses a risk for TLS in the initial 5-week ramp-up phase. Changes in blood chemistries consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the first dose of Venetoclax and at each dose increase. The risk of TLS is a continuum based on multiple factors, including tumor burden (see Table 2) and comorbidities. Reduced renal function (CrCl <80 mL/min) further increases the risk. Patients should be assessed for risk and should receive appropriate prophylaxis for TLS, including hydration and anti-hyperuricemics. Monitor blood chemistries and manage abnormalities promptly. Interrupt dosing if needed. Employ more intensive measures (intravenous hydration, frequent monitoring, hospitalization) as overall risk increases. Concomitant use of Venetoclax with strong or moderate CYP3A inhibitors and P-gp inhibitors increases venetoclax exposure, may increase the risk of TLS at initiation and during ramp-up phase and may require Venetoclax dose adjustment. Grade 3 or 4 neutropenia occurred in 41% (98/240) of patients treated with Venetoclax. Monitor complete blood counts throughout the treatment period. Interrupt dosing or reduce dose for severe neutropenia. Consider supportive measures including antimicrobials for signs of infection and use of growth factors (e.g., G-CSF). Do not administer live attenuated vaccines prior to, during, or after treatment with Venetoclax until B-cell recovery occurs. The safety and efficacy of immunization with live attenuated vaccines during or following Venetoclax therapy have not been studied. Advise patients that vaccinations may be less effective. Based on its mechanism of action and findings in animals, Venetoclax may cause embryo-fetal harm when administered to a pregnant woman. In an embryo-fetal study conducted in mice, administration of Venetoclax to pregnant animals at exposures equivalent to that observed in patients at the recommended dose of 400 mg daily resulted in post-implantation loss and decreased fetal weight. There are no adequate and well-controlled studies in pregnant woman using Venetoclax. Advise females of reproductive potential to avoid pregnancy during treatment. If Venetoclax is used during pregnancy or if the patient becomes pregnant while taking Venetoclax, the patient should be apprised of the potential hazard to the fetus. # Adverse Reactions ## Clinical Trials Experience The following adverse drug reactions are discussed in greater detail in other sections of the label: - Tumor Lysis Syndrome - Neutropenia Because clinical trials are conducted under widely variable conditions, adverse event rates observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of another drug and may not reflect the rates observed in practice. The safety of single agent Venetoclax at the 400 mg recommended daily dose following a dose ramp-up schedule is based on pooled data of 240 patients with previously treated CLL from two phase 2 trials and one phase 1 trial. In the pooled dataset, the median age was 66 years (range: 29 to 85 years), 95% were white, and 69% were male. The median number of prior therapies was 3 (range: 1 to 12). The median duration of treatment with Venetoclax at the time of data analysis was approximately 10.3 months (range: 0 to 34.1 months). Approximately 46% of patients received Venetoclax for more than 48 weeks. The most common adverse reactions (≥20%) of any grade were neutropenia, diarrhea, nausea, anemia, upper respiratory tract infection, thrombocytopenia, and fatigue. Serious adverse reactions were reported in 43.8% of patients. The most frequent serious adverse reactions (≥2%) were pneumonia, febrile neutropenia, pyrexia, autoimmune hemolytic anemia (AIHA), anemia, and TLS. Discontinuations due to adverse reactions occurred in 8.3% of patients. The most frequent adverse reactions leading to drug discontinuation were thrombocytopenia and AIHA. Dosage adjustments due to adverse reactions occurred in 9.6% of patients. The most frequent adverse reactions leading to dose adjustments were neutropenia, febrile neutropenia, and thrombocytopenia. Adverse reactions reported in 3 trials of patients with previously treated CLL using single agent Venetoclax are presented in Table 6. - Table 6: Adverse Reactions Reported in ≥10% (Any Grade) or ≥5% (Grade 3 or 4) of Patients with CLL ### Tumor Lysis Syndrome Tumor lysis syndrome is an important identified risk when initiating Venetoclax. In the initial Phase 1 dose-finding trials, which had shorter (2-3 week) ramp-up phase and higher starting dose, the incidence of TLS was 12% (9/77; 4 laboratory TLS, 5 clinical TLS), including 2 fatal events and 3 events of acute renal failure, 1 requiring dialysis. The risk of TLS was reduced after revision of the dosing regimen and modification to prophylaxis and monitoring measures. In Venetoclax clinical trials, patients with any measurable lymph node ≥10 cm or those with both an ALC ≥25 x 109/L and any measurable lymph node ≥5 cm were hospitalized to enable more intensive hydration and monitoring for the first day of dosing at 20 mg and 50 mg during the ramp-up phase. In 66 patients with CLL starting with a daily dose of 20 mg and increasing over 5 weeks to a daily dose of 400 mg, the rate of TLS was 6%. All events either met laboratory TLS criteria (laboratory abnormalities that met ≥2 of the following within 24 hours of each other: potassium >6 mmol/L, uric acid >476 µmol/L, calcium <1.75 mmol/L, or phosphorus >1.5 mmol/L); or were reported as TLS events. The events occurred in patients who had a lymph node(s) ≥5 cm or ALC ≥25 x 109/L. No TLS with clinical consequences such as acute renal failure, cardiac arrhythmias or sudden death and/or seizures was observed in these patients. All patients had CrCl ≥50 mL/min. Laboratory abnormalities relevant to TLS observed in 66 patients with CLL who followed the dose ramp-up schedule and TLS prophylaxis measures are presented in Table 7. - Table 7: Adverse Reactions of TLS and Relevant Laboratory Abnormalities Reported in Patients with CLL ## Postmarketing Experience There is limited information regarding Venetoclax Postmarketing Experience in the drug label. # Drug Interactions Venetoclax is predominantly metabolized by CYP3A4/5. - Strong CYP3A Inhibitors Concomitant use of Venetoclax with strong CYP3A inhibitors (e.g., ketoconazole, conivaptan, clarithromycin, indinavir, itraconazole, lopinavir, ritonavir, telaprevir, posaconazole and voriconazole) at initiation and during ramp-up phase is contraindicated. For patients who have completed the ramp-up phase and are on a steady daily dose of Venetoclax, reduce the Venetoclax dose by at least 75% when used concomitantly with strong CYP3A inhibitors. Resume the Venetoclax dose that was used prior to initiating the CYP3A inhibitor 2 to 3 days after discontinuation of the inhibitor. Co-administration of ketoconazole increased Venetoclax Cmax by 2.3-fold and AUC∞ by 6.4-fold. - Moderate CYP3A Inhibitors and P-gp Inhibitors Avoid concomitant use of moderate CYP3A inhibitors (e.g., erythromycin, ciprofloxacin, diltiazem, dronedarone, fluconazole, verapamil) or P-gp inhibitors (e.g., amiodarone, azithromycin, captopril, carvedilol, cyclosporine, felodipine, quercetin, quinidine, ranolazine, ticagrelor) with Venetoclax. Consider alternative treatments. If a moderate CYP3A inhibitor or a P-gp inhibitor must be used, reduce the Venetoclax dose by at least 50%. Monitor patients more closely for signs of Venetoclax toxicities. Resume the Venetoclax dose that was used prior to initiating the CYP3A inhibitor or P-gp inhibitor 2 to 3 days after discontinuation of the inhibitor. Avoid grapefruit products, Seville oranges, and starfruit during treatment with Venetoclax, as they contain inhibitors of CYP3A. Co-administration of a single dose of rifampin, a P-gp inhibitor, increased Venetoclax Cmax by 106% and AUC∞ by 78%. - CYP3A Inducers Avoid concomitant use of Venetoclax with strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s wort) or moderate CYP3A inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin). Consider alternative treatments with less CYP3A induction. Co-administration of multiple doses of rifampin, a strong CYP3A inducer, decreased Venetoclax Cmax by 42% and AUC∞ by 71%. - Warfarin In a drug-drug interaction study in healthy subjects, administration of a single dose of Venetoclax with warfarin resulted in an 18% to 28% increase in Cmax and AUC∞ of R-warfarin and S-warfarin. Because Venetoclax was not dosed to steady state, it is recommended that the international normalized ratio (INR) be monitored closely in patients receiving warfarin. - P-gp substrates In vitro data suggest Venetoclax has inhibition potential on P-gp substrates at therapeutic dose levels in the gut. Therefore, co-administration of narrow therapeutic index P-gp substrates (e.g., digoxin, everolimus, and sirolimus) with Venetoclax should be avoided. If a narrow therapeutic index P-gp substrate must be used, it should be taken at least 6 hours before Venetoclax. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Risk Summary There are no available human data on the use of Venetoclax in pregnant women. Based on toxicity observed in mice, Venetoclax may cause fetal harm when administered to pregnant women. In mice, Venetoclax was fetotoxic at exposures 1.2 times the human clinical exposure based on AUC at the recommended human dose of 400 mg daily. If Venetoclax is used during pregnancy or if the patient becomes pregnant while taking Venetoclax, the patient should be apprised of the potential risk to a fetus. The background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. - Data - Animal Data In embryo-fetal development studies, Venetoclax was administered to pregnant mice and rabbits during the period of organogenesis. In mice, Venetoclax was associated with increased post-implantation loss and decreased fetal body weight at 150 mg/kg/day (maternal exposures approximately 1.2 times the human AUC exposure at the recommended dose of 400 mg daily). No teratogenicity was observed in either the mouse or the rabbit. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Venetoclax in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Venetoclax during labor and delivery. ### Nursing Mothers There are no data on the presence of Venetoclax in human milk, the effects of Venetoclax on the breastfed child, or the effects of Venetoclax on milk production. Because many drugs are excreted in human milk and because the potential for serious adverse reactions in breastfed infants from Venetoclax is unknown, advise nursing women to discontinue breastfeeding during treatment with Venetoclax. ### Pediatric Use Safety and effectiveness have not been established in pediatric patients. ### Geriatic Use Of the 106 patients with previously treated CLL with 17p deletion who were evaluated for efficacy, 57% were ≥65 years of age and 17% were ≥75 years of age. Of the 240 patients with previously treated CLL evaluated for safety from 3 open-label trials, 58% were ≥65 years of age and 17% were ≥75 years of age. No overall differences in safety and effectiveness were observed between older and younger patients. ### Gender There is no FDA guidance on the use of Venetoclax with respect to specific gender populations. ### Race There is no FDA guidance on the use of Venetoclax with respect to specific racial populations. ### Renal Impairment Patients with reduced renal function (CrCl <80 mL/min) are at increased risk of TLS. These patients may require more intensive prophylaxis and monitoring to reduce the risk of TLS when initiating treatment with Venetoclax. No specific clinical trials have been conducted in subjects with renal impairment. Less than 0.1% of radioactive Venetoclax dose was detected in urine. No dose adjustment is needed for patients with mild or moderate renal impairment (CrCl ≥30 mL/min) based on results of the population pharmacokinetic analysis. A recommended dose has not been determined for patients with severe renal impairment (CrCl <30 mL/min) or patients on dialysis. ### Hepatic Impairment No specific clinical trials have been conducted in subjects with hepatic impairment, however human mass balance study showed that Venetoclax undergoes hepatic elimination. Although no dose adjustment is recommended in patients with mild or moderate hepatic impairment based on results of the population pharmacokinetic analysis, a trend for increased adverse events was observed in patients with moderate hepatic impairment; monitor these patients more closely for signs of toxicity during the initiation and dose ramp-up phase. A recommended dose has not been determined for patients with severe hepatic impairment. ### Females of Reproductive Potential and Males Venetoclax may cause fetal harm. - Pregnancy Testing Females of reproductive potential should undergo pregnancy testing before initiation of Venetoclax. - Contraception Advise females of reproductive potential to use effective contraception during treatment with Venetoclax and for at least 30 days after the last dose. - Infertility Based on findings in animals, male fertility may be compromised by treatment with Venetoclax. ### Immunocompromised Patients There is no FDA guidance one the use of Venetoclax in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Venetoclax Administration in the drug label. ### Monitoring There is limited information regarding Venetoclax Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Venetoclax and IV administrations. # Overdosage There is no specific antidote for Venetoclax. For patients who experience overdose, closely monitor and provide appropriate supportive treatment; during ramp-up phase interrupt Venetoclax and monitor carefully for signs and symptoms of TLS along with other toxicities. Based on Venetoclax large volume of distribution and extensive protein binding, dialysis is unlikely to result in significant removal of Venetoclax. # Pharmacology ## Mechanism of Action Venetoclax is a selective and orally [bioavailable] small-molecule inhibitor of BCL-2, an anti-apoptotic protein. Overexpression of BCL-2 has been demonstrated in CLL cells where it mediates tumor cell survival and has been associated with resistance to chemotherapeutics. Venetoclax helps restore the process of apoptosis by binding directly to the BCL-2 protein, displacing pro-apoptotic proteins like BIM, triggering mitochondrial outer membrane permeabilization and the activation of caspases. In nonclinical studies, Venetoclax has demonstrated cytotoxic activity in tumor cells that overexpress BCL-2. ## Structure There is limited information regarding Venetoclax Structure in the drug label. ## Pharmacodynamics - Cardiac Electrophysiology The effect of multiple doses of Venetoclax up to 1200 mg once daily on the QTc interval was evaluated in an open-label, single-arm study in 176 patients with previously treated hematologic malignancies. Venetoclax had no large effect on QTc interval (i.e., > 20 ms) and there was no relationship between Venetoclax exposure and change in QTc interval. ## Pharmacokinetics Following multiple oral administrations under fed conditions, maximum plasma concentration of Venetoclax was reached 5-8 hours after dose. Venetoclax steady state AUC increased proportionally over the dose range of 150-800 mg. Under low-fat meal conditions, Venetoclax mean (± standard deviation) steady state Cmax was 2.1 ± 1.1 μg/mL and AUC(0-24) was 32.8 ± 16.9 μg•h/mL at the 400 mg once daily dose. - Food Effect Administration with a low-fat meal increased Venetoclax exposure by approximately 3.4-fold and administration with a high-fat meal increased Venetoclax exposure by 5.1- to 5.3-fold compared to fasting conditions. Venetoclax should be administered with a meal. Venetoclax is highly bound to human plasma protein with unbound fraction in plasma <0.01 across a concentration range of 1-30 µM (0.87-26 µg/mL). The mean blood-to-plasma ratio was 0.57. The population estimate for apparent volume of distribution (Vdss/F) of Venetoclax ranged from 256-321 L in patients. The population estimate for the terminal elimination half-life of Venetoclax was approximately 26 hours. The pharmacokinetics of Venetoclax does not change over time. - Metabolism In vitro studies demonstrated that Venetoclax is predominantly metabolized by CYP3A4/5. M27 was identified as a major metabolite in plasma with an inhibitory activity against BCL-2 that is at least 58-fold lower than Venetoclax in vitro. - Excretion After single oral administration of 200 mg radiolabeled [14C]-Venetoclax dose to healthy subjects, >99.9% of the dose was recovered in feces and <0.1% of the dose was excreted in urine within 9 days, indicating that hepatic elimination is responsible for the clearance of Venetoclax from the systemic circulation. Unchanged Venetoclax accounted for 20.8% of the administered radioactive dose excreted in feces. - Age, Race, Sex, and Weight Based on population pharmacokinetic analyses, age, race, sex, and weight do not have a clinically meaningful effect on Venetoclax clearance. - Renal Impairment Based on a population pharmacokinetic analysis that included 211 subjects with mild renal impairment (CrCl ≥60 and <90 mL/min, calculated by Cockcroft-Gault equation), 83 subjects with moderate renal impairment (CrCl ≥30 and <60 mL/min) and 210 subjects with normal renal function (CrCl ≥90 mL/min), Venetoclax exposures in subjects with mild or moderate renal impairment are similar to those with normal renal function. The pharmacokinetics of Venetoclax has not been studied in subjects with severe renal impairment (CrCl <30 mL/min) or subjects on dialysis. - Hepatic Impairment Based on a population pharmacokinetic analysis that included 69 subjects with mild hepatic impairment, 7 subjects with moderate hepatic impairment and 429 subjects with normal hepatic function, Venetoclax exposures are similar in subjects with mild and moderate hepatic impairment and normal hepatic function. The NCI Organ Dysfunction Working Group criteria for hepatic impairment were used in the analysis. Mild hepatic impairment was defined as normal total bilirubin and aspartate transaminase (AST) > upper limit of normal (ULN) or total bilirubin >1.0 to 1.5 times ULN, moderate hepatic impairment as total bilirubin >1.5 to 3.0 times ULN, and severe hepatic impairment as total bilirubin >3.0 times ULN. The pharmacokinetics of Venetoclax has not been studied in subjects with severe hepatic impairment. - Ketoconazole Co-administration of 400 mg once daily ketoconazole, a strong CYP3A, P-gp and BCRP inhibitor, for 7 days in 11 previously treated NHL patients increased Venetoclax Cmax by 2.3-fold and AUC∞ by 6.4-fold. - Rifampin multiple doses Co-administration of 600 mg once daily rifampin, a strong CYP3A inducer, for 13 days in 10 healthy subjects decreased Venetoclax Cmax by 42% and AUC∞ by 71%. - Rifampin single dose Co-administration of a 600 mg single dose of rifampin, an OATP1B1/1B3 and P-gp inhibitor, in 11 healthy subjects increased Venetoclax Cmax by 106% and AUC∞ by 78%. - Gastric Acid Reducing Agents Based on population pharmacokinetic analysis, gastric acid reducing agents (e.g., proton pump inhibitors, H2-receptor antagonists, antacids) do not affect Venetoclax bioavailability. - Warfarin In a drug-drug interaction study in three healthy subjects, administration of a single 400 mg dose of Venetoclax with 5 mg warfarin resulted in 18% to 28% increase in Cmax and AUC∞ of R-warfarin and S-warfarin. In vitro studies indicated that Venetoclax is not an inhibitor or inducer of CYP1A2, CYP2B6, CYP2C19, CYP2D6, or CYP3A4 at clinically relevant concentrations. Venetoclax is a weak inhibitor of CYP2C8, CYP2C9, and UGT1A1 in vitro, but it is not predicted to cause clinically relevant inhibition due to high plasma protein binding. Venetoclax is not an inhibitor of UGT1A4, UGT1A6, UGT1A9, or UGT2B7. Venetoclax is a P-gp and BCRP substrate as well as a P-gp and BCRP inhibitor and weak OATP1B1 inhibitor in vitro. To avoid a potential interaction in the gastrointestinal tract, co-administration of narrow therapeutic index P-gp substrates such as digoxin with Venetoclax should be avoided. If a narrow therapeutic index P-gp substrate must be used, it should be taken at least 6 hours before Venetoclax. Venetoclax is not expected to inhibit OATP1B3, OCT1, OCT2, OAT1, OAT3, MATE1, or MATE2K at clinically relevant concentrations. ## Nonclinical Toxicology Carcinogenicity studies have not been conducted with Venetoclax . Venetoclax was not mutagenic in an in vitro bacterial mutagenicity (Ames) assay, did not induce numerical or structural aberrations in an in vitro chromosome aberration assay using human peripheral blood lymphocytes, and was not clastogenic in an in vivo mouse bone marrow micronucleus assay at doses up to 835 mg/kg. The M27 metabolite was negative for genotoxic activity in in vitro Ames and chromosome aberration assays. Fertility and early embryonic development studies were conducted in male and female mice. These studies evaluate mating, fertilization, and embryonic development through implantation. There were no effects of Venetoclax on estrus cycles, mating, fertility, corpora lutea, uterine implants or live embryos per litter at dosages up to 600 mg/kg/day. However, a risk to human male fertility exists based on testicular toxicity (germ cell loss) observed in dogs at exposures as low as 0.5 times the human AUC exposure at the recommend dose. In dogs, Venetoclax caused single-cell necrosis in various tissues, including the gallbladder, exocrine pancreas, and stomach with no evidence of disruption of tissue integrity or organ dysfunction; these findings were minimal to mild in magnitude. Following a 4-week dosing period and subsequent 4-week recovery period, minimal single-cell necrosis was still present in some tissues and reversibility has not been assessed following longer periods of dosing or recovery. In addition, after approximately 3 months of daily dosing in dogs, Venetoclax caused progressive white discoloration of the hair coat, due to loss of melanin pigment. # Clinical Studies The efficacy of Venetoclax was established in an open-label, single-arm, multicenter clinical trial of 106 patients with CLL with 17p deletion who had received at least one prior therapy. In the study, 17p deletion was confirmed in peripheral blood specimens from patients using Vysis CLL FISH Probe Kit, which is FDA approved for selection of patients for Venetoclax treatment. Patients received Venetoclax via a weekly ramp-up schedule starting at 20 mg and ramping to 50 mg, 100 mg, 200 mg and finally 400 mg once daily. Patients continued to receive 400 mg of Venetoclax orally once daily until disease progression or unacceptable toxicity. The efficacy of Venetoclax was evaluated by overall response rate (ORR) as assessed by an Independent Review Committee (IRC) using the International Workshop for Chronic Lymphocytic Leukemia (IWCLL) updated National Cancer Institute-sponsored Working Group (NCI-WG) guidelines (2008). Table 8 summarizes the baseline demographic and disease characteristics of the study population. - Table 8: Baseline Patient Characteristics The median time on treatment at the time of evaluation was 12.1 months (range: 0 to 21.5 months). Efficacy results are shown in Table 9. - Table 9: Efficacy Results for Patients with Previously Treated CLL with 17p Deletion by IRC The median time to first response was 0.8 months (range: 0.1 to 8.1 months). Median duration of response (DOR) has not been reached with approximately 12 months median follow-up. The DOR ranged from 2.9 to 19.0+ months. Minimal residual disease (MRD) was evaluated in peripheral blood and bone marrow for patients who achieved CR or CRi, following treatment with Venetoclax. Three percent (3/106) were MRD negative in the peripheral blood and bone marrow (less than one CLL cell per 104 leukocytes). # How Supplied Venetoclax is dispensed as follows: - Venetoclax 10 mg film-coated tablets are round, biconvex shaped, pale yellow debossed with “V” on one side and “10” on the other side. - Venetoclax 50 mg film-coated tablets are oblong, biconvex shaped, beige debossed with “V” on one side and “50” on the other side. - Venetoclax 100 mg film-coated tablets are oblong, biconvex shaped, pale yellow debossed with “V” on one side and “100” on the other side. ## Storage Store at or below 86°F (30°C). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Advise the patient to read the FDA-approved patient labeling. - Tumor Lysis Syndrome Advise patients of the potential risk of TLS, particularly at treatment initiation and during ramp-up phase, and to immediately report any signs and symptoms associated with this event (fever, chills, nausea, vomiting, confusion, shortness of breath, seizure, irregular heartbeat, dark or cloudy urine, unusual tiredness, muscle pain, and/or joint discomfort) to their doctor for evaluation. Advise patients to be adequately hydrated every day when taking Venetoclax to reduce the risk of TLS. The recommended volume is 6 to 8 glasses (approximately 56 ounces total) of water each day. Patients should drink water starting 2 days before and on the day of the first dose, and every time the dose is increased. Advise patients of the importance of keeping scheduled appointments for blood work or other laboratory tests. Advise patients that it may be necessary to take Venetoclax in the presence of a doctor to allow monitoring for TLS. - Neutropenia Advise patients to contact their doctor immediately if they develop a fever or any signs of infection. Advise patients of the need for periodic monitoring of blood counts. - Drug Interactions Advise patients to avoid consuming grapefruit products, Seville oranges, or starfruit during treatment with Venetoclax. Advise patients that Venetoclax may interact with some drugs; therefore, advise patients to inform their doctor of the use of any prescription medication, over-the-counter drugs, vitamins and herbal products. - Immunizations Advise patients to avoid vaccination with live vaccines because they may not be safe or effective during treatment with Venetoclax. - Pregnancy and Lactation Advise women of the potential risk to the fetus and to avoid pregnancy during treatment with Venetoclax. Advise female patients of reproductive potential to use effective contraception during therapy and for at least 30 days after completing of therapy. Advise females to contact their doctor if they become pregnant, or if pregnancy is suspected, during treatment with Venetoclax. Also advise patients not to breastfeed while taking Venetoclax. - Male Infertility Advise patients of the possibility of infertility and possible use of sperm banking for males of reproductive potential. Instructions for Taking Venetoclax - Advise patients to take Venetoclax exactly as prescribed and not to change their dose or to stop taking Venetoclax unless they are told to do so by their doctor. Advise patients to take Venetoclax orally once daily, at approximately the same time each day, according to their doctor's instructions and that the tablets should be swallowed whole with a meal and water without being chewed, crushed, or broken. - Advise patients to keep Venetoclax in the original packaging during the first 4 weeks of treatment, and not to transfer the tablets to a different container. - Advise patients that if a dose of Venetoclax is missed by less than 8 hours, to take the missed dose right away and take the next dose as usual. If a dose of Venetoclax is missed by more than 8 hours, advise patients to wait and take the next dose at the usual time. - Advise patients not to take any additional dose that day if they vomit after taking Venetoclax, and to take the next dose at the usual time the following day. # Precautions with Alcohol Alcohol-Venetoclax interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names VENCLEXTA™ # Look-Alike Drug Names There is limited information regarding Venetoclax Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Venetoclax
93eaa6e54a2999bf641a404cadd1f1440861bbac	wikidoc	Venography	Venography # Overview Venography (also called phlebography) is a procedure in which an x-ray of the veins, a venogram, is taken after a special dye is injected into the vein or even bone marrow. It is the gold standard for diagnosing acute deep venous thrombosis although its use has been largely supplanted by the less invasive Duplex ultrasound scanning. Venography can also be used to distinguish blood clots from obstructions in the veins, to evaluate congenital vein problems, to evaluate veins prior to treatment of chronic venous insufficiency, to see how well the deep leg vein valves are functioning or to identify a vein for coronary artery bypass grafting. # Indications A venogram is indicated to evaluate the following entities: - Deep vein thrombosis - Lower limb edema of unknown origin - Congenital venous abnormalities - Incompetent perforating veins - Evaluation of veins prior to coronary artery bypass grafting # Contraindication Performance of a venogram or administration of iodinated contrast in a patient taking metformin can result in metabolic acidosis. # Procedure - Tile the flouroscopic couch feet down approximately 30 degrees to slow contrast media travel and help dilate the lower veins. Have the patient perform the Valsalva maneuver to further delay the dye transit. - Apply a tourniquet is applied just above the ankle. - Cannulate a vein on the dorsum of the foot with a 19 or 21 gauge needle. - Inject up to 40 cc of contrast media and obtain a series of films from the foot to the pelvis. # Complications - Thrombophlebits - Contrast media extravasation - Arrhythmias in patients with pulmonary hypertension - General contrast media complications allergic reaction or anaphylaxis - Hematoma at site of injection site - Pulmonary embolus # Images - A venographic image of a deep vein thrombosis. Source: www.lakeridgehealth.on.ca - An occluded vein with formation of a collateral vessel. Source: www.lakeridgehealth.on.ca # For Patients In order for the dye to show up on the x-ray it contains iodine. X-rays cannot penetrate iodine and this casts a white shadow on the x-ray film. Because iodine is being injected, you will need let your doctor know if you have had any allergies to iodine in the past. If you have, your doctor may not perform the procedure or your doctor may premedicate you with Benadryl or with steroids. You should also let your doctor know if you are pregnant because the x-ray could harm the fetus. There are certain diseases that put the patient at risk for kidney problems after the procedure. You should let your doctor know if you have any of the following: - Advanced age - Diabetes mellitus - Multiple myeloma - Dehydration - Poor kidney function The night before the procedure, your doctor will ask you to drink plenty of fluids. This is because the dye can be hard on the kidneys and drinking plenty of fluids will help flush the dye out of your body and reduce the concentration of the dye going through the kidneys. Other than this, there is usually very little preparation for a venogram. On the day of the procedure, you should expect to spend 30 to 90 minutes having the test done. Prior to the procedure, your doctor will usually shave the area where the catheter will be inserted and will usually create a sterile area for the procedure to be done. Most often dye is injected through the back of the foot to evaluate the veins in the leg. If your doctor is evaluating the veins in your arm, the catheter may be inserted in the back of your hand. Next, your doctor will numb up the area with a local anesthetic. A catheter will then be inserted into the vein under the skin. During the insertion of the catheter you may feel a pinch or something that feels like a bee sting. Your doctor will next inject the dye. During the injection you may feel a sense of warmth in your leg traveling up and going throughout your body. Rarely, some patients become nauseated during this time. Please let your not doctor know if you have any itching, rash, swelling of your common lips or mouth, or difficulty breathing as these may indicate that you have an allergy to the dye. Prompt treatment is necessary for any allergic reaction. It will also be necessary for you to lie very still when the dye is injected so that there is no movement of your leg to blur the image on the x-ray. Once the injection is done, your doctor will remove the catheter, which is painless and will apply pressure for about 10 minutes to stop any bleeding that occurs. You may also be given fluids to clear the dye from your body. In general venography is very safe. There are a few complications that you should be aware of. A blood clot can form at the site of the injection, a blood clot that was already there can be dislodged and travel upstream in your body to the lungs, you can develop an allergic reaction as described above, and your kidney function can decline.	Venography Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Venography (also called phlebography) is a procedure in which an x-ray of the veins, a venogram, is taken after a special dye is injected into the vein or even bone marrow. It is the gold standard for diagnosing acute deep venous thrombosis although its use has been largely supplanted by the less invasive Duplex ultrasound scanning. Venography can also be used to distinguish blood clots from obstructions in the veins, to evaluate congenital vein problems, to evaluate veins prior to treatment of chronic venous insufficiency, to see how well the deep leg vein valves are functioning or to identify a vein for coronary artery bypass grafting. # Indications A venogram is indicated to evaluate the following entities: - Deep vein thrombosis - Lower limb edema of unknown origin - Congenital venous abnormalities - Incompetent perforating veins - Evaluation of veins prior to coronary artery bypass grafting # Contraindication Performance of a venogram or administration of iodinated contrast in a patient taking metformin can result in metabolic acidosis. # Procedure - Tile the flouroscopic couch feet down approximately 30 degrees to slow contrast media travel and help dilate the lower veins. Have the patient perform the Valsalva maneuver to further delay the dye transit. - Apply a tourniquet is applied just above the ankle. - Cannulate a vein on the dorsum of the foot with a 19 or 21 gauge needle. - Inject up to 40 cc of contrast media and obtain a series of films from the foot to the pelvis. # Complications - Thrombophlebits - Contrast media extravasation - Arrhythmias in patients with pulmonary hypertension - General contrast media complications allergic reaction or anaphylaxis - Hematoma at site of injection site - Pulmonary embolus # Images - A venographic image of a deep vein thrombosis. Source: www.lakeridgehealth.on.ca - An occluded vein with formation of a collateral vessel. Source: www.lakeridgehealth.on.ca # For Patients In order for the dye to show up on the x-ray it contains iodine. X-rays cannot penetrate iodine and this casts a white shadow on the x-ray film. Because iodine is being injected, you will need let your doctor know if you have had any allergies to iodine in the past. If you have, your doctor may not perform the procedure or your doctor may premedicate you with Benadryl or with steroids. You should also let your doctor know if you are pregnant because the x-ray could harm the fetus. There are certain diseases that put the patient at risk for kidney problems after the procedure. You should let your doctor know if you have any of the following: - Advanced age - Diabetes mellitus - Multiple myeloma - Dehydration - Poor kidney function The night before the procedure, your doctor will ask you to drink plenty of fluids. This is because the dye can be hard on the kidneys and drinking plenty of fluids will help flush the dye out of your body and reduce the concentration of the dye going through the kidneys. Other than this, there is usually very little preparation for a venogram. On the day of the procedure, you should expect to spend 30 to 90 minutes having the test done. Prior to the procedure, your doctor will usually shave the area where the catheter will be inserted and will usually create a sterile area for the procedure to be done. Most often dye is injected through the back of the foot to evaluate the veins in the leg. If your doctor is evaluating the veins in your arm, the catheter may be inserted in the back of your hand. Next, your doctor will numb up the area with a local anesthetic. A catheter will then be inserted into the vein under the skin. During the insertion of the catheter you may feel a pinch or something that feels like a bee sting. Your doctor will next inject the dye. During the injection you may feel a sense of warmth in your leg traveling up and going throughout your body. Rarely, some patients become nauseated during this time. Please let your not doctor know if you have any itching, rash, swelling of your common lips or mouth, or difficulty breathing as these may indicate that you have an allergy to the dye. Prompt treatment is necessary for any allergic reaction. It will also be necessary for you to lie very still when the dye is injected so that there is no movement of your leg to blur the image on the x-ray. Once the injection is done, your doctor will remove the catheter, which is painless and will apply pressure for about 10 minutes to stop any bleeding that occurs. You may also be given fluids to clear the dye from your body. In general venography is very safe. There are a few complications that you should be aware of. A blood clot can form at the site of the injection, a blood clot that was already there can be dislodged and travel upstream in your body to the lungs, you can develop an allergic reaction as described above, and your kidney function can decline.	https://www.wikidoc.org/index.php/Venogram
589ea41372371dcc5a2e32baa65fa3f9c12c04f9	wikidoc	Vertebrate	Vertebrate # Overview Vertebrates are members of the subphylum Vertebrata, chordates with backbones or spinal columns. The grouping sometimes includes the hagfish, which have no vertebrae, but are genetically quite closely related to lampreys, which do have vertebrae. For this reason, the sub-phylum is sometimes referred to as "Craniata", as all members do possess a cranium. About 58,000 species of vertebrates have been described. Vertebrata is the largest subphylum of chordates, and contains many familiar groups of large land animals. Vertebrates comprise cyclostomes, bony fish, sharks and rays, amphibians, reptiles, mammals, and birds. Extant vertebrates range in size from the carp species Paedocypris, at as little as 7.9 mm (0.3 inch), to the Blue Whale, at up to 33 m (110 ft). # Anatomy and morphology One characteristic of the subphylum are that all members have muscular systems that mostly consist of paired masses, as well as a central nervous system which is partly located inside the backbone (if one is present). The defining characteristic of a vertebrate is considered the backbone or spinal cord, a brain case, and an internal skeleton, but the latter do not hold true for lampreys, and the former is arguably present in some other chordates. Rather, all vertebrates are most easily distinguished from all other chordates by having a clearly identifiable head, that is, sensory organs - especially eyes are concentrated at the fore end of the body and there is pronounced cephalization. Compare the lancelets which have a mouth but not a well-developed head, and have light-sensitive areas along their entire back. # Evolutionary history Vertebrates originated about 500 million years ago during the Cambrian explosion, which is part of the Cambrian period. The earliest known vertebrate is Myllokunmingia. According to recent molecular analysis Myxini (hagfish) also belong to Vertebrates. Others consider them a sister group of Vertebrates in the common taxon of Craniata. # Fossil record The earliest known fossil records of vertebrates are Myllokunmingia fengjiaoa and Haikouichthys ercaicunensis, dating somewhere between 513-542mya during the Early Cambrian. The fossils were discovered in Yunnan, China. # Taxonomy and classification Classification after Janvier (1981, 1997), Shu et al. (2003), and Benton (2004). - Subphylum Vertebrata (Unranked group) Hyperoartia (lampreys) Class †Conodonta Subclass †Pteraspidomorphi Class †Thelodonti Class †Anaspida Class †Galeaspida Class †Pituriaspida Class †Osteostraci Infraphylum Gnathostomata (jawed vertebrates) - (Unranked group) Hyperoartia (lampreys) - Class †Conodonta - Subclass †Pteraspidomorphi - Class †Thelodonti - Class †Anaspida - Class †Galeaspida - Class †Pituriaspida - Class †Osteostraci - Infraphylum Gnathostomata (jawed vertebrates) - Class †Placodermi (Paleozoic armoured forms) - Class Chondrichthyes (cartilaginous fish) - Class †Acanthodii (Paleozoic "spiny sharks") - Superclass Osteichthyes (bony fish) - Class Actinopterygii (ray-finned fish) - Class Sarcopterygii (lobe-finned fish) - Subclass Coelacanthimorpha (coelacanths) - Subclass Dipnoi (lungfish) - Subclass Tetrapodomorpha (ancestral to tetrapods) - Superclass Tetrapoda (four-limbed vertebrates) - Class Amphibia (amphibians) - Series Amniota (amniotic embryo) - Class Sauropsida (reptiles and birds) - Class Aves (birds) - Class Synapsida (mammal-like reptiles) - Class Mammalia (mammals) # Etymology The word vertebrate derives from Latin vertebrātus (Pliny), meaning having joints. It is closely related to the word vertebra, which refers to any of the bones or segments of the spinal column.	Vertebrate # Overview Vertebrates are members of the subphylum Vertebrata, chordates with backbones or spinal columns. The grouping sometimes includes the hagfish, which have no vertebrae, but are genetically quite closely related to lampreys, which do have vertebrae.[1] For this reason, the sub-phylum is sometimes referred to as "Craniata", as all members do possess a cranium. About 58,000 species of vertebrates have been described.[2] Vertebrata is the largest subphylum of chordates, and contains many familiar groups of large land animals. Vertebrates comprise cyclostomes, bony fish, sharks and rays, amphibians, reptiles, mammals, and birds. Extant vertebrates range in size from the carp species Paedocypris, at as little as 7.9 mm (0.3 inch), to the Blue Whale, at up to 33 m (110 ft). # Anatomy and morphology One characteristic of the subphylum are that all members have muscular systems that mostly consist of paired masses, as well as a central nervous system which is partly located inside the backbone (if one is present). The defining characteristic of a vertebrate is considered the backbone or spinal cord, a brain case, and an internal skeleton, but the latter do not hold true for lampreys, and the former is arguably present in some other chordates. Rather, all vertebrates are most easily distinguished from all other chordates by having a clearly identifiable head, that is, sensory organs - especially eyes are concentrated at the fore end of the body and there is pronounced cephalization. Compare the lancelets which have a mouth but not a well-developed head, and have light-sensitive areas along their entire back.[3] # Evolutionary history Vertebrates originated about 500 million years ago during the Cambrian explosion, which is part of the Cambrian period. The earliest known vertebrate is Myllokunmingia.[4] According to recent molecular analysis Myxini (hagfish) also belong to Vertebrates. Others consider them a sister group of Vertebrates in the common taxon of Craniata.[1] # Fossil record The earliest known fossil records of vertebrates are Myllokunmingia fengjiaoa and Haikouichthys ercaicunensis, dating somewhere between 513-542mya during the Early Cambrian. The fossils were discovered in Yunnan, China[1]. # Taxonomy and classification Classification after Janvier (1981, 1997), Shu et al. (2003), and Benton (2004).[5] - Subphylum Vertebrata (Unranked group) Hyperoartia (lampreys) Class †Conodonta Subclass †Pteraspidomorphi Class †Thelodonti Class †Anaspida Class †Galeaspida Class †Pituriaspida Class †Osteostraci Infraphylum Gnathostomata (jawed vertebrates) - (Unranked group) Hyperoartia (lampreys) - Class †Conodonta - Subclass †Pteraspidomorphi - Class †Thelodonti - Class †Anaspida - Class †Galeaspida - Class †Pituriaspida - Class †Osteostraci - Infraphylum Gnathostomata (jawed vertebrates) - Class †Placodermi (Paleozoic armoured forms) - Class Chondrichthyes (cartilaginous fish) - Class †Acanthodii (Paleozoic "spiny sharks") - Superclass Osteichthyes (bony fish) - Class Actinopterygii (ray-finned fish) - Class Sarcopterygii (lobe-finned fish) - Subclass Coelacanthimorpha (coelacanths) - Subclass Dipnoi (lungfish) - Subclass Tetrapodomorpha (ancestral to tetrapods) - Superclass Tetrapoda (four-limbed vertebrates) - Class Amphibia (amphibians) - Series Amniota (amniotic embryo) - Class Sauropsida (reptiles and birds) - Class Aves (birds) - Class Synapsida (mammal-like reptiles) - Class Mammalia (mammals) # Etymology The word vertebrate derives from Latin vertebrātus (Pliny), meaning having joints. It is closely related to the word vertebra, which refers to any of the bones or segments of the spinal column.[6]	https://www.wikidoc.org/index.php/Vertebrate
36e9bff22cf6a51d16034569ff8e9f5fbbec28b9	wikidoc	Vicky Belo	Vicky Belo Victoria G. Belo, popularly known as Dr. Vicky Belo, is a renowned cosmetic surgeon in the Philippines. She is famous for having performed dermatological services on high-profile members of the Philippine showbiz. # Education Belo earned a Bachelor of Science in Psychology from the University of the Philippines, Diliman in 1978. She attended the University of Santo Tomas Faculty of Medicine and Surgery and graduated with a Doctor of Medicine degree in 1985. She obtained a Diploma in Dermatology from the Institute of Dermatology in Bangkok, Thailand, in 1990. # Training Belo trained in Dermatologic Surgery at the Scripps Clinics in San Diego, California. She also trained in Cutaneous Laser Surgery at Harvard Medical School in Boston, Massachusetts, in 1993. She studied Skin Rejuvenation and Laser Surgery at St. Francis Memorial Hospital in the University of California at San Francisco in 1995.She studied Advance Techniques in Phlebology at the Pauline Raymond-Martimbeau Vein Institute in Texas. She took an intensive course in Liposuction under Dr. Jeffrey Klein in San Juan Capistrano, California; and in Laser Assisted Liposuction under Dr. Rodrigo Neira. Belo pioneereed in the New Aptos Thread Seamless Facelift, training with Doctors Marlen and Georges Sulamanidze. # Career Belo has pioneered the following procedures in cosmetic surgery in the Philippines: First Skin Laser Carbon Dioxide in 1990; Tumescent Liposuction in 1991; Ultrapulse Laser for Resurfacing and Blepharoplasty in 1994; Versapulse Laser for Tattoos and Veins in 1996; Botox in 1997; Restylane/Perlane, Microdermabrasion, and Power Peel in 1998; Endermology in 1999; Laser Assisted Liposuction in 2000; Intense Pulse Light (IPL) and Light Sheer Hair Removal in 2001; Aptos Thread Facelifts and Lift 6 in 2002; Cool Glide, Clearlight for Acne, and Stem Cell Auto Grafting (SCAG) in 2003; Electro-Optical Synergy (ELOS) Technology: Polaris, Aurora and Velasmooth (Lipolite), and Mesotherapy in 2004; and Thermage, Multiclear, Jet Peel, and Carboxytherapy in 2005. She is a frequent resource speaker and guest lecturer in several organizations in the Philippines and abroad, such as the International Society of Cosmetic Laser Surgeons in Washington, D.C.; the American Society of Dermatologic Surgery in Portland, Oregon; the World Congress on Liposuction Surgery in Pasadena, California; the American Academy of Cosmetic Surgery; and the International Darmstadt Convention on Intense Pulsed Light Therapy (Quantum SR): Asian Experience in Frankfurt, Germany and USA. # Business interests Belo is the Medical Director of the Belo Medical Group. The Group owns and operates six (6) medical clinics in highly urbanized locations in Metro Manila--Medical Plaza in Makati City, Tektite Towers in Ortigas Center, Westgate in Alabang, Tomas Morato in Quezon City, Connecticut Street in Greenhills, and Rustan’s Shopping Mall in Makati City. # Organizations Belo is not a member of the Philippine Dermatological Society because she did not train in dermatology locally and passed the local dermatological exam. Nevertheless, she is a member of the American Academy of Dermatology, the American Society of Dermatologic Surgery, the American Academy of Cosmetic Surgery, the American Society of Lipoplastic Surgery, the American Society of Hair Restoration Surgery, the International Society of Cosmetic Laser Surgeons (ISCLS), the International Society of Dermatologic Surgery, the Foundation for Facial Plastic Surgery, and is a Founding Officer of the Philippine Liposuction Surgery. However the American Academy of Dermatology is not the certifying body for dermatology and one can only be called a dermatologist after being Board Certified by the American Board of Dermatology.It is interesting to note that the Phillipines does not recognize Miss Bello as a dermatologist and neither does the United States.She is however a highly skilled aesthetic physician with a special interest in dermatology. # Private life Belo is a former aerobics and group fitness trainer. She hoards chocolate bars and candies imported from trips in the United States and Europe, keeping all of them inside her refrigerator. She is famous for being associated both professionally and personally with prominent members of the Philippine showbiz, such as multi-awarded actress and singer Sharon Cuneta, and talkshow host Boy Abunda.	Vicky Belo Template:Primarysources Victoria G. Belo, popularly known as Dr. Vicky Belo, is a renowned cosmetic surgeon in the Philippines. She is famous for having performed dermatological services on high-profile members of the Philippine showbiz. # Education Belo earned a Bachelor of Science in Psychology from the University of the Philippines, Diliman in 1978. She attended the University of Santo Tomas Faculty of Medicine and Surgery and graduated with a Doctor of Medicine degree in 1985. She obtained a Diploma in Dermatology from the Institute of Dermatology in Bangkok, Thailand, in 1990.[1] # Training Belo trained in Dermatologic Surgery at the Scripps Clinics in San Diego, California. She also trained in Cutaneous Laser Surgery at Harvard Medical School in Boston, Massachusetts, in 1993. She studied Skin Rejuvenation and Laser Surgery at St. Francis Memorial Hospital in the University of California at San Francisco in 1995.She studied Advance Techniques in Phlebology at the Pauline Raymond-Martimbeau Vein Institute in Texas. She took an intensive course in Liposuction under Dr. Jeffrey Klein in San Juan Capistrano, California; and in Laser Assisted Liposuction under Dr. Rodrigo Neira.[2] Belo pioneereed in the New Aptos Thread Seamless Facelift, training with Doctors Marlen and Georges Sulamanidze.[3] # Career Belo has pioneered the following procedures in cosmetic surgery in the Philippines: First Skin Laser Carbon Dioxide in 1990; Tumescent Liposuction in 1991; Ultrapulse Laser for Resurfacing and Blepharoplasty in 1994; Versapulse Laser for Tattoos and Veins in 1996; Botox in 1997; Restylane/Perlane, Microdermabrasion, and Power Peel in 1998; Endermology in 1999; Laser Assisted Liposuction in 2000; Intense Pulse Light (IPL) and Light Sheer Hair Removal in 2001; Aptos Thread Facelifts and Lift 6 in 2002; Cool Glide, Clearlight for Acne, and Stem Cell Auto Grafting (SCAG) in 2003; Electro-Optical Synergy (ELOS) Technology: Polaris, Aurora and Velasmooth (Lipolite), and Mesotherapy in 2004; and Thermage, Multiclear, Jet Peel, and Carboxytherapy in 2005.[4] She is a frequent resource speaker and guest lecturer in several organizations in the Philippines and abroad, such as the International Society of Cosmetic Laser Surgeons in Washington, D.C.; the American Society of Dermatologic Surgery in Portland, Oregon; the World Congress on Liposuction Surgery in Pasadena, California; the American Academy of Cosmetic Surgery; and the International Darmstadt Convention on Intense Pulsed Light Therapy (Quantum SR): Asian Experience in Frankfurt, Germany and USA.[5] # Business interests Belo is the Medical Director of the Belo Medical Group. The Group owns and operates six (6) medical clinics in highly urbanized locations in Metro Manila--Medical Plaza in Makati City, Tektite Towers in Ortigas Center, Westgate in Alabang, Tomas Morato in Quezon City, Connecticut Street in Greenhills, and Rustan’s Shopping Mall in Makati City.[6] # Organizations Belo is not a member of the Philippine Dermatological Society because she did not train in dermatology locally and passed the local dermatological exam. Nevertheless, she is a member of the American Academy of Dermatology, the American Society of Dermatologic Surgery, the American Academy of Cosmetic Surgery, the American Society of Lipoplastic Surgery, the American Society of Hair Restoration Surgery, the International Society of Cosmetic Laser Surgeons (ISCLS), the International Society of Dermatologic Surgery, the Foundation for Facial Plastic Surgery, and is a Founding Officer of the Philippine Liposuction Surgery.[7] However the American Academy of Dermatology is not the certifying body for dermatology and one can only be called a dermatologist after being Board Certified by the American Board of Dermatology.It is interesting to note that the Phillipines does not recognize Miss Bello as a dermatologist and neither does the United States.She is however a highly skilled aesthetic physician with a special interest in dermatology. # Private life Belo is a former aerobics and group fitness trainer. She hoards chocolate bars and candies imported from trips in the United States and Europe, keeping all of them inside her refrigerator. She is famous for being associated both professionally and personally with prominent members of the Philippine showbiz, such as multi-awarded actress and singer Sharon Cuneta, and talkshow host Boy Abunda.[8] # External links - Belo Medical Group	https://www.wikidoc.org/index.php/Vicky_Belo
1efc8ac3049961389ecf7966a08e3be298d3f24c	wikidoc	Vicriviroc	Vicriviroc # Overview Vicriviroc, previously named SCH 417690 and SCH-D, is a pyrimidine CCR5 entry inhibitor of HIV-1. It was developed by the pharmaceutical company Schering-Plough. Merck decided to not pursue regulatory approval for use in treatment-experienced patients because the drug did not meet primary efficacy endpoints in late stage trials. Clinical trials continue in patients previously untreated for HIV. # HIV-1 background The mechanisms of a number of available anti-HIV drugs prevent either viral reverse transcriptase enzyme or protease enzyme, allowing the virus to enter the cell before these drugs take effect. However, CCR5 inhibitors such as vicriviroc, as well as other entry inhibitors of HIV-1, inhibit the initial stages of the virus life cycle. ## HIV-1 entry HIV binds to and fuses with the target T-cells or macrophages with the help of gp120 and gp41, the only two proteins that are currently known to be exhibited on the surface of the viral envelope. One molecule of each protein associates noncovalently with the other on the viral membrane, and three of these units aggregate to form the gp120/gp41 heterotrimer, which traps the gp41 in a conformationally metastable state. Membrane fusion begins with the binding of gp120 to CD4, a glycoprotein which is expressed on the surface of the target cell. Upon binding, gp120 undergoes a conformational change, which causes the formation of the coreceptor binding site on gp120. All strains of HIV-1 use one of two coreceptors: CCR5 or CXCR4; coreceptor specificity will be described below. Once gp120 binds to the coreceptor, gp41 undergoes a conformational change that releases it from its once-metastable position. This change causes the hydrophobic N-terminus of the gp41 protein, also known as the fusion domain, to insert into the host cell membrane and anchor the virus into place. The insertion of gp41 into the target cell causes a subtle rearrangement in the gp41 protein that brings together two trimeric coiled coils, HR1 and HR2, to form a six-helix bundle. The bundle allows the viral and cellular membranes to approximate and eventually fuse together, leading to the release of the viral genome into the cytoplasm of the target cell. ## Coreceptors and tropism The two coreceptors involved in the entry of HIV-1, CCR5 and CXCR4, belong to the larger family of 7-transmembrane segment (7TM) G-protein coupled receptors. HIV-1 can thus be classified according specificity for one coreceptor or the other. R5 virus, also known as M-tropic HIV-1, targets macrophages and uses CCR5 as the coreceptor. X4 virus, or T-tropic HIV-1, targets T-cells and uses CXCR4 as the coreceptor. Dual-tropic strains of HIV-1, which utilize both receptors, also exist. Selectivity for one coreceptor or the other is especially dependent upon the V3 loop, a highly variable and structurally flexible region of gp120 that is composed of approximately 35 amino acids. Tropism can be predicted through the 11/25 method, which looks for basic amino acids at positions 11 and 25 in the V3 loop and suggests the presence of an X4 virus. Coreceptor usage, however, can change throughout the course of infection. 90% of patients in early phases of HIV-1 infection have R5 virus. However, after five years of infection, about 50% of all patients have detectable amounts of X4 virus. Causes for this switch are currently unclear. However, viral changes from CCR5 to CXCR4 coreceptor usage have been associated with a faster rate of CD4+ T-cell loss, rapid viral progression, and an increased rate of development of AIDS and death. ## CCR5-Δ32 A focus on the CCR5 co-receptor as a potential target for anti-HIV medications began in 1996 with the discovery of CCR5-Δ32, or CCR5 delta-32, a mutational variant of the CCR5 coding gene. The deletion of 32 base pairs in this gene results in nonfunctional CCR5 receptors. While the frequency of this mutation within Caucasian populations is 0.0808, people of African or Asian descent do not appear to possess this allele. Δ32 homozygotes, or individuals who possess two copies of the Δ32 variant, have no functional CCR5 receptors and are consequently highly resistant to HIV infection. Individuals who inherit one copy of Δ32 variant and one copy of the normal CCR5 gene are CCR5 heterozygotes. Δ32 heterozygotes are still susceptible to HIV-1 infection, but the progression of the disease is significantly delayed compared to those with two normal copies of the CCR5 gene. CCR5 antagonists have been developed which cause deformation in the CCR5 co-receptor, leading to the cell's failure to bind with the HIV gp120 protein. # SCH-C and vicriviroc In 2001, Schering-Plough developed one of the first small molecule CCR5 antagonists, SCH-C or SCH 351125, which inhibited replication of a number of HIV-1 isolates that used CCR5 as a coreceptor for binding. However, SCH-C caused a modest but dose-dependent prolongation of the corrected cardiac QT interval (QTc), leading to examination of alternative compounds whose antiviral and pharmacokinetic properties exceeded those of first-generation compounds like SCH-C. Vicriviroc was discovered in high-throughput screening and structure-activity relationships (SAR) analysis. When compared with SCH-C, vicriviroc consistently and more actively inhibits viral replication, binds with higher affinity to CCR5 than SCH-C, and possesses a lower affinity for the human ether a-go-go related gene transcript ion channel, which may suggest a lower risk of cardiac effects. # Method of action Vicriviroc is a noncompetitive allosteric antagonist of CCR5. It is orally administered and, because it is effective at nanomolar concentrations, it can be administered once daily. Vicriviroc binds to a small hydrophobic pocket between the transmembrane helices near the extracellular surface of the CCR5 receptor. Binding to this pocket induces a conformational change of the extracellular segment of CCR5 and prevents binding of gp120 to the target cell, consequently preventing the virus from entering the target cell at all. Specific binding interactions between CCR5 and vicriviroc were first described in 2008. Specifically, the trifluoromethyl phenyl group of vicriviroc may interact strongly with I198 residue on the fifth transmembrane helix (TM5) of CCR5 through hydrophobic interactions. Additionally, electrostatic interactions may form between the positively charged tertiary nitrogen group of vicriviroc and the hydrophilic region provided by E238 residue on TM7 of CCR5. Other strong interactions predicted by the group include the Y108 residue on TM3 and Y251 on TM6. # Clinical trials Currently, vicriviroc is undergoing critical trials. Vicriviroc demonstrated a significant decrease of HIV RNA in R5-infected subjects. The mean decline from baseline of HIV RNA achieved 1.5 log10 or greater in all treatment groups (10, 25, 50 mg, b.i.d.) in a 14-day monotherapy trial in HIV-infected adults. A phase II trial in treatment-naïve HIV-1 infected subjects was discontinued after the rate of virologic relapse in those subjects who were administered vicriviroc increased compared to control subjects; however, further investigations suggest that the administered dosage of vicriviroc may have been too low. A new Phase II trial of treatment-naive HIV-1 patients is currently underway. A 48-week phase II trial (ACTG5211) examining the safety and efficacy of 5, 10, and 15 mg doses of vicriviroc found that patients in the 10 mg and 15 mg vicriviroc treatment groups achieved a median decrease in viral load of 1.92 and 1.44 (log10 copies/mL) and a median increase in CD4 cell count of 130 and 96 (cell/uL) from baseline, respectively. More patients in the vicriviroc groups had undetectable virus at 48 weeks (HIV-1 RNA <400/<50 copies/ml) compared to those in the placebo group (57/37 percent and 43/27 percent vs. 14/11 percent, respectively). The results from a 48-week phase II trial (VICTOR-E1) examining administration of 20 or 30 mg dosages of vicriviroc in addition to > 3-drug optimized background therapy (OBT) regimen that included a ritonavir-boosted protease inhibitor were reported in February 2008. Investigators concluded that, “‘Vicriviroc 30 or 20 mg once daily plus ritonavir-containing OBT provided sustained viral suppression in treatment-experienced subjects and increased CD4 cell counts regardless of the number of active drugs in OBT.’" As of May 2008, two phase III trials (VICTOR-E3 and VICTOR E4) in treatment-experienced patients were initiated. The late stage clinical trials by did not meet their primary efficacy endpoints and Merck has decided as of January 2010 to not pursue regulatory approval for the drug. # Concerns surrounding CCR5 antagonists Available clinical trial data suggest that a new method of combating HIV-1 may be found in CCR5 antagonists. Studies into vicriviroc are ongoing, and another CCR5 antagonist, maraviroc, is currently on the market. However, concerns have arisen regarding the use of CCR5 antagonists as anti-HIV treatments because such drugs may facilitate the emergence of resistant strains of HIV-1. Two possibilities for such resistance have been hypothesized: HIV-1 may evolve to use only CXCR4 as the coreceptor; or HIV-1 may mutate in such a way that it is still able to interact with CCR5, despite the presence of a receptor antagonist. In fact, maraviroc-resistant variants of HIV-1 have already been generated in vitro by mutating residues in the V3 loop of gp120.	Vicriviroc Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Vicriviroc, previously named SCH 417690 and SCH-D, is a pyrimidine CCR5 entry inhibitor of HIV-1. It was developed by the pharmaceutical company Schering-Plough. Merck decided to not pursue regulatory approval for use in treatment-experienced patients because the drug did not meet primary efficacy endpoints in late stage trials. Clinical trials continue in patients previously untreated for HIV. # HIV-1 background The mechanisms of a number of available anti-HIV drugs prevent either viral reverse transcriptase enzyme or protease enzyme, allowing the virus to enter the cell before these drugs take effect. However, CCR5 inhibitors such as vicriviroc, as well as other entry inhibitors of HIV-1, inhibit the initial stages of the virus life cycle.[1] ## HIV-1 entry HIV binds to and fuses with the target T-cells or macrophages with the help of gp120 and gp41, the only two proteins that are currently known to be exhibited on the surface of the viral envelope.[2] One molecule of each protein associates noncovalently with the other on the viral membrane, and three of these units aggregate to form the gp120/gp41 heterotrimer, which traps the gp41 in a conformationally metastable state.[2] Membrane fusion begins with the binding of gp120 to CD4, a glycoprotein which is expressed on the surface of the target cell.[1] Upon binding, gp120 undergoes a conformational change, which causes the formation of the coreceptor binding site on gp120.[2] All strains of HIV-1 use one of two coreceptors: CCR5 or CXCR4; coreceptor specificity will be described below. Once gp120 binds to the coreceptor, gp41 undergoes a conformational change that releases it from its once-metastable position.[2] This change causes the hydrophobic N-terminus of the gp41 protein, also known as the fusion domain, to insert into the host cell membrane and anchor the virus into place.[1][2] The insertion of gp41 into the target cell causes a subtle rearrangement in the gp41 protein that brings together two trimeric coiled coils, HR1 and HR2, to form a six-helix bundle.[2] The bundle allows the viral and cellular membranes to approximate and eventually fuse together, leading to the release of the viral genome into the cytoplasm of the target cell.[2] ## Coreceptors and tropism The two coreceptors involved in the entry of HIV-1, CCR5 and CXCR4, belong to the larger family of 7-transmembrane segment (7TM) G-protein coupled receptors.[2] HIV-1 can thus be classified according specificity for one coreceptor or the other. R5 virus, also known as M-tropic HIV-1, targets macrophages and uses CCR5 as the coreceptor. X4 virus, or T-tropic HIV-1, targets T-cells and uses CXCR4 as the coreceptor. Dual-tropic strains of HIV-1, which utilize both receptors, also exist.[1] Selectivity for one coreceptor or the other is especially dependent upon the V3 loop, a highly variable and structurally flexible region of gp120 that is composed of approximately 35 amino acids. Tropism can be predicted through the 11/25 method, which looks for basic amino acids at positions 11 and 25 in the V3 loop and suggests the presence of an X4 virus.[2] Coreceptor usage, however, can change throughout the course of infection. 90% of patients in early phases of HIV-1 infection have R5 virus. However, after five years of infection, about 50% of all patients have detectable amounts of X4 virus.[2] Causes for this switch are currently unclear. However, viral changes from CCR5 to CXCR4 coreceptor usage have been associated with a faster rate of CD4+ T-cell loss, rapid viral progression, and an increased rate of development of AIDS and death.[1][2] ## CCR5-Δ32 A focus on the CCR5 co-receptor as a potential target for anti-HIV medications began in 1996 with the discovery of CCR5-Δ32, or CCR5 delta-32, a mutational variant of the CCR5 coding gene.[1] The deletion of 32 base pairs in this gene results in nonfunctional CCR5 receptors.[1] While the frequency of this mutation within Caucasian populations is 0.0808, people of African or Asian descent do not appear to possess this allele.[1] Δ32 homozygotes, or individuals who possess two copies of the Δ32 variant, have no functional CCR5 receptors and are consequently highly resistant to HIV infection.[1] Individuals who inherit one copy of Δ32 variant and one copy of the normal CCR5 gene are CCR5 heterozygotes.[1] Δ32 heterozygotes are still susceptible to HIV-1 infection, but the progression of the disease is significantly delayed compared to those with two normal copies of the CCR5 gene. CCR5 antagonists have been developed which cause deformation in the CCR5 co-receptor, leading to the cell's failure to bind with the HIV gp120 protein.[1] # SCH-C and vicriviroc In 2001, Schering-Plough developed one of the first small molecule CCR5 antagonists, SCH-C or SCH 351125, which inhibited replication of a number of HIV-1 isolates that used CCR5 as a coreceptor for binding.[3] However, SCH-C caused a modest but dose-dependent prolongation of the corrected cardiac QT interval (QTc),[4] leading to examination of alternative compounds whose antiviral and pharmacokinetic properties exceeded those of first-generation compounds like SCH-C. Vicriviroc was discovered in high-throughput screening and structure-activity relationships (SAR) analysis.[5] When compared with SCH-C, vicriviroc consistently and more actively inhibits viral replication, binds with higher affinity to CCR5 than SCH-C, and possesses a lower affinity for the human ether a-go-go related gene transcript ion channel, which may suggest a lower risk of cardiac effects. [4] # Method of action Vicriviroc is a noncompetitive allosteric antagonist of CCR5.[6] It is orally administered and, because it is effective at nanomolar concentrations, it can be administered once daily.[1][6] Vicriviroc binds to a small hydrophobic pocket between the transmembrane helices near the extracellular surface of the CCR5 receptor.[1] Binding to this pocket induces a conformational change of the extracellular segment of CCR5 and prevents binding of gp120 to the target cell, consequently preventing the virus from entering the target cell at all. Specific binding interactions between CCR5 and vicriviroc were first described in 2008. [7] Specifically, the trifluoromethyl phenyl group of vicriviroc may interact strongly with I198 residue on the fifth transmembrane helix (TM5) of CCR5 through hydrophobic interactions. Additionally, electrostatic interactions may form between the positively charged tertiary nitrogen group of vicriviroc and the hydrophilic region provided by E238 residue on TM7 of CCR5. Other strong interactions predicted by the group include the Y108 residue on TM3 and Y251 on TM6. # Clinical trials Currently, vicriviroc is undergoing critical trials. Vicriviroc demonstrated a significant decrease of HIV RNA in R5-infected subjects. The mean decline from baseline of HIV RNA achieved 1.5 log10 or greater in all treatment groups (10, 25, 50 mg, b.i.d.) in a 14-day monotherapy trial in HIV-infected adults.[8] A phase II trial in treatment-naïve HIV-1 infected subjects was discontinued after the rate of virologic relapse in those subjects who were administered vicriviroc increased compared to control subjects; however, further investigations suggest that the administered dosage of vicriviroc may have been too low.[2] A new Phase II trial of treatment-naive HIV-1 patients is currently underway. A 48-week phase II trial (ACTG5211) examining the safety and efficacy of 5, 10, and 15 mg doses of vicriviroc found that patients in the 10 mg and 15 mg vicriviroc treatment groups achieved a median decrease in viral load of 1.92 and 1.44 (log10 copies/mL) and a median increase in CD4 cell count of 130 and 96 (cell/uL) from baseline, respectively. More patients in the vicriviroc groups had undetectable virus at 48 weeks (HIV-1 RNA <400/<50 copies/ml) compared to those in the placebo group (57/37 percent and 43/27 percent vs. 14/11 percent, respectively).[9] The results from a 48-week phase II trial (VICTOR-E1) examining administration of 20 or 30 mg dosages of vicriviroc in addition to > 3-drug optimized background therapy (OBT) regimen that included a ritonavir-boosted protease inhibitor were reported in February 2008. Investigators concluded that, “‘Vicriviroc 30 or 20 mg once daily plus ritonavir-containing OBT provided sustained viral suppression in treatment-experienced subjects and increased CD4 cell counts regardless of the number of active drugs in OBT.’"[10] As of May 2008, two phase III trials (VICTOR-E3 and VICTOR E4) in treatment-experienced patients were initiated.[11] The late stage clinical trials by did not meet their primary efficacy endpoints and Merck has decided as of January 2010 to not pursue regulatory approval for the drug.[12][13] # Concerns surrounding CCR5 antagonists Available clinical trial data suggest that a new method of combating HIV-1 may be found in CCR5 antagonists. Studies into vicriviroc are ongoing, and another CCR5 antagonist, maraviroc, is currently on the market. However, concerns have arisen regarding the use of CCR5 antagonists as anti-HIV treatments because such drugs may facilitate the emergence of resistant strains of HIV-1. Two possibilities for such resistance have been hypothesized: HIV-1 may evolve to use only CXCR4 as the coreceptor; or HIV-1 may mutate in such a way that it is still able to interact with CCR5, despite the presence of a receptor antagonist.[1] In fact, maraviroc-resistant variants of HIV-1 have already been generated in vitro by mutating residues in the V3 loop of gp120.[2]	https://www.wikidoc.org/index.php/Vicriviroc
08a0cf69c3970a9b61c7eaa66f8f07e019d4ab5e	wikidoc	Vidarabine	Vidarabine # Overview Vidarabine or 9-β-D-arabinofuranosyladenine (ara-A) is an antiviral drug which is active against herpes simplex and varicella zoster viruses. # Category Antiviral # US Brand Names VIRA-A® (DISCONTINUED) # Historical Perspective In the 1950s two nucleosides were isolated from the Caribbean sponge Tethya crypta: spongothymidine and spongouridine; which contained D-arabinose rather than D-ribose. These compounds led to the synthesis of a new generation, sugar modified nucleoside analog vidarabine, and the related compound cytarabine. In 2004 these were the only marine related compounds in clinical use. The drug was first synthesized in 1960 in the Bernard Randall Baker lab at the Stanford Research Institute (now SRI International). The drug was originally intended as an anti-cancer drug. The anti-viral activity of vidarabine was first described by M. Privat de Garilhe and J. De Rudder in 1964. It was the first nucleoside analog antiviral to be given systemically and was the first agent to be licensed for the treatment of systematic herpes virus infection in man. It was University of Alabama at Birmingham researcher and physician Dr. Richard Whitley in 1976 where the clinical effectiveness of vidarabine was first realized, and vidarabine was used in the treatment of many viral diseases. Vidarabine is an analog of adenosine with the D-ribose, replaced with D-arabinose. As you can see from figure 1.1 that it is a stereoisomer of adenosine. It has a half-life of 60 minutes, and its solubility is 0.05%, and is able to cross the blood–brain barrier (BBB) when converted to its active metabolite. # Mechanism of Action Vidarabine works by interfering with the synthesis of viral DNA. It is a nucleoside analog and therefore has to be phosphorylated to be active. This is a three step process in which vidarabine is sequentially phosphorylated by kinases to the triphosphate ara-ATP. This is the active form of vidarabine and is both an inhibitor and a substrate of viral DNA polymerase. When used as a substrate for viral DNA polymerase, ara-ATP competitively inhibits dATP leading to the formation of ‘faulty’ DNA. This is where ara-ATP is incorporated into the DNA strand replacing many of the adenosine bases. This results in the prevention of DNA synthesis, as phosphodiester bridges can longer to be built, destabilizing the strand. Vidarabine triphosphate (ara-ATP) also inhibits RNA polyadenylation; preventing polyadenylation essential for HIV-1 and other retroviruses; and S-adenosylhomocysteine hydrolase, preventing transmethylation reactions. Uniquely to vidarabine, the diphosphorylated vidarabine (ara-ADP) also has an inhibitory effect. Other nucleoside analogs need to be triphosphorlated to give any antiviral effect, but ara-ADP inhibits the enzyme ribonucleotide reductase. This prevents the reduction of nucleotide diphosphates, causing a reduction of viral replication. # Mode of Resistance Vidarabine is more toxic and less metabolically stable than many of the other current antivirals such as acyclovir and ganciclovir. Viral strains resistant to vidarabine show changes in DNA polymerase. It is prone to deamination by adenosine deaminase to inosine. This metabolite still possesses antiviral activity, but is 10-fold less potent than vidarabine. 60% of vidarabine eliminated by the kidney is excreted as 9-β-D-arabinofuranosylhypoxanthine in the urine. Some breakdown of the purine ring may also occur, forming uric acid. Structural modifications of vidarabine have proven partially effective at blocking deamination, such as replacement of the amine with a methoxy group (ara-M). This results in about a 10-fold greater selectivity against Varicella Zoster Virus than ara-A, however analog of vidarabine is inactive against other viruses due to it not being able to be phosphorylated. The use of an inhibitor of adenosine deaminase to increase the half-life of vidarabine has also been tried, and drugs such as dCF and EHNA have been used with a small amount of success. # Synthesis, Preparation, and Isolation Chemical synthesis of Vidarabine was first attained in 1960, as a part of studies on developing potential anticancer agents by B. R. Baker et al. based on unique biological properties of 1-β-D-arabinofuranosyluracil (ara-U). More specifically some of its important reactions include treatments with 2'-deoxyribonucleoside phosphorylase, methyltransferase, or nucleoside phosphorylase, affording the corresponding 5'-phosphate, giving rise to no methylation at its 5-position, or no cleavage of the glycosyl bond in contrast to 5-fluoro-2'-deoxyuridine, respectively. This earlier work gave impetus to further synthetic studies on the nucleosides with the β-D-arabinofuranosyl moiety including Vidarabine, and the isolation of Vidarabine from the fermentation culture broth of Streptomyces antibioticus. In addition to the potential anticancer properties antiviral activity of Vidarabine was also demonstrated in 1965. Particularly worthy of mention is the collaboration of efficient chemical and enzymatic reactions, i.e., transesterification from ethylene carbonate to uridine accompanied by spontaneous intramolecular elimination of carbon dioxide giving 2,2'-O-anhydro-1-β-D-arabinofuranosyluracil (anhydro-ara-U); and acid-hydrolysis of anhydro-ara-U giving ara-U; and subsequent enzymatic transglycosylation of the sugar moiety of ara-U to the 9-position of adenine with perfect retention of the β-configuration. Ultimately, in 1984, these pioneering syntheses led to the first commercial synthesis of Vidarabine in Japan under the trade name of "Arasena-A." An enzymatic approach duplicating the same concept was also later reported. # Selectivity Vidarabine is less susceptible to the development of drug resistant strains than other antivirals such as IDU, and has been used successfully in the treatment of IDU resistant viral strains. The half-life of the active triphosphate metabolite (ara-ATP) is three times longer in HSV-infected cells compared with uninfected cells, however the mechanism of selectivity is not known. # Clinical Indication Vidarabine is an antiviral, active against herpes viruses, poxviruses, rhabdoviruses, hepadnaviruses and some RNA tumour viruses. A 3% ophthalmic ointment Vira-A is used in the treatment of acute keratoconjuctivitis and recurrent superficial keratitis caused by HSV-1 and HSV-2. Vidarabine is also used to treat herpes zoster in AIDS patients, reducing lesions formation and the duration of viral shedding. Many of the previous uses of vidarabine have been superseded by acyclovir, due to the hospitalisation required for intra venous dosing, and acyclovir has a higher selectivity, lower inhibitory concentration and higher potency. Toxic side effects are rare, but have been reported with high concentrations of vidarabine, such as nausea, vomiting, leukopenia and thrombocytopenia in patients receiving high intravenous doses daily.	Vidarabine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Vidarabine or 9-β-D-arabinofuranosyladenine (ara-A) is an antiviral drug which is active against herpes simplex and varicella zoster viruses. # Category Antiviral # US Brand Names VIRA-A® (DISCONTINUED) # Historical Perspective In the 1950s two nucleosides were isolated from the Caribbean sponge Tethya crypta: spongothymidine and spongouridine; which contained D-arabinose rather than D-ribose. These compounds led to the synthesis of a new generation, sugar modified nucleoside analog vidarabine, and the related compound cytarabine. In 2004 these were the only marine related compounds in clinical use.[1] The drug was first synthesized in 1960 in the Bernard Randall Baker lab at the Stanford Research Institute (now SRI International).[2] The drug was originally intended as an anti-cancer drug.[2] The anti-viral activity of vidarabine was first described by M. Privat de Garilhe and J. De Rudder in 1964.[3] It was the first nucleoside analog antiviral to be given systemically and was the first agent to be licensed for the treatment of systematic herpes virus infection in man.[4] It was University of Alabama at Birmingham researcher and physician Dr. Richard Whitley in 1976 where the clinical effectiveness of vidarabine was first realized, and vidarabine was used in the treatment of many viral diseases.[3] Vidarabine is an analog of adenosine with the D-ribose, replaced with D-arabinose. As you can see from figure 1.1 that it is a stereoisomer of adenosine. It has a half-life of 60 minutes, and its solubility is 0.05%, and is able to cross the blood–brain barrier (BBB) when converted to its active metabolite.[5] # Mechanism of Action Vidarabine works by interfering with the synthesis of viral DNA.[6] It is a nucleoside analog and therefore has to be phosphorylated to be active. This is a three step process in which vidarabine is sequentially phosphorylated by kinases to the triphosphate ara-ATP. This is the active form of vidarabine and is both an inhibitor and a substrate of viral DNA polymerase.[7] When used as a substrate for viral DNA polymerase, ara-ATP competitively inhibits dATP leading to the formation of ‘faulty’ DNA. This is where ara-ATP is incorporated into the DNA strand replacing many of the adenosine bases. This results in the prevention of DNA synthesis, as phosphodiester bridges can longer to be built, destabilizing the strand. Vidarabine triphosphate (ara-ATP) also inhibits RNA polyadenylation; preventing polyadenylation essential for HIV-1 and other retroviruses; and S-adenosylhomocysteine hydrolase, preventing transmethylation reactions. Uniquely to vidarabine, the diphosphorylated vidarabine (ara-ADP) also has an inhibitory effect. Other nucleoside analogs need to be triphosphorlated to give any antiviral effect, but ara-ADP inhibits the enzyme ribonucleotide reductase. This prevents the reduction of nucleotide diphosphates, causing a reduction of viral replication.[7] # Mode of Resistance Vidarabine is more toxic and less metabolically stable than many of the other current antivirals such as acyclovir and ganciclovir. Viral strains resistant to vidarabine show changes in DNA polymerase. It is prone to deamination by adenosine deaminase to inosine.[8] This metabolite still possesses antiviral activity, but is 10-fold less potent than vidarabine.[9] 60% of vidarabine eliminated by the kidney is excreted as 9-β-D-arabinofuranosylhypoxanthine in the urine. Some breakdown of the purine ring may also occur, forming uric acid. Structural modifications of vidarabine have proven partially effective at blocking deamination, such as replacement of the amine with a methoxy group (ara-M). This results in about a 10-fold greater selectivity against Varicella Zoster Virus than ara-A, however analog of vidarabine is inactive against other viruses due to it not being able to be phosphorylated.[9] The use of an inhibitor of adenosine deaminase to increase the half-life of vidarabine has also been tried, and drugs such as dCF and EHNA have been used with a small amount of success. # Synthesis, Preparation, and Isolation Chemical synthesis of Vidarabine was first attained in 1960, as a part of studies on developing potential anticancer agents by B. R. Baker et al.[10] based on unique biological properties of 1-β-D-arabinofuranosyluracil (ara-U).[11] More specifically some of its important reactions include treatments with 2'-deoxyribonucleoside phosphorylase, methyltransferase, or nucleoside phosphorylase, affording the corresponding 5'-phosphate, giving rise to no methylation at its 5-position, or no cleavage of the glycosyl bond in contrast to 5-fluoro-2'-deoxyuridine,[12] respectively. This earlier work gave impetus to further synthetic studies on the nucleosides with the β-D-arabinofuranosyl moiety including Vidarabine,[13] and the isolation of Vidarabine from the fermentation culture broth of Streptomyces antibioticus.[14] In addition to the potential anticancer properties antiviral activity of Vidarabine was also demonstrated in 1965.[15] Particularly worthy of mention is the collaboration of efficient chemical and enzymatic reactions, i.e., transesterification from ethylene carbonate to uridine accompanied by spontaneous intramolecular elimination of carbon dioxide giving 2,2'-O-anhydro-1-β-D-arabinofuranosyluracil (anhydro-ara-U);[16] and acid-hydrolysis of anhydro-ara-U giving ara-U; and subsequent enzymatic transglycosylation of the sugar moiety of ara-U to the 9-position of adenine with perfect retention of the β-configuration.[17] Ultimately, in 1984, these pioneering syntheses led to the first commercial synthesis of Vidarabine in Japan under the trade name of "Arasena-A." An enzymatic approach duplicating the same concept was also later reported.[18] # Selectivity Vidarabine is less susceptible to the development of drug resistant strains than other antivirals such as IDU, and has been used successfully in the treatment of IDU resistant viral strains. The half-life of the active triphosphate metabolite (ara-ATP) is three times longer in HSV-infected cells compared with uninfected cells,[9] however the mechanism of selectivity is not known. # Clinical Indication Vidarabine is an antiviral, active against herpes viruses, poxviruses, rhabdoviruses, hepadnaviruses and some RNA tumour viruses. A 3% ophthalmic ointment Vira-A is used in the treatment of acute keratoconjuctivitis and recurrent superficial keratitis caused by HSV-1 and HSV-2.[19] Vidarabine is also used to treat herpes zoster in AIDS patients, reducing lesions formation and the duration of viral shedding. Many of the previous uses of vidarabine have been superseded by acyclovir, due to the hospitalisation required for intra venous dosing, and acyclovir has a higher selectivity, lower inhibitory concentration and higher potency. Toxic side effects are rare, but have been reported with high concentrations of vidarabine, such as nausea, vomiting, leukopenia and thrombocytopenia in patients receiving high intravenous doses daily.	https://www.wikidoc.org/index.php/Vidarabine
dbb03db60ab4e55a3e3282cf140e136ccd528ed2	wikidoc	Vilazodone	Vilazodone # 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 Vilazodone is a antidepressant, serotonine agonist that is FDA approved for the treatment of major depressive disorder (MDD). Common adverse reactions include diarrhea, nausea, vomiting, xerostomia, dizziness, insomnia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - The recommended dose for Vilazodone is 40 mg once daily. Vilazodone should be titrated, starting with an initial dose of 10 mg once daily for 7 days, followed by 20 mg once daily for an additional 7 days, and then an increase to 40 mg once daily. Vilazodone should be taken with food. Vilazodone blood concentrations (AUC) in the fasted state can be decreased by approximately 50% compared to the fed state, and may result in diminished effectiveness in some patients. - The efficacy of Vilazodone has not been systematically studied beyond 8 weeks. It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacologic therapy. Patients should be reassessed periodically to determine the need for maintenance treatment and the appropriate dose for treatment. - Reduce the Vilazodone dose to 20 mg if co-administered with a strong inhibitor of CYP3A4 (e.g., ketoconazole). During co-administration with moderate inhibitors of CYP3A4 (e.g., erythromycin), the Vilazodone dose should be reduced to 20 mg for patients with intolerable adverse events. The Vilazodone dose should be readjusted to the original level when CYP3A4 inhibitors are discontinued. - Based on clinical response, consider increasing the dose of Vilazodone up to 2-fold when concomitantly used with strong CYP3A4 inducers (e.g., carbamazepine) for greater than 14 days. The maximum daily dose should not exceed 80 mg. If CYP3A4 inducers are discontinued, reduce the Vilazodone dose to the original level in 14 days. - Discontinuation symptoms have been reported with discontinuation of serotonergic drugs such as Vilazodone Gradual dose reduction is recommended, instead of abrupt discontinuation, whenever possible. Monitor patients for these symptoms when discontinuing Vilazodone If intolerable symptoms occur following a dose decrease or upon discontinuation of treatment, consider resuming the previously prescribed dose and decreasing the dose at a more gradual rate. - At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with Vilazodone Conversely, at least 14 days should be allowed after stopping Vilazodone before starting an MAOI intended to treat psychiatric disorders. - Do not start Vilazodone in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered. - In some cases, a patient already receiving Vilazodone therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, Vilazodone should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with Vilazodone may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue. - The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with Vilazodone is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Vilazodone in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Vilazodone in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Vilazodone 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 Vilazodone in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Vilazodone in pediatric patients. # Contraindications - The use of MAOIs intended to treat psychiatric disorders with Vilazodone or within 14 days of stopping treatment with Vilazodone is contraindicated because of an increased risk of serotonin syndrome. The use of Vilazodone within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated. - Starting Vilazodone in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome. # Warnings - Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled studies of antidepressant drugs (selective serotonin reuptake inhibitors (SSRIs] and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with MDD and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. - The pooled analyses of placebo-controlled studies in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term studies of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled studies in adults with MDD or other psychiatric disorders included a total of 295 short-term studies (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. - No suicides occurred in any of the pediatric studies. There were suicides in the adult studies, but the number was not sufficient to reach any conclusion about drug effect on suicide. - It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance studies in adults with depression that the use of antidepressants can delay the recurrence of depression. - All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. - The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. - Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. - If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms - Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Vilazodone should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. - A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled studies) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Vilazodone is not approved for use in treating bipolar depression. - The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including Vilazodone alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Symptoms of serotonin syndrome were noted in 0.1% of MDD patients treated with Vilazodone in premarketing clinical trials. - Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome. - The concomitant use of Vilazodone with MAOIs intended to treat psychiatric disorders is contraindicated. Vilazodone should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking Vilazodone Vilazodone should be discontinued before initiating treatment with the MAOI and Dosage and Administration. - If concomitant use of Vilazodone with other serotonergic drugs including, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan and St. John's Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. - Treatment with Vilazodone and any concomitant serotonergic agents, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. - Vilazodone has not been systematically evaluated in patients with a seizure disorder. Patients with a history of seizures were excluded from clinical studies. Like other antidepressants, Vilazodone should be prescribed with caution in patients with a seizure disorder. - The use of drugs that interfere with serotonin reuptake inhibition, including Vilazodone, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages. - Patients should be cautioned about the risk of bleeding associated with the concomitant use of Vilazodone and NSAIDs, aspirin, or other drugs that affect coagulation or bleeding. - Symptoms of mania/hypomania were reported in 0.1% of patients treated with Vilazodone in clinical studies. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorder who were treated with other antidepressants. As with all antidepressants, use Vilazodone cautiously in patients with a history or family history of bipolar disorder, mania, or hypomania. - There have been reports of adverse events occurring upon discontinuation of serotonergic antidepressants, particularly when discontinuation is abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. - Monitor patients for these symptoms when discontinuing Vilazodone Reduce the dose gradually whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, consider resuming the previously prescribed dose. Subsequently, the dose may be decreased, but at a more gradual rate. - Although no cases of hyponatremia resulting from Vilazodone treatment were reported in the clinical studies, hyponatremia has occurred as a result of treatment with SSRIs and SNRIs. In many cases, hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs. Also, patients taking diuretics or who are otherwise volume depleted can be at greater risk. Discontinuation of Vilazodone in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which can lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. # Adverse Reactions ## Clinical Trials Experience The most commonly observed adverse reactions in Vilazodone-treated MDD patients in placebo-controlled studies (incidence ≥ 5% and at least twice the rate of placebo) were: diarrhea, nausea, vomiting, and insomnia. - The safety of Vilazodone was evaluated in 2,177 patients (18-70 years of age) diagnosed with MDD who participated in clinical studies, representing 552 patient-years of exposure. In an open-label 52 week study at 40 mg daily, 599 patients were exposed to Vilazodone for a total of 348 patient-years. The information presented in these sections was derived from studies of Vilazodone 40 mg daily in major depressive disorder including: 1) 2 placebo-controlled 8-week studies in 861 patients, including 436 receiving vilazodone; and 2) an open-label 52-week study of 599 patients. These studies included a titration period of 10 mg daily for 7 days followed by 20 mg daily for 7 days. In these clinical trials, Vilazodone was administered with food. Because clinical trials are conducted under widely varying conditions and varying lengths of time, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect rates observed in practice. - In the placebo-controlled studies of MDD there was no single adverse reaction leading to discontinuation in > 1% of the patients. Overall, 7.1% of the patients who received Vilazodone discontinued treatment due to an adverse reaction, compared with 3.2% of placebo-treated patients in these studies. - Table 2 shows the incidence of common adverse reactions that occurred in ≥ 2% of Vilazodone-treated MDD patients (and greater than in placebo-treated patients) in the placebo-controlled studies. - Vilazodone has not been associated with any clinically important changes in laboratory test parameters in serum chemistry (including liver function tests), hematology and urinalysis, as measured in placebo-controlled studies. These studies include analysis of mean change from baseline and the proportion of patients meeting criteria for potentially clinically significant changes from baseline. Results from a 52-week open-label study were consistent with the findings from the placebo-controlled studies. - Vilazodone has not been associated with any clinically significant effect on ECG parameters, including QT, QTc, PR interval and QRS interval, or with any arrhythmogenic potential. ECGs were evaluated in a thorough QTc study at doses up to 80 mg daily with food and in the placebo-controlled studies. - Vilazodone has not been associated with any clinically significant effect on vital signs, including systolic and diastolic blood pressure and heart rate, as measured in placebo-controlled studies. These studies included analyses of (1) change from baseline, and (2) the proportion of patients meeting criteria for potentially clinically significant changes from baseline. Results from a 52-week open-label study were consistent with the findings from the placebo-controlled studies. - Vilazodone had no effect on body weight as measured by the mean change from baseline in the 8-week, placebo-controlled studies. The mean changes in weight were +0.16 kg in the Vilazodone group and +0.18 kg in the placebo group. The proportions of patients with a weight gain ≥ 7% were 0.9% in the Vilazodone group and 1.2% in the placebo group. The proportions of patients with a weight decrease ≥ 7% were 1.4% in the Vilazodone group and 1.4% in the placebo group. The following listing does not include reactions: 1) already listed in previous tables or elsewhere in labeling 2) for which a drug cause was remote 3) which were so general as to be uninformative 4) which were not considered to have significant clinical implications 5) which occurred at a rate equal to or less than placebo Reactions are categorized by body system according to the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients: - Infrequent: Ventricular extrasystoles - Frequent: vision blurred, dry eye. - Infrequent: cataracts. - Infrequent: feeling abnormal - Frequent: decreased appetite - Frequent: Sedation, migraine - Infrequent: Dysgeusia - Infrequent: Panic attack, mania Infrequent: pollakiuria - Frequent: hyperhidrosis, night sweats ## Postmarketing Experience The following adverse reactions have been identified during postapproval use of Vilazodone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure. These events include: - Irritability - Hallucinations - Suicide attempt - Suicidal ideation # Drug Interactions - The risk of using Vilazodone in combination with other CNS-active drugs has not been systematically evaluated. Consequently, use caution when Vilazodone is prescribed in combination with other CNS-active drugs. - Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of case-control and cohort design have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. These studies have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are co-administered with warfarin. Patients receiving warfarin therapy should be carefully monitored when Vilazodone is initiated or discontinued. - Metabolism by CYP3A4 is a major elimination pathway for vilazodone. Concomitant use of Vilazodone and strong inhibitors of CYP3A4 (e.g., ketoconazole) can increase vilazodone plasma concentrations by approximately 50%. The Vilazodone dose should be reduced to 20 mg if co-administered with a strong inhibitor of CYP3A4. During co-administration with moderate inhibitors of CYP3A4 (e.g., erythromycin), the Vilazodone dose should be reduced to 20 mg for patients with intolerable adverse events. No dose adjustment is recommended when Vilazodone is co-administered with mild inhibitors of CYP3A4 (e.g., cimetidine). - Based on clinical response, consider increasing the dose of Vilazodone up to 2-fold when concomitantly used with strong CYP3A4 inducers (e.g., carbamazepine) for greater than 14 days. The maximum daily dose should not exceed 80 mg. Concomitant use of Vilazodone with strong inducers of CYP3A4 (e.g., carbamazepine) can decrease vilazodone systemic exposure by approximately 45%. If CYP3A4 inducers are discontinued, reduce the Vilazodone dose to the original level in 14 days. - Concomitant administration of Vilazodone with inhibitors of CYP2C19 and CYP2D6 is not expected to alter plasma concentrations of vilazodone. These isoforms are minor elimination pathways in the metabolism of vilazodone. In vitro studies have shown that CYP1A2, CYP2A6, CYP2C9 and CYP2E1 have minimal contribution to the metabolism of vilazodone. - Drugs metabolized by CYP1A2, CYP2C9, CYP2D6, CYP3A4 or CYP2C19. Co-administration of Vilazodone with substrates for CYP1A2, CYP2C9, CYP3A4, or CYP2D6 is unlikely to result in clinically significant changes in the concentrations of the CYP substrates. A study in healthy subjects found that Vilazodone (20 mg/day for 8-10 days) had no effect on the pharmacokinetics of caffeine, flurbiprofen, nifedipine or debrisoquine, probes for CYP1A2, CYP2C9, CYP3A4, and CYP2D6, respectively. Vilazodone co-administration with mephenytoin to healthy subjects resulted in a small (11%) increase in mephenytoin biotransformation, suggestive of a minor induction of CYP2C19. In vitro studies have shown that Vilazodone is a moderate inhibitor of CYP2C19 and CYP2D6. - Co-administration of Vilazodone with a CYP2C8 substrate may lead to an increase in concentration of the other drug. In vitro studies suggest that Vilazodone may inhibit the biotransformation of substrates of CYP2C8. The effect of Vilazodone on CYP2C8 activity has not been tested in vivo. - Vilazodone did not induce CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 or CYP3A5 in an in vitro study in cultured human hepatocytes. Chronic administration of vilazodone is unlikely to induce the metabolism of drugs metabolized by these major CYP isoforms. - The interaction between vilazodone and other highly protein-bound drugs has not been evaluated. Because vilazodone is highly bound to plasma protein, administration of Vilazodone to a patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug. - There are postmarketing reports of serotonin syndrome with concomitant use of a serotonergic antidepressant and a triptan. If concomitant treatment with Vilazodone and a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. - As with other psychotropic medications, the use of alcohol by patients taking Vilazodone is not recommended, because of the potential for pharmacodynamic interactions. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Vilazodone caused some developmental toxicity in rats, but was not teratogenic in rats or rabbits. There are no adequate and well-controlled studies of Vilazodone in pregnant women. When treating pregnant women with Vilazodone, carefully consider whether the potential benefits outweigh the potential risks of treatment. - No teratogenic effects were observed when vilazodone was given to pregnant rats or rabbits during the period of organogenesis at oral doses up to 200 and 36 mg/kg/day, respectively. These doses are 48 and 17 times, in rats and rabbits, respectively, the maximum recommended human dose (MRHD) of 40 mg on a mg/m2 basis. Fetal body weight gain was reduced, and skeletal ossification was delayed in both rats and rabbits at these doses; these effects were not observed at doses up to 10 times the MRHD in rats or 4 times the MRHD in rabbits. - When vilazodone was administered to pregnant rats at an oral dose of 30 times the MRHD during the period of organogenesis and throughout pregnancy and lactation, the number of live born pups was decreased. There was an increase in early postnatal pup mortality, and among surviving pups there was decreased body weight, delayed maturation, and decreased fertility in adulthood. There was some maternal toxicity at this dose. These effects were not seen at 6 times the MRHD. - Neonates exposed to Vilazodone and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome. - Infants exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1-2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Several recent epidemiologic studies suggest a positive statistical association between SSRI use (including Vilazodone) in pregnancy and PPHN. Other studies do not show a significant statistical association. - Physicians should also note the results of a prospective longitudinal study of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy. - When treating a pregnant woman with Vilazodone the physician should carefully consider both the potential risks of taking an SSRI, along with the established benefits of treating depression with an antidepressant. This decision can only be made on a case by case basis. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Vilazodone in women who are pregnant. ### Labor and Delivery - The effect of Vilazodone on labor and delivery in humans is unknown. Vilazodone should be used during labor and delivery only if the potential benefit outweighs the potential risk. ### Nursing Mothers - Vilazodone is excreted into the milk of lactating rats. The effect of Vilazodone on lactation and nursing in humans is unknown. Breast feeding in women treated with Vilazodone should be considered only if the potential benefit outweighs the potential risk to the child. ### Pediatric Use - Clinical studies on the use of Vilazodone in pediatric patients have not been conducted; therefore, the safety and effectiveness of Vilazodone in the pediatric population have not been established. Vilazodone is not approved for use in pediatric patients. ### Geriatic Use - No dose adjustment is recommended on the basis of age. Results from a single-dose (20 mg) pharmacokinetic study in elderly (> 65 years-old) vs. young (24-55 years-old) subjects demonstrated that the pharmacokinetics were generally similar between the two age groups. Of the 2177 patients in clinical studies with Vilazodone 37 (1.7%) were 65 years of age or older, and 272 (12.5%) were 55 to 64 years of age. Greater sensitivity of some older individuals cannot be ruled out. - Serotonergic antidepressants have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event. ### Gender - After adjustment for body weight, the systemic exposures between males and females are similar. ### Race There is no FDA guidance on the use of Vilazodone with respect to specific racial populations. ### Renal Impairment - In mild, moderate, and severe renal impairment, no dose adjustment is necessary ### Hepatic Impairment - Vilazodone is eliminated primarily by hepatic metabolism. In mild, moderate, and severe hepatic impairment, no dose adjustment is necessary. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Vilazodone in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Vilazodone in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Vilazodone Administration in the drug label. ### Monitoring There is limited information regarding Vilazodone Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Vilazodone and IV administrations. # Overdosage - There is limited clinical experience regarding human overdosage with Vilazodone Four patients and 1 patient's child experienced an overdose of Vilazodone all recovered. The adverse reactions associated with overdose of Vilazodone at doses of 200-280 mg as observed in clinical trials included serotonin syndrome, lethargy, restlessness, hallucinations, and disorientation. - Consult a Certified Poison Control Center for up-to-date guidance and advice. Telephone numbers for certified poison control centers are listed in the Physicians' Desk Reference® (PDR). No specific antidotes for vilazodone are known. In case of an overdose, provide supportive care, including close medical supervision and monitoring. Treatment should consist of those general measures employed in the management of overdosage with any drug. Consider the possibility of multiple drug overdose. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be considered. Removal of vilazodone by dialysis has not been studied; however, the high volume of distribution of vilazodone suggests that dialysis will not be effective in reducing vilazodone plasma concentrations. # Pharmacology ## Mechanism of Action - The mechanism of the antidepressant effect of vilazodone is not fully understood but is thought to be related to its enhancement of serotonergic activity in the CNS through selective inhibition of serotonin reuptake. Vilazodone is also a partial agonist at serotonergic 5-HT1A receptors; however, the net result of this action on serotonergic transmission and its role in vilazodone's antidepressant effect are unknown. ## Structure - Vilazodone HCl is 2-benzofurancarboxamide, 5-4-4-(5-cyano-1H-indol-3-yl)butyl-1-piperazinyl-, hydrochloride (1:1). Its molecular weight is 477.99. The structural formula is: ## Pharmacodynamics - Vilazodone binds with high affinity to the serotonin reuptake site (Ki= 0.1 nM), but not to the norepinephrine (Ki=56 nM) or dopamine (Ki=37 nM) reuptake sites. Vilazodone potently and selectively inhibits reuptake of serotonin (IC50= 1.6 nM). Vilazodone also binds selectively with high affinity to 5-HT1A receptors (IC50=2.1 nM) and is a 5-HT1A receptor partial agonist. - Thorough QT Study: Treatment with Vilazodone did not prolong the QTc interval. The effect of vilazodone (20, 40, 60, and 80 mg) on the QTc interval was evaluated in a randomized, placebo-, and active-controlled (moxifloxacin 400 mg), parallel-group, thorough QTc study in 157 healthy subjects. The study demonstrated an ability to detect small effects. The upper bound of the 90% confidence interval for the largest placebo-adjusted, baseline-corrected QTc interval was below 10 msec, based on the individual correction method (QTcI). This is below the threshold for clinical concern. However, it is unknown whether 80 mg is adequate to represent a high clinical exposure condition. ## Pharmacokinetics - Vilazodone activity is due primarily to the parent drug. The pharmacokinetics of vilazodone (5 mg – 80 mg) are dose-proportional. Accumulation of vilazodone is predictable from single dose data, does not vary with dose, and steady-state is achieved in about 3 days. Elimination of vilazodone is primarily by hepatic metabolism with a terminal half-life of approximately 25 hours. At steady-state, after daily dosing of Vilazodone 40 mg under fed conditions, the mean Cmax value is 156 ng/mL, and the mean AUC (0-24 hours) value is 1645 ngh/mL. - Vilazodone concentrations peak at a median of 4-5 hours (Tmax) after administration and decline with a terminal half-life of approximately 25 hours. The absolute bioavailability of vilazodone is 72% with food. Administration of Vilazodone with food (high fat or light meal) increases oral bioavailability (Cmax increased by approximately 147-160%, and AUC increased by approximately 64-85%). - Co-administration of Vilazodone with ethanol or with a proton pump inhibitor (pantoprazole) did not affect the rate or extent of vilazodone absorption. In addition, neither the Tmax nor terminal elimination rate of vilazodone was altered by co-administration with either pantoprazole or ethanol. Absorption is decreased by approximately 25% if vomiting occurs within 7 hours of ingestion; no replacement dose is needed. - Vilazodone is widely distributed and approximately 96-99% protein-bound - Vilazodone is extensively metabolized through CYP and non-CYP pathways (possibly by carboxylesterase), with only 1% of the dose recovered in the urine and 2% of the dose recovered in the feces as unchanged vilazodone. CYP3A4 is primarily responsible for its metabolism among CYP pathways, with minor contributions from CYP2C19 and CYP2D6. In vitro studies with human microsomes and human hepatocytes indicate that vilazodone is unlikely to inhibit or induce the metabolism of other CYP (except for CYP2C8) substrates; and an in vivo study with probe substrates for CYP2C19, CYP2D6 and CYP3A4 showed vilazodone did not alter the pharmacokinetics of the probe substrates. However, an in vivo study with probe substrate for CYP2C19 demonstrated a minor induction of CYP2C19. Strong inhibitors of CYP3A4 (e.g., ketoconazole) can reduce the metabolism of vilazodone in vivo and increase exposure. Conversely, strong inducers of CYP3A4 (e.g., carbamazepine) can decrease vilazodone exposure. - The presence of mild or moderate renal impairment, or mild, moderate, or severe hepatic impairment did not affect the apparent clearance of vilazodone. ## Nonclinical Toxicology There is limited information regarding Vilazodone Nonclinical Toxicology in the drug label. # Clinical Studies - The efficacy of Vilazodone as a treatment for major depressive disorder was established in two 8-week, multicenter, randomized, double-blind, placebo-controlled studies in adult (18-70 years of age) outpatients who met the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria for MDD. In these studies, patients were titrated over 2 weeks to a dose of 40 mg of Vilazodone with food (n=436) or placebo (n = 433) once daily. Vilazodone was superior to placebo in the improvement of depressive symptoms as measured by the mean change from baseline to Week 8 in the Montgomery-Asberg Depression Rating Scale (MADRS) total score. Examination of population subgroups based on age (there were few patients over 65), gender, and race did not reveal any clear evidence of differential responsiveness. # How Supplied - 10 mg, pink, oval tablet, debossed with 10 on one side 0456-1110-30: 30-count bottles - 0456-1110-30: 30-count bottles - 20 mg, orange, oval tablet, debossed with 20 on one side 0456-1120-30: 30-count bottles - 0456-1120-30: 30-count bottles - 40 mg, blue, oval tablet, debossed with 40 on one side 0456-1140-30: 30-count bottles - 0456-1140-30: 30-count bottles - Patient Starter Kit 0456-1100-31: blister card containing 30 tablets: 10 mg, pink, oval, debossed with 10 on one side: 7 tablets 20 mg, orange, oval, debossed with 20 on one side: 7 tablets 40 mg, blue, oval, debossed with 40 on one side: 16 tablets - 0456-1100-31: blister card containing 30 tablets: 10 mg, pink, oval, debossed with 10 on one side: 7 tablets 20 mg, orange, oval, debossed with 20 on one side: 7 tablets 40 mg, blue, oval, debossed with 40 on one side: 16 tablets - 10 mg, pink, oval, debossed with 10 on one side: 7 tablets - 20 mg, orange, oval, debossed with 20 on one side: 7 tablets - 40 mg, blue, oval, debossed with 40 on one side: 16 tablets ## Storage - Stored at 25°C (77°F) with excursions permitted to 15°C - 30°C (59°F - 86°F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Vilazodone Patient Counseling Information in the drug label. # Precautions with Alcohol - Alcohol-Vilazodone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Viibryd - Viibryd Titration Pack # Look-Alike Drug Names There is limited information regarding Vilazodone Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Vilazodone Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [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 Vilazodone is a antidepressant, serotonine agonist that is FDA approved for the treatment of major depressive disorder (MDD). Common adverse reactions include diarrhea, nausea, vomiting, xerostomia, dizziness, insomnia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - The recommended dose for Vilazodone is 40 mg once daily. Vilazodone should be titrated, starting with an initial dose of 10 mg once daily for 7 days, followed by 20 mg once daily for an additional 7 days, and then an increase to 40 mg once daily. Vilazodone should be taken with food. Vilazodone blood concentrations (AUC) in the fasted state can be decreased by approximately 50% compared to the fed state, and may result in diminished effectiveness in some patients. - The efficacy of Vilazodone has not been systematically studied beyond 8 weeks. It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacologic therapy. Patients should be reassessed periodically to determine the need for maintenance treatment and the appropriate dose for treatment. - Reduce the Vilazodone dose to 20 mg if co-administered with a strong inhibitor of CYP3A4 (e.g., ketoconazole). During co-administration with moderate inhibitors of CYP3A4 (e.g., erythromycin), the Vilazodone dose should be reduced to 20 mg for patients with intolerable adverse events. The Vilazodone dose should be readjusted to the original level when CYP3A4 inhibitors are discontinued. - Based on clinical response, consider increasing the dose of Vilazodone up to 2-fold when concomitantly used with strong CYP3A4 inducers (e.g., carbamazepine) for greater than 14 days. The maximum daily dose should not exceed 80 mg. If CYP3A4 inducers are discontinued, reduce the Vilazodone dose to the original level in 14 days. - Discontinuation symptoms have been reported with discontinuation of serotonergic drugs such as Vilazodone Gradual dose reduction is recommended, instead of abrupt discontinuation, whenever possible. Monitor patients for these symptoms when discontinuing Vilazodone If intolerable symptoms occur following a dose decrease or upon discontinuation of treatment, consider resuming the previously prescribed dose and decreasing the dose at a more gradual rate. - At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with Vilazodone Conversely, at least 14 days should be allowed after stopping Vilazodone before starting an MAOI intended to treat psychiatric disorders. - Do not start Vilazodone in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered. - In some cases, a patient already receiving Vilazodone therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, Vilazodone should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with Vilazodone may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue. - The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with Vilazodone is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Vilazodone in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Vilazodone in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Vilazodone 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 Vilazodone in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Vilazodone in pediatric patients. # Contraindications - The use of MAOIs intended to treat psychiatric disorders with Vilazodone or within 14 days of stopping treatment with Vilazodone is contraindicated because of an increased risk of serotonin syndrome. The use of Vilazodone within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated. - Starting Vilazodone in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome. # Warnings - Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled studies of antidepressant drugs (selective serotonin reuptake inhibitors (SSRIs] and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with MDD and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. - The pooled analyses of placebo-controlled studies in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term studies of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled studies in adults with MDD or other psychiatric disorders included a total of 295 short-term studies (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. - No suicides occurred in any of the pediatric studies. There were suicides in the adult studies, but the number was not sufficient to reach any conclusion about drug effect on suicide. - It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance studies in adults with depression that the use of antidepressants can delay the recurrence of depression. - All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. - The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. - Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. - If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms - Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Vilazodone should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. - A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled studies) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Vilazodone is not approved for use in treating bipolar depression. - The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including Vilazodone alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Symptoms of serotonin syndrome were noted in 0.1% of MDD patients treated with Vilazodone in premarketing clinical trials. - Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome. - The concomitant use of Vilazodone with MAOIs intended to treat psychiatric disorders is contraindicated. Vilazodone should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking Vilazodone Vilazodone should be discontinued before initiating treatment with the MAOI and Dosage and Administration. - If concomitant use of Vilazodone with other serotonergic drugs including, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan and St. John's Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. - Treatment with Vilazodone and any concomitant serotonergic agents, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. - Vilazodone has not been systematically evaluated in patients with a seizure disorder. Patients with a history of seizures were excluded from clinical studies. Like other antidepressants, Vilazodone should be prescribed with caution in patients with a seizure disorder. - The use of drugs that interfere with serotonin reuptake inhibition, including Vilazodone, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages. - Patients should be cautioned about the risk of bleeding associated with the concomitant use of Vilazodone and NSAIDs, aspirin, or other drugs that affect coagulation or bleeding. - Symptoms of mania/hypomania were reported in 0.1% of patients treated with Vilazodone in clinical studies. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorder who were treated with other antidepressants. As with all antidepressants, use Vilazodone cautiously in patients with a history or family history of bipolar disorder, mania, or hypomania. - There have been reports of adverse events occurring upon discontinuation of serotonergic antidepressants, particularly when discontinuation is abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. - Monitor patients for these symptoms when discontinuing Vilazodone Reduce the dose gradually whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, consider resuming the previously prescribed dose. Subsequently, the dose may be decreased, but at a more gradual rate. - Although no cases of hyponatremia resulting from Vilazodone treatment were reported in the clinical studies, hyponatremia has occurred as a result of treatment with SSRIs and SNRIs. In many cases, hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs. Also, patients taking diuretics or who are otherwise volume depleted can be at greater risk. Discontinuation of Vilazodone in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which can lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. # Adverse Reactions ## Clinical Trials Experience The most commonly observed adverse reactions in Vilazodone-treated MDD patients in placebo-controlled studies (incidence ≥ 5% and at least twice the rate of placebo) were: diarrhea, nausea, vomiting, and insomnia. - The safety of Vilazodone was evaluated in 2,177 patients (18-70 years of age) diagnosed with MDD who participated in clinical studies, representing 552 patient-years of exposure. In an open-label 52 week study at 40 mg daily, 599 patients were exposed to Vilazodone for a total of 348 patient-years. The information presented in these sections was derived from studies of Vilazodone 40 mg daily in major depressive disorder including: 1) 2 placebo-controlled 8-week studies in 861 patients, including 436 receiving vilazodone; and 2) an open-label 52-week study of 599 patients. These studies included a titration period of 10 mg daily for 7 days followed by 20 mg daily for 7 days. In these clinical trials, Vilazodone was administered with food. Because clinical trials are conducted under widely varying conditions and varying lengths of time, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect rates observed in practice. - In the placebo-controlled studies of MDD there was no single adverse reaction leading to discontinuation in > 1% of the patients. Overall, 7.1% of the patients who received Vilazodone discontinued treatment due to an adverse reaction, compared with 3.2% of placebo-treated patients in these studies. - Table 2 shows the incidence of common adverse reactions that occurred in ≥ 2% of Vilazodone-treated MDD patients (and greater than in placebo-treated patients) in the placebo-controlled studies. - Vilazodone has not been associated with any clinically important changes in laboratory test parameters in serum chemistry (including liver function tests), hematology and urinalysis, as measured in placebo-controlled studies. These studies include analysis of mean change from baseline and the proportion of patients meeting criteria for potentially clinically significant changes from baseline. Results from a 52-week open-label study were consistent with the findings from the placebo-controlled studies. - Vilazodone has not been associated with any clinically significant effect on ECG parameters, including QT, QTc, PR interval and QRS interval, or with any arrhythmogenic potential. ECGs were evaluated in a thorough QTc study at doses up to 80 mg daily with food and in the placebo-controlled studies. - Vilazodone has not been associated with any clinically significant effect on vital signs, including systolic and diastolic blood pressure and heart rate, as measured in placebo-controlled studies. These studies included analyses of (1) change from baseline, and (2) the proportion of patients meeting criteria for potentially clinically significant changes from baseline. Results from a 52-week open-label study were consistent with the findings from the placebo-controlled studies. - Vilazodone had no effect on body weight as measured by the mean change from baseline in the 8-week, placebo-controlled studies. The mean changes in weight were +0.16 kg in the Vilazodone group and +0.18 kg in the placebo group. The proportions of patients with a weight gain ≥ 7% were 0.9% in the Vilazodone group and 1.2% in the placebo group. The proportions of patients with a weight decrease ≥ 7% were 1.4% in the Vilazodone group and 1.4% in the placebo group. The following listing does not include reactions: 1) already listed in previous tables or elsewhere in labeling 2) for which a drug cause was remote 3) which were so general as to be uninformative 4) which were not considered to have significant clinical implications 5) which occurred at a rate equal to or less than placebo Reactions are categorized by body system according to the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients: - Infrequent: Ventricular extrasystoles - Frequent: vision blurred, dry eye. - Infrequent: cataracts. - Infrequent: feeling abnormal - Frequent: decreased appetite - Frequent: Sedation, migraine - Infrequent: Dysgeusia - Infrequent: Panic attack, mania Infrequent: pollakiuria - Frequent: hyperhidrosis, night sweats ## Postmarketing Experience The following adverse reactions have been identified during postapproval use of Vilazodone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure. These events include: - Irritability - Hallucinations - Suicide attempt - Suicidal ideation # Drug Interactions - The risk of using Vilazodone in combination with other CNS-active drugs has not been systematically evaluated. Consequently, use caution when Vilazodone is prescribed in combination with other CNS-active drugs. - Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of case-control and cohort design have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. These studies have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are co-administered with warfarin. Patients receiving warfarin therapy should be carefully monitored when Vilazodone is initiated or discontinued. - Metabolism by CYP3A4 is a major elimination pathway for vilazodone. Concomitant use of Vilazodone and strong inhibitors of CYP3A4 (e.g., ketoconazole) can increase vilazodone plasma concentrations by approximately 50%. The Vilazodone dose should be reduced to 20 mg if co-administered with a strong inhibitor of CYP3A4. During co-administration with moderate inhibitors of CYP3A4 (e.g., erythromycin), the Vilazodone dose should be reduced to 20 mg for patients with intolerable adverse events. No dose adjustment is recommended when Vilazodone is co-administered with mild inhibitors of CYP3A4 (e.g., cimetidine). - Based on clinical response, consider increasing the dose of Vilazodone up to 2-fold when concomitantly used with strong CYP3A4 inducers (e.g., carbamazepine) for greater than 14 days. The maximum daily dose should not exceed 80 mg. Concomitant use of Vilazodone with strong inducers of CYP3A4 (e.g., carbamazepine) can decrease vilazodone systemic exposure by approximately 45%. If CYP3A4 inducers are discontinued, reduce the Vilazodone dose to the original level in 14 days. - Concomitant administration of Vilazodone with inhibitors of CYP2C19 and CYP2D6 is not expected to alter plasma concentrations of vilazodone. These isoforms are minor elimination pathways in the metabolism of vilazodone. In vitro studies have shown that CYP1A2, CYP2A6, CYP2C9 and CYP2E1 have minimal contribution to the metabolism of vilazodone. - Drugs metabolized by CYP1A2, CYP2C9, CYP2D6, CYP3A4 or CYP2C19. Co-administration of Vilazodone with substrates for CYP1A2, CYP2C9, CYP3A4, or CYP2D6 is unlikely to result in clinically significant changes in the concentrations of the CYP substrates. A study in healthy subjects found that Vilazodone (20 mg/day for 8-10 days) had no effect on the pharmacokinetics of caffeine, flurbiprofen, nifedipine or debrisoquine, probes for CYP1A2, CYP2C9, CYP3A4, and CYP2D6, respectively. Vilazodone co-administration with mephenytoin to healthy subjects resulted in a small (11%) increase in mephenytoin biotransformation, suggestive of a minor induction of CYP2C19. In vitro studies have shown that Vilazodone is a moderate inhibitor of CYP2C19 and CYP2D6. - Co-administration of Vilazodone with a CYP2C8 substrate may lead to an increase in concentration of the other drug. In vitro studies suggest that Vilazodone may inhibit the biotransformation of substrates of CYP2C8. The effect of Vilazodone on CYP2C8 activity has not been tested in vivo. - Vilazodone did not induce CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 or CYP3A5 in an in vitro study in cultured human hepatocytes. Chronic administration of vilazodone is unlikely to induce the metabolism of drugs metabolized by these major CYP isoforms. - The interaction between vilazodone and other highly protein-bound drugs has not been evaluated. Because vilazodone is highly bound to plasma protein, administration of Vilazodone to a patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug. - There are postmarketing reports of serotonin syndrome with concomitant use of a serotonergic antidepressant and a triptan. If concomitant treatment with Vilazodone and a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. - As with other psychotropic medications, the use of alcohol by patients taking Vilazodone is not recommended, because of the potential for pharmacodynamic interactions. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Vilazodone caused some developmental toxicity in rats, but was not teratogenic in rats or rabbits. There are no adequate and well-controlled studies of Vilazodone in pregnant women. When treating pregnant women with Vilazodone, carefully consider whether the potential benefits outweigh the potential risks of treatment. - No teratogenic effects were observed when vilazodone was given to pregnant rats or rabbits during the period of organogenesis at oral doses up to 200 and 36 mg/kg/day, respectively. These doses are 48 and 17 times, in rats and rabbits, respectively, the maximum recommended human dose (MRHD) of 40 mg on a mg/m2 basis. Fetal body weight gain was reduced, and skeletal ossification was delayed in both rats and rabbits at these doses; these effects were not observed at doses up to 10 times the MRHD in rats or 4 times the MRHD in rabbits. - When vilazodone was administered to pregnant rats at an oral dose of 30 times the MRHD during the period of organogenesis and throughout pregnancy and lactation, the number of live born pups was decreased. There was an increase in early postnatal pup mortality, and among surviving pups there was decreased body weight, delayed maturation, and decreased fertility in adulthood. There was some maternal toxicity at this dose. These effects were not seen at 6 times the MRHD. - Neonates exposed to Vilazodone and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome. - Infants exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1-2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Several recent epidemiologic studies suggest a positive statistical association between SSRI use (including Vilazodone) in pregnancy and PPHN. Other studies do not show a significant statistical association. - Physicians should also note the results of a prospective longitudinal study of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy. - When treating a pregnant woman with Vilazodone the physician should carefully consider both the potential risks of taking an SSRI, along with the established benefits of treating depression with an antidepressant. This decision can only be made on a case by case basis. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Vilazodone in women who are pregnant. ### Labor and Delivery - The effect of Vilazodone on labor and delivery in humans is unknown. Vilazodone should be used during labor and delivery only if the potential benefit outweighs the potential risk. ### Nursing Mothers - Vilazodone is excreted into the milk of lactating rats. The effect of Vilazodone on lactation and nursing in humans is unknown. Breast feeding in women treated with Vilazodone should be considered only if the potential benefit outweighs the potential risk to the child. ### Pediatric Use - Clinical studies on the use of Vilazodone in pediatric patients have not been conducted; therefore, the safety and effectiveness of Vilazodone in the pediatric population have not been established. Vilazodone is not approved for use in pediatric patients. ### Geriatic Use - No dose adjustment is recommended on the basis of age. Results from a single-dose (20 mg) pharmacokinetic study in elderly (> 65 years-old) vs. young (24-55 years-old) subjects demonstrated that the pharmacokinetics were generally similar between the two age groups. Of the 2177 patients in clinical studies with Vilazodone 37 (1.7%) were 65 years of age or older, and 272 (12.5%) were 55 to 64 years of age. Greater sensitivity of some older individuals cannot be ruled out. - Serotonergic antidepressants have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event. ### Gender - After adjustment for body weight, the systemic exposures between males and females are similar. ### Race There is no FDA guidance on the use of Vilazodone with respect to specific racial populations. ### Renal Impairment - In mild, moderate, and severe renal impairment, no dose adjustment is necessary ### Hepatic Impairment - Vilazodone is eliminated primarily by hepatic metabolism. In mild, moderate, and severe hepatic impairment, no dose adjustment is necessary. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Vilazodone in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Vilazodone in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Vilazodone Administration in the drug label. ### Monitoring There is limited information regarding Vilazodone Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Vilazodone and IV administrations. # Overdosage - There is limited clinical experience regarding human overdosage with Vilazodone Four patients and 1 patient's child experienced an overdose of Vilazodone all recovered. The adverse reactions associated with overdose of Vilazodone at doses of 200-280 mg as observed in clinical trials included serotonin syndrome, lethargy, restlessness, hallucinations, and disorientation. - Consult a Certified Poison Control Center for up-to-date guidance and advice. Telephone numbers for certified poison control centers are listed in the Physicians' Desk Reference® (PDR). No specific antidotes for vilazodone are known. In case of an overdose, provide supportive care, including close medical supervision and monitoring. Treatment should consist of those general measures employed in the management of overdosage with any drug. Consider the possibility of multiple drug overdose. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be considered. Removal of vilazodone by dialysis has not been studied; however, the high volume of distribution of vilazodone suggests that dialysis will not be effective in reducing vilazodone plasma concentrations. # Pharmacology ## Mechanism of Action - The mechanism of the antidepressant effect of vilazodone is not fully understood but is thought to be related to its enhancement of serotonergic activity in the CNS through selective inhibition of serotonin reuptake. Vilazodone is also a partial agonist at serotonergic 5-HT1A receptors; however, the net result of this action on serotonergic transmission and its role in vilazodone's antidepressant effect are unknown. ## Structure - Vilazodone HCl is 2-benzofurancarboxamide, 5-4-4-(5-cyano-1H-indol-3-yl)butyl-1-piperazinyl-, hydrochloride (1:1). Its molecular weight is 477.99. The structural formula is: ## Pharmacodynamics - Vilazodone binds with high affinity to the serotonin reuptake site (Ki= 0.1 nM), but not to the norepinephrine (Ki=56 nM) or dopamine (Ki=37 nM) reuptake sites. Vilazodone potently and selectively inhibits reuptake of serotonin (IC50= 1.6 nM). Vilazodone also binds selectively with high affinity to 5-HT1A receptors (IC50=2.1 nM) and is a 5-HT1A receptor partial agonist. - Thorough QT Study: Treatment with Vilazodone did not prolong the QTc interval. The effect of vilazodone (20, 40, 60, and 80 mg) on the QTc interval was evaluated in a randomized, placebo-, and active-controlled (moxifloxacin 400 mg), parallel-group, thorough QTc study in 157 healthy subjects. The study demonstrated an ability to detect small effects. The upper bound of the 90% confidence interval for the largest placebo-adjusted, baseline-corrected QTc interval was below 10 msec, based on the individual correction method (QTcI). This is below the threshold for clinical concern. However, it is unknown whether 80 mg is adequate to represent a high clinical exposure condition. ## Pharmacokinetics - Vilazodone activity is due primarily to the parent drug. The pharmacokinetics of vilazodone (5 mg – 80 mg) are dose-proportional. Accumulation of vilazodone is predictable from single dose data, does not vary with dose, and steady-state is achieved in about 3 days. Elimination of vilazodone is primarily by hepatic metabolism with a terminal half-life of approximately 25 hours. At steady-state, after daily dosing of Vilazodone 40 mg under fed conditions, the mean Cmax value is 156 ng/mL, and the mean AUC (0-24 hours) value is 1645 ng•h/mL. - Vilazodone concentrations peak at a median of 4-5 hours (Tmax) after administration and decline with a terminal half-life of approximately 25 hours. The absolute bioavailability of vilazodone is 72% with food. Administration of Vilazodone with food (high fat or light meal) increases oral bioavailability (Cmax increased by approximately 147-160%, and AUC increased by approximately 64-85%). - Co-administration of Vilazodone with ethanol or with a proton pump inhibitor (pantoprazole) did not affect the rate or extent of vilazodone absorption. In addition, neither the Tmax nor terminal elimination rate of vilazodone was altered by co-administration with either pantoprazole or ethanol. Absorption is decreased by approximately 25% if vomiting occurs within 7 hours of ingestion; no replacement dose is needed. - Vilazodone is widely distributed and approximately 96-99% protein-bound - Vilazodone is extensively metabolized through CYP and non-CYP pathways (possibly by carboxylesterase), with only 1% of the dose recovered in the urine and 2% of the dose recovered in the feces as unchanged vilazodone. CYP3A4 is primarily responsible for its metabolism among CYP pathways, with minor contributions from CYP2C19 and CYP2D6. In vitro studies with human microsomes and human hepatocytes indicate that vilazodone is unlikely to inhibit or induce the metabolism of other CYP (except for CYP2C8) substrates; and an in vivo study with probe substrates for CYP2C19, CYP2D6 and CYP3A4 showed vilazodone did not alter the pharmacokinetics of the probe substrates. However, an in vivo study with probe substrate for CYP2C19 demonstrated a minor induction of CYP2C19. Strong inhibitors of CYP3A4 (e.g., ketoconazole) can reduce the metabolism of vilazodone in vivo and increase exposure. Conversely, strong inducers of CYP3A4 (e.g., carbamazepine) can decrease vilazodone exposure. - The presence of mild or moderate renal impairment, or mild, moderate, or severe hepatic impairment did not affect the apparent clearance of vilazodone. ## Nonclinical Toxicology There is limited information regarding Vilazodone Nonclinical Toxicology in the drug label. # Clinical Studies - The efficacy of Vilazodone as a treatment for major depressive disorder was established in two 8-week, multicenter, randomized, double-blind, placebo-controlled studies in adult (18-70 years of age) outpatients who met the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria for MDD. In these studies, patients were titrated over 2 weeks to a dose of 40 mg of Vilazodone with food (n=436) or placebo (n = 433) once daily. Vilazodone was superior to placebo in the improvement of depressive symptoms as measured by the mean change from baseline to Week 8 in the Montgomery-Asberg Depression Rating Scale (MADRS) total score. Examination of population subgroups based on age (there were few patients over 65), gender, and race did not reveal any clear evidence of differential responsiveness. # How Supplied - 10 mg, pink, oval tablet, debossed with 10 on one side 0456-1110-30: 30-count bottles - 0456-1110-30: 30-count bottles - 20 mg, orange, oval tablet, debossed with 20 on one side 0456-1120-30: 30-count bottles - 0456-1120-30: 30-count bottles - 40 mg, blue, oval tablet, debossed with 40 on one side 0456-1140-30: 30-count bottles - 0456-1140-30: 30-count bottles - Patient Starter Kit 0456-1100-31: blister card containing 30 tablets: 10 mg, pink, oval, debossed with 10 on one side: 7 tablets 20 mg, orange, oval, debossed with 20 on one side: 7 tablets 40 mg, blue, oval, debossed with 40 on one side: 16 tablets - 0456-1100-31: blister card containing 30 tablets: 10 mg, pink, oval, debossed with 10 on one side: 7 tablets 20 mg, orange, oval, debossed with 20 on one side: 7 tablets 40 mg, blue, oval, debossed with 40 on one side: 16 tablets - 10 mg, pink, oval, debossed with 10 on one side: 7 tablets - 20 mg, orange, oval, debossed with 20 on one side: 7 tablets - 40 mg, blue, oval, debossed with 40 on one side: 16 tablets ## Storage - Stored at 25°C (77°F) with excursions permitted to 15°C - 30°C (59°F - 86°F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Vilazodone Patient Counseling Information in the drug label. # Precautions with Alcohol - Alcohol-Vilazodone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Viibryd - Viibryd Titration Pack # Look-Alike Drug Names There is limited information regarding Vilazodone Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Viibryd
bb1c8fdef9b2d62bb3571dd2beea35cd2fb03181	wikidoc	Viloxazine	Viloxazine # Overview Viloxazine (Emovit®, Vivalan®, Vivarint®, Vicilan®) is a bicyclic antidepressant morpholine derivative that inhibits the reuptake of norepinephrine. It is a racemic compound with two isomers, the S(-)-isomer being five times as pharmacologically active as the R(+)-isomer. # Uses ## Approved Viloxazine hydrochloride was approved in Italy, Belgium, the United States, England, Ireland, Germany, Portugal, Spain, the former Yugoslavia, France, Slovakia, for the treatment of clinical depression. ## Unapproved/off-Label/investigational Viloxazine has undergone two randomized controlled trials for nocturnal enuresis (bed-wetting) in children, both of those times versus imipramine., By 1990, it was seen as a less cardiotoxic alternative to imipramine, and to be especially effective in heavy sleepers. In narcolepsy, viloxazine has been shown to suppress auxiliary symptoms such as cataplexy and also abnormal sleep-onset REM without really improving daytime somnolence. Viloxazine has also been studied for the treatment of alcoholism, with some success. While viloxazine may be effective in clinical depression, it did relatively poorly in a double-blind randomized controlled trial versus amisulpride in the treatment of dysthymia, according to Leon and colleagues at the University of Valle in Colombia. # Mechanism of action In 1976, Lippman and Pugsley reported that viloxazine, like imipramine, inhibited norepinephrine reuptake in the hearts of rats and mice; unlike imipramine, (or desipramine or amitriptyline, for that matter) it did not block reuptake of norepinephrine in neither the medullae nor the hypothalami of rats. As for serotonin, while its reuptake inhibition was comparable to that of desipramine (i.e., very weak), viloxazine did potentiate serotonin-mediated brain functions in a manner similar to amitriptyline and imipramine, which are relatively potent inhibitors of serotonin reuptake. Unlike any of the other drugs tested, it did not exhibit any anticholinergic effects. It is also known to up-regulate GABAB receptors in the frontal cortex. # Side effects Side effects include nausea, vomiting, insomnia, loss of appetite, increased erythrocyte sedimentation, EKG and EEG anomalies, epigastric pain, diarrhea, constipation, vertigo, orthostatic hypotension, edema of the lower extremities, dysarthria, tremor, psychomotor agitation, mental confusion, inappropriate secretion of antidiuretic hormone, increased transaminases, seizure, (there were three cases worldwide, and most animal studies (and clinical trials that included epilepsy patients) indicated the presence of anticonvulsant properties, so is not completely contraindicated in epilepsy), and increased libido. # Drug interactions Viloxazine is known to increase plasma levels of phenytoin by an average of 37%. It is also known to significantly increase plasma levels of theophylline and decrease its clearance from the body, sometimes resulting in accidental overdose of theophylline.	Viloxazine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [6] # Overview Viloxazine (Emovit®, Vivalan®, Vivarint®, Vicilan®) is a bicyclic antidepressant[7] morpholine derivative that inhibits the reuptake of norepinephrine.[8] It is a racemic compound with two isomers, the S(-)-isomer being five times as pharmacologically active as the R(+)-isomer.[9] # Uses ## Approved Viloxazine hydrochloride was approved in Italy, Belgium, the United States, England, Ireland, Germany, Portugal, Spain, the former Yugoslavia, France,[10] Slovakia,[11] for the treatment of clinical depression.[12] ## Unapproved/off-Label/investigational Viloxazine has undergone two randomized controlled trials for nocturnal enuresis (bed-wetting) in children, both of those times versus imipramine.[13],[14] By 1990, it was seen as a less cardiotoxic alternative to imipramine, and to be especially effective in heavy sleepers.[15] In narcolepsy, viloxazine has been shown to suppress auxiliary symptoms such as cataplexy and also abnormal sleep-onset REM[16] without really improving daytime somnolence.[17] Viloxazine has also been studied for the treatment of alcoholism, with some success.[18] While viloxazine may be effective in clinical depression, it did relatively poorly in a double-blind randomized controlled trial versus amisulpride in the treatment of dysthymia, according to Leon and colleagues at the University of Valle in Colombia.[19] # Mechanism of action In 1976, Lippman and Pugsley reported that viloxazine, like imipramine, inhibited norepinephrine reuptake in the hearts of rats and mice; unlike imipramine, (or desipramine or amitriptyline, for that matter) it did not block reuptake of norepinephrine in neither the medullae nor the hypothalami of rats. As for serotonin, while its reuptake inhibition was comparable to that of desipramine (i.e., very weak), viloxazine did potentiate serotonin-mediated brain functions in a manner similar to amitriptyline and imipramine, which are relatively potent inhibitors of serotonin reuptake.[20] Unlike any of the other drugs tested, it did not exhibit any anticholinergic effects.[21] It is also known to up-regulate GABAB receptors in the frontal cortex.[22] # Side effects Side effects include nausea, vomiting, insomnia, loss of appetite, increased erythrocyte sedimentation, EKG and EEG anomalies, epigastric pain, diarrhea, constipation, vertigo, orthostatic hypotension, edema of the lower extremities, dysarthria, tremor, psychomotor agitation, mental confusion, inappropriate secretion of antidiuretic hormone, increased transaminases, seizure,[23] (there were three cases worldwide, and most animal studies (and clinical trials that included epilepsy patients) indicated the presence of anticonvulsant properties, so is not completely contraindicated in epilepsy[24]), and increased libido.[25] # Drug interactions Viloxazine is known to increase plasma levels of phenytoin by an average of 37%.[26] It is also known to significantly increase plasma levels of theophylline and decrease its clearance from the body,[27] sometimes resulting in accidental overdose of theophylline.[28]	https://www.wikidoc.org/index.php/Viloxazine
d407bcd412a9a1c0accfe717d77107052d9e03a6	wikidoc	Viral load	Viral load # Overview Viral load is a measure of the severity of a viral infection, and can be calculated by estimating the amount of virus in an involved body fluid, for example, it can be given in RNA copies per milliliter of blood plasma. Determination of viral load is part of the therapy monitoring during chronic viral infections and in immunocompromised patients, e.g. after bone marrow or solid organ transplantation. Currently, routine testing is available for HIV-1, cytomegalovirus, hepatitis B virus, and hepatitis C virus. # HIV viral load test Several different HIV viral load tests have been developed, and three are currently approved for use in the US: - Amplicor HIV-1 Monitor test (Hoffman-La Roche), better known as the PCR test - NucliSens HIV-1 QT, or NASBA (bioMerieux) - Versant/Quantiplex HIV-1 RNA, or bDNA (Chiron/Bayer) These tests have been approved by the Food and Drug Administration in the United States for use in monitoring the health of people with HIV, in conjunction with other markers. Higher numbers in the viral load tests indicate an increased risk of getting sick from opportunistic diseases. These tests are also approved for monitoring the effects of anti-HIV therapy, to track viral suppression and detect treatment failure. Successful combination antiretroviral therapy should give a fall in viral load of 1.5 to 2 logs (30-100 fold) within six weeks, with the viral load falling below the limit of detection within four to six months. An inexpensive, largely manual HIV viral load assay has also been developed which depends on measuring virus-associated reverse transcriptase (RT) activity (ExaVir Load Version 2)(, Uppsala, Sweden). This test has a lower limit of detection of 400 RNA copies/ml. The test was developed primarily for use in resource-limited environments, such as southern Africa. Viral load tests can also be used to diagnose HIV infection, especially in children under 18 months born to mothers with HIV, where the presence of maternal antibodies prevents the use of antibody-based (ELISA) diagnostic tests. Persons with HIV are most contagious during the earliest stages of infection, when an antibody test would yield a negative result. Therefore, the importance of viral load testing is deemed important for yielding an earlier HIV diagnosis. Since persons are most contagious during early infection, widespread testing could provide significant public health benefits. ## Results The results of these tests are usually given as number of HIV RNA copies per milliliter (ml) of blood. The PCR test may give the number of HIV RNA copies per 0.05/ml, so one would multiply the result by 20 to get the standard result.	Viral load # Overview Viral load is a measure of the severity of a viral infection, and can be calculated by estimating the amount of virus in an involved body fluid, for example, it can be given in RNA copies per milliliter of blood plasma. Determination of viral load is part of the therapy monitoring during chronic viral infections and in immunocompromised patients, e.g. after bone marrow or solid organ transplantation. Currently, routine testing is available for HIV-1, cytomegalovirus, hepatitis B virus, and hepatitis C virus. # HIV viral load test Several different HIV viral load tests have been developed, and three are currently approved for use in the US: - Amplicor HIV-1 Monitor test (Hoffman-La Roche), better known as the PCR test - NucliSens HIV-1 QT, or NASBA (bioMerieux) - Versant/Quantiplex HIV-1 RNA, or bDNA (Chiron/Bayer) These tests have been approved by the Food and Drug Administration in the United States for use in monitoring the health of people with HIV, in conjunction with other markers. Higher numbers in the viral load tests indicate an increased risk of getting sick from opportunistic diseases. These tests are also approved for monitoring the effects of anti-HIV therapy, to track viral suppression and detect treatment failure. Successful combination antiretroviral therapy should give a fall in viral load of 1.5 to 2 logs (30-100 fold) within six weeks, with the viral load falling below the limit of detection within four to six months.[1] An inexpensive, largely manual HIV viral load assay has also been developed which depends on measuring virus-associated reverse transcriptase (RT) activity (ExaVir Load Version 2)([Cavidi AB][1], Uppsala, Sweden). This test has a lower limit of detection of 400 RNA copies/ml. The test was developed primarily for use in resource-limited environments, such as southern Africa. Viral load tests can also be used to diagnose HIV infection, especially in children under 18 months born to mothers with HIV, where the presence of maternal antibodies prevents the use of antibody-based (ELISA) diagnostic tests. Persons with HIV are most contagious during the earliest stages of infection, when an antibody test would yield a negative result. Therefore, the importance of viral load testing is deemed important for yielding an earlier HIV diagnosis. Since persons are most contagious during early infection, widespread testing could provide significant public health benefits. ## Results The results of these tests are usually given as number of HIV RNA copies per milliliter (ml) of blood. The PCR test may give the number of HIV RNA copies per 0.05/ml, so one would multiply the result by 20 to get the standard result.	https://www.wikidoc.org/index.php/Viral_load
85c9bcce5132030da629f3cb38019be3c622a8b2	wikidoc	Viramidine	Viramidine Viramidine (ICN 3142, also known as taribavirin) is an anti-viral drug in Phase III human trials, but not yet approved for pharmaceutical use. It is a prodrug of ribavirin, active against a number of DNA and RNA viruses. Viramidine has better liver-targeting than ribavirin, and has a shorter life in the body due to less penetration and storage in red blood cells. It is expected eventually to be the drug of choice for viral hepatitis syndromes in which ribavirin is active. These include hepatitis C and perhaps also hepatitis B and yellow fever. Viramidine is as active against influenza as ribavirin in animal models, with slightly less toxicity, so it may also eventually replace ribavirin as an anti-influenza agent. Viramidine is being developed by Valeant Pharmaceuticals International, the parent company of Ribapharm, the company which first reported synthesis and testing of the drug in 1973. Valeant is testing the drug as a treatment for chronic hepatitis C. Note on formulas: The carboxamidine group of this molecule is somewhat basic, and therefore this drug is also known and administered as the hydrochloride salt (with a corresponding .HCl chemical formula and different ChemID / PubChem number). At physiologic pH, the positive charge on the molecule from partial protonation of the carboximide group contributes to the relative slowness with which the drug crosses cell membranes (such as in red blood cells) until it has been metabolized into ribavirin. In the liver, however, the transformation from carboxamidine to carboxamide happens on first-pass metabolism and contributes to the higher levels of ribavirin found in liver cells and bile when viramidine is administered.	Viramidine Viramidine (ICN 3142, also known as taribavirin) is an anti-viral drug in Phase III human trials, but not yet approved for pharmaceutical use. It is a prodrug of ribavirin, active against a number of DNA and RNA viruses. Viramidine has better liver-targeting than ribavirin, and has a shorter life in the body due to less penetration and storage in red blood cells. It is expected eventually to be the drug of choice for viral hepatitis syndromes in which ribavirin is active. These include hepatitis C and perhaps also hepatitis B and yellow fever. Viramidine is as active against influenza as ribavirin in animal models, with slightly less toxicity, so it may also eventually replace ribavirin as an anti-influenza agent. Viramidine is being developed by Valeant Pharmaceuticals International, the parent company of Ribapharm, the company which first reported synthesis and testing of the drug in 1973. Valeant is testing the drug as a treatment for chronic hepatitis C. Note on formulas: The carboxamidine group of this molecule is somewhat basic, and therefore this drug is also known and administered as the hydrochloride salt (with a corresponding .HCl chemical formula and different ChemID / PubChem number). At physiologic pH, the positive charge on the molecule from partial protonation of the carboximide group contributes to the relative slowness with which the drug crosses cell membranes (such as in red blood cells) until it has been metabolized into ribavirin. In the liver, however, the transformation from carboxamidine to carboxamide happens on first-pass metabolism and contributes to the higher levels of ribavirin found in liver cells and bile when viramidine is administered.	https://www.wikidoc.org/index.php/Viramidine
f90fe9b2d9c6b738a9b6f6c5f17d77c2187408ee	wikidoc	ViroPharma	ViroPharma ViroPharma Incorporated, a pharmaceutical company, develops and sells drugs that address serious diseases treated by physician specialists and in hospital settings. The company focuses on product development activities on viral diseases, including those caused by cytomegalovirus (CMV) and hepatitis C virus (HCV) infections. The company has strategic relationships with GlaxoSmithKline, Wyeth, Schering-Plough, and Sanofi-Aventis. ViroPharma acquired 1,000,000 shares of Siga Technologies Template:Nasdaq, when Siga purchased ViroPharma's bio-defense compounds. ViroPharma is a member of the NASDAQ Biotechnology Index and the S&P 600. # History ViroPharma Incorporated was founded in 1994 by Claude H. Nash (Chief Executive Officer), Mark A. McKinlay (Vice President, Research & Development), Marc S. Collett (Vice President, Discovery Research), Johanna A. Griffin (Vice President, Business Development), and Guy D. Diana (Vice President, Chemistry Research.) None of the founders are still with the company. # Corporate Governance - Michel de Rosen Chairman since September 2002, President and Chief Executive Officer since August 2000, Director since May 2000 - Paul A. Brooke Director since February 2001 - William D. Claypool Director since December 2003 - Michael R. Dougherty Director since January 2004 - Robert J. Glaser Director since August 1997 - John R. Leone Director since January 2006 - Howard H. Pien Director since 2006 # Marketed Products - Vancocin Pulvules HCl: licensed from Eli Lilly in 2004. Oral Vancocin is an antibiotic for treatment of staphylococcal enterocolitis and antibiotic associated pseudomembranous colitis caused by Clostridium difficile. # Pipeline ## Maribavir Maribavir is an oral antiviral drug candidate licensed from GlaxoSmithKline in 2003 for the prevention and treatment of human cytomegalovirus disease in hematopoietic stem cell/bone marrow transplant patients. In March 2006, the company announced that a Phase II study with maribavir demonstrated that prophylaxis with maribavir displays strong antiviral activity, as measured by statistically significant reduction in the rate of reactivation of CMV in recipients of hematopoietic stem cell/bone marrow transplants. In an intent-to-treat analysis of the first 100 days after the transplant, the number of subjects who required pre-emptive anti-CMV therapy was statistically significantly reduced (p-value = 0.051 to 0.001) in each of the maribavir groups compared to the placebo group (57% for placebo vs. 15%, 30%, and 15% for maribavir 100 mg twice daily, 400 mg daily, and 400 mg twice daily, respectively). In February 2006, ViroPharma announced that the United States Food and Drug Administration (FDA) had granted the company Fast Track status for Maribavir. The Fast Track program is designed to facilitate the development, and expedite the review, of new drugs that are intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs. In September 2006, ViroPharma announced the start of a Phase III clinical study to evaluate the prophylactic use for the prevention of cytomegalovirus disease in recipients of allogeneic stem cell transplant patients. ## HCV-796 A non-nucleoside polymerase inhibitor for the treatment of Hepatitis C, jointly developed with Wyeth. In November 2005, ViroPharma announced preliminary results from a proof of concept study. In this study, HCV-796 demonstrated antiviral effects in adult patients with chronic hepatitis C infection. The patient cohort with the highest exposure to HCV-796 achieved a peak mean HCV viral load reduction of 1.4 log10, or 96 percent, on day four of a 14 day dosing period. HCV-796 was generally well tolerated, with a favorable pharmacokinetic profile and no dose-limiting toxicities. In August 2006, the company released results of a Phase I study of HCV-796 in combination with pegylated interferon that demonstrated a 3.3 to 3.5 log10 decrease in viral load. In August 2007, Phase II trials were discontinued due to safety concerns. # Pleconaril Oral pleconaril was ViroPharma's first compound, licensed from Sanofi in 1997. Pleconaril is active against viruses in the picornavirus family. ViroPharma's first indication was for enteroviral meningitis, but that indication was abandoned when the clinical trials did not demonstrate efficacy. In 2001, ViroPharma submitted an New Drug Application of pleconaril to the FDA for the common cold. On 2002-03-19, the FDA Antiviral Advisory Committee recommended that the company had failed to show adequate safety, and the FDA subsequently issued a not-approvable letter. After the Advisory Committee meeting the stock price fell from 22 USD at the beginning of 2002 to an all time low of 0.87 USD on 2002-10-28. (The stock price recovered in 2005.) In November 2003, ViroPharma licensed pleconaril to Schering-Plough, who are developing an intranasal formulation for the common cold and asthma exacerbations. (Schering-Plough Development Pipeline). In August 2006, Schering-Plough started a Phase II clinical trial. ## FDA Advisory Committee Meeting for pleconaril in the common cold - Briefing Information - Slides - Meeting Transcript	ViroPharma Template:Infobox Company ViroPharma Incorporated, a pharmaceutical company, develops and sells drugs that address serious diseases treated by physician specialists and in hospital settings. The company focuses on product development activities on viral diseases, including those caused by cytomegalovirus (CMV) and hepatitis C virus (HCV) infections. The company has strategic relationships with GlaxoSmithKline, Wyeth, Schering-Plough, and Sanofi-Aventis. ViroPharma acquired 1,000,000 shares of Siga Technologies Template:Nasdaq, when Siga purchased ViroPharma's bio-defense compounds. ViroPharma is a member of the NASDAQ Biotechnology Index and the S&P 600. # History ViroPharma Incorporated was founded in 1994 by Claude H. Nash (Chief Executive Officer), Mark A. McKinlay (Vice President, Research & Development), Marc S. Collett (Vice President, Discovery Research), Johanna A. Griffin (Vice President, Business Development), and Guy D. Diana (Vice President, Chemistry Research.) None of the founders are still with the company. # Corporate Governance - Michel de Rosen Chairman since September 2002, President and Chief Executive Officer since August 2000, Director since May 2000 - Paul A. Brooke Director since February 2001 - William D. Claypool Director since December 2003 - Michael R. Dougherty Director since January 2004 - Robert J. Glaser Director since August 1997 - John R. Leone Director since January 2006 - Howard H. Pien Director since 2006 # Marketed Products - Vancocin Pulvules HCl: licensed from Eli Lilly in 2004.[1] Oral Vancocin is an antibiotic for treatment of staphylococcal enterocolitis and antibiotic associated pseudomembranous colitis caused by Clostridium difficile. # Pipeline ## Maribavir Maribavir is an oral antiviral drug candidate licensed from GlaxoSmithKline in 2003 for the prevention and treatment of human cytomegalovirus disease in hematopoietic stem cell/bone marrow transplant patients. In March 2006, the company announced that a Phase II study with maribavir demonstrated that prophylaxis with maribavir displays strong antiviral activity, as measured by statistically significant reduction in the rate of reactivation of CMV in recipients of hematopoietic stem cell/bone marrow transplants. In an intent-to-treat analysis of the first 100 days after the transplant, the number of subjects who required pre-emptive anti-CMV therapy was statistically significantly reduced (p-value = 0.051 to 0.001) in each of the maribavir groups compared to the placebo group (57% for placebo vs. 15%, 30%, and 15% for maribavir 100 mg twice daily, 400 mg daily, and 400 mg twice daily, respectively). In February 2006, ViroPharma announced that the United States Food and Drug Administration (FDA) had granted the company Fast Track status for Maribavir. The Fast Track program is designed to facilitate the development, and expedite the review, of new drugs that are intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs. In September 2006, ViroPharma announced the start of a Phase III clinical study to evaluate the prophylactic use for the prevention of cytomegalovirus disease in recipients of allogeneic stem cell transplant patients. ## HCV-796 A non-nucleoside polymerase inhibitor for the treatment of Hepatitis C, jointly developed with Wyeth. In November 2005, ViroPharma announced preliminary results from a proof of concept study. In this study, HCV-796 demonstrated antiviral effects in adult patients with chronic hepatitis C infection. The patient cohort with the highest exposure to HCV-796 achieved a peak mean HCV viral load reduction of 1.4 log10, or 96 percent, on day four of a 14 day dosing period. HCV-796 was generally well tolerated, with a favorable pharmacokinetic profile and no dose-limiting toxicities. In August 2006, the company released results of a Phase I study of HCV-796 in combination with pegylated interferon that demonstrated a 3.3 to 3.5 log10 decrease in viral load. In August 2007, Phase II trials were discontinued due to safety concerns.[2] # Pleconaril Oral pleconaril was ViroPharma's first compound, licensed from Sanofi in 1997. Pleconaril is active against viruses in the picornavirus family. ViroPharma's first indication was for enteroviral meningitis, but that indication was abandoned when the clinical trials did not demonstrate efficacy. In 2001, ViroPharma submitted an New Drug Application of pleconaril to the FDA for the common cold.[3] On 2002-03-19, the FDA Antiviral Advisory Committee recommended that the company had failed to show adequate safety, and the FDA subsequently issued a not-approvable letter. [4] After the Advisory Committee meeting the stock price fell from 22 USD at the beginning of 2002 to an all time low of 0.87 USD on 2002-10-28. (The stock price recovered in 2005.) In November 2003, ViroPharma licensed pleconaril to Schering-Plough, who are developing an intranasal formulation for the common cold and asthma exacerbations. (Schering-Plough Development Pipeline). In August 2006, Schering-Plough started a Phase II clinical trial. ## FDA Advisory Committee Meeting for pleconaril in the common cold - Briefing Information - Slides - Meeting Transcript	https://www.wikidoc.org/index.php/ViroPharma
29b9ce412a57102d0f190b9c2e8c8246559be22c	wikidoc	Vismodegib	Vismodegib # 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 Vismodegib is a hedgehog pathway inhibitor that is FDA approved for the treatment of metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation. Common adverse reactions include muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - ERIVEDGE capsule is indicated for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation. - The recommended dose of ERIVEDGE is 150 mg taken orally once daily until disease progression or until unacceptable toxicity. - ERIVEDGE may be taken with or without food. Swallow capsules whole. Do not open or crush capsules. - If a dose of ERIVEDGE is missed, do not make up that dose; resume dosing with the next scheduled dose. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Vismodegib in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Vismodegib in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Vismodegib in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Vismodegib in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Vismodegib in pediatric patients. # Contraindications - None. # Warnings ### Precautions - Embryo-Fetal Death and Severe Birth Defects - ERIVEDGE capsules can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Vismodegib is teratogenic, embryotoxic, and fetotoxic in rats at maternal exposures lower than the human exposures at the recommended dose of 150 mg/day. In rats, malformations included craniofacial anomalies, open perineum, and absent or fused digits. Fetal retardations and variations were also observed. - Verify pregnancy status prior to the initiation of ERIVEDGE. Advise male and female patients of the risks of embryo-fetal death and severe birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant. Female and male patients of reproductive potential should be counseled regarding pregnancy prevention and planning. If ERIVEDGE is used during pregnancy or if a patient becomes pregnant while taking (or for a male patient, if his female partner is exposed to) ERIVEDGE, the patient should be apprised of the potential hazard to the fetus. Report immediately exposure to ERIVEDGE during pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may have been exposed to ERIVEDGE during pregnancy, either directly or through seminal fluid, to participate in the ERIVEDGE pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at 1-888-835-2555. - Blood Donation - Advise patients not to donate blood or blood products while receiving ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. # 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. - ERIVEDGE capsule was administered as monotherapy at doses ≥ 150 mg orally daily in four open-label, uncontrolled, dose-ranging or fixed single dose clinical trials enrolling a total of 138 patients with advanced basal cell carcinoma (BCC). The median age of these patients was 61 years (range 21 to 101), 100% were White (including Hispanics), and 64% were male. The median duration of treatment was approximately 10 months (305 days; range 0.7 to 36 months); 111 patients received ERIVEDGE for 6 months or longer. - The most common adverse reactions (≥ 10%) were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia (Table 1). - Amenorrhea: - In clinical trials, a total of 3 of 10 pre-menopausal women developed amenorrhea while receiving ERIVEDGE. - Laboratory Abnormalities: - Treatment-emergent Grade 3 laboratory abnormalities observed in clinical trials were hyponatremia in 6 patients (4%), hypokalemia in 2 patients (1%), and azotemia in 3 patients (2%). ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Vismodegib in the drug label. # Drug Interactions - Effects of Other Drugs on Vismodegib - Drugs that Inhibit or Induce Drug Metabolizing Enzymes - Vismodegib elimination involves multiple pathways. Vismodegib is predominantly excreted as an unchanged drug. Several minor metabolites are produced by multiple CYP enzymes. Although vismodegib is a substrate of CYP2C9 and CYP3A4 in vitro, CYP inhibition is not predicted to alter vismodegib systemic exposure since similar steady-state plasma vismodegib concentrations were observed in patients in clinical trials concomitantly treated with CYP3A4 inducers (i.e., carbamazepine, modafinil, phenobarbital) and those concomitantly treated with CYP3A4 inhibitors (i.e., erythromycin, fluconazole). - Drugs that Inhibit Drug Transport Systems - In vitro studies indicate that vismodegib is a substrate of the efflux transporter P-glycoprotein (P-gp). When ERIVEDGE is coadministered with drugs that inhibit P-gp (e.g. clarithromycin, erythromycin, azithromycin), systemic exposure of vismodegib and incidence of adverse events of ERIVEDGE may be increased. - Drugs that Affect Gastric pH - Drugs that alter the pH of the upper GI tract (e.g. proton pump inhibitors, H2-receptor antagonists, and antacids) may alter the solubility of vismodegib and reduce its bioavailability. However, no formal clinical study has been conducted to evaluate the effect of gastric pH altering agents on the systemic exposure of vismodegib. Increasing the dose of ERIVEDGE when coadministered with such agents is not likely to compensate for the loss of exposure. When ERIVEDGE is coadministered with a proton pump inhibitor, H2-receptor antagonist or antacid, systemic exposure of vismodegib may be decreased and the effect on efficacy of ERIVEDGE is unknown. - Effects of Vismodegib on Other Drugs - Results of a drug-drug interaction study conducted in cancer patients demonstrated that the systemic exposure of rosiglitazone (a CYP2C8 substrate) or oral contraceptives (ethinyl estradiol and norethindrone) is not altered when either drug is co-administered with vismodegib. - In vitro studies indicate that vismodegib is an inhibitor of CYP2C8, CYP2C9, CYP2C19 and the transporter BCRP. Vismodegib does not induce CYP1A2, CYP2B6, or CYP3A4/5 in human hepatocytes. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category D - ERIVEDGE capsule can cause fetal harm when administered to a pregnant female based on its mechanism of action. Vismodegib is teratogenic in rats at doses corresponding to an exposure of 20% of the exposure at the recommended human dose (estimated AUC0-24hr steady-state exposure). In rats, malformations included craniofacial anomalies, open perineum, and absent or fused digits. Fetal retardations and variations were also observed. Vismodegib is embryolethal in rats at exposures within the range achieved at the recommended human dose. If ERIVEDGE 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 embryo or fetus. Report immediately exposure to ERIVEDGE during pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may have been exposed to ERIVEDGE during pregnancy, either directly or through seminal fluid, to participate in the ERIVEDGE pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at 1-888-835-2555. - In an embryo-fetal developmental toxicity study, pregnant rats were administered oral vismodegib at doses of 10, 60, or 300 mg/kg/day during the period of organogenesis. Pre- and post-implantation loss were increased at doses of ≥ 60 mg/kg/day (approximately ≥ 2 times the systemic exposure (AUC) in patients at the recommended human dose), which included early resorption of 100% of the fetuses. A dose of 10 mg/kg/day (approximately 0.2 times the AUC in patients at the recommended dose) resulted in malformations (including missing and/or fused digits, open perineum and craniofacial anomalies) and retardations or variations (including dilated renal pelvis, dilated ureter, and incompletely or unossified sternal elements, centra of vertebrae, or proximal phalanges and claws). Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Vismodegib in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Vismodegib during labor and delivery. ### Nursing Mothers - It is not known whether vismodegib is excreted in human breast milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ERIVEDGE, 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 ERIVEDGE capsule have not been established in pediatric patients. - In repeat-dose toxicology studies in rats, administration of oral vismodegib resulted in toxicities in bone and teeth. Effects on bone consisted of closure of the epiphyseal growth plate when oral vismodegib was administered for 26 weeks at ≥ 50 mg/kg/day (approximately ≥ 0.4 times the systemic exposure (AUC) in patients at the recommended human dose). Abnormalities in growing incisor teeth (including degeneration/necrosis of odontoblasts, formation of fluid-filled cysts in the dental pulp, ossification of the root canal, and hemorrhage resulting in breakage or loss of teeth) were observed after administration of oral vismodegib at ≥ 15 mg/kg/day (approximately ≥ 0.2 times the AUC in patients at the recommended human dose). ### Geriatic Use - Clinical studies of ERIVEDGE capsule did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. ### Gender - ERIVEDGE capsule can cause harm to the embryo or fetus when administered during pregnancy. Counsel female and male patients regarding pregnancy prevention and planning. Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant. - Female patients - Determine pregnancy status within 7 days prior to initiation of treatment in females of reproductive potential. For females with a negative pregnancy test, initiate a highly effective form of contraception (failure rate of less than 1%) prior to the first dose. Continue highly effective contraception during therapy and for 7 months after the last dose of ERIVEDGE. If a patient becomes pregnant while taking ERIVEDGE, or during the 7 months after the last dose of treatment, report the pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage pregnant females to participate in the ERIVEDGE pregnancy pharmacovigilance program by calling the Genentech Adverse Event Line at 1-888-835-2555. Counsel pregnant females about the teratogenic risk to the fetus. - Amenorrhea has been observed in clinical trials in females of reproductive potential. Reversibility of amenorrhea is unknown. - Male patients - Male patients should use condoms with spermicide, even after a vasectomy, during sexual intercourse with female partners while being treated with ERIVEDGE capsule and for 2 months after the last dose to avoid exposing an embryo or fetus to vismodegib. ### Race There is no FDA guidance on the use of Vismodegib with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Vismodegib in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Vismodegib in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Vismodegib in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Vismodegib in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Vismodegib in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Vismodegib in the drug label. # Overdosage ## Chronic Overdose There is limited information regarding Chronic Overdose of Vismodegib in the drug label. # Pharmacology ## Mechanism of Action - Vismodegib is an inhibitor of the Hedgehog pathway. Vismodegib binds to and inhibits Smoothened, a transmembrane protein involved in Hedgehog signal transduction. ## Structure - Vismodegib is an inhibitor of the hedgehog (Hh) signaling pathway, which is described chemically as 2-Chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide. The molecular formula is C19H14Cl2N2O3S. The molecular weight is 421.30 g/mol and the structural formula is: - Vismodegib is a crystalline free base with a pKa (pyridinium cation) of 3.8, appearing as a white to tan powder. The solubility of vismodegib is pH dependent with 0.1 μg/mL at pH 7 and 0.99 mg/mL at pH 1. The partition coefficient (log P) is 2.7. - Each ERIVEDGE (vismodegib) capsule for oral administration contains 150 mg vismodegib and the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, sodium lauryl sulfate, povidone, sodium starch glycolate, talc, and magnesium stearate (non-bovine). The capsule shell contains gelatin, titanium dioxide, red iron oxide, and black iron oxide. The black printing ink contains shellac and black iron oxide. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Vismodegib in the drug label. ## Pharmacokinetics - Absorption - Vismodegib is a highly permeable compound with low aqueous solubility (BCS Class 2). The single dose absolute bioavailability of vismodegib is 31.8%. Absorption is saturable as evidenced by the lack of dose proportional increase in exposure after a single dose of 270 mg or 540 mg vismodegib. ERIVEDGE capsule may be taken without regard to meals because the systemic exposure of vismodegib at steady state is not affected by food. - Distribution - The volume of distribution of vismodegib ranges from 16.4 to 26.6 L. Vismodegib plasma protein binding in patients is greater than 99%. Vismodegib binds to both human serum albumin and alpha-1-acid glycoprotein (AAG) and binding to AAG is saturable. - Metabolism - Greater than 98% of the total circulating drug-related components are the parent drug. Metabolic pathways of vismodegib in humans include oxidation, glucuronidation, and pyridine ring cleavage. The two most abundant oxidative metabolites recovered in feces are produced in vitro by recombinant CYP2C9 and CYP3A4/5. - Elimination - Vismodegib and its metabolites are eliminated primarily by the hepatic route with 82% of the administered dose recovered in the feces and 4.4% recovered in urine. The estimated elimination half-life (t1/2) of vismodegib is 4 days after continuous once-daily dosing and 12 days after a single dose. - Pharmacokinetics in Specific Populations - Hepatic Impairment: The effect of hepatic impairment on the systemic exposure of vismodegib has not been studied. - Renal Impairment: The effect of renal impairment on the systemic exposure of vismodegib has not been studied. - Population pharmacokinetic analyses showed that weight (range: 41-140 kg), age (range: 26-89 years), creatinine clearance (range: 30 to 80 mL/min), and sex do not have a clinically meaningful influence on the systemic exposure of vismodegib. - Cardiac Electrophysiology - In a thorough QTc study in 60 healthy subjects, there was no effect of therapeutic doses of ERIVEDGE on the QTc interval. ## Nonclinical Toxicology - Carcinogenicity studies with vismodegib have not been conducted. Pilomatricoma (a benign cutaneous neoplasm) was observed in rats administered oral vismodegib for 26 weeks at 100 mg/kg/day (approximately 0.8 times the systemic exposure (AUC) in patients at the recommended human dose). - Vismodegib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay and was not clastogenic in the in vitro human chromosomal aberration assay in human peripheral blood lymphocytes or in the in vivo rat bone marrow micronucleus assay. - Studies to assess the potential of vismodegib to affect fertility have not been conducted; however, data from repeat-dose toxicology studies in rats and dogs indicate that male and female reproductive function and fertility may be impaired in patients receiving ERIVEDGE capsule. In a 26-week toxicology study in rats, a relative decrease in percent motile sperm was observed at ≥ 15 mg/kg/day (approximately ≥ 0.3 times the AUC in patients at the recommended human dose). In dogs, increased numbers of degenerating germ cells and hypospermia were observed in young animals administered oral vismodegib for 4 weeks at ≥ 50 mg/kg/day (approximately ≥ 2 times the AUC in patients at the recommended human dose). No corresponding findings were observed in sexually mature dogs at similar doses in 13-week and 26-week toxicology studies. A decrease in the number of corpora lutea was observed in female rats administered oral vismodegib for 26 weeks at 100 mg/kg/day (approximately 0.8 times the AUC in patients at the recommended human dose). - Animal Toxicology - Neurologic effects characterized as limb or body tremors or twitching were observed in rats administered oral vismodegib for 4 weeks or longer at ≥ 50 mg/kg/day (approximately ≥ 0.4 times the AUC in patients at the recommended human dose). These observations resolved upon discontinuation of dosing and were not associated with microscopic findings. # Clinical Studies - There is limited information reA single, international, single-arm, multi-center, open-label, 2-cohort trial was conducted in 104 patients with either metastatic basal cell carcinoma (mBCC) (n = 33) or locally advanced BCC (laBCC) (n = 71). Patients with laBCC were required to have lesions that had recurred after radiotherapy, unless radiotherapy was contraindicated or inappropriate (e.g. Gorlin syndrome; limitations because of location of tumor or cumulative prior radiotherapy dose), and where the lesions were either unresectable or surgical resection would result in substantial deformity. Patients were to receive 150 mg vismodegib per day orally until disease progression or unacceptable toxicity. - The major efficacy outcome measure of the trial was objective response rate (ORR) as assessed by an independent review facility (IRF). In the mBCC cohort, tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0. In the laBCC cohort, tumor response evaluation included measurement of externally assessable tumor (including scar) and assessment for ulceration in photographs, radiographic assessment of target lesions (if appropriate), and tumor biopsy. An objective response in laBCC required at least one of the following criteria and absence of any criterion for disease progression: (1) ≥ 30% reduction in lesion size from baseline in target lesions by radiographic assessment; (2) ≥ 30% reduction in SLD from baseline in externally visible dimension of target lesions; (3) complete resolution of ulceration in all target lesions. Complete response was defined as objective response (as defined above) with no residual BCC on sampling tumor biopsy. Disease progression was defined as any of the following: (1) ≥ 20% increase in the SLD from nadir in target lesions (either by radiography or by externally visible dimension); (2) new ulceration of target lesions persisting without evidence of healing for at least 2 weeks; (3) new lesions by radiographic assessment or physical examination; (4) progression of non-target lesions by RECIST. - Of the 104 patients enrolled, 96 patients were evaluable for ORR. Twenty-one percent of patients carried a diagnosis of Gorlin syndrome. The median age of the efficacy evaluable population was 62 years (46% were at least 65 years old), 61% male and 100% White. For the mBCC cohort (n = 33), 97% of patients had prior therapy including surgery (97%), radiotherapy (58%), and systemic therapies (30%). For the laBCC cohort (n = 63), 94% of patients had prior therapies including surgery (89%), radiotherapy (27%), and systemic/topical therapies (11%). The median duration of treatment was 10.2 months (range 0.7 to 18.7 months). - The key outcome measures are presented in Table 2, below. # How Supplied - Each ERIVEDGE (vismodegib) capsule has a pink opaque body and a grey opaque cap with "150 mg" printed on the capsule body and "VISMO" printed on the capsule cap in black ink. ERIVEDGE capsules are available in bottles of 28 capsules (NDC 50242-140-01). - Store at room temperature 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). ## Storage There is limited information regarding Vismodegib Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise patients that ERIVEDGE exposure during pregnancy can cause embryo-fetal death or severe birth defects. - Instruct female patients of reproductive potential to use a highly effective form of contraception (failure rate of less than 1%) while taking ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. - Instruct all male patients, even those with prior vasectomy, to use condoms with spermicide, during sexual intercourse with female partners while taking ERIVEDGE and for at least 2 months after the last dose of ERIVEDGE. - Instruct patients to immediately contact their healthcare provider if they (or, for males, their female partner) become pregnant or if pregnancy is suspected following exposure to ERIVEDGE. - Instruct patients to immediately report any pregnancy exposure to ERIVEDGE and encourage participation in the ERIVEDGE pregnancy pharmacovigilance program by calling the Genentech Adverse Event Line at 1-888-835-2555. - Inform female patients of the potential for serious adverse reactions in nursing infants from ERIVEDGE, taking into account the importance of the drug to the mother. - Advise patients not to donate blood or blood products while taking ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. - Advise patients to swallow ERIVEDGE capsules whole and not to crush or open the capsules. # Precautions with Alcohol - Alcohol-Vismodegib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - ERIVEDGE® # Look-Alike Drug Names There is limited information regarding Vismodegib Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Vismodegib 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 Vismodegib is a hedgehog pathway inhibitor that is FDA approved for the treatment of metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation. Common adverse reactions include muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - ERIVEDGE capsule is indicated for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation. - The recommended dose of ERIVEDGE is 150 mg taken orally once daily until disease progression or until unacceptable toxicity. - ERIVEDGE may be taken with or without food. Swallow capsules whole. Do not open or crush capsules. - If a dose of ERIVEDGE is missed, do not make up that dose; resume dosing with the next scheduled dose. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Vismodegib in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Vismodegib in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Vismodegib in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Vismodegib in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Vismodegib in pediatric patients. # Contraindications - None. # Warnings ### Precautions - Embryo-Fetal Death and Severe Birth Defects - ERIVEDGE capsules can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Vismodegib is teratogenic, embryotoxic, and fetotoxic in rats at maternal exposures lower than the human exposures at the recommended dose of 150 mg/day. In rats, malformations included craniofacial anomalies, open perineum, and absent or fused digits. Fetal retardations and variations were also observed. - Verify pregnancy status prior to the initiation of ERIVEDGE. Advise male and female patients of the risks of embryo-fetal death and severe birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant. Female and male patients of reproductive potential should be counseled regarding pregnancy prevention and planning. If ERIVEDGE is used during pregnancy or if a patient becomes pregnant while taking (or for a male patient, if his female partner is exposed to) ERIVEDGE, the patient should be apprised of the potential hazard to the fetus. Report immediately exposure to ERIVEDGE during pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may have been exposed to ERIVEDGE during pregnancy, either directly or through seminal fluid, to participate in the ERIVEDGE pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at 1-888-835-2555. - Blood Donation - Advise patients not to donate blood or blood products while receiving ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. # 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. - ERIVEDGE capsule was administered as monotherapy at doses ≥ 150 mg orally daily in four open-label, uncontrolled, dose-ranging or fixed single dose clinical trials enrolling a total of 138 patients with advanced basal cell carcinoma (BCC). The median age of these patients was 61 years (range 21 to 101), 100% were White (including Hispanics), and 64% were male. The median duration of treatment was approximately 10 months (305 days; range 0.7 to 36 months); 111 patients received ERIVEDGE for 6 months or longer. - The most common adverse reactions (≥ 10%) were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia (Table 1). - Amenorrhea: - In clinical trials, a total of 3 of 10 pre-menopausal women developed amenorrhea while receiving ERIVEDGE. - Laboratory Abnormalities: - Treatment-emergent Grade 3 laboratory abnormalities observed in clinical trials were hyponatremia in 6 patients (4%), hypokalemia in 2 patients (1%), and azotemia in 3 patients (2%). ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Vismodegib in the drug label. # Drug Interactions - Effects of Other Drugs on Vismodegib - Drugs that Inhibit or Induce Drug Metabolizing Enzymes - Vismodegib elimination involves multiple pathways. Vismodegib is predominantly excreted as an unchanged drug. Several minor metabolites are produced by multiple CYP enzymes. Although vismodegib is a substrate of CYP2C9 and CYP3A4 in vitro, CYP inhibition is not predicted to alter vismodegib systemic exposure since similar steady-state plasma vismodegib concentrations were observed in patients in clinical trials concomitantly treated with CYP3A4 inducers (i.e., carbamazepine, modafinil, phenobarbital) and those concomitantly treated with CYP3A4 inhibitors (i.e., erythromycin, fluconazole). - Drugs that Inhibit Drug Transport Systems - In vitro studies indicate that vismodegib is a substrate of the efflux transporter P-glycoprotein (P-gp). When ERIVEDGE is coadministered with drugs that inhibit P-gp (e.g. clarithromycin, erythromycin, azithromycin), systemic exposure of vismodegib and incidence of adverse events of ERIVEDGE may be increased. - Drugs that Affect Gastric pH - Drugs that alter the pH of the upper GI tract (e.g. proton pump inhibitors, H2-receptor antagonists, and antacids) may alter the solubility of vismodegib and reduce its bioavailability. However, no formal clinical study has been conducted to evaluate the effect of gastric pH altering agents on the systemic exposure of vismodegib. Increasing the dose of ERIVEDGE when coadministered with such agents is not likely to compensate for the loss of exposure. When ERIVEDGE is coadministered with a proton pump inhibitor, H2-receptor antagonist or antacid, systemic exposure of vismodegib may be decreased and the effect on efficacy of ERIVEDGE is unknown. - Effects of Vismodegib on Other Drugs - Results of a drug-drug interaction study conducted in cancer patients demonstrated that the systemic exposure of rosiglitazone (a CYP2C8 substrate) or oral contraceptives (ethinyl estradiol and norethindrone) is not altered when either drug is co-administered with vismodegib. - In vitro studies indicate that vismodegib is an inhibitor of CYP2C8, CYP2C9, CYP2C19 and the transporter BCRP. Vismodegib does not induce CYP1A2, CYP2B6, or CYP3A4/5 in human hepatocytes. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category D - ERIVEDGE capsule can cause fetal harm when administered to a pregnant female based on its mechanism of action. Vismodegib is teratogenic in rats at doses corresponding to an exposure of 20% of the exposure at the recommended human dose (estimated AUC0-24hr steady-state exposure). In rats, malformations included craniofacial anomalies, open perineum, and absent or fused digits. Fetal retardations and variations were also observed. Vismodegib is embryolethal in rats at exposures within the range achieved at the recommended human dose. If ERIVEDGE 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 embryo or fetus. Report immediately exposure to ERIVEDGE during pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may have been exposed to ERIVEDGE during pregnancy, either directly or through seminal fluid, to participate in the ERIVEDGE pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at 1-888-835-2555. - In an embryo-fetal developmental toxicity study, pregnant rats were administered oral vismodegib at doses of 10, 60, or 300 mg/kg/day during the period of organogenesis. Pre- and post-implantation loss were increased at doses of ≥ 60 mg/kg/day (approximately ≥ 2 times the systemic exposure (AUC) in patients at the recommended human dose), which included early resorption of 100% of the fetuses. A dose of 10 mg/kg/day (approximately 0.2 times the AUC in patients at the recommended dose) resulted in malformations (including missing and/or fused digits, open perineum and craniofacial anomalies) and retardations or variations (including dilated renal pelvis, dilated ureter, and incompletely or unossified sternal elements, centra of vertebrae, or proximal phalanges and claws). Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Vismodegib in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Vismodegib during labor and delivery. ### Nursing Mothers - It is not known whether vismodegib is excreted in human breast milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ERIVEDGE, 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 ERIVEDGE capsule have not been established in pediatric patients. - In repeat-dose toxicology studies in rats, administration of oral vismodegib resulted in toxicities in bone and teeth. Effects on bone consisted of closure of the epiphyseal growth plate when oral vismodegib was administered for 26 weeks at ≥ 50 mg/kg/day (approximately ≥ 0.4 times the systemic exposure (AUC) in patients at the recommended human dose). Abnormalities in growing incisor teeth (including degeneration/necrosis of odontoblasts, formation of fluid-filled cysts in the dental pulp, ossification of the root canal, and hemorrhage resulting in breakage or loss of teeth) were observed after administration of oral vismodegib at ≥ 15 mg/kg/day (approximately ≥ 0.2 times the AUC in patients at the recommended human dose). ### Geriatic Use - Clinical studies of ERIVEDGE capsule did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. ### Gender - ERIVEDGE capsule can cause harm to the embryo or fetus when administered during pregnancy. Counsel female and male patients regarding pregnancy prevention and planning. Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant. - Female patients - Determine pregnancy status within 7 days prior to initiation of treatment in females of reproductive potential. For females with a negative pregnancy test, initiate a highly effective form of contraception (failure rate of less than 1%) prior to the first dose. Continue highly effective contraception during therapy and for 7 months after the last dose of ERIVEDGE. If a patient becomes pregnant while taking ERIVEDGE, or during the 7 months after the last dose of treatment, report the pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage pregnant females to participate in the ERIVEDGE pregnancy pharmacovigilance program by calling the Genentech Adverse Event Line at 1-888-835-2555. Counsel pregnant females about the teratogenic risk to the fetus. - Amenorrhea has been observed in clinical trials in females of reproductive potential. Reversibility of amenorrhea is unknown. - Male patients - Male patients should use condoms with spermicide, even after a vasectomy, during sexual intercourse with female partners while being treated with ERIVEDGE capsule and for 2 months after the last dose to avoid exposing an embryo or fetus to vismodegib. ### Race There is no FDA guidance on the use of Vismodegib with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Vismodegib in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Vismodegib in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Vismodegib in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Vismodegib in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Vismodegib in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Vismodegib in the drug label. # Overdosage ## Chronic Overdose There is limited information regarding Chronic Overdose of Vismodegib in the drug label. # Pharmacology ## Mechanism of Action - Vismodegib is an inhibitor of the Hedgehog pathway. Vismodegib binds to and inhibits Smoothened, a transmembrane protein involved in Hedgehog signal transduction. ## Structure - Vismodegib is an inhibitor of the hedgehog (Hh) signaling pathway, which is described chemically as 2-Chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide. The molecular formula is C19H14Cl2N2O3S. The molecular weight is 421.30 g/mol and the structural formula is: - Vismodegib is a crystalline free base with a pKa (pyridinium cation) of 3.8, appearing as a white to tan powder. The solubility of vismodegib is pH dependent with 0.1 μg/mL at pH 7 and 0.99 mg/mL at pH 1. The partition coefficient (log P) is 2.7. - Each ERIVEDGE (vismodegib) capsule for oral administration contains 150 mg vismodegib and the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, sodium lauryl sulfate, povidone, sodium starch glycolate, talc, and magnesium stearate (non-bovine). The capsule shell contains gelatin, titanium dioxide, red iron oxide, and black iron oxide. The black printing ink contains shellac and black iron oxide. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Vismodegib in the drug label. ## Pharmacokinetics - Absorption - Vismodegib is a highly permeable compound with low aqueous solubility (BCS Class 2). The single dose absolute bioavailability of vismodegib is 31.8%. Absorption is saturable as evidenced by the lack of dose proportional increase in exposure after a single dose of 270 mg or 540 mg vismodegib. ERIVEDGE capsule may be taken without regard to meals because the systemic exposure of vismodegib at steady state is not affected by food. - Distribution - The volume of distribution of vismodegib ranges from 16.4 to 26.6 L. Vismodegib plasma protein binding in patients is greater than 99%. Vismodegib binds to both human serum albumin and alpha-1-acid glycoprotein (AAG) and binding to AAG is saturable. - Metabolism - Greater than 98% of the total circulating drug-related components are the parent drug. Metabolic pathways of vismodegib in humans include oxidation, glucuronidation, and pyridine ring cleavage. The two most abundant oxidative metabolites recovered in feces are produced in vitro by recombinant CYP2C9 and CYP3A4/5. - Elimination - Vismodegib and its metabolites are eliminated primarily by the hepatic route with 82% of the administered dose recovered in the feces and 4.4% recovered in urine. The estimated elimination half-life (t1/2) of vismodegib is 4 days after continuous once-daily dosing and 12 days after a single dose. - Pharmacokinetics in Specific Populations - Hepatic Impairment: The effect of hepatic impairment on the systemic exposure of vismodegib has not been studied. - Renal Impairment: The effect of renal impairment on the systemic exposure of vismodegib has not been studied. - Population pharmacokinetic analyses showed that weight (range: 41-140 kg), age (range: 26-89 years), creatinine clearance (range: 30 to 80 mL/min), and sex do not have a clinically meaningful influence on the systemic exposure of vismodegib. - Cardiac Electrophysiology - In a thorough QTc study in 60 healthy subjects, there was no effect of therapeutic doses of ERIVEDGE on the QTc interval. ## Nonclinical Toxicology - Carcinogenicity studies with vismodegib have not been conducted. Pilomatricoma (a benign cutaneous neoplasm) was observed in rats administered oral vismodegib for 26 weeks at 100 mg/kg/day (approximately 0.8 times the systemic exposure (AUC) in patients at the recommended human dose). - Vismodegib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay and was not clastogenic in the in vitro human chromosomal aberration assay in human peripheral blood lymphocytes or in the in vivo rat bone marrow micronucleus assay. - Studies to assess the potential of vismodegib to affect fertility have not been conducted; however, data from repeat-dose toxicology studies in rats and dogs indicate that male and female reproductive function and fertility may be impaired in patients receiving ERIVEDGE capsule. In a 26-week toxicology study in rats, a relative decrease in percent motile sperm was observed at ≥ 15 mg/kg/day (approximately ≥ 0.3 times the AUC in patients at the recommended human dose). In dogs, increased numbers of degenerating germ cells and hypospermia were observed in young animals administered oral vismodegib for 4 weeks at ≥ 50 mg/kg/day (approximately ≥ 2 times the AUC in patients at the recommended human dose). No corresponding findings were observed in sexually mature dogs at similar doses in 13-week and 26-week toxicology studies. A decrease in the number of corpora lutea was observed in female rats administered oral vismodegib for 26 weeks at 100 mg/kg/day (approximately 0.8 times the AUC in patients at the recommended human dose). - Animal Toxicology - Neurologic effects characterized as limb or body tremors or twitching were observed in rats administered oral vismodegib for 4 weeks or longer at ≥ 50 mg/kg/day (approximately ≥ 0.4 times the AUC in patients at the recommended human dose). These observations resolved upon discontinuation of dosing and were not associated with microscopic findings. # Clinical Studies - There is limited information reA single, international, single-arm, multi-center, open-label, 2-cohort trial was conducted in 104 patients with either metastatic basal cell carcinoma (mBCC) (n = 33) or locally advanced BCC (laBCC) (n = 71). Patients with laBCC were required to have lesions that had recurred after radiotherapy, unless radiotherapy was contraindicated or inappropriate (e.g. Gorlin syndrome; limitations because of location of tumor or cumulative prior radiotherapy dose), and where the lesions were either unresectable or surgical resection would result in substantial deformity. Patients were to receive 150 mg vismodegib per day orally until disease progression or unacceptable toxicity. - The major efficacy outcome measure of the trial was objective response rate (ORR) as assessed by an independent review facility (IRF). In the mBCC cohort, tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0. In the laBCC cohort, tumor response evaluation included measurement of externally assessable tumor (including scar) and assessment for ulceration in photographs, radiographic assessment of target lesions (if appropriate), and tumor biopsy. An objective response in laBCC required at least one of the following criteria and absence of any criterion for disease progression: (1) ≥ 30% reduction in lesion size [sum of the longest diameter (SLD)] from baseline in target lesions by radiographic assessment; (2) ≥ 30% reduction in SLD from baseline in externally visible dimension of target lesions; (3) complete resolution of ulceration in all target lesions. Complete response was defined as objective response (as defined above) with no residual BCC on sampling tumor biopsy. Disease progression was defined as any of the following: (1) ≥ 20% increase in the SLD from nadir in target lesions (either by radiography or by externally visible dimension); (2) new ulceration of target lesions persisting without evidence of healing for at least 2 weeks; (3) new lesions by radiographic assessment or physical examination; (4) progression of non-target lesions by RECIST. - Of the 104 patients enrolled, 96 patients were evaluable for ORR. Twenty-one percent of patients carried a diagnosis of Gorlin syndrome. The median age of the efficacy evaluable population was 62 years (46% were at least 65 years old), 61% male and 100% White. For the mBCC cohort (n = 33), 97% of patients had prior therapy including surgery (97%), radiotherapy (58%), and systemic therapies (30%). For the laBCC cohort (n = 63), 94% of patients had prior therapies including surgery (89%), radiotherapy (27%), and systemic/topical therapies (11%). The median duration of treatment was 10.2 months (range 0.7 to 18.7 months). - The key outcome measures are presented in Table 2, below. # How Supplied - Each ERIVEDGE (vismodegib) capsule has a pink opaque body and a grey opaque cap with "150 mg" printed on the capsule body and "VISMO" printed on the capsule cap in black ink. ERIVEDGE capsules are available in bottles of 28 capsules (NDC 50242-140-01). - Store at room temperature 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). ## Storage There is limited information regarding Vismodegib Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise patients that ERIVEDGE exposure during pregnancy can cause embryo-fetal death or severe birth defects. - Instruct female patients of reproductive potential to use a highly effective form of contraception (failure rate of less than 1%) while taking ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. - Instruct all male patients, even those with prior vasectomy, to use condoms with spermicide, during sexual intercourse with female partners while taking ERIVEDGE and for at least 2 months after the last dose of ERIVEDGE. - Instruct patients to immediately contact their healthcare provider if they (or, for males, their female partner) become pregnant or if pregnancy is suspected following exposure to ERIVEDGE. - Instruct patients to immediately report any pregnancy exposure to ERIVEDGE and encourage participation in the ERIVEDGE pregnancy pharmacovigilance program by calling the Genentech Adverse Event Line at 1-888-835-2555. - Inform female patients of the potential for serious adverse reactions in nursing infants from ERIVEDGE, taking into account the importance of the drug to the mother. - Advise patients not to donate blood or blood products while taking ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. - Advise patients to swallow ERIVEDGE capsules whole and not to crush or open the capsules. # Precautions with Alcohol - Alcohol-Vismodegib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - ERIVEDGE®[1] # Look-Alike Drug Names There is limited information regarding Vismodegib Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Vismodegib
cd0afa4fe0b133d60dd2eb42c16a707692ff3335	wikidoc	Vitamin B6	Vitamin B6 # Overview Vitamin B6 is a water-soluble vitamin. Pyridoxal phosphate (PLP) is the active form and is a cofactor in many reactions of amino acid metabolism, including transamination, deamination, and decarboxylation. PLP also is necessary for the enzymatic reaction governing the release of glucose from glycogen. # History Vitamin B6 is a water-soluble compound that was discovered in the 1930s during nutrition studies on rats. The vitamin was named pyridoxine to indicate its structural homology to pyridine. Later it was shown that vitamin B6 could exist in two other, slightly different, chemical forms, termed pyridoxal and pyridoxamine. All three forms of vitamin B6 are precursors of an activated compound known as pyridoxal 5'-phosphate (PLP), which plays a vital role as the cofactor of a large number of essential enzymes in the human body. Enzymes dependent on PLP focus a wide variety of chemical reactions mainly involving amino acids. The reactions carried out by the PLP-dependent enzymes that act on amino acids include transfer of the amino group, decarboxylation, racemization, and beta- or gamma-elimination or replacement. Such versatility arises from the ability of PLP to covalently bind the substrate, and then to act as an electrophilic catalyst, thereby stabilizing different types of carbanionic reaction intermediates. Overall, the Enzyme Commission (EC; / ) has catalogued more than 140 PLP-dependent activities, corresponding to ~4% of all classified activities. In the early 1990s, it was suggested in megadoses as treatment for PMS and clinical depression, but this is no longer considered effective. # Forms Seven forms of this vitamin are known: - pyridoxine (PN). PN is the form that is given as vitamin B6 supplement. - pyridoxine 5'-phosphate (PNP). - pyridoxal (PL). - pyridoxal 5'-phosphate (PLP). PLP is the metabolically active form. - pyridoxamine (PM). - pyridoxamine 5'-phosphate (PMP). - 4-pyridoxic acid (PA). PA is the catabolite which is excreted in the urine. All forms except PA can be interconverted. # Functions Pyridoxal phosphate, the metabolically active form of vitamin B6, is involved in many aspects of macronutrient metabolism, neurotransmitter synthesis, histamine synthesis, hemoglobin synthesis and function and gene expression. Pyridoxal phosphate generally serves as a coenzyme for many reactions and can help facilitate decarboxylation, transamination, racemization, elimination, replacement and beta-group interconversion reactions. ## Amino Acid Metabolism Pyridoxal phosphate (PLP) is a cofactor in transaminases that can catabolize amino acids. PLP is also an essential component of two enzymes that converts methionine to cysteine via two reactions. Low vitamin B6 status will result in decreased activity of these enzymes. PLP is also an essential cofactor for enzymes involved in the metabolism of selenomethionine to selenohomocysteine and then from selenohomocysteine to hydrogen selenide. Vitamin B6 is also required for the conversion of tryptophan to niacin and low vitamin B6 status will impair this conversion. PLP is also used to create physiologically active amines by decarboxylation of amino acids. Some notable examples of this include: histadine to histamine, tryptophan to serotonin, glutamate to GABA (gamma-aminobutyric acid), and dihydroxyphenylalanine to dopamine. ## Gluconeogenesis Vitamin B6 also plays a role in gluconeogenesis. Pyridoxal phosphate can catalyze transamination reactions that are essential for the providing amino acids as a substrate for gluconeogenesis. Also, vitamin B6 is a required coenzyme of glycogen phosphorylase<, the enzyme that is necessary for glycogenolysis to occur. ## Lipid Metabolism Vitamin B6 is an essential component of enzymes that facilitate the biosynthesis of sphingolipids. Particularly, the synthesis of ceramide requires PLP. In this reaction serine is decarboxylated and combined with palmitoyl-CoA to form sphinganine which is combined with a fatty acyl CoA to form ceramide. # Metabolic Functions The primary role of vitamin B6 is to act as a coenzyme to many other enzymes in the body that are involved predominately in metabolism. This role is performed by the active form, pyridoxal phosphate. This active form is converted from the two other natural forms founds in food: pyridoxal, pyridoxine and pyridoxamine. Vitamin B6 is involved in the following metabolic processes: - Amino acid, glucose and lipid metabolism - neurotransmitter synthesis - histamine synthesis - hemoglobin synthesis and function - gene expression ## Amino Acid Metabolism Pyridoxal phosphate is involved in almost all amino acid metabolism, from synthesis to breakdown. 1. Transamination: transaminase enzymes needed to breakdown amino acids are dependent on the presence of pyridoxal phosphate. The proper activity of these enzymes are crucial for the process of moving amine groups from one amino acid to another. 2. Transsulfuration: Pyridoxal phosphate is a coenzyme needed for the proper function of the enzymes cystathionine synthase and cystathionase. These enzymes work to transform methionine into cysteine. 3. Selenoamino acid metabolism: Selenomethionine is the primary dietary form of selenium. Pyridoxal phosphate is needed as a cofactor for the enzymes that allow selenium to be used from the dietary form. Pyridoxal phosphate also plays a cofactor role in releasing selenium from selenohomocysteine to produce hydrogen selenide. This hydrogen selenide can then be used to incorporate selenium into selenoproteins<. 4. Vitamin B6 is also required for the conversion of tryptophan to niacin and low vitamin B6 status will impair this conversion. ## Gluconeogenesis Vitamin B6 also plays a role in gluconeogenesis. Pyridoxal phosphate can catalyze transamination reactions that are essential for providing amino acids as a substrate for gluconeogenesis. Also, vitamin B6 is a required coenzyme of glycogen phosphorylase, the enzyme that is necessary for glycogenolysis to occur. ## Neurotransmitter Synthesis Pyridoxal phosphate-dependent enzymes play a role in the biosynthesis of four important neurotranmsitters: serotonin, epinephrine, norepinephrine and gamma-aminobutyric acid. ## Histamine Synthesis Pyridoxal phosphate is involved in the metabolism of histamine. ## Hemoglobin Synthesis and Function Pyridoxal phosphate aids in the synthesis of heme and can also bind to two sites on hemoglobin to enhance the oxygen binding of hemoglobin. ## Gene Expression Pyridoxal phosphate has been implicated in increasing or decreasing the expression of certain genes. Increased intracellular levels of the vitamin will lead to a decrease in the transcription of glucocorticoid hormones. Also, vitamin B6 deficiency will lead to the increased expression of albumin mRNA. Also, pyridoxal phosphate will influence gene expression of glycoprotein IIb by interacting with various transcription factors. The result is inhibition of platelet aggregation. # Dietary Reference Intakes The Institute of Medicine notes that "No adverse effects associated with Vitamin B6 from food have been reported. This does not mean that there is no potential for adverse effects resulting from high intakes. Because data on the adverse effects of Vitamin B6 are limited, caution may be warranted. Sensory neuropathy has occurred from high intakes of supplemental forms."Click on the pdf at the end of this sentence to see the Institute of Medicine's Dietary Reference Intake tables for vitamins. # Sources Vitamin B6 is widely distributed in foods in both its free and bound forms. Good sources include meats, whole grain products, vegetables, and nuts. Cooking, storage and processing losses of vitamin B6 vary and in some foods may be more than 50%, depending on the form of vitamer present in the food. Plant foods lose the least during processing as they contain mostly pyridoxine which is far more stable than the pyridoxal or pyridoxamine found in animal foods. For example, milk can lose 30-70% of its vitamin B6 content when dried. # Absorption Vitamin B6 is absorbed in the jejunum and ileum via passive diffusion. With the capacity for absorption being so great, animals are able to absorb quantities much greater than what is needed for physiological demands. The absorption of pyridoxal phosphate and pyridoxamine phosphate involves their phosphorylation catalyzed by a membrane-bound alkaline phosphatase. Those products and non-phosphorylated vitamers in the digestive tract are absorbed by diffusion, which is driven by trapping of the vitamin as 5'-phosphates through the action of phosphorylation (by a pyridoxal kinase) in the jejunal mucosa. The trapped pyridoxine and pyridoxamine are oxidized to pyridoxal phosphate in the tissue. # Excretion The products of vitamin B6 metabolism are excreted in the urine; the major product of which is 4-pyridoxic acid. It has been estimated that 40-60% of ingested vitamin B6is oxidized to 4-pyridoxic acid. Several studies have shown that 4-pyridoxic acid is undetectable in the urine of vitamin B6 deficient subjects, making it a useful clinical marker to assess the vitamin B6 status of an individual. Other products of vitamin B6metabolism that are excreted in the urine when high doses of the vitamin have been given include pyridoxal, pyridoxamine, and pyridoxine and their phosphates. # Deficiencies The classic clinical syndrome for B6 deficiency is a seborrheic dermatitis-like eruption, atrophic glossitis with ulceration, angular cheilitis, conjunctivitis, intertrigo, and neurologic symptoms of somnolence, confusion, and neuropathy. While severe vitamin B6 deficiency results in dermatologic and neurologic changes, less severe cases present with metabolic lesions associated with insufficient acitivities of the coenzyme pyridoxal phosphate. The most prominent of the lesions is due to impaired tryptophan-niacin conversion. This can be detected based on urinary excretion of xanthurenic acid after an oral tryptophan load. Vitamin B6 deficiency can also result from impaired transsulfuration of methionine to cysteine. The pyridoxal phosphate-dependent transaminases and glycogen phosphorylase provide the vitamin with its role in gluconeogenesis, so deprivation of vitamin B6 results in impaired glucose tolerance. A deficiency of vitamin B6 alone is relatively uncommon and often occurs in association with other vitamins of the B complex. The elderly and alcoholics have an increased risk of vitamin B6 deficiency, as well as other micronutrient deficiencies. # Toxicity An overdose of pyridoxine can cause a temporary deadening of certain nerves such as the proprioceptory nerves; causing a feeling of disembodiment common with the loss of proprioception. This condition is reversible when supplementation is stopped. Because adverse effects have only been documented from vitamin B6 supplements and never from food sources, this article only discusses the safety of the supplemental form of vitamin B6 (pyridoxine). Although vitamin B6 is a water-soluble vitamin and is excreted in the urine, very high doses of pyridoxine over long periods of time may result in painful neurological symptoms known as sensory neuropathy. Symptoms include pain and numbness of the extremities, and in severe cases difficulty walking. Sensory neuropathy typically develops at doses of pyridoxine in excess of 1,000 mg per day. However, there have been a few case reports of individuals who developed sensory neuropathies at doses of less than 500 mg daily over a period of months. None of the studies, in which an objective neurological examination was performed, found evidence of sensory nerve damage at intakes of pyridoxine below 200 mg/day. In order to prevent sensory neuropathy in virtually all individuals, the Food and Nutrition Board of the Institute of Medicine set the tolerable upper intake level (UL) for pyridoxine at 100 mg/day for adults. Because placebo-controlled studies have generally failed to show therapeutic benefits of high doses of pyridoxine, there is little reason to exceed the UL of 100 mg/day. Studies have shown, however, that in the case of individuals diagnosed with autism, high doses of vitamin B6 given with magnesium have been found to be beneficial. # Preventive roles and therapeutic uses At least one preliminary study has found that this vitamin may increase dream vividness or the ability to recall dreams. It is thought that this effect may be due to the role this vitamin plays in the conversion of tryptophan to serotonin. The intake of vitamin B6, from either diet or supplements, could cut the risk of Parkinson’s disease by half according to a prospective study from the Netherlands. "Stratified analyses showed that this association was restricted to smokers," wrote the authors. Nutritional supplementation with high dose vitamin B6 and magnesium is claimed to alleviate the symptoms of autism and is one of the most popular complementary and alternative medicine choices for autism. Three small randomized controlled trials have studied this therapy; the smallest one (with 8 individuals) found improved verbal IQ in the treatment group and the other two (with 10 and 15 individuals, respectively) found no significant difference. The short-term side effects seem to be mild, but there may be significant long-term side effects of peripheral neuropathy. Some studies suggest that the B6-magnesium combination can also help attention deficit disorder , citing improvements in hyperactivity, hyperemotivity/aggressiveness and improved school attention. It is also suggested that ingestion of vitamin B6 can alleviate some of the many symptoms of an alcoholic hangover and morning sickness from pregnancy. This might be due to B6's mild diuretic effect.	Vitamin B6 Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Vitamin B6 is a water-soluble vitamin. Pyridoxal phosphate (PLP) is the active form and is a cofactor in many reactions of amino acid metabolism, including transamination, deamination, and decarboxylation. PLP also is necessary for the enzymatic reaction governing the release of glucose from glycogen. # History Vitamin B6 is a water-soluble compound that was discovered in the 1930s during nutrition studies on rats. The vitamin was named pyridoxine to indicate its structural homology to pyridine. Later it was shown that vitamin B6 could exist in two other, slightly different, chemical forms, termed pyridoxal and pyridoxamine. All three forms of vitamin B6 are precursors of an activated compound known as pyridoxal 5'-phosphate (PLP), which plays a vital role as the cofactor of a large number of essential enzymes in the human body. Enzymes dependent on PLP focus a wide variety of chemical reactions mainly involving amino acids. The reactions carried out by the PLP-dependent enzymes that act on amino acids include transfer of the amino group, decarboxylation, racemization, and beta- or gamma-elimination or replacement. Such versatility arises from the ability of PLP to covalently bind the substrate, and then to act as an electrophilic catalyst, thereby stabilizing different types of carbanionic reaction intermediates. Overall, the Enzyme Commission (EC; http://www.chem.qmul.ac.uk/iubmb/enzyme/ ) has catalogued more than 140 PLP-dependent activities, corresponding to ~4% of all classified activities. In the early 1990s, it was suggested in megadoses as treatment for PMS and clinical depression, but this is no longer considered effective. [1] # Forms Seven forms of this vitamin are known: - pyridoxine (PN). PN is the form that is given as vitamin B6 supplement. - pyridoxine 5'-phosphate (PNP). - pyridoxal (PL). - pyridoxal 5'-phosphate (PLP). PLP is the metabolically active form. - pyridoxamine (PM). - pyridoxamine 5'-phosphate (PMP). - 4-pyridoxic acid (PA). PA is the catabolite which is excreted in the urine. All forms except PA can be interconverted. # Functions Pyridoxal phosphate, the metabolically active form of vitamin B6, is involved in many aspects of macronutrient metabolism, neurotransmitter synthesis, histamine synthesis, hemoglobin synthesis and function and gene expression. Pyridoxal phosphate generally serves as a coenzyme for many reactions and can help facilitate decarboxylation, transamination, racemization, elimination, replacement and beta-group interconversion reactions[2]. ## Amino Acid Metabolism Pyridoxal phosphate (PLP) is a cofactor in transaminases that can catabolize amino acids. PLP is also an essential component of two enzymes that converts methionine to cysteine via two reactions. Low vitamin B6 status will result in decreased activity of these enzymes. PLP is also an essential cofactor for enzymes involved in the metabolism of selenomethionine to selenohomocysteine and then from selenohomocysteine to hydrogen selenide. Vitamin B6 is also required for the conversion of tryptophan to niacin and low vitamin B6 status will impair this conversion[2]. PLP is also used to create physiologically active amines by decarboxylation of amino acids. Some notable examples of this include: histadine to histamine, tryptophan to serotonin, glutamate to GABA (gamma-aminobutyric acid), and dihydroxyphenylalanine to dopamine. ## Gluconeogenesis Vitamin B6 also plays a role in gluconeogenesis. Pyridoxal phosphate can catalyze transamination reactions that are essential for the providing amino acids as a substrate for gluconeogenesis. Also, vitamin B6 is a required coenzyme of glycogen phosphorylase<[2], the enzyme that is necessary for glycogenolysis to occur. ## Lipid Metabolism Vitamin B6 is an essential component of enzymes that facilitate the biosynthesis of sphingolipids[2]. Particularly, the synthesis of ceramide requires PLP. In this reaction serine is decarboxylated and combined with palmitoyl-CoA to form sphinganine which is combined with a fatty acyl CoA to form ceramide. # Metabolic Functions The primary role of vitamin B6 is to act as a coenzyme to many other enzymes in the body that are involved predominately in metabolism. This role is performed by the active form, pyridoxal phosphate. This active form is converted from the two other natural forms founds in food: pyridoxal, pyridoxine and pyridoxamine. Vitamin B6 is involved in the following metabolic processes: - Amino acid, glucose and lipid metabolism - neurotransmitter synthesis - histamine synthesis - hemoglobin synthesis and function - gene expression ## Amino Acid Metabolism Pyridoxal phosphate is involved in almost all amino acid metabolism, from synthesis to breakdown. 1. Transamination: transaminase enzymes needed to breakdown amino acids are dependent on the presence of pyridoxal phosphate. The proper activity of these enzymes are crucial for the process of moving amine groups from one amino acid to another. 2. Transsulfuration: Pyridoxal phosphate is a coenzyme needed for the proper function of the enzymes cystathionine synthase and cystathionase. These enzymes work to transform methionine into cysteine. 3. Selenoamino acid metabolism: Selenomethionine is the primary dietary form of selenium. Pyridoxal phosphate is needed as a cofactor for the enzymes that allow selenium to be used from the dietary form. Pyridoxal phosphate also plays a cofactor role in releasing selenium from selenohomocysteine to produce hydrogen selenide. This hydrogen selenide can then be used to incorporate selenium into selenoproteins<[2]. 4. Vitamin B6 is also required for the conversion of tryptophan to niacin and low vitamin B6 status will impair this conversion[2]. ## Gluconeogenesis Vitamin B6 also plays a role in gluconeogenesis. Pyridoxal phosphate can catalyze transamination reactions that are essential for providing amino acids as a substrate for gluconeogenesis. Also, vitamin B6 is a required coenzyme of glycogen phosphorylase[2], the enzyme that is necessary for glycogenolysis to occur. ## Neurotransmitter Synthesis Pyridoxal phosphate-dependent enzymes play a role in the biosynthesis of four important neurotranmsitters: serotonin, epinephrine, norepinephrine and gamma-aminobutyric acid[2]. ## Histamine Synthesis Pyridoxal phosphate is involved in the metabolism of histamine[2]. ## Hemoglobin Synthesis and Function Pyridoxal phosphate aids in the synthesis of heme and can also bind to two sites on hemoglobin to enhance the oxygen binding of hemoglobin[2]. ## Gene Expression Pyridoxal phosphate has been implicated in increasing or decreasing the expression of certain genes. Increased intracellular levels of the vitamin will lead to a decrease in the transcription of glucocorticoid hormones. Also, vitamin B6 deficiency will lead to the increased expression of albumin mRNA. Also, pyridoxal phosphate will influence gene expression of glycoprotein IIb by interacting with various transcription factors. The result is inhibition of platelet aggregation.[2] # Dietary Reference Intakes The Institute of Medicine notes that "No adverse effects associated with Vitamin B6 from food have been reported. This does not mean that there is no potential for adverse effects resulting from high intakes. Because data on the adverse effects of Vitamin B6 are limited, caution may be warranted. Sensory neuropathy has occurred from high intakes of supplemental forms."[3]Click on the pdf at the end of this sentence to see the Institute of Medicine's Dietary Reference Intake tables for vitamins.[2] # Sources Vitamin B6 is widely distributed in foods in both its free and bound forms. Good sources include meats, whole grain products, vegetables, and nuts. Cooking, storage and processing losses of vitamin B6 vary and in some foods may be more than 50%,[4] depending on the form of vitamer present in the food. Plant foods lose the least during processing as they contain mostly pyridoxine which is far more stable than the pyridoxal or pyridoxamine found in animal foods. For example, milk can lose 30-70% of its vitamin B6 content when dried.[2] # Absorption Vitamin B6 is absorbed in the jejunum and ileum via passive diffusion. With the capacity for absorption being so great, animals are able to absorb quantities much greater than what is needed for physiological demands. The absorption of pyridoxal phosphate and pyridoxamine phosphate involves their phosphorylation catalyzed by a membrane-bound alkaline phosphatase. Those products and non-phosphorylated vitamers in the digestive tract are absorbed by diffusion, which is driven by trapping of the vitamin as 5'-phosphates through the action of phosphorylation (by a pyridoxal kinase) in the jejunal mucosa. The trapped pyridoxine and pyridoxamine are oxidized to pyridoxal phosphate in the tissue.[2] # Excretion The products of vitamin B6 metabolism are excreted in the urine; the major product of which is 4-pyridoxic acid. It has been estimated that 40-60% of ingested vitamin B6is oxidized to 4-pyridoxic acid. Several studies have shown that 4-pyridoxic acid is undetectable in the urine of vitamin B6 deficient subjects, making it a useful clinical marker to assess the vitamin B6 status of an individual.[2] Other products of vitamin B6metabolism that are excreted in the urine when high doses of the vitamin have been given include pyridoxal, pyridoxamine, and pyridoxine and their phosphates. # Deficiencies The classic clinical syndrome for B6 deficiency is a seborrheic dermatitis-like eruption, atrophic glossitis with ulceration, angular cheilitis, conjunctivitis, intertrigo, and neurologic symptoms of somnolence, confusion, and neuropathy.[5] While severe vitamin B6 deficiency results in dermatologic and neurologic changes, less severe cases present with metabolic lesions associated with insufficient acitivities of the coenzyme pyridoxal phosphate. The most prominent of the lesions is due to impaired tryptophan-niacin conversion. This can be detected based on urinary excretion of xanthurenic acid after an oral tryptophan load. Vitamin B6 deficiency can also result from impaired transsulfuration of methionine to cysteine. The pyridoxal phosphate-dependent transaminases and glycogen phosphorylase provide the vitamin with its role in gluconeogenesis, so deprivation of vitamin B6 results in impaired glucose tolerance.[2] A deficiency of vitamin B6 alone is relatively uncommon and often occurs in association with other vitamins of the B complex. The elderly and alcoholics have an increased risk of vitamin B6 deficiency, as well as other micronutrient deficiencies.[6] # Toxicity An overdose of pyridoxine can cause a temporary deadening of certain nerves such as the proprioceptory nerves; causing a feeling of disembodiment common with the loss of proprioception. This condition is reversible when supplementation is stopped.[7] Because adverse effects have only been documented from vitamin B6 supplements and never from food sources, this article only discusses the safety of the supplemental form of vitamin B6 (pyridoxine). Although vitamin B6 is a water-soluble vitamin and is excreted in the urine, very high doses of pyridoxine over long periods of time may result in painful neurological symptoms known as sensory neuropathy. Symptoms include pain and numbness of the extremities, and in severe cases difficulty walking. Sensory neuropathy typically develops at doses of pyridoxine in excess of 1,000 mg per day. However, there have been a few case reports of individuals who developed sensory neuropathies at doses of less than 500 mg daily over a period of months. None of the studies, in which an objective neurological examination was performed, found evidence of sensory nerve damage at intakes of pyridoxine below 200 mg/day. In order to prevent sensory neuropathy in virtually all individuals, the Food and Nutrition Board of the Institute of Medicine set the tolerable upper intake level (UL) for pyridoxine at 100 mg/day for adults. Because placebo-controlled studies have generally failed to show therapeutic benefits of high doses of pyridoxine, there is little reason to exceed the UL of 100 mg/day. Studies have shown, however, that in the case of individuals diagnosed with autism, high doses of vitamin B6 given with magnesium have been found to be beneficial.[8] # Preventive roles and therapeutic uses At least one preliminary study has found that this vitamin may increase dream vividness or the ability to recall dreams.[9] It is thought that this effect may be due to the role this vitamin plays in the conversion of tryptophan to serotonin.[9] The intake of vitamin B6, from either diet or supplements, could cut the risk of Parkinson’s disease by half according to a prospective study from the Netherlands. "Stratified analyses showed that this association was restricted to smokers," wrote the authors.[10] Nutritional supplementation with high dose vitamin B6 and magnesium is claimed to alleviate the symptoms of autism and is one of the most popular complementary and alternative medicine choices for autism. Three small randomized controlled trials have studied this therapy; the smallest one (with 8 individuals) found improved verbal IQ in the treatment group and the other two (with 10 and 15 individuals, respectively) found no significant difference. The short-term side effects seem to be mild, but there may be significant long-term side effects of peripheral neuropathy.[11] Some studies suggest that the B6-magnesium combination can also help attention deficit disorder , citing improvements in hyperactivity, hyperemotivity/aggressiveness and improved school attention. [12] It is also suggested that ingestion of vitamin B6 can alleviate some of the many symptoms of an alcoholic hangover and morning sickness from pregnancy. This might be due to B6's mild diuretic effect.[13]	https://www.wikidoc.org/index.php/Vitamin_B6
6bd37cc9b100d9df74942b7f9c6fc61602d51168	wikidoc	Vulvodynia	Vulvodynia # Overview Vulvodynia refers to a disorder of vulvar pain, burning, and discomfort that interferes with the quality of life. No discernible physical lesion other than perhaps some redness of the skin is present. The cause can sometimes be attributed to trauma, but in other cases its origin is unknown. # Localized Vulvodynia/Vulvar Vestibulitis The condition is one of exclusion and the diseases listed in the differential diagnosis need to be considered. The pain may be generalized or localized in the vulvar region. Localized vulvodynia in the vestibular region is referred to as vulvar vestibulitis and also vestibulodynia. It is unclear if these conditions are manifestations of the same disease process as the differential diagnosis is the same and the cause unknown. The pain may be provoked by contact with an object, or it may be constant. # Possible Causes A wide variety of possible causes and treatments for vulvodynia are currently being explored. Some possible causes include: allergy or other sensitivity to chemicals or organisms normally found in the environment, autoimmune disorder similar to lupus erythematosus, chronic tension or spasm of the muscles of the vulvar area, infection, injury, chemical sensitivity and neuropathy. Some cases seem to be negative outcomes of genital surgery, such as a labiectomy. Dr. John Willems, head, division of obstetrics and gynecology, Scripps Clinic believes that vulvodynia is a subset of fibromyalgia. Vulvodynia is also frequently found in patients suffering from interstitial cystitis. Causes include: - Infections: candidiasis, herpes, HPV - Inflammation: lichen planus - Neoplasm: Paget's disease, vulvar carcinoma - Neurologic disorder: neuralgia secondary to herpes virus, spinal nerve injury # Diagnosis The diagnosis is based on the typical complaints of the patient, essentially normal physical findings, and the absence of identifiable causes per the differential diagnosis. A cotton “swab test” is used to delineate the areas of pain and categorize their severity. Patients often will describe the touch of a cotton ball as extremely painful, like the scraping of a knife. Many sufferers will see several doctors before a correct diagnosis is made. Many gynecologists are not familiar with this family of conditions, but awareness has spread with time. Sufferers are also often hesitant to seek treatment for chronic vulvar pain, especially since many women begin experiencing symptoms around the same time they become sexually active. Moreover, the absence of any visible symptoms means that before being successfully diagnosed many patients are told that the pain is "in their head". # Treatment There is no uniform treatment approach and numerous proposed treatments are based primarily on empirical experience and opinion. Treatment is often very different from physician to physician and many patients will have to change their course of treatment when primary attempts fail. Treatments include: - Vulvar care measures: cotton underwear, no synthetics; avoidance of vulvar irritants (douching, shampoos, perfumes, detergents); water cleaning only (no soaps); cotton menstrual pads; lubrication for intercourse; rinsing and patting dry the vulva after micturition. - Medications: topicals, oral, and injectable medication that include anesthetics, estrogens, tricyclic antidepressants compounded into a topical form or systemic, local steroids. - Diet: a low-oxalate diet (for vulvodynia associated with oxalate kidney stones). - Biofeedback and physical therapy. - Surgery: vestibulectomy. During a vestibulectomy, the innervated fibers are excised. A vaginal extension may be performed, in which vaginal tissue is pulled forward and sewn in place of the removed skin. The guidelines in Vulvovaginal health may be of some help.Patients may also change birth control methods: active birth control may be taken continuously so as to eliminate menstration, which can aggravate symptoms. Sufferers are often encouraged to explore sexual activity besides intercourse, which is often a major source of pain. Dry sex is strongly discouraged as it may cause further irritation, whilst oral sex will often be less painful. Patients may seek the assistance of a sex therapist.	Vulvodynia Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Vulvodynia refers to a disorder of vulvar pain, burning, and discomfort that interferes with the quality of life. No discernible physical lesion other than perhaps some redness of the skin is present. The cause can sometimes be attributed to trauma, but in other cases its origin is unknown. # Localized Vulvodynia/Vulvar Vestibulitis The condition is one of exclusion and the diseases listed in the differential diagnosis need to be considered. The pain may be generalized or localized in the vulvar region. Localized vulvodynia in the vestibular region is referred to as vulvar vestibulitis and also vestibulodynia. It is unclear if these conditions are manifestations of the same disease process as the differential diagnosis is the same and the cause unknown. The pain may be provoked by contact with an object, or it may be constant. # Possible Causes A wide variety of possible causes and treatments for vulvodynia are currently being explored. Some possible causes include: allergy or other sensitivity to chemicals or organisms normally found in the environment, autoimmune disorder similar to lupus erythematosus, chronic tension or spasm of the muscles of the vulvar area, infection, injury, chemical sensitivity and neuropathy. Some cases seem to be negative outcomes of genital surgery, such as a labiectomy. Dr. John Willems, head, division of obstetrics and gynecology, Scripps Clinic believes that vulvodynia is a subset of fibromyalgia. Vulvodynia is also frequently found in patients suffering from interstitial cystitis. Causes include:[1] [2] - Infections: candidiasis, herpes, HPV - Inflammation: lichen planus - Neoplasm: Paget's disease, vulvar carcinoma - Neurologic disorder: neuralgia secondary to herpes virus, spinal nerve injury # Diagnosis The diagnosis is based on the typical complaints of the patient, essentially normal physical findings, and the absence of identifiable causes per the differential diagnosis. A cotton “swab test” is used to delineate the areas of pain and categorize their severity. Patients often will describe the touch of a cotton ball as extremely painful, like the scraping of a knife. Many sufferers will see several doctors before a correct diagnosis is made. Many gynecologists are not familiar with this family of conditions, but awareness has spread with time. Sufferers are also often hesitant to seek treatment for chronic vulvar pain, especially since many women begin experiencing symptoms around the same time they become sexually active. Moreover, the absence of any visible symptoms means that before being successfully diagnosed many patients are told that the pain is "in their head". # Treatment There is no uniform treatment approach and numerous proposed treatments are based primarily on empirical experience and opinion. Treatment is often very different from physician to physician and many patients will have to change their course of treatment when primary attempts fail. Treatments include: - Vulvar care measures: cotton underwear, no synthetics; avoidance of vulvar irritants (douching, shampoos, perfumes, detergents); water cleaning only (no soaps); cotton menstrual pads; lubrication for intercourse; rinsing and patting dry the vulva after micturition. - Medications: topicals, oral, and injectable medication that include anesthetics, estrogens, tricyclic antidepressants compounded into a topical form or systemic, local steroids. - Diet: a low-oxalate diet (for vulvodynia associated with oxalate kidney stones). - Biofeedback and physical therapy. - Surgery: vestibulectomy. During a vestibulectomy, the innervated fibers are excised. A vaginal extension may be performed, in which vaginal tissue is pulled forward and sewn in place of the removed skin. The guidelines in Vulvovaginal health may be of some help.Patients may also change birth control methods: active birth control may be taken continuously so as to eliminate menstration, which can aggravate symptoms. Sufferers are often encouraged to explore sexual activity besides intercourse, which is often a major source of pain. Dry sex is strongly discouraged as it may cause further irritation, whilst oral sex will often be less painful. Patients may seek the assistance of a sex therapist.	https://www.wikidoc.org/index.php/Vulvar_vestibulitis
17753e24d90f03f1aacb901c0e55c8858ac45fde	wikidoc	W:MeSH/doc	W:MeSH/doc # Notes on use The MeSH template helps markup links to /, the U.S. National Library of Medicine (part of National Institutes of Health). ## Parameters - OPTIONAL- the MeSH term. - This is obtained by searching . A search plugin for FireFox, Internet Explorer 7+, and other browsers that use the OpenSearch standard is available at /. - If no MeSH term is specified, the page name is used. ## Examples ### Articles This template may be used within a ref tag when using the scope note field of the MeSH term to define the term at the start of an article. If this is done, be sure that the page name is either a valid MeSH term or a MeSH entry term. Example from the article Diabetes insipidus: Example from the article Syncope: ### Definitions When using MeSH terms for definitions, it is best to state the source only on the bottom of the definition page itself and not to transclude it onto the Related Articles pages which display the definition. For an example, see Amnesia/Definition, which the {{r}} template displays as: This is achieved in the following way, using the {{DefMeSH}} template: # MeSH URLs This template configures the url for: =>>	W:MeSH/doc # Notes on use The MeSH template helps markup links to http://www.nlm.nih.gov/mesh/, the U.S. National Library of Medicine (part of National Institutes of Health). ## Parameters - OPTIONAL- the MeSH term. - This is obtained by searching http://www.nlm.nih.gov/mesh/MBrowser.html. A search plugin for FireFox, Internet Explorer 7+, and other browsers that use the OpenSearch standard is available at http://sumsearch.org/searchplugins/. - If no MeSH term is specified, the page name is used. ## Examples ### Articles This template may be used within a ref tag when using the scope note field of the MeSH term to define the term at the start of an article. If this is done, be sure that the page name is either a valid MeSH term or a MeSH entry term. Example from the article Diabetes insipidus: Example from the article Syncope: ### Definitions When using MeSH terms for definitions, it is best to state the source only on the bottom of the definition page itself and not to transclude it onto the Related Articles pages which display the definition. For an example, see Amnesia/Definition, which the {{r}} template displays as: [1]. This is achieved in the following way, using the {{DefMeSH}} template: # MeSH URLs This template configures the url for: http://www.nlm.nih.gov/cgi/mesh/2015/MB_cgi?term=<<<MeSH term or entry term>>> - ↑	https://www.wikidoc.org/index.php/W:MeSH/doc
d11ad3b37ffa30dca0ab25bf895bbdd201dc4209	wikidoc	Wannarexia	Wannarexia # Background Wannarexia, or anorexic yearning, is a label applied to someone who claims to have anorexia nervosa, or wishes they did. These individuals are also called wannarexic “wanna-be ana” or "anorexic wannabe". The neologism wannarexia is a portmanteau of the latter two terms. The condition is a cultural phenomenon, not a diagnosis. Some people fitting this description may also be diagnosed with eating disorder not otherwise specified (EDNOS). Wannarexia is most common in teenage girls who want to be popular. Wannarexia is likely caused by a combination of cultural and media influences. Author and Personal Performance Coach Susan Kano has written, "Most young women have "anorexic thoughts" and attitudes, and there are no diagnostic criteria for wannarexia. The distinction between anorexia and wannarexia is that anorexics aren't satisfied by their weight loss, while wannarexics are more likely to derive pleasure from weight loss. Many people who actually suffer from the eating disorder anorexia are angry, offended, or frustrated about wannarexia. Although wannarexics may be inspired or motivated by the pro-anorexia, or pro-ana, community that promotes or supports anorexia as a lifestyle choice rather than an eating disorder, they are not welcome in this subculture. Participants in pro-ana web forums only want to associate with "real anorexics" and will shun wannarexics who only diet occasionally, and are not dedicated to the lifestyle full-time. In this context, wannarexic is a pejorative term. # Further reading - Drummond, Katie (2007-08-08). "Wannarexia: When Death Becomes Trendy". Her Active Life. The Final Sprint, LLC. Retrieved 2007-08-25. ...but for many young women, anorexia has become a hot new trend, so common that medical experts have coined a new name, ‘wannarexia,’ to describe the dangerous fad..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} - Forman-Brunell, Miriam (2001). Girlhood in America: an encyclopedia. Santa Barbara, Calif: ABC-CLIO. pp. p. 245. ISBN 1-57607-206-1. With this widespread popularization of the illness, susceptible girls could be heard to say, not "I want to be thin" but "I want to be anorexic.CS1 maint: Extra text (link) - Hardin, P.K. (2003). "Shape-shifting discourses of anorexia nervosa: reconstituting psychopathology". Nursing Inquiry. 10 (4): 209–217. doi:10.1046/j. Retrieved 2007-08-07. ...the focus of this article is on how discourses and institutional practices operate to position young women who take up the subject position of wanting to be diagnosed as anorexic. - Rachael Oakes-Ash (2001). "So you want to be anorexic—join the queue". Good girls do swallow. Edinburgh: Mainstream. ISBN 1-84018-480-9.	Wannarexia Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Background Wannarexia, or anorexic yearning,[1] is a label applied to someone who claims to have anorexia nervosa, or wishes they did.[2] These individuals are also called wannarexic[3] “wanna-be ana”[4] or "anorexic wannabe".[5] The neologism wannarexia is a portmanteau of the latter two terms. The condition is a cultural phenomenon, not a diagnosis.[6] Some people fitting this description may also be diagnosed with eating disorder not otherwise specified (EDNOS). Wannarexia is most common in teenage girls who want to be popular.[6] Wannarexia is likely caused by a combination of cultural and media influences.[3] Author and Personal Performance Coach Susan Kano has written, "Most young women have "anorexic thoughts" and attitudes,[7] and there are no diagnostic criteria for wannarexia.[3] The distinction between anorexia and wannarexia is that anorexics aren't satisfied by their weight loss, while wannarexics are more likely to derive pleasure from weight loss.[3] Many people who actually suffer from the eating disorder anorexia are angry, offended, or frustrated about wannarexia.[3] Although wannarexics may be inspired or motivated by the pro-anorexia, or pro-ana, community that promotes or supports anorexia as a lifestyle choice rather than an eating disorder,[8] they are not welcome in this subculture. Participants in pro-ana web forums only want to associate with "real anorexics" and will shun wannarexics who only diet occasionally, and are not dedicated to the lifestyle full-time. In this context, wannarexic is a pejorative term.[9] # Further reading - Drummond, Katie (2007-08-08). "Wannarexia: When Death Becomes Trendy". Her Active Life. The Final Sprint, LLC. Retrieved 2007-08-25. ...but for many young women, anorexia has become a hot new trend, so common that medical experts have coined a new name, ‘wannarexia,’ to describe the dangerous fad..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} - Forman-Brunell, Miriam (2001). Girlhood in America: an encyclopedia. Santa Barbara, Calif: ABC-CLIO. pp. p. 245. ISBN 1-57607-206-1. With this widespread popularization of the illness, susceptible girls could be heard to say, not "I want to be thin" but "I want to be anorexic.CS1 maint: Extra text (link) - Hardin, P.K. (2003). "Shape-shifting discourses of anorexia nervosa: reconstituting psychopathology". Nursing Inquiry. 10 (4): 209–217. doi:10.1046/j. Retrieved 2007-08-07. ...the focus of this article is on how discourses and institutional practices operate to position young women who take up the subject position of wanting to be diagnosed as anorexic. - Rachael Oakes-Ash (2001). "So you want to be anorexic—join the queue". Good girls do swallow. Edinburgh: Mainstream. ISBN 1-84018-480-9.[5]	https://www.wikidoc.org/index.php/Wannarexia
62c4c579d2d10d599d59d6c14820849a76dcb344	wikidoc	Warming up	Warming up A warm-up is usually performed before participating in technical sports or exercising. A warm-up generally consists of a gradual increase in intensity in physical activity (pulse raiser), a joint mobility exercise, stretching and a sport related activity. For example, before running or playing an intense sport one might slowly jog to warm muscles and increase heart rate. It is important that warm ups should be specific to the exercise that will follow, which means that exercises (of warm up) should prepare the muscles to be used and to activate the energy systems that are required for that particular activity. The risks and benefits of combining stretching with warming up are mixed and in some cases disputed. Warming up prepares the body mentally & physically. # Benefits A warm-up will improve the effectiveness of training and should be done before every training session. This is fundamental to a safe practice. - Direct physical effects: Release of adrenaline Increased heart rate Enables oxygen in the blood to travel with greater speed Increased production of synovial fluid located between the joints to reduce friction Allows joints to move more efficiently Dilation of capillaries Enables oxygen in the blood to travel at a higher volume Increase of temperature in the muscles Decreased viscosity of blood Enables oxygen in the blood to travel with greater speed Facilitates enzyme activity Encourages the dissociation of oxygen from haemoglobin Decreased viscosity within the muscle Greater extensibility and elasticity of muscle fibres Increased force and speed of contraction Increase of muscle metabolism Supply of energy through breakdown of glycogen Increase in speed of nerve impulse conduction. - Release of adrenaline Increased heart rate Enables oxygen in the blood to travel with greater speed Increased production of synovial fluid located between the joints to reduce friction Allows joints to move more efficiently Dilation of capillaries Enables oxygen in the blood to travel at a higher volume - Increased heart rate Enables oxygen in the blood to travel with greater speed Increased production of synovial fluid located between the joints to reduce friction Allows joints to move more efficiently - Enables oxygen in the blood to travel with greater speed - Increased production of synovial fluid located between the joints to reduce friction Allows joints to move more efficiently - Allows joints to move more efficiently - Dilation of capillaries Enables oxygen in the blood to travel at a higher volume - Enables oxygen in the blood to travel at a higher volume - Increase of temperature in the muscles Decreased viscosity of blood Enables oxygen in the blood to travel with greater speed Facilitates enzyme activity Encourages the dissociation of oxygen from haemoglobin Decreased viscosity within the muscle Greater extensibility and elasticity of muscle fibres Increased force and speed of contraction - Decreased viscosity of blood Enables oxygen in the blood to travel with greater speed - Enables oxygen in the blood to travel with greater speed - Facilitates enzyme activity - Encourages the dissociation of oxygen from haemoglobin - Decreased viscosity within the muscle Greater extensibility and elasticity of muscle fibres Increased force and speed of contraction - Greater extensibility and elasticity of muscle fibres Increased force and speed of contraction - Increased force and speed of contraction - Increase of muscle metabolism Supply of energy through breakdown of glycogen - Supply of energy through breakdown of glycogen - Increase in speed of nerve impulse conduction. A comprehensive warm-up programme has been found to decrease injuries in soccer. # Why athletes warm up Athletes not only warm up to physically prepare their bodies for training or competition but also to mentally warm themselves up. Warm ups are a crucial part of performance. If completed correctly they enable the body to perform at its peak performing ability at the current time. There are three different types of warm ups; gradual increase of physical activity to raise the pulse (Eg. cycling), a joint mobility exercise, stretching and a sport related activity (Eg. dribbling for basketball). A warm up should be specific to the task required to perform in order to activate the correct energy systems and prepare the correct muscles. There are many beneficial effects from warm ups including; - Increased heart rate. This enables oxygen in the blood to travel faster meaning the muscles fatigue slower, also, the synovial fluid between the joints is produced more to reduce friction in the joints, the capillaries dilate and it lets more oxygen travel in the blood. - Higher temperature in the muscles. This decreases the thickness of the blood-letting the oxygen travel to different parts of the body quicker, it also decreases the viscosity within the muscle, removes lactic acid, lets the muscles fibres have greater extensibility and elasticity and an increase in force and contraction of muscles. # Types of warm-up - Ballistic Stretches: Ballistic Stretches (involving bouncing or jerking) are purported to help extend limbs more during exercise to allow an individual to be more agile and flexible. However this type of stretching can cause injury and is not generally recommended. - Static Stretches: Flexing the muscles to help prevent injury and allow greater flexibility and agility. Note that some sources discourage static stretching as muscles are more prone to damage if stretched while cold.	Warming up Template:Articleissues A warm-up is usually performed before participating in technical sports or exercising. A warm-up generally consists of a gradual increase in intensity in physical activity (pulse raiser), a joint mobility exercise, stretching and a sport related activity. For example, before running or playing an intense sport one might slowly jog to warm muscles and increase heart rate. It is important that warm ups should be specific to the exercise that will follow, which means that exercises (of warm up) should prepare the muscles to be used and to activate the energy systems that are required for that particular activity. The risks and benefits of combining stretching with warming up are mixed and in some cases disputed. Warming up prepares the body mentally & physically. # Benefits A warm-up will improve the effectiveness of training and should be done before every training session. This is fundamental to a safe practice. - Direct physical effects: Release of adrenaline Increased heart rate Enables oxygen in the blood to travel with greater speed Increased production of synovial fluid located between the joints to reduce friction Allows joints to move more efficiently Dilation of capillaries Enables oxygen in the blood to travel at a higher volume Increase of temperature in the muscles Decreased viscosity of blood Enables oxygen in the blood to travel with greater speed Facilitates enzyme activity Encourages the dissociation of oxygen from haemoglobin Decreased viscosity within the muscle Greater extensibility and elasticity of muscle fibres Increased force and speed of contraction Increase of muscle metabolism Supply of energy through breakdown of glycogen Increase in speed of nerve impulse conduction. - Release of adrenaline Increased heart rate Enables oxygen in the blood to travel with greater speed Increased production of synovial fluid located between the joints to reduce friction Allows joints to move more efficiently Dilation of capillaries Enables oxygen in the blood to travel at a higher volume - Increased heart rate Enables oxygen in the blood to travel with greater speed Increased production of synovial fluid located between the joints to reduce friction Allows joints to move more efficiently - Enables oxygen in the blood to travel with greater speed - Increased production of synovial fluid located between the joints to reduce friction Allows joints to move more efficiently - Allows joints to move more efficiently - Dilation of capillaries Enables oxygen in the blood to travel at a higher volume - Enables oxygen in the blood to travel at a higher volume - Increase of temperature in the muscles Decreased viscosity of blood Enables oxygen in the blood to travel with greater speed Facilitates enzyme activity Encourages the dissociation of oxygen from haemoglobin Decreased viscosity within the muscle Greater extensibility and elasticity of muscle fibres Increased force and speed of contraction - Decreased viscosity of blood Enables oxygen in the blood to travel with greater speed - Enables oxygen in the blood to travel with greater speed - Facilitates enzyme activity - Encourages the dissociation of oxygen from haemoglobin - Decreased viscosity within the muscle Greater extensibility and elasticity of muscle fibres Increased force and speed of contraction - Greater extensibility and elasticity of muscle fibres Increased force and speed of contraction - Increased force and speed of contraction - Increase of muscle metabolism Supply of energy through breakdown of glycogen - Supply of energy through breakdown of glycogen - Increase in speed of nerve impulse conduction. A comprehensive warm-up programme has been found to decrease injuries in soccer.[1] # Why athletes warm up Athletes not only warm up to physically prepare their bodies for training or competition but also to mentally warm themselves up. Warm ups are a crucial part of performance. If completed correctly they enable the body to perform at its peak performing ability at the current time. There are three different types of warm ups; gradual increase of physical activity to raise the pulse (Eg. cycling), a joint mobility exercise, stretching and a sport related activity (Eg. dribbling for basketball). A warm up should be specific to the task required to perform in order to activate the correct energy systems and prepare the correct muscles. There are many beneficial effects from warm ups including; • Increased heart rate. This enables oxygen in the blood to travel faster meaning the muscles fatigue slower, also, the synovial fluid between the joints is produced more to reduce friction in the joints, the capillaries dilate and it lets more oxygen travel in the blood. • Higher temperature in the muscles. This decreases the thickness of the blood-letting the oxygen travel to different parts of the body quicker, it also decreases the viscosity within the muscle, removes lactic acid, lets the muscles fibres have greater extensibility and elasticity and an increase in force and contraction of muscles. # Types of warm-up - Ballistic Stretches: Ballistic Stretches (involving bouncing or jerking) are purported to help extend limbs more during exercise to allow an individual to be more agile and flexible. However this type of stretching can cause injury and is not generally recommended. - Static Stretches: Flexing the muscles to help prevent injury and allow greater flexibility and agility. Note that some sources discourage static stretching as muscles are more prone to damage if stretched while cold.	https://www.wikidoc.org/index.php/Warming_up
092b1feafe6d01c33134d4bfd8837d47cc5f75d2	wikidoc	Wastewater	Wastewater Wastewater is any water that has been adversely affected in quality by anthropogenic influence. It comprises liquid waste discharged by domestic residences, commercial properties, industry, and/or agriculture and can encompass a wide range of potential contaminants and concentrations. In the most common usage, it refers to the municipal wastewater that contains a broad spectrum of contaminants resulting from the mixing of wastewaters from different sources. Sewage is correctly the subset of wastewater that is contaminated with faeces or urine, but is often used to mean any waste water. "Sewage" includes domestic, municipal, or industrial liquid waste products disposed of, usually via a pipe or sewer or similar structure, sometimes in a cesspool emptier. The physical infrastructure, including pipes, pumps, screens, channels etc. used to convey sewage from its origin to the point of eventual treatment or disposal is termed sewerage. # Wastewater origin Wastewater or sewage can come from (text in brackets indicates likely inclusions or contaminants) :- - Human waste, usually from lavatories: (fæces, used toilet paper, wipes, urine, other bodily fluids) also known as black water - Cesspit leakage - Septic tank discharge - Sewage treatment plant discharge - Washing water (personal, clothes, floors, dishes, etc.) also known as greywater or sullage - Rainfall collected on roofs, yards, hard-standings, etc. (traces of oils and fuel but generally clean) - Groundwater infiltrated into sewerage. - Surplus manufactured liquids from domestic sources (drinks, cooking oil, pesticides, lubricating oil, paint, cleaning liquids, etc.) - Urban rainfall run-off from roads, car-parks, roofs, side-walks or pavements (contains oils, animal faeces, litter, fuel residues, rubber residues, metals from vehicle exhausts etc) - Seawater ingress (salt, micro-biota, high volumes) - Direct ingress of river water (micro-biota, high volumes) - Direct ingress of man-made liquids (illegal disposal of pesticides, used oils, etc.) - Highway drainage (oil, de-icing agents, rubber residues) - Storm drains (almost anything including cars, shopping trolleys, trees, cattle etc.) - Black water - surface water contaminated by sewage - Industrial waste:- - industrial site drainage (silt, sand, alkali, oil, chemical) Industrial cooling waters (biocides, heat, slimes, silt) Industrial process waters Organic - bio-degradable - includes waste from abattoirs and creameries and ice-cream manufacture. Organic - non bio-degradable or difficult to treat - for example Pharmaceutical or Pesticide manufacturing Inorganic - for example from the metalworking industry extreme pH - from acid/alkali manufacturing, metal plating Toxic - e.g. from metal plating, cyanide production, pesticide manufacturing Solids and Emulsions - e.g. Paper manufacturing, food stuffs, lubricating and hydraulic oil manufacture agricultural drainage - direct and diffuse - Industrial cooling waters (biocides, heat, slimes, silt) - Industrial process waters - Organic - bio-degradable - includes waste from abattoirs and creameries and ice-cream manufacture. - Organic - non bio-degradable or difficult to treat - for example Pharmaceutical or Pesticide manufacturing - Inorganic - for example from the metalworking industry - extreme pH - from acid/alkali manufacturing, metal plating - Toxic - e.g. from metal plating, cyanide production, pesticide manufacturing - Solids and Emulsions - e.g. Paper manufacturing, food stuffs, lubricating and hydraulic oil manufacture - agricultural drainage - direct and diffuse # Wastewater constituents The composition of wastewater varies widely. This is a partial list of what it may contain: - Water ( > 95%) which is often added during flushing to carry the waste down a drain - Pathogens such as bacteria, viruses, prions and parasitic worms. - Non-pathogenic bacteria (> 100,000 / ml for sewage) - Organic particles such as faeces, hairs, food, vomit, paper fibers, plant material, humus, etc. - Soluble organic material such as urea, fruit sugars, soluble proteins, drugs, pharmaceuticals, etc. - Inorganic particles such as sand, grit, metal particles, ceramics, etc. - Soluble inorganic material such as ammonia, road-salt, sea-salt, cyanide, hydrogen sulfide, thiocyanates, thiosulfates, etc. - Animals such as protozoa, insects, arthropods, small fish, etc. - Macro-solids such as sanitary napkins, nappies/diapers, condoms, needles, children's toys, dead pets, body parts, etc. - Gases such as hydrogen sulfide, carbon dioxide, methane, etc. - Emulsions such as paints, adhesives, mayonnaise, hair colorants, emulsified oils, etc. - Toxins such as pesticides, poisons, herbicides, etc. # Wastewater quality indicators Any oxidizable material present in a natural waterway or in an industrial wastewater will be oxidized both by biochemical (bacterial) or chemical processes. The result is that the oxygen content of the water will be decreased. Basically, the reaction for biochemical oxidation may be written as: Oxygen consumption by reducing chemicals such as sulfides and nitrites is typified as follows: Since all natural waterways contain bacteria and nutrient, almost any waste compounds introduced into such waterways will initiate biochemical reactions (such as shown above). Those biochemical reactions create what is measured in the laboratory as the Biochemical oxygen demand (BOD). Oxidizable chemicals (such as reducing chemicals) introduced into a natural water will similarly initiate chemical reactions (such as shown above). Those chemical reactions create what is measured in the laboratory as the Chemical oxygen demand (COD). Both the BOD and COD tests are a measure of the relative oxygen-depletion effect of a waste contaminant. Both have been widely adopted as a measure of pollution effect. The BOD test measures the oxygen demand of biodegradable pollutants whereas the COD test measures the oxygen demand of biogradable pollutants plus the oxygen demand of non-biodegradable oxidizable pollutants. The so-called 5-day BOD measures the amount of oxygen consumed by biochemical oxidation of waste contaminants in a 5-day period. The total amount of oxygen consumed when the biochemical reaction is allowed to proceed to completion is called the Ultimate BOD. The Ultimate BOD is too time consuming, so the 5-day BOD has almost universally been adopted as a measure of relative pollution effect. There are also many different COD tests. Perhaps, the most common is the 4-hour COD. It should be emphasized that there is no generalized correlation between the 5-day BOD and the Ultimate BOD. Likewise, there is no generalized correlation between BOD and COD. It is possible to develop such correlations for a specific waste contaminant in a specific wastewater stream ... but such correlations cannot be generalized for use with any other waste contaminants or wastewater streams. The laboratory test procedures for the determining the above oxygen demands are detailed in the following sections of the "Standard Methods For the Examination Of Water and Wastewater" available at www.standardmethods.org: - 5-day BOD and Ultimate BOD: Sections 5210B and 5210C - COD: Section 5220 # Sewage disposal In some urban areas, sewage is carried separately in sanitary sewers and runoff from streets is carried in storm drains. Access to either of these is typically through a manhole. During high precipitation periods a sanitary sewer overflow can occur, causing potential public health and ecological damage. Sewage may drain directly into major watersheds with minimal or no treatment. When untreated, sewage can have serious impacts on the quality of an environment and on the health of people. Pathogens can cause a variety of illnesses. Some chemicals pose risks even at very low concentrations and can remain a threat for long periods of time because of bioaccumulation in animal or human tissue. # Treatment There are numerous processes that can be used to clean up waste waters depending on the type and extent of contamination. Most wastewater is treated in industrial-scale wastewater treatment plants (WWTPs) which may include physical, chemical and biological treatment processes. However, the use of septic tanks and other On-Site Sewage Facilities (OSSF) is widespread in rural areas, serving up to one quarter of the homes in the U.S. The most important aerobic treatment system is the activated sludge process, based on the maintenance and recirculation of a complex biomass composed by micro-organisms able to absorb and adsorb the organic matter carried in the wastewater. Anaerobic processes are widely applied in the treatment of industrial wastewaters and biological sludge. Some wastewater may be highly treated and reused as reclaimed water. For some waste waters ecological approaches using reed bed systems such as constructed wetlands may be appropriate. Modern systems include tertiary treatment by micro filtration or synthetic membranes. After membrane filtration, the treated wastewater is indistinguishable from waters of natural origin of drinking quality. Nitrates can be removed from wastewater by microbial denitrification, for which a small amount of methanol is typically added to provide the bacteria with a source of carbon. Ozone Waste Water Treatment is also growing in popularity, and requires the use of an ozone generator, which decontaminates the water as Ozone bubbles percolate through the tank. Disposal of wastewaters from an industrial plant is a difficult and costly problem. Most petroleum refineries, chemical and petrochemical plants have onsite facilities to treat their wastewaters so that the pollutant concentrations in the treated wastewater comply with the local and/or national regulations regarding disposal of wastewaters into community treatment plants or into rivers, lakes or oceans. # Reuse Treated wastewater can be reused as drinking water (Singapore), in industry (cooling towers), in artificial recharge of aquifers, in agriculture (70% of Israel's irrigated agriculture is based on highly purified wastewater) and in the rehabilitation of natural ecosystems (Florida's Everglades). # Etymology The words "sewage" and "sewer" came from Old French essouier = "to drain", which came from Latin exaquāre. Their formal Latin antecedents are exaquāticum and exaquārium.	Wastewater Template:Pollution Wastewater is any water that has been adversely affected in quality by anthropogenic influence. It comprises liquid waste discharged by domestic residences, commercial properties, industry, and/or agriculture and can encompass a wide range of potential contaminants and concentrations. In the most common usage, it refers to the municipal wastewater that contains a broad spectrum of contaminants resulting from the mixing of wastewaters from different sources. Sewage is correctly the subset of wastewater that is contaminated with faeces or urine, but is often used to mean any waste water. "Sewage" includes domestic, municipal, or industrial liquid waste products disposed of, usually via a pipe or sewer or similar structure, sometimes in a cesspool emptier. The physical infrastructure, including pipes, pumps, screens, channels etc. used to convey sewage from its origin to the point of eventual treatment or disposal is termed sewerage. # Wastewater origin Template:Prose Wastewater or sewage can come from (text in brackets indicates likely inclusions or contaminants) :- - Human waste, usually from lavatories: (fæces, used toilet paper, wipes, urine, other bodily fluids) also known as black water - Cesspit leakage - Septic tank discharge - Sewage treatment plant discharge - Washing water (personal, clothes, floors, dishes, etc.) also known as greywater or sullage - Rainfall collected on roofs, yards, hard-standings, etc. (traces of oils and fuel but generally clean) - Groundwater infiltrated into sewerage. - Surplus manufactured liquids from domestic sources (drinks, cooking oil, pesticides, lubricating oil, paint, cleaning liquids, etc.) - Urban rainfall run-off from roads, car-parks, roofs, side-walks or pavements (contains oils, animal faeces, litter, fuel residues, rubber residues, metals from vehicle exhausts etc) - Seawater ingress (salt, micro-biota, high volumes) - Direct ingress of river water (micro-biota, high volumes) - Direct ingress of man-made liquids (illegal disposal of pesticides, used oils, etc.) - Highway drainage (oil, de-icing agents, rubber residues) - Storm drains (almost anything including cars, shopping trolleys, trees, cattle etc.) - Black water - surface water contaminated by sewage - Industrial waste:- - industrial site drainage (silt, sand, alkali, oil, chemical) Industrial cooling waters (biocides, heat, slimes, silt) Industrial process waters Organic - bio-degradable - includes waste from abattoirs and creameries and ice-cream manufacture. Organic - non bio-degradable or difficult to treat - for example Pharmaceutical or Pesticide manufacturing Inorganic - for example from the metalworking industry extreme pH - from acid/alkali manufacturing, metal plating Toxic - e.g. from metal plating, cyanide production, pesticide manufacturing Solids and Emulsions - e.g. Paper manufacturing, food stuffs, lubricating and hydraulic oil manufacture agricultural drainage - direct and diffuse - Industrial cooling waters (biocides, heat, slimes, silt) - Industrial process waters - Organic - bio-degradable - includes waste from abattoirs and creameries and ice-cream manufacture. - Organic - non bio-degradable or difficult to treat - for example Pharmaceutical or Pesticide manufacturing - Inorganic - for example from the metalworking industry - extreme pH - from acid/alkali manufacturing, metal plating - Toxic - e.g. from metal plating, cyanide production, pesticide manufacturing - Solids and Emulsions - e.g. Paper manufacturing, food stuffs, lubricating and hydraulic oil manufacture - agricultural drainage - direct and diffuse # Wastewater constituents Template:Prose The composition of wastewater varies widely. This is a partial list of what it may contain: - Water ( > 95%) which is often added during flushing to carry the waste down a drain - Pathogens such as bacteria, viruses, prions and parasitic worms. - Non-pathogenic bacteria (> 100,000 / ml for sewage) - Organic particles such as faeces, hairs, food, vomit, paper fibers, plant material, humus, etc. - Soluble organic material such as urea, fruit sugars, soluble proteins, drugs, pharmaceuticals, etc. - Inorganic particles such as sand, grit, metal particles, ceramics, etc. - Soluble inorganic material such as ammonia, road-salt, sea-salt, cyanide, hydrogen sulfide, thiocyanates, thiosulfates, etc. - Animals such as protozoa, insects, arthropods, small fish, etc. - Macro-solids such as sanitary napkins, nappies/diapers, condoms, needles, children's toys, dead pets, body parts, etc. - Gases such as hydrogen sulfide, carbon dioxide, methane, etc. - Emulsions such as paints, adhesives, mayonnaise, hair colorants, emulsified oils, etc. - Toxins such as pesticides, poisons, herbicides, etc. # Wastewater quality indicators Any oxidizable material present in a natural waterway or in an industrial wastewater will be oxidized both by biochemical (bacterial) or chemical processes. The result is that the oxygen content of the water will be decreased. Basically, the reaction for biochemical oxidation may be written as: Oxygen consumption by reducing chemicals such as sulfides and nitrites is typified as follows: Since all natural waterways contain bacteria and nutrient, almost any waste compounds introduced into such waterways will initiate biochemical reactions (such as shown above). Those biochemical reactions create what is measured in the laboratory as the Biochemical oxygen demand (BOD). Oxidizable chemicals (such as reducing chemicals) introduced into a natural water will similarly initiate chemical reactions (such as shown above). Those chemical reactions create what is measured in the laboratory as the Chemical oxygen demand (COD). Both the BOD and COD tests are a measure of the relative oxygen-depletion effect of a waste contaminant. Both have been widely adopted as a measure of pollution effect. The BOD test measures the oxygen demand of biodegradable pollutants whereas the COD test measures the oxygen demand of biogradable pollutants plus the oxygen demand of non-biodegradable oxidizable pollutants. The so-called 5-day BOD measures the amount of oxygen consumed by biochemical oxidation of waste contaminants in a 5-day period. The total amount of oxygen consumed when the biochemical reaction is allowed to proceed to completion is called the Ultimate BOD. The Ultimate BOD is too time consuming, so the 5-day BOD has almost universally been adopted as a measure of relative pollution effect. There are also many different COD tests. Perhaps, the most common is the 4-hour COD. It should be emphasized that there is no generalized correlation between the 5-day BOD and the Ultimate BOD. Likewise, there is no generalized correlation between BOD and COD. It is possible to develop such correlations for a specific waste contaminant in a specific wastewater stream ... but such correlations cannot be generalized for use with any other waste contaminants or wastewater streams. The laboratory test procedures for the determining the above oxygen demands are detailed in the following sections of the "Standard Methods For the Examination Of Water and Wastewater" available at www.standardmethods.org: - 5-day BOD and Ultimate BOD: Sections 5210B and 5210C - COD: Section 5220 # Sewage disposal In some urban areas, sewage is carried separately in sanitary sewers and runoff from streets is carried in storm drains. Access to either of these is typically through a manhole. During high precipitation periods a sanitary sewer overflow can occur, causing potential public health and ecological damage. Sewage may drain directly into major watersheds with minimal or no treatment. When untreated, sewage can have serious impacts on the quality of an environment and on the health of people. Pathogens can cause a variety of illnesses. Some chemicals pose risks even at very low concentrations and can remain a threat for long periods of time because of bioaccumulation in animal or human tissue. # Treatment There are numerous processes that can be used to clean up waste waters depending on the type and extent of contamination. Most wastewater is treated in industrial-scale wastewater treatment plants (WWTPs) which may include physical, chemical and biological treatment processes. However, the use of septic tanks and other On-Site Sewage Facilities (OSSF) is widespread in rural areas, serving up to one quarter of the homes in the U.S. The most important aerobic treatment system is the activated sludge process, based on the maintenance and recirculation of a complex biomass composed by micro-organisms able to absorb and adsorb the organic matter carried in the wastewater. Anaerobic processes are widely applied in the treatment of industrial wastewaters and biological sludge. Some wastewater may be highly treated and reused as reclaimed water. For some waste waters ecological approaches using reed bed systems such as constructed wetlands may be appropriate. Modern systems include tertiary treatment by micro filtration or synthetic membranes. After membrane filtration, the treated wastewater is indistinguishable from waters of natural origin of drinking quality. Nitrates can be removed from wastewater by microbial denitrification, for which a small amount of methanol is typically added to provide the bacteria with a source of carbon. Ozone Waste Water Treatment is also growing in popularity, and requires the use of an ozone generator, which decontaminates the water as Ozone bubbles percolate through the tank. Disposal of wastewaters from an industrial plant is a difficult and costly problem. Most petroleum refineries, chemical and petrochemical plants[1][2] have onsite facilities to treat their wastewaters so that the pollutant concentrations in the treated wastewater comply with the local and/or national regulations regarding disposal of wastewaters into community treatment plants or into rivers, lakes or oceans. # Reuse Treated wastewater can be reused as drinking water (Singapore), in industry (cooling towers), in artificial recharge of aquifers, in agriculture (70% of Israel's irrigated agriculture is based on highly purified wastewater)[citation needed] and in the rehabilitation of natural ecosystems (Florida's Everglades). # Etymology The words "sewage" and "sewer" came from Old French essouier = "to drain", which came from Latin exaquāre. Their formal Latin antecedents are exaquāticum and exaquārium.	https://www.wikidoc.org/index.php/Wastewater
c9a094c52219f8e45d62a89999d5e522d24228af	wikidoc	Web colors	Web colors # Overview Here are some colors that you should be able to reference directly by Color Name, rather than having to put in an obscure Hexacode. # Understanding WebSafe Colors: The Color Palette Used on WikiDoc: A number of colors are defined by web browsers such as Internet Explorer or Mozilla Firefox. A particular browser may not recognize all of these colors, but as of 2005 all modern general-use browsers support the full list. Many of these colors are from the list of X11 color names distributed with the X Window System. ... The complete list of web X11 colors from the CSS3 specification, along with their hexadecimal equivalents, are listed below. For an alphabetical list and the original reference, see #x11-color. However, according to w3schools.com, there are only 16 color names supported by the W3C - aqua, black, blue, fuchsia, gray, green, lime, maroon, navy, olive, purple, red, silver, teal, white, and yellow - and you should use the hexadecimal color values for anything else. Why this Table has been copied from Wikipedia: All of these color words should be safe to use on the wikidoc. If one of these colors does not appear (the colorbox looks white instead of colored), please STRIKETHROUGH the color name and write "broken" in the colorbox, as shown in the first example in the Table. Thanks! # X11 Color Names	Web colors Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Here are some colors that you should be able to reference directly by Color Name, rather than having to put in an obscure Hexacode. # Understanding WebSafe Colors: The Color Palette Used on WikiDoc: A number of colors are defined by web browsers such as Internet Explorer or Mozilla Firefox. A particular browser may not recognize all of these colors, but as of 2005 all modern general-use browsers support the full list. Many of these colors are from the list of X11 color names distributed with the X Window System. ... The complete list of web X11 colors from the CSS3 specification, along with their hexadecimal equivalents, are listed below. For an alphabetical list and the original reference, see http://www.w3.org/TR/2001/WD-css3-color-20010305#x11-color. However, according to w3schools.com, there are only 16 color names supported by the W3C - aqua, black, blue, fuchsia, gray, green, lime, maroon, navy, olive, purple, red, silver, teal, white, and yellow - and you should use the hexadecimal color values for anything else. Why this Table has been copied from Wikipedia: All of these color words should be safe to use on the wikidoc. If one of these colors does not appear (the colorbox looks white instead of colored), please STRIKETHROUGH the color name and write "broken" in the colorbox, as shown in the first example in the Table. Thanks! # X11 Color Names Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Web_colors
022bef4bd4cd00b41705d6ce75917f0a5f1a028c	wikidoc	Weber test	Weber test The Weber test is a quick screening test for hearing. It can detect unilateral (one-sided) conductive hearing loss and unilateral sensorineural hearing loss. # Performance In the Weber test a tuning fork (either 256 or 512 Hz) is struck and the stem of the fork is placed on the top of the patient's skull - equal distance from the patient's ears, in the middle of the forehead - equal distance from the patient's ears or above the upper lip over the teeth. The patient is asked to report in which ear the sound is heard louder. (Images courtesy of Charlie Goldberg, M.D., UCSD School of Medicine and VA Medical Center, San Diego, California) - 512 hertz tuning fork - Weber test # Detection of conductive hearing loss A patient with a unilateral (one-sided) conductive hearing loss would hear the tuning fork loudest in the affected ear. This is because the conduction problem masks the ambient noise of the room, whilst the well-functioning inner ear picks the sound up via the bones of the skull causing it to be perceived as a louder sound than in the unaffected ear. Another theory, however, is based on the occlusion effect described by Tonndorf et al in 1966. Lower frequency sounds (as made by the 512Hz fork) that are transferred through the bone to the ear canal escapes from the canal. If an occulusion is present, the sound cannot escape and appears louder on the ear with the conductive hearing loss Conductive hearing loss can be mimicked by plugging one ear with a finger and performing the Rinne and Weber tests, which will help clarify the above. The simulation of the Weber test is the basic for the Bing test. # Detection of sensorineural hearing loss A patient with a unilateral sensorineural hearing loss would hear the sound loudest in the unaffected ear, because the affected ear is less effective at picking up sound even if it is transmitted directly by conduction into the inner ear. # Incompleteness This test is most useful in individuals with hearing that is different between the two ears. It cannot confirm normal hearing because it does not measure sound sensitivity in a quantitative manner. Hearing defects affecting both ears equally, as in Presbycusis will produce an apparently normal test result. ## Additional Rinne test Nevertheless, by complementing with the Rinne test, a quick screening test can be made. Still, these and are no replacement for formal audiometry. An additional Rinne test determines if unilateral (one-sided) hearing loss is due to sensorineural loss ("nerve deafness") or due to conductive loss (i.e. from ear wax impaction, ruptured/ scarred eardrum, or ear ossicle dysfunction). The Rinne test is almost always performed with the Weber test to establish in which ear bone conduction is loudest. Using the information from the Weber test (which ear has the loudest perceived sound through bone conduction) and the Rinne test (which ear has better hearing by air conduction) and the perceived hearing loss (which ear is hard of hearing), a determination of sensorineural or conductive hearing loss can be made. If the Rinne test shows that air conduction is greater than bone conduction in both ears and the Weber test lateralizes to a particular ear, then there is sensorineural hearing loss in the opposite (weaker) ear. If the Weber test lateralizes to the "weaker" ear and the Rinne test demonstrates better bone conduction than air conduction in the "weak" ear, conductive hearing loss is confirmed. If the Weber test lateralizes to the "stronger" ear and the Rinne test indicates weaker air conduction in the "weaker" ear, a combined hearing loss is likely. # See Also - Neurological examination it:Prova di Weber	Weber test Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] The Weber test is a quick screening test for hearing. It can detect unilateral (one-sided) conductive hearing loss and unilateral sensorineural hearing loss. # Performance In the Weber test a tuning fork (either 256 or 512 Hz) is struck and the stem of the fork is placed on the top of the patient's skull - equal distance from the patient's ears, in the middle of the forehead - equal distance from the patient's ears or above the upper lip over the teeth. The patient is asked to report in which ear the sound is heard louder. (Images courtesy of Charlie Goldberg, M.D., UCSD School of Medicine and VA Medical Center, San Diego, California) - 512 hertz tuning fork - Weber test # Detection of conductive hearing loss A patient with a unilateral (one-sided) conductive hearing loss would hear the tuning fork loudest in the affected ear. This is because the conduction problem masks the ambient noise of the room, whilst the well-functioning inner ear picks the sound up via the bones of the skull causing it to be perceived as a louder sound than in the unaffected ear. Another theory, however, is based on the occlusion effect described by Tonndorf et al in 1966. Lower frequency sounds (as made by the 512Hz fork) that are transferred through the bone to the ear canal escapes from the canal. If an occulusion is present, the sound cannot escape and appears louder on the ear with the conductive hearing loss Conductive hearing loss can be mimicked by plugging one ear with a finger and performing the Rinne and Weber tests, which will help clarify the above. The simulation of the Weber test is the basic for the Bing test. # Detection of sensorineural hearing loss A patient with a unilateral sensorineural hearing loss would hear the sound loudest in the unaffected ear, because the affected ear is less effective at picking up sound even if it is transmitted directly by conduction into the inner ear. # Incompleteness This test is most useful in individuals with hearing that is different between the two ears. It cannot confirm normal hearing because it does not measure sound sensitivity in a quantitative manner. Hearing defects affecting both ears equally, as in Presbycusis will produce an apparently normal test result. ## Additional Rinne test Nevertheless, by complementing with the Rinne test, a quick screening test can be made. Still, these and are no replacement for formal audiometry. An additional Rinne test determines if unilateral (one-sided) hearing loss is due to sensorineural loss ("nerve deafness") or due to conductive loss (i.e. from ear wax impaction, ruptured/ scarred eardrum, or ear ossicle dysfunction). The Rinne test is almost always performed with the Weber test to establish in which ear bone conduction is loudest. Using the information from the Weber test (which ear has the loudest perceived sound through bone conduction) and the Rinne test (which ear has better hearing by air conduction) and the perceived hearing loss (which ear is hard of hearing), a determination of sensorineural or conductive hearing loss can be made. If the Rinne test shows that air conduction is greater than bone conduction in both ears and the Weber test lateralizes to a particular ear, then there is sensorineural hearing loss in the opposite (weaker) ear. If the Weber test lateralizes to the "weaker" ear and the Rinne test demonstrates better bone conduction than air conduction in the "weak" ear, conductive hearing loss is confirmed. If the Weber test lateralizes to the "stronger" ear and the Rinne test indicates weaker air conduction in the "weaker" ear, a combined hearing loss is likely. # See Also - Neurological examination it:Prova di Weber Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Weber_test
26ea311cdaeebff706ee289b23682c2292b2cea2	wikidoc	Wheatgrass	Wheatgrass Wheatgrass is a young plant of the genus Caroline, (especially Agropyron cristatum, a relative of wheat although some wheatgrass products are made from Triticum aestivum: common wheat). Fresh leaf buds of this plant can be pressed into juice or dried to a powder, both providing chlorophyll, amino acids, minerals, vitamins, and enzymes. The unprocessed plant contains fiber, which promotes colon health. # History The consumption of wheatgrass in the occident began in the 1930s with the attempts of Charles F Schnabel to popularize the plant. Ann Wigmore continued to contribute to the popularization of wheatgrass in the 1940s. Believing that it contributed to the remission of her cancer, Wigmore wrote several books on the subject. # Usage The average dosage taken by consumers of wheatgrass is 3.5 grams (powder or tablets). Some also have a fresh squeezed 30ml shot once daily or for more therapeutic benefits a higher dose up to 2–4 oz taken 1-3 times per day on an empty stomach and before meals. For detoxification, some users may increase their intake to 3–4 times per day. It should be noted that consumers with a poor diet may experience nausea on high dosages of wheatgrass. Wheatgrass grown indoors does not have as many nutrients as wheatgrass grown outdoors under natural conditions. Fresh squeezed wheat grass juice is especially nutrient deficient because it is 95% water and only 5% dry matter, unlike the dehydrated forms.. Outdoor wheatgrass is only available for a few days each year from plants grown in regions renown for winter wheat, the "bread basket" regions of the US and Canada. Winter wheat requires more than 200 days of slow growth in cold temperatures to reach the peak nutritional content. Even after that long of time, the plant is only 7 to 10 inches high because it was allowed to grow during the cold winter months in climates like midwestern United States, which is natural to the plant. Compared to wheat grass grown outdoors in the proper climate, the leaves of tray-grown wheatgrass are very thin, pale and contain a much lower in nutritional content. Much higher nutritional benefit comes from wheatgrass grown under natural conditions and harvested at the one time of year when the nutritional value reaches its peak. Most people who seek such high nutritional content wheatgrass use dehydrated powders and tablets from reputable companies that grow the wheatgrass organically under natural conditions in an ideal climate such as the midwest of the United States and Canada. It is also important that the wheatgrass be harvested before the "jointing stage" which usually occurs for only a few days for winter wheat grown in breadbasket areas in the United States and Canada. # Health claims Proponents of wheatgrass use claims that regular ingestion of the plant can give more energy, alkalize the body, improve the digestive system, prevent cancer, diabetes and heart disease, cure constipation, detoxify heavy metals from the bloodstream, cleanse the liver, prevent hair loss and help to make menopause more manageable, and aiding in general well being. "The claims include prevention of cancer, prevention of heart disease, prevention of diabetes, chelation or detoxification of heavy metals, cleansing, liver cleansing and prevention of hair loss and none of these claims have actually been substantiated in the scientific literature." ~ Dr Samir Samman One of the most popular claims about wheatgrass, and one that is frequently made by both supporters and retailers, is that 1 serving of wheatgrass is as nutritionally valuable as a kilogram of green vegetables. This claim most likely originates from a statement commonly attributed to the "father of wheatgrass", Charles F. Schnabel, who is alleged to have said that "Fifteen pounds of wheatgrass is equivalent to 350 pounds of the choicest vegetables". Although it does seem to be quite an exaggerated statement, it was most probably coined due to Schnabel trying to express its unknown and seemingly miraculous health attributes. Schnabel's research was with wheatgrass grown outdoors in Kansas. Schnabel's wheatgrass grew slowly through the cold of winter and was harvested at a very specific time in the early spring, which farmers refer to as the "jointing stage." It was then dehydrated and made into powders and tablets for human consumption. Schnabel's wheatgrass required 200 days of slow growth through the winter and early spring in Kansas to build those high nutritional levels. When wheatgrass is allowed to develop normally in its natural climate, a dense root structure combines with more than 200 days of sunlight to produce a plant with extremely high nutritional values. To use Schnabel's research to promote wheatgrass grown for ten days in a hot house is an obvious invalid comparison. Wheatgrass grown quickly and unnaturally in trays for ten days under artificial conditions contains considerably less nutrional content that wheatgrass grown outdoors in a climate like the midwestern United States and Canada, harvested at once-per-year jointing stage. Comparison: Artificial vs. Natural The nutritionally dense wheatgrass of the kind grown by Schnable is still available in tablet and powder form through natural food stores and online in the United States and most other countries. Seven tablets (3.5 grams) or a teaspoon of wheatgrass powder grown organically through the winter and harvested before the jointing state is equal in nutrition to a USDA serving of spinach or other dark green vegetables. Not all dehydrated wheatgrass is grown in accordance with Schnabel's research. The chlorophyll molecule is structurally similar to hemoglobin, leading some to believe that wheatgrass helps blood flow, digestion and general detoxification of the body. Although no research exists that directly connects chlorophyll with blood building, many nutrients associated with dark green leafy vegetables have been shown to be important for healthy blood. It has been shown by comparative analysis that dehydrated wheatgras powder, if grown under natural conditions, has a much higher nutritional value than so-called "fresh juice" grown under unnatural hot-house conditions. Comparison: Artificial vs. Natural Ann Wigmore encouraged her students to dehydrate raw foods at low temperatures to preserve their nutrients. She inappropriately used the scientific findings of Schnable on dehydrated wheatgrass to support growing wheatgrass rapidly under artificial conditions. # Popular culture In the FX Networks television series Nip/Tuck, Dr. Christian Troy grows and drinks wheatgrass in numerous episodes. In The Simpsons episode "When You Dish upon a Star", Homer invents a cocktail made of wheatgrass and vodka called a "lawnmower". Also appears in the episode "Make Room for Lisa" where Lisa is given a shot of wheatgrass juice by the owner of the New Age store who interprets Lisa's disgust at the taste as a sign of working taste buds. Wheatgrass is referenced in Sex and the City when a character that Samantha is dating has 'funky tasting spunk.' Wheatgrass was referenced as a good way to change this. # Notes - ↑ Jump up to: 1.0 1.1 1.2 Murphy, Sean (2002-10-13). "Wheatgrass, healthy for the body and the bank account". ABC Landline. Retrieved 2006-10-06. Check date values in: \|date= (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} - ↑ Jarvis, William T. Wheatgrass Therapy. National Council Against Health Fraud (1998). Retrieved on 2007-05-22 - ↑ Jump up to: 3.0 3.1	Wheatgrass Wheatgrass is a young plant of the genus Caroline, (especially Agropyron cristatum, a relative of wheat although some wheatgrass products are made from Triticum aestivum: common wheat). Fresh leaf buds of this plant can be pressed into juice or dried to a powder, both providing chlorophyll, amino acids, minerals, vitamins, and enzymes. The unprocessed plant contains fiber, which promotes colon health. # History The consumption of wheatgrass in the occident began in the 1930s with the attempts of Charles F Schnabel to popularize the plant.[1] Ann Wigmore continued to contribute to the popularization of wheatgrass in the 1940s. Believing that it contributed to the remission of her cancer, Wigmore wrote several books on the subject.[2] # Usage Template:Disputed The average dosage taken by consumers of wheatgrass is 3.5 grams (powder or tablets). Some also have a fresh squeezed 30ml shot once daily or for more therapeutic benefits a higher dose up to 2–4 oz taken 1-3 times per day on an empty stomach and before meals. For detoxification, some users may increase their intake to 3–4 times per day. It should be noted that consumers with a poor diet may experience nausea on high dosages of wheatgrass. Wheatgrass grown indoors does not have as many nutrients as wheatgrass grown outdoors under natural conditions. Fresh squeezed wheat grass juice is especially nutrient deficient because it is 95% water and only 5% dry matter, unlike the dehydrated forms.[citation needed]. Outdoor wheatgrass is only available for a few days each year from plants grown in regions renown for winter wheat, the "bread basket" regions of the US and Canada. Winter wheat requires more than 200 days of slow growth in cold temperatures to reach the peak nutritional content. Even after that long of time, the plant is only 7 to 10 inches high because it was allowed to grow during the cold winter months in climates like midwestern United States, which is natural to the plant. Compared to wheat grass grown outdoors in the proper climate, the leaves of tray-grown wheatgrass are very thin, pale and contain a much lower in nutritional content[citation needed]. Much higher nutritional benefit comes from wheatgrass grown under natural conditions and harvested at the one time of year when the nutritional value reaches its peak[citation needed]. Most people who seek such high nutritional content wheatgrass use dehydrated powders and tablets from reputable companies that grow the wheatgrass organically under natural conditions in an ideal climate such as the midwest of the United States and Canada.[citation needed] It is also important that the wheatgrass be harvested before the "jointing stage" which usually occurs for only a few days for winter wheat grown in breadbasket areas in the United States and Canada. # Health claims Proponents of wheatgrass use claims that regular ingestion of the plant can give more energy, alkalize the body, improve the digestive system, prevent cancer, diabetes and heart disease, cure constipation, detoxify heavy metals from the bloodstream, cleanse the liver, prevent hair loss and help to make menopause more manageable, and aiding in general well being.[1] "The claims [of wheatgrass proponents] include prevention of cancer, prevention of heart disease, prevention of diabetes, chelation or detoxification of heavy metals, cleansing, liver cleansing and prevention of hair loss and none of these claims have actually been substantiated in the scientific literature." ~ Dr Samir Samman[1] One of the most popular claims about wheatgrass, and one that is frequently made by both supporters and retailers, is that 1 serving of wheatgrass is as nutritionally valuable as a kilogram of green vegetables.[3] This claim most likely originates from a statement commonly attributed to the "father of wheatgrass", Charles F. Schnabel, who is alleged to have said that "Fifteen pounds of wheatgrass is equivalent to 350 pounds of the choicest vegetables".[3] Although it does seem to be quite an exaggerated statement, it was most probably coined due to Schnabel trying to express its unknown and seemingly miraculous health attributes. Schnabel's research was with wheatgrass grown outdoors in Kansas. Schnabel's wheatgrass grew slowly through the cold of winter and was harvested at a very specific time in the early spring, which farmers refer to as the "jointing stage." It was then dehydrated and made into powders and tablets for human consumption. Schnabel's wheatgrass required 200 days of slow growth through the winter and early spring in Kansas to build those high nutritional levels. When wheatgrass is allowed to develop normally in its natural climate, a dense root structure combines with more than 200 days of sunlight to produce a plant with extremely high nutritional values. To use Schnabel's research to promote wheatgrass grown for ten days in a hot house is an obvious invalid comparison. Wheatgrass grown quickly and unnaturally in trays for ten days under artificial conditions contains considerably less nutrional content that wheatgrass grown outdoors in a climate like the midwestern United States and Canada, harvested at once-per-year jointing stage. Comparison: Artificial vs. Natural The nutritionally dense wheatgrass of the kind grown by Schnable is still available in tablet and powder form through natural food stores and online in the United States and most other countries. Seven tablets (3.5 grams) or a teaspoon of wheatgrass powder grown organically through the winter and harvested before the jointing state is equal in nutrition to a USDA serving of spinach or other dark green vegetables. Not all dehydrated wheatgrass is grown in accordance with Schnabel's research. The chlorophyll molecule is structurally similar to hemoglobin, leading some to believe that wheatgrass helps blood flow, digestion and general detoxification of the body. Although no research exists that directly connects chlorophyll with blood building, many nutrients associated with dark green leafy vegetables have been shown to be important for healthy blood.[citation needed] It has been shown by comparative analysis that dehydrated wheatgras powder, if grown under natural conditions, has a much higher nutritional value than so-called "fresh juice" grown under unnatural hot-house conditions. Comparison: Artificial vs. Natural Ann Wigmore encouraged her students to dehydrate raw foods at low temperatures to preserve their nutrients. She inappropriately used the scientific findings of Schnable on dehydrated wheatgrass to support growing wheatgrass rapidly under artificial conditions. # Popular culture In the FX Networks television series Nip/Tuck, Dr. Christian Troy grows and drinks wheatgrass in numerous episodes. In The Simpsons episode "When You Dish upon a Star", Homer invents a cocktail made of wheatgrass and vodka called a "lawnmower". Also appears in the episode "Make Room for Lisa" where Lisa is given a shot of wheatgrass juice by the owner of the New Age store who interprets Lisa's disgust at the taste as a sign of working taste buds. Wheatgrass is referenced in Sex and the City when a character that Samantha is dating has 'funky tasting spunk.' Wheatgrass was referenced as a good way to change this.[citation needed] # Notes - ↑ Jump up to: 1.0 1.1 1.2 Murphy, Sean (2002-10-13). "Wheatgrass, healthy for the body and the bank account". ABC Landline. Retrieved 2006-10-06. Check date values in: \|date= (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} - ↑ Jarvis, William T. Wheatgrass Therapy. National Council Against Health Fraud (1998). Retrieved on 2007-05-22 - ↑ Jump up to: 3.0 3.1 # External links - Internet Health Library - Wheatgrass and Mold	https://www.wikidoc.org/index.php/Wheatgrass
f6aacf6ed7a8401187afd5e171fea94517dea45b	wikidoc	Wheelbench	Wheelbench A wheelbench is a wheeled mobility device in which the user lies down. The device is propelled manually. The user pushes the wheels with their hands in the same manner as propelling a wheelchair or the wheelbench can be moved by a second person pulling or pushing it by the handles. A wheelbench is constructed in a similar way to a wheelchair, except that it has a stretcher on the top instead of a seat. A wheelbench is collapsible, just like a wheelchair. Wheelbenches are used by people for whom both sitting and walking is difficult or impossible. The term sitting disability is used to describe a condition in which sitting is difficult, painful and perhaps medically injurious and which may be due to illness, injury, or other disability. A notable symptom of sitting disability is severe back pain. While mobility impairment is widely recognised, sitting disability is rarely mentioned in research or legal documents. Hence, wheelbenches are not as well known to society as wheelchairs. A wheelbench has some resemblance to a hospital gurney or wheel chair. The difference is that the gurney is primarily made to move patients around in a hospital and is less comfortable for long distances or outdoors. A wheelbench has bigger wheels, just like a wheelchair. Wheelbenches are usually produced by companies producing wheelchairs. # Access for wheelbenches During the last decades it has been a political objective of the Western world to ensure “full equality and active participation” for persons with disabilities. Volunteer organizations that represent people with back pain, have worked hard to gain equal access for people with sitting disability by integrating Universal design into society. Public buildings are asked to be made accessible, with room for wheelbenches in elevators, doors and hallways. Large chrome wheels and flashy paint jobs set some wheelbenches apart.	Wheelbench A wheelbench is a wheeled mobility device in which the user lies down. The device is propelled manually. The user pushes the wheels with their hands in the same manner as propelling a wheelchair or the wheelbench can be moved by a second person pulling or pushing it by the handles. A wheelbench is constructed in a similar way to a wheelchair, except that it has a stretcher on the top instead of a seat. A wheelbench is collapsible, just like a wheelchair. Wheelbenches are used by people for whom both sitting and walking is difficult or impossible. The term sitting disability is used to describe a condition in which sitting is difficult, painful and perhaps medically injurious and which may be due to illness, injury, or other disability. A notable symptom of sitting disability is severe back pain. While mobility impairment is widely recognised, sitting disability is rarely mentioned in research or legal documents. Hence, wheelbenches are not as well known to society as wheelchairs. A wheelbench has some resemblance to a hospital gurney or wheel chair. The difference is that the gurney is primarily made to move patients around in a hospital and is less comfortable for long distances or outdoors. A wheelbench has bigger wheels, just like a wheelchair. Wheelbenches are usually produced by companies producing wheelchairs. # Access for wheelbenches During the last decades it has been a political objective of the Western world to ensure “full equality and active participation” for persons with disabilities. Volunteer organizations [1] that represent people with back pain, have worked hard to gain equal access for people with sitting disability by integrating Universal design into society. Public buildings are asked to be made accessible, with room for wheelbenches in elevators, doors and hallways. Large chrome wheels and flashy paint jobs set some wheelbenches apart. # External links - Sitting disability	https://www.wikidoc.org/index.php/Wheelbench
e3b60dea4516168184a12d2bb1f91f3f849addf5	wikidoc	White cane	White cane A white cane is used by many people who are blind or visually impaired, both as a mobility tool and as a courtesy to others. Not all modern white canes are designed to fulfill the same primary function, however: There are at least five different varieties of this tool, each serving a slightly different need. # Types - Long cane: This "traditional" white cane, also known as a "Hoover" cane, after Dr. Richard Hoover, is designed primarily as a mobility tool used to feel obstacles in the path of a user. Cane length depends upon the height of a user, and traditionally extends from the floor to the user's sternum. Some organizers favour the use of much longer canes. - "Kiddie" cane: This version works in the same way as an adult's long cane, but is designed for use by children. - Identification cane ("Symbol Cane" in British English): The ID cane is used primarily to alert others as to the bearer's visual impairment. It is often lighter and shorter than the long cane, and is more limited as a mobility tool. - Support cane: The white support cane is designed primarily to offer physical stability to a visually impaired user. By virtue of its colour, the cane also works as a means of identification. This tool has very limited potential as a mobility device. - Mobility canes are often made from aluminium, graphite-reinforced plastic or other fibre-reinforced plastic, and can come with a wide variety of tips depending upon user preference. # History Blind people have used canes as mobility tools for centuries, but it was not until after World War I that the white cane was introduced. In 1921 James Biggs, a photographer from Bristol who became blind after an accident and was uncomfortable with the amount of traffic around his home, painted his walking stick white to be more easily visible. In 1931 in France, Guilly d'Herbemont launched a national white stick movement for blind people. In the United States, the introduction of the white cane is attributed to George A. Bonham of the Lions Clubs International . In 1930, a Lions Club member watched as a man who was blind attempted to cross the street with a black cane that was barely visible to motorists against the dark pavement. The Lions decided to paint the cane white to make it more visible. In 1931, Lions Clubs International began a program promoting the use of white canes for people who are blind. The first special White Cane Ordinance was passed in December 1930 in Peoria, Illinois granting blind pedestrians protections and the right-of-way while carrying a white cane. On October 6, 1964, a joint resolution of the Congress, HR 753, was signed into law authorizing the President of the United States to proclaim October 15 of each year as "White Cane Safety Day". President Lyndon Johnson was the first to make this proclamation. # Canes around the world While the white cane is commonly accepted as a "symbol of blindness", different countries still have different rules concerning what constitutes a "cane for the blind". In the United Kingdom, for example, the white cane is recognised as being used by visually impaired persons; with two red bands added it indicates that the user is deafblind. In the United States, laws vary from state to state, but in all cases, those carrying white canes are afforded the right-of-way when crossing a road. They are afforded the right to use their cane in any public place as well. In some cases, it is illegal for a non-blind person to carry a white cane. # Controversy There is much debate among blind people about issues relating to white canes. Though most blind people who use canes support using the long white cane, there is much disagreement over whether canes should be collapsible or not. During the 1970s, the National Federation of the Blind started a campaign to promote the use of noncollapsible, straight canes. Though they are harder to store, the NFB and some others believe that the lightness and greater length of the straight canes allows greater mobility and safety. Those who support the collapsible canes, which can be folded for storage, say that the benefits of the straight cane do not outweigh the inconvenience of having to store them carefully in crowded areas such as classrooms and public events. There is also a movement among blind people which believes that guide dogs, the other major mobility tool for blind people, should be used by blind adults. They claim that canes are not safe enough to cross streets and go in other insecure places with, because the dog can interactively warn the user. Despite the high profile of guide dogs, however, most blind people still use canes at least sometimes, and many still use canes entirely. Additionally, some people are allergic to dogs which may make them unsuitable for certain blind people. Some educators of blind people, particularly those who are not totally blind, have been reluctant to have children use canes until they are older. Many organizations, such as the National Federation of the Blind, have attempted to change this, largely with success.	White cane A white cane is used by many people who are blind or visually impaired, both as a mobility tool and as a courtesy to others. Not all modern white canes are designed to fulfill the same primary function, however: There are at least five different varieties of this tool, each serving a slightly different need. # Types - Long cane: This "traditional" white cane, also known as a "Hoover" cane, after Dr. Richard Hoover, is designed primarily as a mobility tool used to feel obstacles in the path of a user. Cane length depends upon the height of a user, and traditionally extends from the floor to the user's sternum. Some organizers favour the use of much longer canes.[1] - "Kiddie" cane: This version works in the same way as an adult's long cane, but is designed for use by children. - Identification cane ("Symbol Cane" in British English): The ID cane is used primarily to alert others as to the bearer's visual impairment. It is often lighter and shorter than the long cane, and is more limited as a mobility tool. - Support cane: The white support cane is designed primarily to offer physical stability to a visually impaired user. By virtue of its colour, the cane also works as a means of identification. This tool has very limited potential as a mobility device. - Mobility canes are often made from aluminium, graphite-reinforced plastic or other fibre-reinforced plastic, and can come with a wide variety of tips depending upon user preference. # History Blind people have used canes as mobility tools for centuries, but it was not until after World War I that the white cane was introduced. In 1921 James Biggs, a photographer from Bristol who became blind after an accident and was uncomfortable with the amount of traffic around his home, painted his walking stick white to be more easily visible. In 1931 in France, Guilly d'Herbemont launched a national white stick movement for blind people. In the United States, the introduction of the white cane is attributed to George A. Bonham of the Lions Clubs International [1]. In 1930, a Lions Club member watched as a man who was blind attempted to cross the street with a black cane that was barely visible to motorists against the dark pavement. The Lions decided to paint the cane white to make it more visible. In 1931, Lions Clubs International began a program promoting the use of white canes for people who are blind. The first special White Cane Ordinance was passed in December 1930 in Peoria, Illinois granting blind pedestrians protections and the right-of-way while carrying a white cane. On October 6, 1964, a joint resolution of the Congress, HR 753, was signed into law authorizing the President of the United States to proclaim October 15 of each year as "White Cane Safety Day". President Lyndon Johnson was the first to make this proclamation. # Canes around the world While the white cane is commonly accepted as a "symbol of blindness", different countries still have different rules concerning what constitutes a "cane for the blind". In the United Kingdom, for example, the white cane is recognised as being used by visually impaired persons; with two red bands added it indicates that the user is deafblind. In the United States, laws vary from state to state, but in all cases, those carrying white canes are afforded the right-of-way when crossing a road. They are afforded the right to use their cane in any public place as well. In some cases, it is illegal for a non-blind person to carry a white cane.[2] # Controversy There is much debate among blind people about issues relating to white canes. Though most blind people who use canes support using the long white cane, there is much disagreement over whether canes should be collapsible or not. During the 1970s, the National Federation of the Blind started a campaign to promote the use of noncollapsible, straight canes. Though they are harder to store, the NFB and some others believe that the lightness and greater length of the straight canes allows greater mobility and safety. Those who support the collapsible canes, which can be folded for storage, say that the benefits of the straight cane do not outweigh the inconvenience of having to store them carefully in crowded areas such as classrooms and public events. There is also a movement among blind people which believes that guide dogs, the other major mobility tool for blind people, should be used by blind adults. They claim that canes are not safe enough to cross streets and go in other insecure places with, because the dog can interactively warn the user. Despite the high profile of guide dogs, however, most blind people still use canes at least sometimes, and many still use canes entirely. Additionally, some people are allergic to dogs which may make them unsuitable for certain blind people. Some educators of blind people, particularly those who are not totally blind, have been reluctant to have children use canes until they are older. Many organizations, such as the National Federation of the Blind, have attempted to change this, largely with success.[citation needed]	https://www.wikidoc.org/index.php/White_cane
16aeca733160e64d966375cdae0789d861383165	wikidoc	Wild thyme	Wild thyme Wild Thyme or Creeping Thyme (Thymus serpyllum) is a species of thyme native to most of Europe and North Africa. It is a low, usually prostrate subshrub growing to 2 cm tall with creeping stems up to 10 cm long, with oval evergreen leaves 3-8 mm long. The strongly scented flowers are either lilac, pink-purple, magenta, or a rare white, all 4-6 mm long and produced in clusters. The hardy plant tolerates some pedestrian traffic and produces odors ranging from heavily herbal to lightly lemon, depending on the plant. # Uses It is a source of oil of Serpolet by distillation, and is used in herbal medicine. The dried leaves are used for an herbal tea throughout Europe and the States. It is an important nectar source plant for honeybees as well as the large blue butterfly which feeds exclusively on wild thyme. All thyme species are nectar sources, but wild thyme covers large areas of droughty, rocky soils in southern Europe. Croatia, Greece, North Africa, Malta, the Berkshire Mountains and Catskill Mountains of the northeastern United States, and New Zealand are especially famous for wild thyme honey. See also: Monofloral honey	Wild thyme Wild Thyme or Creeping Thyme (Thymus serpyllum) is a species of thyme native to most of Europe and North Africa. It is a low, usually prostrate subshrub growing to 2 cm tall with creeping stems up to 10 cm long, with oval evergreen leaves 3-8 mm long. The strongly scented flowers are either lilac, pink-purple, magenta, or a rare white, all 4-6 mm long and produced in clusters. The hardy plant tolerates some pedestrian traffic and produces odors ranging from heavily herbal to lightly lemon, depending on the plant. # Uses It is a source of oil of Serpolet by distillation, and is used in herbal medicine. The dried leaves are used for an herbal tea throughout Europe and the States. It is an important nectar source plant for honeybees as well as the large blue butterfly which feeds exclusively on wild thyme. All thyme species are nectar sources, but wild thyme covers large areas of droughty, rocky soils in southern Europe. Croatia, Greece, North Africa, Malta, the Berkshire Mountains and Catskill Mountains of the northeastern United States, and New Zealand are especially famous for wild thyme honey. See also: Monofloral honey # External links - 'A Modern Herbal' (Grieves, 1931) Template:Vegetable-stub ca:Serpoll cs:Tymián obecný da:Smalbladet Timian de:Wilder Thymian hr:Majčina dušica lt:Paprastasis čiobrelis nl:Kleine tijm se:Deanutimjan sk:Materina dúška fi:Kangasajuruoho sv:Backtimjan uk:Чебрець звичайний wa:Såvaedje pilé	https://www.wikidoc.org/index.php/Wild_thyme
d709156cebe26821974079c5e4f319ba2e1c2987	wikidoc	Wine fault	Wine fault A wine fault or defect is an unpleasant characteristic of a wine often resulting from poor winemaking practices or storage conditions, and leading to wine spoilage. Many of the compounds that cause wine faults are already naturally present in wine but at insufficient concentrations to adversely affect it. In fact, depending on perception, these concentrations may impart positive characters to the wine. However when the concentration of these compounds greatly exceeds the sensory threshold, they replace or obscure the flavours and aromas that the wine should be expressing. Ultimately the quality of the wine is reduced, making it less appealing and sometimes undrinkable. # Oxidation The oxidation of wine is perhaps the most common of wine faults, as the presence of oxygen and a catalyst are the only requirements for the process to occur. Oxidation can occur throughout the winemaking process, and even after the wine has been bottled. Anthocyanins, catechins, epicatechins and other phenols present in wine are those most easily oxidised , which leads to a loss of colour, flavour and aroma - sometimes referred to as flattening. In most cases compounds such as sulfur dioxide or erythorbic acid are added to wine by winemakers, which protect the wine from oxidation and also bind with some of the oxidation products to reduce their organoleptic effect. Apart from phenolic oxidation, the ethanol present within wine can also be oxidised into other compounds responsible for flavour and aroma taints. ## Acetaldehyde Acetaldehyde is an intermediate product of yeast fermentation; however, it is more commonly associated with ethanol oxidation catalysed by the enzyme ethanol dehydrogenase. Acetaldehyde production is also associated with the presence of surface film forming yeasts and bacteria, such as acetic acid bacteria, which form the compound by the decarboxylation of pyruvate. The sensory threshold for acetaldehyde is 100-125 mg/L. Beyond this level it imparts a sherry type character to the wine which can also be described as green apple, sour and metallic. Acetaldehyde intoxication is also implicated in hangovers. ## Acetic acid Acetic acid in wine, often referred to as volatile acidity (VA) or vinegar taint, can be contributed by many wine spoilage yeasts and bacteria. This can be from either a by-product of fermentation, or due to the spoilage of finished wine. Acetic acid bacteria, such as those from the genera Acetobacter and Gluconobacter produce high levels of acetic acid. The sensory threshold for acetic acid is >700 mg/L, with concentrations greater than 1.2-1.3 g/L becoming unpleasant. There are different opinions as to what level of volatile acidity is appropriate for higher quality wine. Although too high a concentration is sure to leave an undesirable, 'vinegar' tasting wine, some wine's acetic acid levels are developed to create a more 'complex', desirable taste. ## Ethyl acetate Ethyl acetate is formed in wine by the esterification of ethanol and acetic acid. Therefore wines with high acetic acid levels are more likely to see ethyl acetate formation, but the compound does not contribute to the volatile acidity. It is a common microbial fault produced by wine spoilage yeasts, particularly Pichia anomala, Kloeckera apiculata, and Hanseniaspora uvarum. High levels of ethyl acetate are also produced by lactic acid bacteria and acetic acid bacteria. The sensory threshold for ethyl acetate is 150-200 mg/L. Levels below this can give an added richness and sweetness, whereas levels above impart nail polish remover, glue, or varnish type aromas. # Sulfur compounds Sulfur is used as an additive throughout the winemaking process, primarily to stop oxidation as mentioned above but also as an antimicrobial agent. When managed properly in wine, its presence there is often undetected, however when used recklessly it can contribute to flavour and aroma taints which are very volatile and potent. Sulfur compounds typically have low sensory thresholds. ## Sulfur dioxide Sulfur dioxide is a common wine additive, used for its antioxidant and preservative properties. When its use is not managed well it can be overadded, with its perception in wine reminiscent of matchsticks, burnt rubber, or mothballs. Wines such as these are often termed sulfitic. ## Hydrogen sulfide Hydrogen sulfide (H2S) is generally thought to be a metabolic by-product of yeast fermentation in nitrogen limited environments. It is formed when yeast ferment via the sulfate reduction pathway. Fermenting wine is often supplemented with diammonium phosphate (DAP) as a nitrogen source to prevent formation. The sensory threshold for hydrogen sulfide is 40-50 μg/L, with levels above this imparting a distinct rotten egg aroma to the wine. Hydrogen sulfide can further react with wine compounds to form mercaptans and disulfides. ## Mercaptans Mercaptans (thiols) are produced in wine by the reaction of hydrogen sulfide with other wine components such as ethanol or sulfur containing amino acids, such as methionine. They can be formed if finished wine is allowed prolonged contact with the lees. This can be prevented by racking the wine. Mercaptans have a very low sensory threshold, around 1.5 µg/L, with levels above causing onion, rubber, and skunk type odours. ## Dimethyl sulfide Dimethyl sulfide (DMS) is naturally present in most wines, probably from the breakdown of sulfur containing amino acids. It can also be formed when wines containing mercaptans are oxidised, which can occur during oak barrel ageing. Like ethyl acetate, levels of DMS below the sensory threshold can have a positive effect on flavour, contributing to fruityness, fullness, and complexity. Levels above the sensory threshold of >30 µg/L in white wines and >50 µg/L for red wines, give the wine vegetative characteristics of cooked cabbage. # Environmental ## Cork taint Cork taint is a wine fault mostly attributed to the compound 2,4,6-trichloroanisole (TCA), although other compounds such as guaiacol, geosmin, 2-methylisoborneol, octen-3-ol, octen-3-one, 2,3,4,6-tetrachloroanisole, pentachloroanisole, and 2,4,6-tribromoanisole are also thought to be involved. TCA most likely originates as a metabolite of mould growth on chlorine bleached wine corks and barrels. It causes earthy, mouldy, and musty aromas in wine that easily mask the natural fruit aromas, making the wine very unappealing. Wines in this state are often described as "corked". As cork taint has gained a wide reputation as a wine fault, other faults are often falsely identified as it. ## Heat damage Heat damaged wines are often casually referred to as cooked, which suggests how heat can affect a wine. The ideal storage temperature for wine is generally accepted to be 13°C (55°F). Wines that are stored at temperatures greatly higher than this will experience an increased ageing rate. Wines exposed to extreme temperatures will thermally expand, and may even push up between the cork and bottle and leak from the top. When opening a bottle of wine, if a track of wine is visible along the length of the cork, the cork is partially pushed out of the bottle, or wine is visible on the top of the cork while it is still in the bottle, it has most likely been heat damaged. Heat damaged wines often become oxidised, and red wines may take on a brick colour. Reputedly, heat damage is the most widespread and common problem found in wines. It often goes unnoticed because of the prevalence of the problem, consumers don't know it's possible, and most often would just chalk the problem to poor quality or other factors. ## Lightstrike Lightstruck wines are those that have had excessive exposure to ultraviolet light, particularly in the range 325 to 450 nm. Very delicate wines, such as Champagnes, are generally worst affected, with the fault causing a wet cardboard or wet wool type flavour and aroma. Red wines rarely becomes lightstruck because the phenolic compounds present within the wine protects it. Lightstrike is thought to be caused by sulfur compounds such as dimethyl sulfide. In France lightstrike is known as "goûts de lumière", which translates to tastes of light. The fault explains why wines are generally bottled in coloured glass, which blocks the ultraviolet light, and why wine should be stored in dark environments. ## Ladybug taint Some insects present in the grapes at harvest inevitably end up in the press and for the most part are inoffensive. Others, notably types of ladybugs, release unpleasant volatile compounds as a defensive mechanism when disturbed. In sufficient quantities this can affect the bouquet and taste of wines. With an olfactory detection threshold of a few ppb, the principal active compounds are methoxypyrazines, or just pyrazines, that are perceived as rancid peanut butter, bitter herbaceous, green bell pepper or cat pee. This is also a naturally occurring compound in Sauvignon grapes and so ladybugs taint has been known to make Rieslings taste like Sauvignon Blanc. # Microbiological ## Brettanomyces (Dekkera) The yeast Brettanomyces produces an array of metabolites when growing in wine, some of which are volatile phenolic compounds. Together these compounds are often referred to as "Brettanomyces character", or simply "Brett". The main constituents are listed below, with their sensory threshold and common sensory descriptors: - 4-Ethylphenol (>140 µg/L): Band-aids, barnyard, horse stable, antiseptic - 4-ethylguaiacol (>600 µg/L): Bacon, spice, cloves, smoky - isovaleric acid: Sweaty saddle, cheese, rancidity ## Geosmin Geosmin is a compound with a very distinct earthy, musty, beetroot, even turnip flavour and aroma and has an extremely low sensory threshold of down to 10 parts per trillion. Its presence in wine is usually derived as metabolite from the growth of filamentous actinomycetes such as Streptomyces, and moulds such as Botritis cinerea and Penicillium expansum, on grapes. Wines affected by but not attributed to geosmins are often thought to have earthy properties due to terroir. The geosmin fault occurs worldwide and has been found in recent vintages of red wines from Beaujolais, Bordeaux, Burgundy and the Loire in France. Geosmin is also thought to be a contributing factor in cork taint. ## Lactic acid bacteria Lactic acid bacteria have a useful role in winemaking converting malic acid to lactic acid in malolactic fermentation. However after this function has completed the bacteria may still be present within the wine, where they can metabolise other compounds and produce wine faults. Wines that have not undergone malolactic fermentation may be contaminated with lactic acid bacteria, leading to refermentation of the wine with it becoming turbid, swampy, and slightly effervescent or spritzy. This can be avoided by sterile filtering wine directly before bottling. Lactic acid bacteria can also be responsible for other wine faults such as those below. ### Bitterness taint Bitterness taint or amertume is rather uncommon and is produced by certain strains of bacteria from the genera Pediococcus, Lactobacillus, and Oenococcus. It begins by the degradation of glycerol, a compound naturally found in wine at levels of 5-8 g/L, via a dehydratase enzyme to 3-hydroxypropionaldehyde. During ageing this is further dehydrated to acrolein which reacts with the anthocyanins and other phenols present within the wine to form the taint. As red wines contain high levels of anthocyanins they are generally more susceptible. ### Diacetyl Diacetyl in wine is produced by lactic acid bacteria, mainly Oenococcus oeni. In low levels it can impart positive nutty or caramel characters, however at levels above 5 mg/L it creates an intense buttery or butterscotch flavour, where it is perceived as a flaw. The sensory threshold for the compound can vary depending on the levels of certain wine components, such as sulfur dioxide. It can be produced as a metabolite of citric acid when all of the malic acid has been consumed. Diacetyl rarely taints wine to levels where it becomes undrinkable. ### Geranium taint Geranium taint, as the name suggests, is a flavour and aroma taint in wine reminiscent of geranium leaves. The compound responsible is 2-ethoxyhexa-3,5-diene, which has a low sensory threshold concentration of 0.1 mg/L. In wine it is formed during the metabolism of potassium sorbate by lactic acid bacteria. Potassium sorbate is sometimes added to wine as a preservative against yeast, however its use is generally kept to a minimum due to the possibility of the taint developing. The production of the taint begins with the conversion of sorbic acid to the alcohol sorbinol. The alcohol is then isomerised in the presence of acid to 3,5-hexadiene-2-ol, which is then esterified with ethanol to form 2-ethoxy-3,5-hexadiene. As ethanol is necessary for the conversion, the geranium taint is not usually found in must. ### Mannitol Mannitol is a polyol, and in wine it is produced by heterofermentative lactic acid bacteria, such as Lactobacillus brevis, by the reduction of fructose. Its perception is often complicated as it generally exists in wine alongside other faults, but it is usually described as viscous, ester-like combined with a sweet and irritating finish. Mannitol is usually produced in wines that undergo malolactic fermentation with a high level of residual sugars still present. ### Ropiness Ropiness is manifested as an increase in viscosity and a slimey or fatty mouthfeel of a wine. In France the fault is known as "graisse", which translates to fat. The problem stems from the production of dextrins and polysaccharides by certain lactic acid bacteria, particularly of the genera Leuconostoc and Pediococcus. ## Mousiness Mousiness is a wine fault most often attributed to Brettanomyces but can also originate from the lactic acid bacteria Lactobacillus brevis, Lactobacillus fermentum, and Lactobacillus hilgardii. The compounds responsible are lysine derivatives, mainly; - 2-acetyl-3,4,5,6-tetrahydropyridine - 2-acetyl-1,4,5,6-tetrahydropyridine - 2-ethyltetrahydropyridine - 2-acetyl-1-pyrrolene The taints are not volatile at the pH of wine, and therefore not obvious as an aroma. However, when mixed with the neutral pH of saliva they can become very apparent on the palate, especially at the back of the mouth, as mouse cage or mouse urine. ## Refermentation Refermentation, sometimes called secondary fermentation, is caused by yeasts refermenting the residual sugar present within bottled wine. It occurs when sweet wines are bottled in non-sterile conditions, allowing the presence of microorganisms. The most common yeast to referment wine is the standard wine fermentation yeast Saccharomyces cerevisiae, but has also been attributed to Schizosaccharomyces pombe and Zygosaccharomyces bailii. The main issues associated with the fault include turbidity (from yeast biomass production), excess ethanol production (may violate labelling laws), slight carbonation, and some coarse odours. Refermentation can be prevented by bottling wines dry (with residual sugar levels <1.0g/L), sterile filtering wine prior to bottling, or adding preservative chemicals such as dimethyl dicarbonate. The Portuguese wine style known as "vinhos verdes" relies on this secondary fermentation in bottle to impart a slight spritziness to the wine.	Wine fault A wine fault or defect is an unpleasant characteristic of a wine often resulting from poor winemaking practices or storage conditions, and leading to wine spoilage. Many of the compounds that cause wine faults are already naturally present in wine but at insufficient concentrations to adversely affect it. In fact, depending on perception, these concentrations may impart positive characters to the wine. However when the concentration of these compounds greatly exceeds the sensory threshold, they replace or obscure the flavours and aromas that the wine should be expressing. Ultimately the quality of the wine is reduced, making it less appealing and sometimes undrinkable. # Oxidation The oxidation of wine is perhaps the most common of wine faults, as the presence of oxygen and a catalyst are the only requirements for the process to occur. Oxidation can occur throughout the winemaking process, and even after the wine has been bottled. Anthocyanins, catechins, epicatechins and other phenols present in wine are those most easily oxidised [1], which leads to a loss of colour, flavour and aroma - sometimes referred to as flattening. In most cases compounds such as sulfur dioxide or erythorbic acid are added to wine by winemakers, which protect the wine from oxidation and also bind with some of the oxidation products to reduce their organoleptic effect[2]. Apart from phenolic oxidation, the ethanol present within wine can also be oxidised into other compounds responsible for flavour and aroma taints. ## Acetaldehyde Acetaldehyde is an intermediate product of yeast fermentation; however, it is more commonly associated with ethanol oxidation catalysed by the enzyme ethanol dehydrogenase. Acetaldehyde production is also associated with the presence of surface film forming yeasts and bacteria, such as acetic acid bacteria, which form the compound by the decarboxylation of pyruvate. The sensory threshold for acetaldehyde is 100-125 mg/L. Beyond this level it imparts a sherry type character to the wine which can also be described as green apple, sour and metallic. Acetaldehyde intoxication is also implicated in hangovers. ## Acetic acid Acetic acid in wine, often referred to as volatile acidity (VA) or vinegar taint, can be contributed by many wine spoilage yeasts and bacteria. This can be from either a by-product of fermentation, or due to the spoilage of finished wine. Acetic acid bacteria, such as those from the genera Acetobacter and Gluconobacter produce high levels of acetic acid. The sensory threshold for acetic acid is >700 mg/L, with concentrations greater than 1.2-1.3 g/L becoming unpleasant. There are different opinions as to what level of volatile acidity is appropriate for higher quality wine. Although too high a concentration is sure to leave an undesirable, 'vinegar' tasting wine, some wine's acetic acid levels are developed to create a more 'complex', desirable taste.[3] ## Ethyl acetate Ethyl acetate is formed in wine by the esterification of ethanol and acetic acid. Therefore wines with high acetic acid levels are more likely to see ethyl acetate formation, but the compound does not contribute to the volatile acidity. It is a common microbial fault produced by wine spoilage yeasts, particularly Pichia anomala, Kloeckera apiculata, and Hanseniaspora uvarum. High levels of ethyl acetate are also produced by lactic acid bacteria and acetic acid bacteria. The sensory threshold for ethyl acetate is 150-200 mg/L. Levels below this can give an added richness and sweetness, whereas levels above impart nail polish remover, glue, or varnish type aromas. # Sulfur compounds Sulfur is used as an additive throughout the winemaking process, primarily to stop oxidation as mentioned above but also as an antimicrobial agent. When managed properly in wine, its presence there is often undetected, however when used recklessly it can contribute to flavour and aroma taints which are very volatile and potent. Sulfur compounds typically have low sensory thresholds. ## Sulfur dioxide Sulfur dioxide is a common wine additive, used for its antioxidant and preservative properties. When its use is not managed well it can be overadded, with its perception in wine reminiscent of matchsticks, burnt rubber, or mothballs. Wines such as these are often termed sulfitic. ## Hydrogen sulfide Hydrogen sulfide (H2S) is generally thought to be a metabolic by-product of yeast fermentation in nitrogen limited environments. It is formed when yeast ferment via the sulfate reduction pathway. Fermenting wine is often supplemented with diammonium phosphate (DAP) as a nitrogen source to prevent formation. The sensory threshold for hydrogen sulfide is 40-50 μg/L, with levels above this imparting a distinct rotten egg aroma to the wine. Hydrogen sulfide can further react with wine compounds to form mercaptans and disulfides. ## Mercaptans Mercaptans (thiols) are produced in wine by the reaction of hydrogen sulfide with other wine components such as ethanol or sulfur containing amino acids, such as methionine. They can be formed if finished wine is allowed prolonged contact with the lees. This can be prevented by racking the wine. Mercaptans have a very low sensory threshold, around 1.5 µg/L[4], with levels above causing onion, rubber, and skunk type odours. ## Dimethyl sulfide Dimethyl sulfide (DMS) is naturally present in most wines, probably from the breakdown of sulfur containing amino acids. It can also be formed when wines containing mercaptans are oxidised, which can occur during oak barrel ageing[5]. Like ethyl acetate, levels of DMS below the sensory threshold can have a positive effect on flavour, contributing to fruityness, fullness, and complexity. Levels above the sensory threshold of >30 µg/L in white wines and >50 µg/L for red wines, give the wine vegetative characteristics of cooked cabbage. # Environmental ## Cork taint Cork taint is a wine fault mostly attributed to the compound 2,4,6-trichloroanisole (TCA), although other compounds such as guaiacol, geosmin, 2-methylisoborneol, octen-3-ol, octen-3-one, 2,3,4,6-tetrachloroanisole, pentachloroanisole, and 2,4,6-tribromoanisole are also thought to be involved[6]. TCA most likely originates as a metabolite of mould growth on chlorine bleached wine corks and barrels. It causes earthy, mouldy, and musty aromas in wine that easily mask the natural fruit aromas, making the wine very unappealing. Wines in this state are often described as "corked". As cork taint has gained a wide reputation as a wine fault, other faults are often falsely identified as it. ## Heat damage Heat damaged wines are often casually referred to as cooked, which suggests how heat can affect a wine. The ideal storage temperature for wine is generally accepted to be 13°C (55°F). Wines that are stored at temperatures greatly higher than this will experience an increased ageing rate. Wines exposed to extreme temperatures will thermally expand, and may even push up between the cork and bottle and leak from the top. When opening a bottle of wine, if a track of wine is visible along the length of the cork, the cork is partially pushed out of the bottle, or wine is visible on the top of the cork while it is still in the bottle, it has most likely been heat damaged. Heat damaged wines often become oxidised, and red wines may take on a brick colour. Reputedly, heat damage is the most widespread and common problem found in wines. It often goes unnoticed because of the prevalence of the problem, consumers don't know it's possible, and most often would just chalk the problem to poor quality or other factors. ## Lightstrike Lightstruck wines are those that have had excessive exposure to ultraviolet light, particularly in the range 325 to 450 nm[7]. Very delicate wines, such as Champagnes, are generally worst affected, with the fault causing a wet cardboard or wet wool type flavour and aroma. Red wines rarely becomes lightstruck because the phenolic compounds present within the wine protects it. Lightstrike is thought to be caused by sulfur compounds such as dimethyl sulfide. In France lightstrike is known as "goûts de lumière", which translates to tastes of light. The fault explains why wines are generally bottled in coloured glass, which blocks the ultraviolet light, and why wine should be stored in dark environments. ## Ladybug taint Some insects present in the grapes at harvest inevitably end up in the press and for the most part are inoffensive. Others, notably types of ladybugs, release unpleasant volatile compounds as a defensive mechanism when disturbed. In sufficient quantities this can affect the bouquet and taste of wines. With an olfactory detection threshold of a few ppb, the principal active compounds are methoxypyrazines, or just pyrazines, that are perceived as rancid peanut butter, bitter herbaceous, green bell pepper or cat pee. This is also a naturally occurring compound in Sauvignon grapes and so ladybugs taint has been known to make Rieslings taste like Sauvignon Blanc. # Microbiological ## Brettanomyces (Dekkera) The yeast Brettanomyces produces an array of metabolites when growing in wine, some of which are volatile phenolic compounds. Together these compounds are often referred to as "Brettanomyces character", or simply "Brett". The main constituents are listed below, with their sensory threshold and common sensory descriptors: - 4-Ethylphenol (>140 µg/L): Band-aids, barnyard, horse stable, antiseptic - 4-ethylguaiacol (>600 µg/L): Bacon, spice, cloves, smoky - isovaleric acid: Sweaty saddle, cheese, rancidity ## Geosmin Geosmin is a compound with a very distinct earthy, musty, beetroot, even turnip flavour and aroma and has an extremely low sensory threshold of down to 10 parts per trillion. Its presence in wine is usually derived as metabolite from the growth of filamentous actinomycetes such as Streptomyces, and moulds such as Botritis cinerea and Penicillium expansum, on grapes. Wines affected by but not attributed to geosmins are often thought to have earthy properties due to terroir[8]. The geosmin fault occurs worldwide and has been found in recent vintages of red wines from Beaujolais, Bordeaux, Burgundy and the Loire in France. Geosmin is also thought to be a contributing factor in cork taint. ## Lactic acid bacteria Lactic acid bacteria have a useful role in winemaking converting malic acid to lactic acid in malolactic fermentation. However after this function has completed the bacteria may still be present within the wine, where they can metabolise other compounds and produce wine faults. Wines that have not undergone malolactic fermentation may be contaminated with lactic acid bacteria, leading to refermentation of the wine with it becoming turbid, swampy, and slightly effervescent or spritzy. This can be avoided by sterile filtering wine directly before bottling. Lactic acid bacteria can also be responsible for other wine faults such as those below. ### Bitterness taint Bitterness taint or amertume is rather uncommon and is produced by certain strains of bacteria from the genera Pediococcus, Lactobacillus, and Oenococcus. It begins by the degradation of glycerol, a compound naturally found in wine at levels of 5-8 g/L, via a dehydratase enzyme to 3-hydroxypropionaldehyde. During ageing this is further dehydrated to acrolein which reacts with the anthocyanins and other phenols present within the wine to form the taint[9]. As red wines contain high levels of anthocyanins they are generally more susceptible. ### Diacetyl Diacetyl in wine is produced by lactic acid bacteria, mainly Oenococcus oeni. In low levels it can impart positive nutty or caramel characters, however at levels above 5 mg/L it creates an intense buttery or butterscotch flavour, where it is perceived as a flaw. The sensory threshold for the compound can vary depending on the levels of certain wine components, such as sulfur dioxide. It can be produced as a metabolite of citric acid when all of the malic acid has been consumed. Diacetyl rarely taints wine to levels where it becomes undrinkable[10]. ### Geranium taint Geranium taint, as the name suggests, is a flavour and aroma taint in wine reminiscent of geranium leaves. The compound responsible is 2-ethoxyhexa-3,5-diene, which has a low sensory threshold concentration of 0.1 mg/L[11]. In wine it is formed during the metabolism of potassium sorbate by lactic acid bacteria. Potassium sorbate is sometimes added to wine as a preservative against yeast, however its use is generally kept to a minimum due to the possibility of the taint developing. The production of the taint begins with the conversion of sorbic acid to the alcohol sorbinol. The alcohol is then isomerised in the presence of acid to 3,5-hexadiene-2-ol, which is then esterified with ethanol to form 2-ethoxy-3,5-hexadiene[11]. As ethanol is necessary for the conversion, the geranium taint is not usually found in must. ### Mannitol Mannitol is a polyol, and in wine it is produced by heterofermentative lactic acid bacteria, such as Lactobacillus brevis, by the reduction of fructose. Its perception is often complicated as it generally exists in wine alongside other faults, but it is usually described as viscous, ester-like combined with a sweet and irritating finish[9]. Mannitol is usually produced in wines that undergo malolactic fermentation with a high level of residual sugars still present. ### Ropiness Ropiness is manifested as an increase in viscosity and a slimey or fatty mouthfeel of a wine. In France the fault is known as "graisse", which translates to fat. The problem stems from the production of dextrins and polysaccharides by certain lactic acid bacteria, particularly of the genera Leuconostoc and Pediococcus. ## Mousiness Mousiness is a wine fault most often attributed to Brettanomyces but can also originate from the lactic acid bacteria Lactobacillus brevis, Lactobacillus fermentum, and Lactobacillus hilgardii[9]. The compounds responsible are lysine derivatives, mainly; - 2-acetyl-3,4,5,6-tetrahydropyridine - 2-acetyl-1,4,5,6-tetrahydropyridine - 2-ethyltetrahydropyridine[12] - 2-acetyl-1-pyrrolene The taints are not volatile at the pH of wine, and therefore not obvious as an aroma. However, when mixed with the neutral pH of saliva they can become very apparent on the palate[13], especially at the back of the mouth, as mouse cage or mouse urine. ## Refermentation Refermentation, sometimes called secondary fermentation, is caused by yeasts refermenting the residual sugar present within bottled wine. It occurs when sweet wines are bottled in non-sterile conditions, allowing the presence of microorganisms. The most common yeast to referment wine is the standard wine fermentation yeast Saccharomyces cerevisiae, but has also been attributed to Schizosaccharomyces pombe and Zygosaccharomyces bailii[9]. The main issues associated with the fault include turbidity (from yeast biomass production), excess ethanol production (may violate labelling laws), slight carbonation, and some coarse odours. Refermentation can be prevented by bottling wines dry (with residual sugar levels <1.0g/L), sterile filtering wine prior to bottling, or adding preservative chemicals such as dimethyl dicarbonate. The Portuguese wine style known as "vinhos verdes" relies on this secondary fermentation in bottle to impart a slight spritziness to the wine.	https://www.wikidoc.org/index.php/Wine_fault
43782117d17c313d497f3e9e1cecc661342c0e80	wikidoc	Wolf's Law	Wolf's Law Wolff's law is a theory developed by the German Anatomist/Surgeon Julius Wolff (1836-1902) in the 19th century that states that bone in a healthy person or animal will adapt to the loads it is placed under. If loading on a particular bone increases, the bone will remodel itself over time to become stronger to resist that sort of loading.The external cortical portion of the bone becomes thicker as a result. The converse is true as well: if the loading on a bone decreases, the bone will become weaker due to turnover, it is less metabolically costly to maintain and there is no stimulus for continued remodeling that is required to maintain bone mass. # Associated laws In relation to soft tissue, Davis's Law explains how soft tissue remolds itself according to imposed demands. # Examples - The racquet-holding arm bones of tennis players become much stronger than those of the other arm. Their bodies have strengthened the bones in their racquet-holding arm since it is routinely placed under higher than normal stresses. - Surfers who knee-paddle frequently will develop bone bumps, aka exostoses, on the tibial eminence and the dorsal part of the navicular tarsal bone from the pressure of the surfboard's surface. These are often called "surf knots." - Astronauts who spend a long time in space will often return to Earth with weaker bones, since gravity hasn't been exerting a load on their bones. Their bodies have reabsorbed much of the mineral that was previously in their bones. - Weightlifters often display increases in bone density in response to their training. - Martial artists who punch or kick objects with increasing intensity (or of increasing hardness) to develop striking power to damage opponents, often display increases in bone density in the striking area. Others may do this specifically to reduce pain response in the nerve endings of the striking tissue and to increase the bone density. Due to the ballistic and inconsistent nature of striking practise, load-bearing exercises are generally a safer form of measurable progression for increases in both bone and muscle strength. Many fighters will do things like knuckle push-ups as a form of conditioning, for example, so the impacts of strikes are only supplementary conditioning, as ideally in both sparring and striking practise as well as competitive contest your body should not be experiencing adequate stress for microtrauma adaptation. This is so the body can solely focus on technique and nervous recruitment and not tissue adaptation which can be distracting. Not including supplementary exercise does however guarantee that the body will not over-adapt and develop toughness specifically in response to training demands, which can be a factor for those concerned with making weight, and not wanting to develop bone or muscle weight they may not need for contest.	Wolf's Law Wolff's law is a theory developed by the German Anatomist/Surgeon Julius Wolff (1836-1902) in the 19th century that states that bone in a healthy person or animal will adapt to the loads it is placed under. If loading on a particular bone increases, the bone will remodel itself over time to become stronger to resist that sort of loading.The external cortical portion of the bone becomes thicker as a result. The converse is true as well: if the loading on a bone decreases, the bone will become weaker due to turnover, it is less metabolically costly to maintain and there is no stimulus for continued remodeling that is required to maintain bone mass.[1] # Associated laws In relation to soft tissue, Davis's Law explains how soft tissue remolds itself according to imposed demands. # Examples - The racquet-holding arm bones of tennis players become much stronger than those of the other arm. Their bodies have strengthened the bones in their racquet-holding arm since it is routinely placed under higher than normal stresses. - Surfers who knee-paddle frequently will develop bone bumps, aka exostoses, on the tibial eminence and the dorsal part of the navicular tarsal bone from the pressure of the surfboard's surface. These are often called "surf knots." - Astronauts who spend a long time in space will often return to Earth with weaker bones, since gravity hasn't been exerting a load on their bones. Their bodies have reabsorbed much of the mineral that was previously in their bones. - Weightlifters often display increases in bone density in response to their training. - Martial artists who punch or kick objects with increasing intensity (or of increasing hardness) to develop striking power to damage opponents, often display increases in bone density in the striking area. Others may do this specifically to reduce pain response in the nerve endings of the striking tissue and to increase the bone density. Due to the ballistic and inconsistent nature of striking practise, load-bearing exercises are generally a safer form of measurable progression for increases in both bone and muscle strength. Many fighters will do things like knuckle push-ups as a form of conditioning, for example, so the impacts of strikes are only supplementary conditioning, as ideally in both sparring and striking practise as well as competitive contest your body should not be experiencing adequate stress for microtrauma adaptation. This is so the body can solely focus on technique and nervous recruitment and not tissue adaptation which can be distracting. Not including supplementary exercise does however guarantee that the body will not over-adapt and develop toughness specifically in response to training demands, which can be a factor for those concerned with making weight, and not wanting to develop bone or muscle weight they may not need for contest.	https://www.wikidoc.org/index.php/Wolf%27s_Law
38e76ab2d5efc7bf0585db27d6847990cb94d281	wikidoc	Xenobiotic	Xenobiotic # Overview A xenobiotic is a chemical which is found in an organism but which is not normally produced or expected to be present in it. It can also cover substances which are present in much higher concentrations than are usual. Specifically, drugs such as antibiotics are xenobiotics in humans because the human body does not produce them itself nor would they be expected to be present as part of a normal diet. However, the term is also used in the context of pollutants such as dioxins and polychlorinated biphenyls and their effect on the biota. Natural compounds can also become xenobiotics if they are taken up by another organism (e.g., uptake of natural human hormones by fish found downstream of sewage treatment plant outfalls). # Xenobiotic metabolism The body removes xenobiotics by xenobiotic metabolism. This consists of the deactivation and the secretion of xenobiotics, and happens mostly in the liver. Secretion routes are urine, feces, breath, and sweat. Hepatic enzymes are responsible for the metabolism of xenobiotics by first activating them (oxidation, reduction, hydrolysis and/or hydration of the xenobiotic), and then conjugating the active secondary metabolite with glucuronic or sulphuric acid, or glutathione, followed by excretion in bile or urine. An example of a group of enzymes involved in xenobiotic metabolism is hepatic microsomal cytochrome P450. These enzymes that metabolize xenobiotics are very important for the pharmaceutical industry, because they are responsible for the breakdown of medications. # Xenobiotics in the environment Xenobiotic substances are becoming an increasingly large problem in Sewage Treatment systems, since they are relatively new substances and are very difficult to categorize. Antibiotics, for example, were derived from plants originally, and so mimic naturally occurring substances. This, along with the natural monopoly nature of municipal Waste Water Treatment Plants makes it nearly impossible to remove this new pollutant load. Some xenobiotics are resistant to degradation. For example, they may be synthetic organochlorides such as plastics and pesticides, or naturally occurring organic chemicals such as polyaromatic hydrocarbons (PAHs) and some fractions of crude oil and coal. However, it is believed that microorganisms are capable of degrading all the different complex and resistant xenobiotics found on the earth. # Inter-species organ transplantation The term xenobiotic is also used to refer to organs transplanted from one species to another. For example, some researchers hope that hearts and other organs could be transplanted from pigs to humans. Many people die every year whose lives could have been saved if a critical organ had been available for transplant. Kidneys are currently the most commonly transplanted organ. Xenobiotic organs would need to be developed in such a way that they would not be rejected by the immune system. With the development of vitrification transplantable organs could be stored in organ banks for long periods.	Xenobiotic # Overview A xenobiotic is a chemical which is found in an organism but which is not normally produced or expected to be present in it. It can also cover substances which are present in much higher concentrations than are usual. Specifically, drugs such as antibiotics are xenobiotics in humans because the human body does not produce them itself nor would they be expected to be present as part of a normal diet. However, the term is also used in the context of pollutants such as dioxins and polychlorinated biphenyls and their effect on the biota. Natural compounds can also become xenobiotics if they are taken up by another organism (e.g., uptake of natural human hormones by fish found downstream of sewage treatment plant outfalls). # Xenobiotic metabolism The body removes xenobiotics by xenobiotic metabolism. This consists of the deactivation and the secretion of xenobiotics, and happens mostly in the liver. Secretion routes are urine, feces, breath, and sweat. Hepatic enzymes are responsible for the metabolism of xenobiotics by first activating them (oxidation, reduction, hydrolysis and/or hydration of the xenobiotic), and then conjugating the active secondary metabolite with glucuronic or sulphuric acid, or glutathione, followed by excretion in bile or urine. An example of a group of enzymes involved in xenobiotic metabolism is hepatic microsomal cytochrome P450. These enzymes that metabolize xenobiotics are very important for the pharmaceutical industry, because they are responsible for the breakdown of medications. # Xenobiotics in the environment Xenobiotic substances are becoming an increasingly large problem in Sewage Treatment systems, since they are relatively new substances and are very difficult to categorize. Antibiotics, for example, were derived from plants originally, and so mimic naturally occurring substances. This, along with the natural monopoly nature of municipal Waste Water Treatment Plants makes it nearly impossible to remove this new pollutant load. Some xenobiotics are resistant to degradation. For example, they may be synthetic organochlorides such as plastics and pesticides, or naturally occurring organic chemicals such as polyaromatic hydrocarbons (PAHs) and some fractions of crude oil and coal. However, it is believed that microorganisms are capable of degrading all the different complex and resistant xenobiotics found on the earth. # Inter-species organ transplantation The term xenobiotic is also used to refer to organs transplanted from one species to another. For example, some researchers hope that hearts and other organs could be transplanted from pigs to humans. Many people die every year whose lives could have been saved if a critical organ had been available for transplant. Kidneys are currently the most commonly transplanted organ. Xenobiotic organs would need to be developed in such a way that they would not be rejected by the immune system. With the development of vitrification transplantable organs could be stored in organ banks for long periods.	https://www.wikidoc.org/index.php/Xenobiotic
b77ad81d4f14248f0dd06e1078384a9fa70efb36	wikidoc	Xyloglucan	Xyloglucan Xyloglucan is the main hemicellulose in the primary cell wall of dicotyledonous plants. Xyloglucan links cellulose microfibrils together, as well as avoid their adhesion and allow controlled creep. # Chemistry Xyloglucan has a cellulosic semirigid backbone of β1→4-linked glucose residues that are substituted with a variety of 1-6 flexibly linked glycosidic sidechains. The most common sidechain is a single xylose residue, but longer sidechains that include the sugars galactose and fucose are also common. # Biosynthesis Xyloglucan is synthesised in Golgi trans cisternae and in the trans Golgi network (TGN) and is transported to the cell membrane by vesicles, where it is expelled and adsorbs on nascent cellulosic microfibrils .	Xyloglucan Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Xyloglucan is the main hemicellulose in the primary cell wall of dicotyledonous plants. Xyloglucan links cellulose microfibrils together, as well as avoid their adhesion and allow controlled creep. # Chemistry Xyloglucan has a cellulosic semirigid backbone of β1→4-linked glucose residues that are substituted with a variety of 1-6 flexibly linked glycosidic sidechains. The most common sidechain is a single xylose residue, but longer sidechains that include the sugars galactose and fucose are also common. # Biosynthesis Xyloglucan is synthesised in Golgi trans cisternae and in the trans Golgi network (TGN) and is transported to the cell membrane by vesicles, where it is expelled and adsorbs on nascent cellulosic microfibrils [1].	https://www.wikidoc.org/index.php/Xyloglucan
1492e39b0e5256adf03b458930ccabaacb0f2ef4	wikidoc	Yellowroot	Yellowroot The Yellowroot (Xanthorhiza simplicissima, syn. X. apiifolia) is the only member of the genus Xanthorhiza, and one of very few genera in the family Ranunculaceae with a woody stem (the other notable example being Clematis). It is native to the eastern United States from Maine south to northern Florida and west to Ohio and eastern Texas. The genus name as well as the common name refer to the plant's yellow roots (xantho- meaning "yellow" and rhiza meaning "root"), which was used to produce a yellow dye by Native Americans. The species name refers to the simple (not branched) root. In the wild, it grows on the edges of streams in sandy soil under a canopy of dappled sunlight. In cultivation, it is often provided with more sunlight so that the fall colors are more vivid. It is a subshrub, reaching 20-70 cm (rarely 90 cm) in height, with stems up to 6 mm diameter. The leaves are spirally arranged, 10-18 cm long, each divided into 5 toothed leaflets, and flowers emerge only from the upper portion of the unbranched stem. The flowers are produced in broad panicles 6-20 cm long, each flower small, star-shaped, reddish brown to purple brown, with five petals. Yellowroot propagates asexually by sending out many underground runners, and it reproduces sexually with seeds. Yellowroot is considered an endangered species in Florida. ## Cultivation and uses It is cultivated for the stunning fall color, which is a dark red to purple, and lasts for months. While yellowroot is toxic in large doses, a reason why deer do not eat it, it has been used to adulterate or as a substitute for Hydrastis canadensis. Native Americans made a tea and drank it for ulcers in the mouth and in the stomach. It may have also been used as a tonic, and externally on sores. Native Americans also used it to treat various skin ailments. According to Foster & Duke (1998), the plant contains berberine which is anti-inflammatory, astringent, hemostatic, antimicrobial, anticonvulsant, immunostimulant, uterotonic and can produce a transient drop in blood pressure. In addition it stimulates the secretion of bile and bilirubin which may be helpful in cirrhosis of the liver. # References and external links - Flora of North America: Xanthorhiza simplicissima - Description with a picture of the fall colors - site with a picture of the root - Medicinal uses - Foster, S. & Duke, J. A. (1998). Field Guide to Medicinal Plants: Eastern and Central North America. Houghton Mifflin. ISBN 0-395-92066-3.	Yellowroot The Yellowroot (Xanthorhiza simplicissima, syn. X. apiifolia) is the only member of the genus Xanthorhiza, and one of very few genera in the family Ranunculaceae with a woody stem (the other notable example being Clematis). It is native to the eastern United States from Maine south to northern Florida and west to Ohio and eastern Texas. The genus name as well as the common name refer to the plant's yellow roots (xantho- meaning "yellow" and rhiza meaning "root"), which was used to produce a yellow dye by Native Americans. The species name refers to the simple (not branched) root. In the wild, it grows on the edges of streams in sandy soil under a canopy of dappled sunlight. In cultivation, it is often provided with more sunlight so that the fall colors are more vivid. It is a subshrub, reaching 20-70 cm (rarely 90 cm) in height, with stems up to 6 mm diameter. The leaves are spirally arranged, 10-18 cm long, each divided into 5 toothed leaflets, and flowers emerge only from the upper portion of the unbranched stem. The flowers are produced in broad panicles 6-20 cm long, each flower small, star-shaped, reddish brown to purple brown, with five petals. Yellowroot propagates asexually by sending out many underground runners, and it reproduces sexually with seeds. Yellowroot is considered an endangered species in Florida. ## Cultivation and uses It is cultivated for the stunning fall color, which is a dark red to purple, and lasts for months. While yellowroot is toxic in large doses, a reason why deer do not eat it, it has been used to adulterate or as a substitute for Hydrastis canadensis. Native Americans made a tea and drank it for ulcers in the mouth and in the stomach. It may have also been used as a tonic, and externally on sores. Native Americans also used it to treat various skin ailments. According to Foster & Duke (1998), the plant contains berberine which is anti-inflammatory, astringent, hemostatic, antimicrobial, anticonvulsant, immunostimulant, uterotonic and can produce a transient drop in blood pressure. In addition it stimulates the secretion of bile and bilirubin which may be helpful in cirrhosis of the liver. # References and external links - Flora of North America: Xanthorhiza simplicissima - Description with a picture of the fall colors - site with a picture of the root - Medicinal uses - Foster, S. & Duke, J. A. (1998). Field Guide to Medicinal Plants: Eastern and Central North America. Houghton Mifflin. ISBN 0-395-92066-3. Template:Ranunculales-stub Template:WS	https://www.wikidoc.org/index.php/Yellowroot
aa718e2af747c066b1991c04510338d8caa62eca	wikidoc	Yerba mate	Yerba mate Yerba mate / Erva-mate*, Ilex paraguariensis, is a species of holly (family Aquifoliaceae) native to subtropical South America in Argentina, eastern Paraguay, western Uruguay and southern Brazil. The yerba mate plant is a shrub or small tree growing up to 15 meters tall. The leaves are evergreen, 7–11 cm long and 3–5.5 cm wide, with a serrated margin. The flowers are small, greenish-white, with four petals. The fruit is a red berry 4–6 mm diameter. # Infusion The infusion called mate is prepared by steeping dry leaves (and twigs) of yerba mate in hot water, rather than boiling water like black tea or coffee. It is a slightly less potent stimulant than coffee and much gentler on the stomach. Drinking mate with friends from a shared hollow gourd (also called a mate in Spanish, or cabaça or cuia in Portuguese) with a metal straw (a bombilla in Spanish, bomba or canudo in Portuguese) is an extremely common social practice in Argentina, Uruguay, Paraguay, southern Chile, eastern Bolivia and Brazil and also Syria and Lebanon. The flavor of brewed yerba mate is strongly vegetal, herbal, and grassy, reminiscent of some varieties of green tea. Many consider the flavor to be very agreeable, but it is generally bitter if steeped in boiling water, so it is made using hot but not boiling water. Unlike most teas, it does not become bitter and astringent when steeped for extended periods, and the leaves may be infused several times. Additionally, one can purchase flavored mate in many varieties. In Brazil, a toasted version of mate, known as chá mate or "mate tea", is sold in teabag and loose form, and served, sweetened, in specialized shops, either hot or iced with fruit juice or milk. An iced, sweetened version of toasted mate is sold as an uncarbonated soft drink, with or without fruit flavoring. The toasted variety of mate has less of a bitter flavor and more of a spicy fragrance. It is more popular in the coastal cities of Brazil, as opposed to the far southern states where it is consumed in the traditional way (green, drunk with a silver straw from a shared gourd). Similarly, a form of mate is sold in Argentina, Uruguay and Paraguay in tea bags to be drunk in a similar way to tea. This is known in Spanish as mate cocido or cocido. In Argentina this is commonly drunk with breakfast or as part of merienda (roughly, afternoon tea), often with a selection of facturas (sweet pastries). It is also made by heating yerba in water and straining it as it cools. In Paraguay, yerba mate is also drunk as a cold beverage. Usually drunk out of a cows horn in the countryside, terrerre as it is known in the guaraní language, is served with cold or iced water. Medicinal herbs mixed in a mortar and pestle are added to the water for taste or medicinal reasons. # Nomenclature The pronunciation of yerba mate in standard Spanish is Template:IPA. The Rioplatense dialect spoken in most of Argentina turns the first sound in yerba into a postalveolar fricative consonant, giving Template:IPA in regions closer to Buenos Aires, gradually blending into Template:IPA as one goes farther from the city, and eventually to Template:IPA around Mendoza. The word hierba is Spanish for grass or herb; yerba is a variant spelling of it which is quite common in Argentina. Mate is from the Quechua mati, meaning "cup". Yerba mate is therefore literally the "cup herb". The (Brazilian) Portuguese name is erva-mate Template:IPA (also pronounced as Template:IPA in some regions) and is also used to prepare the drinks chimarrão (hot) or tereré (cold). While the tea is made with the toasted leaves, these drinks are made with green ones, and are very popular in the south of the country. The name given to the plant in Guaraní (Guarani, in Portuguese), language of the indigenous people who first cultivated and enjoyed erva-mate / yerba mate, is ka'a, which has the same meaning as erva/yerba. In English-speaking countries, the spelling used is yerba maté (with an accented é)—where the acute accent indicates that the e is not silent, and thus that the word should not be pronounced as the English word mate. # Cultivation The plant is grown mainly in South America, more specifically in Northern Argentina (Corrientes, Misiones), Paraguay, Uruguay and southern Brazil (Rio Grande do Sul, Santa Catarina and Paraná). The Guaraní are reputed to be the first people who cultivated the plant; the first Europeans to do this were Jesuit missionaries, who spread the drinking habit as far as Ecuador. When the yerba is harvested, the branches are dried sometimes with a wood fire, imparting a smoky flavor. Then the leaves and sometimes the twigs are broken up. There are many brands and types of yerba, with and without twigs, some with low powder content. Some types are less strong in flavor (suave, "soft") and there are blends flavored with mint, orange and grapefruit skin, etc. # Chemical composition and properties Mate contains xanthines, which are alkaloids in the same family as caffeine, theophylline, and theobromine, well-known stimulants also found in coffee and chocolate. Mate also contains elements such as potassium, magnesium and manganese. Caffeine content varies between 0.3% and 1.7% of dry weight (compare this to 2.5–4.5% for tea leaves, and 1.5% for ground coffee). Mate products are sometimes marketed as "caffeine-free" alternatives to coffee and tea, and said to have fewer negative effects. This is often based on a claim that the primary active xanthine in mate is "mateine", erroneously said to be a stereoisomer of caffeine (as it is not chemically possible for caffeine to have a stereoisomer). "Mateine" is an official synonym of caffeine in the chemical databases. Researchers at Florida International University in Miami have found that yerba mate does contain caffeine, but some people seem to tolerate a mate drink better than coffee or tea. This is expected since mate contains different chemicals (other than caffeine) from tea or coffee. From reports of personal experience with mate, its physiological effects are similar to (yet distinct from) more widespread caffeinated beverages like coffee, tea, or guarana drinks. Users report a mental state of wakefulness, focus and alertness reminiscent of most stimulants, but often remark on mate's unique lack of the negative effects typically created by other such compounds, such as anxiety, diarrhea, "jitteriness", and heart palpitations. (The laxative effect of coffee derives from a substance that surrounds the raw bean, not the caffeine itself.) Reasons for mate's unique physiological attributes are beginning to emerge in scientific research. Studies of mate, though very limited, have shown preliminary evidence that the mate xanthine cocktail is different from other plants containing caffeine most significantly in its effects on muscle tissue, as opposed to those on the central nervous system, which are similar to those of other natural stimulants. Mate has been shown to have a relaxing effect on smooth muscle tissue, and a stimulating effect on myocardial (heart) tissue. Mate's negative effects are anecdotally claimed to be of a lesser degree than those of coffee, though no explanation for this is offered or even credibly postulated, except for its potential as a placebo effect. Many users report that drinking yerba mate does not prevent them from being able to fall asleep, as is often the case with some more common stimulating beverages, while still enhancing their energy and ability to remain awake at will. However, the net amount of caffeine in one preparation of yerba mate is typically quite high, in large part because the repeated filling of the mate with hot water is able to extract the highly-soluble xanthines extremely effectively. It is for this reason that one mate may be shared among several people and yet produce the desired stimulating effect in all of them. In vivo and in vitro studies are showing yerba mate to exhibit significant cancer-fighting activity. Researchers at the University of Illinois (2005) found yerba mate to be "rich in phenolic constituents" and to "inhibit oral cancer cell proliferation". On the other hand, a study by the International Agency for Research on Cancer showed a limited correlation between oral cancer and the drinking of hot mate (no data were collected on drinkers of cold mate). Given the influence of the temperature of water, as well as the lack of complete adjustment for age, alcohol consumption and smoking, the study concludes that mate is "not classifiable as to its carcinogenicity to humans". Yerba mate consumption has been associated with increased incidence of bladder, esophageal, oral, squamous cell of the head and neck, and lung cancer. It should be noted that the consumption of hot beverages itself is a risk factor for several kinds of cancer. An August 11, 2005, United States patent application (documents #20050176777, #20030185908, and #20020054926) cites yerba mate extract as an inhibitor of MAO activity; the maximal inhibition observed in vitro was 40–50%. A monoamine oxidase inhibitor is a type of antidepressant, so there is some data to suggest that yerba mate has a calming effect in this regard. In addition, it has been noted by the U.S. Army Center for Health Promotion and Preventive Medicine that yerba mate can cause high blood pressure when used in conjunction with other MAO inhibitors (such as Nardil and Parnate). Emerging research also shows that Yerba Mate preparations can alter the concentration of members of the ecto-nucleoside triphosphate diphosphohydrolase (E-NTPDase) family, resulting in an elevated level of extracellular ATP,ADP, and AMP. This was found with chronic ingestion (15 days)of an aqueous Yerba extract, and can lead to a novel mechanism for manipulation of vascular regenerative factors, i.e., treating heart disease.. Mate contains both caffeine and theobromine (which antagonize adenosine receptors) and reduces the bodies production of adenosine in the blood (prolongs half life of ATP, ADP, and AMP). These two processes will synergize to provide a much cleaner stimulation than a simple dose of caffeine (only blocking adenosine receptors).	Yerba mate Yerba mate / Erva-mate*, Ilex paraguariensis, is a species of holly (family Aquifoliaceae) native to subtropical South America in Argentina, eastern Paraguay, western Uruguay and southern Brazil. [1] The yerba mate plant is a shrub or small tree growing up to 15 meters tall. The leaves are evergreen, 7–11 cm long and 3–5.5 cm wide, with a serrated margin. The flowers are small, greenish-white, with four petals. The fruit is a red berry 4–6 mm diameter. [2] # Infusion The infusion called mate is prepared by steeping dry leaves (and twigs) of yerba mate in hot water, rather than boiling water like black tea or coffee. It is a slightly less potent stimulant than coffee and much gentler on the stomach. Drinking mate with friends from a shared hollow gourd (also called a mate in Spanish, or cabaça or cuia in Portuguese) with a metal straw (a bombilla in Spanish, bomba or canudo in Portuguese) is an extremely common social practice in Argentina, [3][4] Uruguay, Paraguay, southern Chile, eastern Bolivia and Brazil [5] and also Syria and Lebanon. The flavor of brewed yerba mate is strongly vegetal, herbal, and grassy, reminiscent of some varieties of green tea. Many consider the flavor to be very agreeable, but it is generally bitter if steeped in boiling water, so it is made using hot but not boiling water. Unlike most teas, it does not become bitter and astringent when steeped for extended periods, and the leaves may be infused several times. Additionally, one can purchase flavored mate in many varieties. In Brazil, a toasted version of mate, known as chá mate or "mate tea", is sold in teabag and loose form, and served, sweetened, in specialized shops, either hot or iced with fruit juice or milk. An iced, sweetened version of toasted mate is sold as an uncarbonated soft drink, with or without fruit flavoring. The toasted variety of mate has less of a bitter flavor and more of a spicy fragrance. It is more popular in the coastal cities of Brazil, as opposed to the far southern states where it is consumed in the traditional way (green, drunk with a silver straw from a shared gourd). Similarly, a form of mate is sold in Argentina, Uruguay and Paraguay in tea bags to be drunk in a similar way to tea. This is known in Spanish as mate cocido or cocido. In Argentina this is commonly drunk with breakfast or as part of merienda (roughly, afternoon tea), often with a selection of facturas (sweet pastries). It is also made by heating yerba in water and straining it as it cools. In Paraguay, yerba mate is also drunk as a cold beverage. Usually drunk out of a cows horn in the countryside, terrerre as it is known in the guaraní language, is served with cold or iced water. Medicinal herbs mixed in a mortar and pestle are added to the water for taste or medicinal reasons. # Nomenclature The pronunciation of yerba mate in standard Spanish is Template:IPA. The Rioplatense dialect spoken in most of Argentina turns the first sound in yerba into a postalveolar fricative consonant, giving Template:IPA in regions closer to Buenos Aires, gradually blending into Template:IPA as one goes farther from the city, and eventually to Template:IPA around Mendoza. The word hierba is Spanish for grass or herb; yerba is a variant spelling of it which is quite common in Argentina. Mate is from the Quechua mati, meaning "cup". Yerba mate is therefore literally the "cup herb". The (Brazilian) Portuguese name is erva-mate Template:IPA (also pronounced as Template:IPA in some regions) and is also used to prepare the drinks chimarrão (hot) or tereré (cold). While the tea is made with the toasted leaves, these drinks are made with green ones, and are very popular in the south of the country. The name given to the plant in Guaraní (Guarani, in Portuguese), language of the indigenous people who first cultivated and enjoyed erva-mate / yerba mate, is ka'a, which has the same meaning as erva/yerba. In English-speaking countries, the spelling used is yerba maté (with an accented é)[6][7][8][9]—where the acute accent indicates that the e is not silent, and thus that the word should not be pronounced as the English word mate. # Cultivation The plant is grown mainly in South America, more specifically in Northern Argentina (Corrientes, Misiones), Paraguay, Uruguay and southern Brazil (Rio Grande do Sul, Santa Catarina and Paraná). The Guaraní are reputed to be the first people who cultivated the plant; the first Europeans to do this were Jesuit missionaries, who spread the drinking habit as far as Ecuador.[10] When the yerba is harvested, the branches are dried sometimes with a wood fire, imparting a smoky flavor. Then the leaves and sometimes the twigs are broken up. There are many brands and types of yerba, with and without twigs, some with low powder content. Some types are less strong in flavor (suave, "soft") and there are blends flavored with mint, orange and grapefruit skin, etc. # Chemical composition and properties Mate contains xanthines, which are alkaloids in the same family as caffeine, theophylline, and theobromine, well-known stimulants also found in coffee and chocolate. Mate also contains elements such as potassium, magnesium and manganese. [11] Caffeine content varies between 0.3% and 1.7% of dry weight (compare this to 2.5–4.5% for tea leaves, and 1.5% for ground coffee). Mate products are sometimes marketed as "caffeine-free" alternatives to coffee and tea, and said to have fewer negative effects. This is often based on a claim that the primary active xanthine in mate is "mateine", erroneously said to be a stereoisomer of caffeine (as it is not chemically possible for caffeine to have a stereoisomer). "Mateine" is an official synonym of caffeine in the chemical databases. [12] Researchers at Florida International University in Miami have found that yerba mate does contain caffeine, but some people seem to tolerate a mate drink better than coffee or tea. This is expected since mate contains different chemicals (other than caffeine) from tea or coffee. From reports of personal experience with mate, its physiological effects are similar to (yet distinct from) more widespread caffeinated beverages like coffee, tea, or guarana drinks. Users report a mental state of wakefulness, focus and alertness reminiscent of most stimulants, but often remark on mate's unique lack of the negative effects typically created by other such compounds, such as anxiety, diarrhea, "jitteriness", and heart palpitations. (The laxative effect of coffee derives from a substance that surrounds the raw bean, not the caffeine itself.) Reasons for mate's unique physiological attributes are beginning to emerge in scientific research. Studies of mate, though very limited, have shown preliminary evidence that the mate xanthine cocktail is different from other plants containing caffeine most significantly in its effects on muscle tissue, as opposed to those on the central nervous system, which are similar to those of other natural stimulants. Mate has been shown to have a relaxing effect on smooth muscle tissue, and a stimulating effect on myocardial (heart) tissue.[13] Mate's negative effects are anecdotally claimed to be of a lesser degree than those of coffee, though no explanation for this is offered or even credibly postulated, except for its potential as a placebo effect. Many users report that drinking yerba mate does not prevent them from being able to fall asleep, as is often the case with some more common stimulating beverages, while still enhancing their energy and ability to remain awake at will. However, the net amount of caffeine in one preparation of yerba mate is typically quite high, in large part because the repeated filling of the mate with hot water is able to extract the highly-soluble xanthines extremely effectively. It is for this reason that one mate may be shared among several people and yet produce the desired stimulating effect in all of them. In vivo and in vitro studies are showing yerba mate to exhibit significant cancer-fighting activity. Researchers at the University of Illinois (2005) found yerba mate to be "rich in phenolic constituents" and to "inhibit oral cancer cell proliferation". [14] On the other hand, a study by the International Agency for Research on Cancer showed a limited correlation between oral cancer and the drinking of hot mate (no data were collected on drinkers of cold mate). Given the influence of the temperature of water, as well as the lack of complete adjustment for age, alcohol consumption and smoking, the study concludes that mate is "not classifiable as to its carcinogenicity to humans". [15] Yerba mate consumption has been associated with increased incidence of bladder, esophageal, oral, squamous cell of the head and neck, and lung cancer. [16][17][18][19][20][21] It should be noted that the consumption of hot beverages itself is a risk factor for several kinds of cancer. An August 11, 2005, United States patent application (documents #20050176777, #20030185908,[22] and #20020054926) cites yerba mate extract as an inhibitor of MAO activity; the maximal inhibition observed in vitro was 40–50%. A monoamine oxidase inhibitor is a type of antidepressant, so there is some data to suggest that yerba mate has a calming effect in this regard. In addition, it has been noted by the U.S. Army Center for Health Promotion and Preventive Medicine that yerba mate can cause high blood pressure when used in conjunction with other MAO inhibitors (such as Nardil and Parnate). [23] Emerging research also shows that Yerba Mate preparations can alter the concentration of members of the ecto-nucleoside triphosphate diphosphohydrolase (E-NTPDase) family, resulting in an elevated level of extracellular ATP,ADP, and AMP. This was found with chronic ingestion (15 days)of an aqueous Yerba extract, and can lead to a novel mechanism for manipulation of vascular regenerative factors, i.e., treating heart disease.[1]. Mate contains both caffeine and theobromine (which antagonize adenosine receptors) and reduces the bodies production of adenosine in the blood (prolongs half life of ATP, ADP, and AMP). These two processes will synergize to provide a much cleaner stimulation than a simple dose of caffeine (only blocking adenosine receptors).	https://www.wikidoc.org/index.php/Yerba_mate
d57c230201ee7fc52cba8299396e248457d980b9	wikidoc	Yves Morin	Yves Morin Yves Morin (born November 28, 1929) is a Canadian cardiologist, physician, scientist, and former Senator. Born in Quebec City, Quebec, he received a Bachelor of Arts degree in 1948 and a Doctor of Medicine degree in 1953 from the Université Laval. He was Dean of the Faculty of Medicine at Université Laval. In 2001, he was appointed to the Senate of Canada representing the senatorial division of Lauzon, Quebec. A Liberal, he served until his mandatory retirement on his 75th birthday in 2004. In 1990, he was made an Officer of the Order of Canada for having "a major influence on the training of a generation of doctors". In 1995, he was made an Officer of the National Order of Quebec.	Yves Morin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Yves Morin (born November 28, 1929) is a Canadian cardiologist, physician, scientist, and former Senator. Born in Quebec City, Quebec, he received a Bachelor of Arts degree in 1948 and a Doctor of Medicine degree in 1953 from the Université Laval. He was Dean of the Faculty of Medicine at Université Laval. In 2001, he was appointed to the Senate of Canada representing the senatorial division of Lauzon, Quebec. A Liberal, he served until his mandatory retirement on his 75th birthday in 2004. In 1990, he was made an Officer of the Order of Canada for having "a major influence on the training of a generation of doctors". [2] In 1995, he was made an Officer of the National Order of Quebec. # External links - Synopsis of federal political experience from the Library of Parliament - Cititation at the official National Order of Quebec website Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Yves_Morin
5ecdebdb576a3731d367056ffe47daaecf21ed6f	wikidoc	Zaspopathy	Zaspopathy # Overview Zaspopathy, also called ZASP-related myofibril myopathy, is a novel autosomal dominant form of progressive muscular dystrophy, first described in 2005. The disease encompasses multiple forms of both distal and proximal myopathies, and is caused by mutations in the gene referred to as ZASP. # Pathophysiology The ZASP gene is located at chromosome 10, and encodes a so-called Z-disk-associated protein. Mutation in this protein causes disintergration of the Z-disk of contractile elements (myofibrils) in muscle cells. Mutations of several other Z-disk related proteins, such as desmin, alfa-B-crystallin and myotilin can cause disorders similar to zaspopathy.	Zaspopathy # Overview Zaspopathy,[1] also called ZASP-related myofibril myopathy,[2] is a novel autosomal dominant[3] form of progressive muscular dystrophy, first described in 2005. The disease encompasses multiple forms of both distal and proximal myopathies, and is caused by mutations in the gene referred to as ZASP.[3] # Pathophysiology The ZASP gene is located at chromosome 10, and encodes a so-called Z-disk-associated protein. Mutation in this protein causes disintergration of the Z-disk of contractile elements (myofibrils) in muscle cells. Mutations of several other Z-disk related proteins, such as desmin, alfa-B-crystallin and myotilin can cause disorders similar to zaspopathy.	https://www.wikidoc.org/index.php/ZASP-related_myofibril_myopathy
96b4f51f89631b8b362a856f2163f6055e8577f0	wikidoc	Zika virus	Zika virus # Overview Zika virus infection is caused by Zika virus, an enveloped, single stranded positive sense RNA virus. Zika virus is a type of flavivirus. Mosquitoes are the primary disease vector of Zika virus. # Microbiological Characteristics - Zika virus, also known as ZIKV is an enveloped, icosahedral virus with a single-stranded, positive sense RNA genome. The most closely related virus is the Spondweni virus and is one of the two viruses in the Spondweni virus clade. - The Zika virus genome consists of 10,794 nucleotides that encode 3,419 amino acids. - Zika virus is a member of the Flaviviridae family and of the flavivirus genus. - There are two lineages for Zika virus: African and Asian. # Transmission ## Mosquito Vector Transmission Transmission of Zika virus to humans is thought to occur mainly through infected mosquitoes. - The following species have been identified as vectors for Zika virus: The table below compares the characteristics of 2 common Aedes species: Ae. aegypti and Ae. albopictus Table adapted from the Centers for Disease Control and Prevention (CDC) Read the CDC infographic on life cycle of Aedes aegypti mosquito here ## Human-to-Human Transmission Zika virus can be trasmitted via mother to child and sexual trasmission. ### Mother to child - A pregnant woman who is already infected with Zika virus can pass the virus to her fetus during the pregnancy or around the time of birth. - Zika virus has been detected in amniotic fluid, which suggests that Zika virus may cross the placental barrier and vertical transmission is possible. Mosquito-borne ZIKV is thought to initially replicate in dendritic cells near the site of inoculation before spreading to lymph nodes and then the bloodstream. ZIKV can be killed by potassium permanganate, ether, temperatures >60°C, but is not effectively neutralized by 10% ethanol. - There are no reported cases of Zika virus spread through breastfeeding. Due to the nutritional benefits of breastmilk, mothers are encouraged to breastfeed their infants even in areas where Zika virus is endemic. ### Sexual transmission - Zika virus can be sexually transmitted between humans. - It can be transmitted even if the infected person does not have symptoms. - Zika virus remains in semen longer than in other body fluids (vaginal fluids, urine, and blood). ## Blood transfusion - Zika virus can be transmitted via blood transfusion but there are no cases reported in United States. - The transmission of virus through blood transfusion has been reported in Brazil. These cases are under investigation. - On August 26, 2016, the US Food and Drug Administration (FDA) issued revised guidelines recommending universal testing of donated whole blood and blood components for Zika virus in the United States and its territories. ## Laboratory exposure - There has been one reported laboratory-acquired Zika virus disease in United States. # Virology - Following a mosquito bite, the incubation period for Zika virus in humans is approximately 3 to 12 days. - Detection of Zika virus is primarily based on the isolation of RNA from blood serum through PCR in acutely ill patients. - An ELISA has also been developed by the Centers for Disease Control and Prevention to detect IgM against ZIKV. - Zika virus has a short viremic period, such that the virus may be detected in serum 3-5 days following the onset of symptoms. Zika virus can be detected in urine up to 10 days following the onset of symptoms. # Refererences - ↑ FIELDS, B. N., KNIPE, D. M., & HOWLEY, P. M. (2007). Fields virology. Philadelphia, Wolters Kluwer Health/Lippincott Williams & Wilkins. - ↑ Jump up to: 2.0 2.1 2.2 2.3 Hayes EB (2009). "Zika virus outside Africa". Emerg Infect Dis. 15 (9): 1347–50. doi:10.3201/eid1509.090442. PMC 2819875. PMID 19788800.CS1 maint: PMC format (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} - ↑ Duffy, Mark R.; Chen, Tai-Ho; Hancock, W. Thane; Powers, Ann M.; Kool, Jacob L.; Lanciotti, Robert S.; Pretrick, Moses; Marfel, Maria; Holzbauer, Stacey; Dubray, Christine; Guillaumot, Laurent; Griggs, Anne; Bel, Martin; Lambert, Amy J.; Laven, Janeen; Kosoy, Olga; Panella, Amanda; Biggerstaff, Brad J.; Fischer, Marc; Hayes, Edward B. (2009). "Zika Virus Outbreak on Yap Island, Federated States of Micronesia". New England Journal of Medicine. 360 (24): 2536–2543. doi:10.1056/NEJMoa0805715. ISSN 0028-4793. - ↑ CDC Transmission - ↑ Musso D, Roche C, Robin E, Nhan T, Teissier A, Cao-Lormeau VM (2015). "Potential sexual transmission of Zika virus". Emerg Infect Dis. 21 (2): 359–61. doi:10.3201/eid2102.141363. PMC 4313657. PMID 25625872.CS1 maint: Multiple names: authors list (link) - ↑ Foy, B. D.; Kobylinski, K. C.; Foy, J. L. C.; Blitvich, B. J.; Travassos Da Rosa, A.; Haddow, A. D.; Lanciotti, R. S.; Tesh, R. B. (2011). "Probable Non–Vector-borne Transmission of Zika Virus, Colorado, USA". Emerging Infectious Diseases. 17 (5): 880–882. doi:10.3201/eid1705.101939. PMC 3321795. PMID 21529401. - ↑ Zika virus transmission (August 27, 2016) Accessed on September 15, 2016 - ↑ Zika Virus Transmission. Centers for Disease Control and Prevention (August 27, 2016). Accessed on September 14, 2016 - ↑ Jump up to: 9.0 9.1 ECDC Zika virus infection factsheet	Zika virus Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yazan Daaboul, M.D., Nate Michalak, B.A., Serge Korjian M.D., Yamuna Kondapally, M.B.B.S[2] # Overview Zika virus infection is caused by Zika virus, an enveloped, single stranded positive sense RNA virus. Zika virus is a type of flavivirus. Mosquitoes are the primary disease vector of Zika virus. # Microbiological Characteristics - Zika virus, also known as ZIKV is an enveloped, icosahedral virus with a single-stranded, positive sense RNA genome. The most closely related virus is the Spondweni virus and is one of the two viruses in the Spondweni virus clade.[1] - The Zika virus genome consists of 10,794 nucleotides that encode 3,419 amino acids.[2] - Zika virus is a member of the Flaviviridae family and of the flavivirus genus. - There are two lineages for Zika virus: African and Asian.[2] # Transmission ## Mosquito Vector Transmission Transmission of Zika virus to humans is thought to occur mainly through infected mosquitoes. - The following species have been identified as vectors for Zika virus:[3] The table below compares the characteristics of 2 common Aedes species: Ae. aegypti and Ae. albopictus Table adapted from the Centers for Disease Control and Prevention (CDC)[3] Read the CDC infographic on life cycle of Aedes aegypti mosquito here ## Human-to-Human Transmission Zika virus can be trasmitted via mother to child and sexual trasmission. ### Mother to child - A pregnant woman who is already infected with Zika virus can pass the virus to her fetus during the pregnancy or around the time of birth. - Zika virus has been detected in amniotic fluid, which suggests that Zika virus may cross the placental barrier and vertical transmission is possible.[4] Mosquito-borne ZIKV is thought to initially replicate in dendritic cells near the site of inoculation before spreading to lymph nodes and then the bloodstream. ZIKV can be killed by potassium permanganate, ether, temperatures >60°C, but is not effectively neutralized by 10% ethanol.[2] - There are no reported cases of Zika virus spread through breastfeeding. Due to the nutritional benefits of breastmilk, mothers are encouraged to breastfeed their infants even in areas where Zika virus is endemic. ### Sexual transmission - Zika virus can be sexually transmitted between humans.[5][6] - It can be transmitted even if the infected person does not have symptoms. - Zika virus remains in semen longer than in other body fluids (vaginal fluids, urine, and blood).[7] ## Blood transfusion - Zika virus can be transmitted via blood transfusion but there are no cases reported in United States. - The transmission of virus through blood transfusion has been reported in Brazil. These cases are under investigation. - On August 26, 2016, the US Food and Drug Administration (FDA) issued revised guidelines recommending universal testing of donated whole blood and blood components for Zika virus in the United States and its territories. ## Laboratory exposure - There has been one reported laboratory-acquired Zika virus disease in United States.[8] # Virology - Following a mosquito bite, the incubation period for Zika virus in humans is approximately 3 to 12 days. - Detection of Zika virus is primarily based on the isolation of RNA from blood serum through PCR in acutely ill patients.[9] - An ELISA has also been developed by the Centers for Disease Control and Prevention to detect IgM against ZIKV.[2] - Zika virus has a short viremic period, such that the virus may be detected in serum 3-5 days following the onset of symptoms. Zika virus can be detected in urine up to 10 days following the onset of symptoms.[9] # Refererences - ↑ FIELDS, B. N., KNIPE, D. M., & HOWLEY, P. M. (2007). Fields virology. Philadelphia, Wolters Kluwer Health/Lippincott Williams & Wilkins. - ↑ Jump up to: 2.0 2.1 2.2 2.3 Hayes EB (2009). "Zika virus outside Africa". Emerg Infect Dis. 15 (9): 1347–50. doi:10.3201/eid1509.090442. PMC 2819875. PMID 19788800.CS1 maint: PMC format (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} - ↑ Duffy, Mark R.; Chen, Tai-Ho; Hancock, W. Thane; Powers, Ann M.; Kool, Jacob L.; Lanciotti, Robert S.; Pretrick, Moses; Marfel, Maria; Holzbauer, Stacey; Dubray, Christine; Guillaumot, Laurent; Griggs, Anne; Bel, Martin; Lambert, Amy J.; Laven, Janeen; Kosoy, Olga; Panella, Amanda; Biggerstaff, Brad J.; Fischer, Marc; Hayes, Edward B. (2009). "Zika Virus Outbreak on Yap Island, Federated States of Micronesia". New England Journal of Medicine. 360 (24): 2536–2543. doi:10.1056/NEJMoa0805715. ISSN 0028-4793. - ↑ http://www.cdc.gov/zika/transmission/index.html CDC Transmission - ↑ Musso D, Roche C, Robin E, Nhan T, Teissier A, Cao-Lormeau VM (2015). "Potential sexual transmission of Zika virus". Emerg Infect Dis. 21 (2): 359–61. doi:10.3201/eid2102.141363. PMC 4313657. PMID 25625872.CS1 maint: Multiple names: authors list (link) - ↑ Foy, B. D.; Kobylinski, K. C.; Foy, J. L. C.; Blitvich, B. J.; Travassos Da Rosa, A.; Haddow, A. D.; Lanciotti, R. S.; Tesh, R. B. (2011). "Probable Non–Vector-borne Transmission of Zika Virus, Colorado, USA". Emerging Infectious Diseases. 17 (5): 880–882. doi:10.3201/eid1705.101939. PMC 3321795. PMID 21529401. - ↑ Zika virus transmission https://www.cdc.gov/zika/transmission/index.html (August 27, 2016) Accessed on September 15, 2016 - ↑ Zika Virus Transmission. Centers for Disease Control and Prevention (August 27, 2016). http://www.cdc.gov/zika/transmission/index.html Accessed on September 14, 2016 - ↑ Jump up to: 9.0 9.1 http://ecdc.europa.eu/en/healthtopics/zika_virus_infection/factsheet-health-professionals/Pages/factsheet_health_professionals.aspx ECDC Zika virus infection factsheet	https://www.wikidoc.org/index.php/ZIKV
89b57ed3333148b1ff9608b61616a78849b30032	wikidoc	Zeaxanthin	Zeaxanthin Zeaxanthin is one of the two carotenoids contained within the retina. Within the central macula, zeaxanthin is the dominant component, whereas in the peripheral retina, lutein predominates. Lutein and zeaxanthin have identical chemical formulas and are isomers, but they are not stereoisomers. The main difference between them is in the location of a double bond in one of the end rings. This difference gives lutein three chiral centers whereas zeaxanthin has two. As a food additive, zeaxanthin is a food dye with E number E161h. # Isomers Because of symmetry, the (3R,3'S) and (3S,3'R) stereoisomers of zeaxanthin are identical. Therefore, zeaxanthin has only three stereoisomeric forms. The (3R,3'S) stereoisomer is called meso-zeaxanthin. The principal natural form of zeaxanthin is (3R,3'R)-zeaxanthin. The macula mainly contains the (3R,3'R)- and meso-zeaxanthin forms, but it also contains much smaller amounts of the third (3S,3'S) form. # Relationship with diseases of the eye There is epidemiological evidence of a relationship between low plasma concentrations of lutein and zeaxanthin on the one hand, and the risk of developing age-related macular degeneration (AMD) on the other. Some studies support the view that supplemental lutein and/or zeaxanthin help protect against AMD. There is also epidemiological evidence that increasing lutein and zeaxanthin intake lowers the risk of cataract development. On September 10, 2007, in a 6-year study, researchers, led by John Paul SanGiovanni of the National Eye Institute, Maryland found that Lutein and zeaxanthin (nutrients in eggs, spinach and other green vegetables) protect against blindness (macular degeneration), affecting 1.2 million Americans, mostly after age 65. Lutein and zeaxanthin reduce the risk of AMD (journal Archives of Ophthalmology). Foods considered good sources of the nutrients also include kale, turnip greens, collard greens, romaine lettuce, broccoli, zucchini, corn, garden peas and Brussels sprouts. # Natural occurrence Zeaxanthin is one of the most common carotenoid alcohols found in nature. It is the pigment that gives corn, saffron, and many other plants their characteristic color. Zeaxanthin breaks down to form picrocrocin and safranal, which are responsible for the taste and aroma of saffron.	Zeaxanthin Zeaxanthin is one of the two carotenoids contained within the retina. Within the central macula, zeaxanthin is the dominant component, whereas in the peripheral retina, lutein predominates. Lutein and zeaxanthin have identical chemical formulas and are isomers, but they are not stereoisomers. The main difference between them is in the location of a double bond in one of the end rings. This difference gives lutein three chiral centers whereas zeaxanthin has two. As a food additive, zeaxanthin is a food dye with E number E161h. # Isomers Because of symmetry, the (3R,3'S) and (3S,3'R) stereoisomers of zeaxanthin are identical. Therefore, zeaxanthin has only three stereoisomeric forms. The (3R,3'S) stereoisomer is called meso-zeaxanthin. The principal natural form of zeaxanthin is (3R,3'R)-zeaxanthin. The macula mainly contains the (3R,3'R)- and meso-zeaxanthin forms, but it also contains much smaller amounts of the third (3S,3'S) form. # Relationship with diseases of the eye There is epidemiological evidence of a relationship between low plasma concentrations of lutein and zeaxanthin on the one hand, and the risk of developing age-related macular degeneration (AMD) on the other. Some studies support the view that supplemental lutein and/or zeaxanthin help protect against AMD. There is also epidemiological evidence that increasing lutein and zeaxanthin intake lowers the risk of cataract development. On September 10, 2007, in a 6-year study, researchers, led by John Paul SanGiovanni of the National Eye Institute, Maryland found that Lutein and zeaxanthin (nutrients in eggs, spinach and other green vegetables) protect against blindness (macular degeneration), affecting 1.2 million Americans, mostly after age 65. Lutein and zeaxanthin reduce the risk of AMD (journal Archives of Ophthalmology). Foods considered good sources of the nutrients also include kale, turnip greens, collard greens, romaine lettuce, broccoli, zucchini, corn, garden peas and Brussels sprouts.[1] # Natural occurrence Zeaxanthin is one of the most common carotenoid alcohols found in nature. It is the pigment that gives corn, saffron, and many other plants their characteristic color. Zeaxanthin breaks down to form picrocrocin and safranal, which are responsible for the taste and aroma of saffron. # External links - BioCyc	https://www.wikidoc.org/index.php/Zeaxanthin
26a85bd000af27a22c6930a938fe2d2b504a1f36	wikidoc	Zestoretic	Zestoretic Synonyms / Brand Names: # Dosing and Administration Lisinopril monotherapy is an effective treatment of hypertension in once-daily doses of 10-80 mg, while hydrochlorothiazide monotherapy is effective in doses of 12.5-50 mg per day. In clinical trials of lisinopril/hydrochlorothiazide combination therapy using lisinopril doses of 10-80 mg and hydrochlorothiazide doses of 6.25-50 mg, the antihypertensive response rates generally increased with increasing dose of either component. For further information please refer to Instructions for administration FDA Package Insert Resources Indications, Contraindications, Side Effects, Drug Interactions, etc. Calculate Creatine Clearance On line calculator of your patients Cr Cl by a variety of formulas. Convert pounds to Kilograms On line calculator of your patients weight in pounds to Kg for dosing estimates. Publication Resources Recent articles, WikiDoc State of the Art Review, Textbook Information Trial Resources Ongoing Trials, Trial Results Guidelines & Evidence Based Medicine Resources US National Guidelines, Cochrane Collaboration, etc. Media Resources Slides, Video, Images, MP3, Podcasts, etc. Patient Resources Discussion Groups, Handouts, Blogs, News, etc. International Resources en Español # FDA Package Insert Resources Indications Contraindications Side Effects Drug Interactions Precautions Overdose Instructions for Administration How Supplied Pharmacokinetics and Molecular Data FDA label FDA on Zestoretic Return to top # Publication Resources Most Recent Articles on Zestoretic Review Articles on Zestoretic Articles on Zestoretic in N Eng J Med, Lancet, BMJ WikiDoc State of the Art Review Textbook Information on Zestoretic Return to top # Trial Resources Ongoing Trials with Zestoretic at Clinical Trials.gov Trial Results with Zestoretic Return to top # Guidelines & Evidence Based Medicine Resources US National Guidelines Clearinghouse on Zestoretic Cochrane Collaboration on Zestoretic Cost Effectiveness of Zestoretic Return to top # Media Resources Powerpoint Slides on Zestoretic Images of Zestoretic Podcasts & MP3s on Zestoretic Videos on Zestoretic Return to top # Patient Resources Patient Information from National Library of Medicine Patient Resources on Zestoretic Discussion Groups on Zestoretic Patient Handouts on Zestoretic Blogs on Zestoretic Zestoretic in the News Zestoretic in the Marketplace Return to top # International Resources Zestoretic en Español Return to top Adapted from the FDA Package Insert.	Zestoretic Synonyms / Brand Names: Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Dosing and Administration Lisinopril monotherapy is an effective treatment of hypertension in once-daily doses of 10-80 mg, while hydrochlorothiazide monotherapy is effective in doses of 12.5-50 mg per day. In clinical trials of lisinopril/hydrochlorothiazide combination therapy using lisinopril doses of 10-80 mg and hydrochlorothiazide doses of 6.25-50 mg, the antihypertensive response rates generally increased with increasing dose of either component. For further information please refer to Instructions for administration FDA Package Insert Resources Indications, Contraindications, Side Effects, Drug Interactions, etc. Calculate Creatine Clearance On line calculator of your patients Cr Cl by a variety of formulas. Convert pounds to Kilograms On line calculator of your patients weight in pounds to Kg for dosing estimates. Publication Resources Recent articles, WikiDoc State of the Art Review, Textbook Information Trial Resources Ongoing Trials, Trial Results Guidelines & Evidence Based Medicine Resources US National Guidelines, Cochrane Collaboration, etc. Media Resources Slides, Video, Images, MP3, Podcasts, etc. Patient Resources Discussion Groups, Handouts, Blogs, News, etc. International Resources en Español # FDA Package Insert Resources Indications Contraindications Side Effects Drug Interactions Precautions Overdose Instructions for Administration How Supplied Pharmacokinetics and Molecular Data FDA label FDA on Zestoretic Return to top # Publication Resources Most Recent Articles on Zestoretic Review Articles on Zestoretic Articles on Zestoretic in N Eng J Med, Lancet, BMJ WikiDoc State of the Art Review Textbook Information on Zestoretic Return to top # Trial Resources Ongoing Trials with Zestoretic at Clinical Trials.gov Trial Results with Zestoretic Return to top # Guidelines & Evidence Based Medicine Resources US National Guidelines Clearinghouse on Zestoretic Cochrane Collaboration on Zestoretic Cost Effectiveness of Zestoretic Return to top # Media Resources Powerpoint Slides on Zestoretic Images of Zestoretic Podcasts & MP3s on Zestoretic Videos on Zestoretic Return to top # Patient Resources Patient Information from National Library of Medicine Patient Resources on Zestoretic Discussion Groups on Zestoretic Patient Handouts on Zestoretic Blogs on Zestoretic Zestoretic in the News Zestoretic in the Marketplace Return to top # International Resources Zestoretic en Español Return to top Adapted from the FDA Package Insert.	https://www.wikidoc.org/index.php/Zestoretic
803d79895d4867bf6605c40f6b421f4528e8a2a2	wikidoc	Zimelidine	Zimelidine # Overview Zimelidine (Normud®, Zelmid®) was the first marketed selective serotonin reuptake inhibitor (SSRI) antidepressant. It is a pyridylallylamine, structurally different from other antidepressants. The substance was developed in the early 1980s by the Swedish company Astra AB following a search for drugs with structures similar to chlorpheniramine (it is a derivative of Chlorphenamine), an antihistamine with antidepressant activity. It was then licensed to other drug producers. Zimelidine has been banned worldwide due to serious, sometimes fatal, cases of central and/or peripheral neuropathy known as Guillain-Barré syndrome and due to a peculiar hypersensitivity reaction involving many organs including skin exanthema, flu-like symptoms, arthralgias, and sometimes eosinophilia. Additionally, zimelidine was charged to cause an increase in suicidal ideation and/or attempts among depressive patients. After its ban, it was succeeded by fluvoxamine and fluoxetine (derived from the antihistamine diphenhydramine) in that order, and the other SSRIs. # Mechanism of action The mode of action is a strong reuptake inhibition of serotonin from the synaptic cleft. Postsynaptic receptors are not acted upon. # Other uses Zimelidine was reported by Montplaisir and Godbout to be very effective for cataplexy in 1986, back when this was usually controlled by tricyclic antidepressants, which often had anticholinergic effects. Zimelidine was able to improve cataplexy without causing daytime sleepiness. # Side effects Most often reported were: - Dry mouth, dryness of pharyngeal and nasal membranes - Increased sweating (hyperhidrosis) - Vertigo - Nausea # Interactions - MAO inhibitors - severe or life-threatening reactions possible # Dosage The former doses were 200 to 400mg daily in outpatients and up to 600mg in inpatients.	Zimelidine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Zimelidine (Normud®, Zelmid®) was the first marketed selective serotonin reuptake inhibitor (SSRI) antidepressant. It is a pyridylallylamine, structurally different from other antidepressants. The substance was developed in the early 1980s by the Swedish company Astra AB following a search for drugs with structures similar to chlorpheniramine (it is a derivative of Chlorphenamine), an antihistamine with antidepressant activity. It was then licensed to other drug producers. Zimelidine has been banned worldwide due to serious, sometimes fatal, cases of central and/or peripheral neuropathy known as Guillain-Barré syndrome and due to a peculiar hypersensitivity reaction involving many organs including skin exanthema, flu-like symptoms, arthralgias, and sometimes eosinophilia. Additionally, zimelidine was charged to cause an increase in suicidal ideation and/or attempts among depressive patients. After its ban, it was succeeded by fluvoxamine and fluoxetine (derived from the antihistamine diphenhydramine) in that order, and the other SSRIs. # Mechanism of action The mode of action is a strong reuptake inhibition of serotonin from the synaptic cleft. Postsynaptic receptors are not acted upon. # Other uses Zimelidine was reported by Montplaisir and Godbout to be very effective for cataplexy in 1986, back when this was usually controlled by tricyclic antidepressants, which often had anticholinergic effects.[2] Zimelidine was able to improve cataplexy without causing daytime sleepiness.[3] # Side effects Most often reported were: - Dry mouth, dryness of pharyngeal and nasal membranes - Increased sweating (hyperhidrosis) - Vertigo - Nausea # Interactions - MAO inhibitors - severe or life-threatening reactions possible # Dosage The former doses were 200 to 400mg daily in outpatients and up to 600mg in inpatients.	https://www.wikidoc.org/index.php/Zimelidine
8bfb338a7eb3d34f784ea38e4963cff4de1d9fc6	wikidoc	Zinc oxide	Zinc oxide # Overview Zinc oxide is a chemical compound with the formula ZnO. It is nearly insoluble in water but soluble in acids and alkalis. It occurs as white hexagonal crystals or a white powder commonly known as zinc white. It remains white when exposed to hydrogen sulfide or ultraviolet light. Crystalline zinc oxide exhibits the piezoelectric effect and is thermochromic (it will change colour from white to yellow when heated, and back again when cooled down). Zinc oxide decomposes into zinc vapor and oxygen at around 1975 °C. High-quality single-crystalline ZnO is almost transparent. Zinc oxide occurs in nature as the mineral zincite. # Applications ## Medical applications Zinc oxide lozenges are a popular over-the-counter cold remedy, but numerous studies have failed to demonstrate any significant effect. Zinc oxide in a mixture with about 0.5% iron(III) oxide (Fe2O3) is called calamine and is used in calamine lotion. There are also two minerals, zincite and hemimorphite, which have been called calamine historically (see: calamine (mineral)). When mixed with eugenol, zinc oxide eugenol forms which has restorative and prosthodontic applications in dentistry. Zinc peroxide, ZnO2 .½ H2O, is a white to yellow powder that is used in antiseptic ointments. ## As a pigment Zinc white is used as a pigment in paints and is more opaque than lithopone, but less opaque than titanium dioxide. It is also used in coatings for paper. Chinese white is a special grade of zinc white used in artists' pigments. Because it absorbs both UVA and UVB rays of ultraviolet light, zinc oxide can be used in ointments, creams, and lotions to protect against sunburn and other damage to the skin caused by ultraviolet light (see sunscreen). It is the broadest spectrum UVA and UVB absorber that is approved for use as a sunscreen by FDA, and is completely photostable. Additionally, since zinc oxide has antimicrobial and antifungal activities, it is the number one active ingredient recommended by pediatricians for the treatment of diaper rash. ## Rubber manufacture Zinc oxide and stearic acid are ingredients in the commercial manufacture of rubber goods. A mixture of these two compounds allows a quicker and more controllable rubber cure. Zinc oxide can also be used as a filler in some rubber mixtures. ## Electronic materials ZnO is a semiconductor with a direct bandgap energy of 3.37 eV at room temperature. The most common applications are in laser diodes and light emitting diodes since it has a exciton and biexciton energies of 60 meV and 15 meV, respectively. It is expected that this exciton properties of ZnO will be improved further by epitaxy. n-type doped films are often used in thin film technology, where zinc oxide serves as a TCO (transparent conducting oxide). n-type doping is possible by introduction of aluminum, indium, or excess zinc. Oxygen vacancies generate states in the band gap and hence also cause an increase in conductivity. p-type doping is difficult and is currently an active area of research, with arsenic as the leading candidate dopant. Thin-film solar cells, LCD and flat panel displays are typical applications of this material. Appropriately doped Zinc oxide may be transparent and conductive, and can therefore be used as a transparent electrode. Indium tin oxide (ITO) is another transparent conducting oxide often used in microelectronics. ZnO has also been considered for spintronics applications because of theoretical predictions of room temperature ferromagnetism. Unsubstantiated reports of ferromagnetism have been made, but presence of dilute magnetic semiconductors remains a large unanswered question in physics. ZnO layers are mainly deposited by sputter deposition and chemical vapor deposition (CVD). The latter method allows the growth of a rough layer, which can diffuse the incoming light by scattering, increasing the efficiency of solar cells. ZnO has been observed to act as a chemical reagent for Friedel-Craft Acylation Reaction. ### Pyroelectric coefficients - Primary pyroelectric coefficient: -6.8 µC/m²·K - Secondary pyroelectric coefficient: -2.5 µC/m²·K - Total pyroelectric coefficient: -9.4 µC/m²·K # Production methods Zinc oxide is produced by two main processes: ## French process Metallic zinc is melted in a graphite crucible and vaporized above 907 °C. Zinc vapor instantaneously reacts with the oxygen in the air to give ZnO, accompanied by a drop in its temperature and bright luminescence. Zinc oxide particles are transported into a cooling duct and collected in a bag house. This indirect method is commonly known as the French process (FP) which was popularised by LeClaire (France) in 1844. A typical FP, zinc oxide normally consists of agglomerated zinc oxide particles with an average size of 0.1 micrometres to a few micrometres. By weight, most of the world's zinc oxide is manufactured via French process and major applications involve industries related to rubber, varistors, suncreens, paints, healthcare, and poultry nutrients. Recent developments involve acicular nanostructures (rods, wires, tripods, tetrapods, plates) synthesized using a modified French process known as catalyst-free combust-oxidized mesh (CFCOM) process. Acicular nanostructures usually have micrometre-length nanorods with nanometric diameters (below 100 nm). The so-called direct method is related to the FP. In this process, zinc ores or roasted sulfide concentrates are mixed with coal. In a reduction furnace, ore is reduced to metallic zinc and the vaporized zinc is allowed to react with oxygen to form zinc oxide. ## American process In this process ore of zinc (zinc ash) is dissolved (as ZnCl2) and precipitated with alkali. Zinc oxide made from this process is known as "Active Zinc Oxide" # Safety Fumes of zinc oxide are generated when melting brass, because the melting point of brass is close to the boiling point of zinc. Exposure to zinc oxide in the air (also while welding) can result in a nervous malady called metal fume fever.	Zinc oxide Template:Chembox new Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Zinc oxide is a chemical compound with the formula ZnO. It is nearly insoluble in water but soluble in acids and alkalis. It occurs as white hexagonal crystals or a white powder commonly known as zinc white. It remains white when exposed to hydrogen sulfide or ultraviolet light. Crystalline zinc oxide exhibits the piezoelectric effect and is thermochromic (it will change colour from white to yellow when heated, and back again when cooled down). Zinc oxide decomposes into zinc vapor and oxygen at around 1975 °C. High-quality single-crystalline ZnO is almost transparent. Zinc oxide occurs in nature as the mineral zincite. # Applications ## Medical applications Zinc oxide lozenges are a popular over-the-counter cold remedy, but numerous studies have failed to demonstrate any significant effect.[1] Zinc oxide in a mixture with about 0.5% iron(III) oxide (Fe2O3) is called calamine and is used in calamine lotion. There are also two minerals, zincite and hemimorphite, which have been called calamine historically (see: calamine (mineral)). When mixed with eugenol, zinc oxide eugenol forms which has restorative and prosthodontic applications in dentistry. Zinc peroxide, ZnO2 .½ H2O, is a white to yellow powder that is used in antiseptic ointments. ## As a pigment Zinc white is used as a pigment in paints and is more opaque than lithopone, but less opaque than titanium dioxide. It is also used in coatings for paper. Chinese white is a special grade of zinc white used in artists' pigments. Because it absorbs both UVA and UVB rays of ultraviolet light, zinc oxide can be used in ointments, creams, and lotions to protect against sunburn and other damage to the skin caused by ultraviolet light (see sunscreen). It is the broadest spectrum UVA and UVB absorber that is approved for use as a sunscreen by FDA, and is completely photostable. Additionally, since zinc oxide has antimicrobial and antifungal activities, it is the number one active ingredient recommended by pediatricians for the treatment of diaper rash. ## Rubber manufacture Zinc oxide and stearic acid are ingredients in the commercial manufacture of rubber goods. A mixture of these two compounds allows a quicker and more controllable rubber cure. Zinc oxide can also be used as a filler in some rubber mixtures. ## Electronic materials ZnO is a semiconductor with a direct bandgap energy of 3.37 eV at room temperature. The most common applications are in laser diodes and light emitting diodes since it has a exciton and biexciton energies of 60 meV and 15 meV, respectively. It is expected that this exciton properties of ZnO will be improved further by epitaxy. n-type doped films are often used in thin film technology, where zinc oxide serves as a TCO (transparent conducting oxide). n-type doping is possible by introduction of aluminum, indium, or excess zinc[2]. Oxygen vacancies generate states in the band gap and hence also cause an increase in conductivity.[3] p-type doping is difficult and is currently an active area of research, with arsenic as the leading candidate dopant[4]. Thin-film solar cells, LCD and flat panel displays are typical applications of this material. Appropriately doped Zinc oxide may be transparent and conductive, and can therefore be used as a transparent electrode. Indium tin oxide (ITO) is another transparent conducting oxide often used in microelectronics. ZnO has also been considered for spintronics applications because of theoretical predictions of room temperature ferromagnetism. Unsubstantiated reports of ferromagnetism have been made, but presence of dilute magnetic semiconductors remains a large unanswered question in physics. ZnO layers are mainly deposited by sputter deposition and chemical vapor deposition (CVD). The latter method allows the growth of a rough layer, which can diffuse the incoming light by scattering, increasing the efficiency of solar cells. ZnO has been observed to act as a chemical reagent for Friedel-Craft Acylation Reaction. ### Pyroelectric coefficients - Primary pyroelectric coefficient: -6.8 µC/m²·K - Secondary pyroelectric coefficient: -2.5 µC/m²·K - Total pyroelectric coefficient: -9.4 µC/m²·K # Production methods Zinc oxide is produced by two main processes: ## French process Metallic zinc is melted in a graphite crucible and vaporized above 907 °C. Zinc vapor instantaneously reacts with the oxygen in the air to give ZnO, accompanied by a drop in its temperature and bright luminescence. Zinc oxide particles are transported into a cooling duct and collected in a bag house. This indirect method is commonly known as the French process (FP) which was popularised by LeClaire (France) in 1844. A typical FP, zinc oxide normally consists of agglomerated zinc oxide particles with an average size of 0.1 micrometres to a few micrometres. By weight, most of the world's zinc oxide is manufactured via French process and major applications involve industries related to rubber, varistors, suncreens, paints, healthcare, and poultry nutrients. Recent developments involve acicular nanostructures (rods, wires, tripods, tetrapods, plates) synthesized using a modified French process known as catalyst-free combust-oxidized mesh (CFCOM) process. Acicular nanostructures usually have micrometre-length nanorods with nanometric diameters (below 100 nm). The so-called direct method is related to the FP. In this process, zinc ores or roasted sulfide concentrates are mixed with coal. In a reduction furnace, ore is reduced to metallic zinc and the vaporized zinc is allowed to react with oxygen to form zinc oxide. ## American process In this process ore of zinc (zinc ash) is dissolved (as ZnCl2) and precipitated with alkali. Zinc oxide made from this process is known as "Active Zinc Oxide" # Safety Fumes of zinc oxide are generated when melting brass, because the melting point of brass is close to the boiling point of zinc.[5] Exposure to zinc oxide in the air (also while welding) can result in a nervous malady called metal fume fever.[6] # External links - International Chemical Safety Card 0208. - NIOSH Pocket Guide to Chemical Hazards. - Nav Bharat Metallic Oxide Industries. (describes industrial uses of zinc oxide) - External MSDS (Material Safety Data Sheet) on zinc oxide.	https://www.wikidoc.org/index.php/Zinc_oxide
1e70cc00ae4d81511002cdce971e65758031d61b	wikidoc	Zonisamide	Zonisamide # 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 Zonisamide is an antiepileptic that is FDA approved for the {{{indicationType}}} of partial seizure. Common adverse reactions include pruritus, loss of appetite, ataxia, dizziness, somnolence, amblyopia, agitation, depression and disturbance in speech. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Zonisamide capsules, USP are indicated as adjunctive therapy in the treatment of partial seizures in adults with epilepsy. - Zonisamide capsules are recommended as adjunctive therapy for the treatment of partial seizures in adults. Safety and efficacy in pediatric patients below the age of 16 have not been established. Zonisamide capsules should be administered once or twice daily, using 25 mg, 50 mg or 100 mg capsules. Zonisamide capsules are given orally and can be taken with or without food. Capsules should be swallowed whole. - Adults over Age 16 - The prescriber should be aware that, because of the long half-life of zonisamide, up to two weeks may be required to achieve steady state levels upon reaching a stable dose or following dosage adjustment. Although the regimen described below is one that has been shown to be tolerated, the prescriber may wish to prolong the duration of treatment at the lower doses in order to fully assess the effects of zonisamide at steady state, noting that many of the side effects of zonisamide are more frequent at doses of 300 mg per day and above. Although there is some evidence of greater response at doses above 100 to 200 mg/day, the increase appears small and formal dose-response studies have not been conducted. - The initial dose of zonisamide capsules should be 100 mg daily. After two weeks, the dose may be increased to 200 mg/day for at least two weeks. It can be increased to 300 mg/day and 400 mg/day, with the dose stable for at least two weeks to achieve steady state at each level. Evidence from controlled trials suggests that zonisamide capsules doses of 100 to 600 mg/day are effective, but there is no suggestion of increasing response above 400 mg/day. There is little experience with doses greater than 600 mg/day. - Patients with Renal or Hepatic Disease - Because zonisamide is metabolized in the liver and excreted by the kidneys, patients with renal or hepatic disease should be treated with caution, and might require slower titration and more frequent monitoring. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Zonisamide in adult patients. ### Non–Guideline-Supported Use - Oral Zonisamide, initially at a dose of 100 mg/day. Based on tolerance, dosage was increased in 100-mg increments weekly over 3 weeks to 400 mg/day. - 12 weeks of zonisamide 25 mg. - Oral Zonisamide 200 to 500 mg once daily. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Zonisamide in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Zonisamide in pediatric patients. ### Non–Guideline-Supported Use - Oral Zonisamide 5.8 mg/kg. # Contraindications - Zonisamide capsules are contraindicated in patients who have demonstrated hypersensitivity to sulfonamides or zonisamide. # Warnings - Potentially Fatal Reactions to Sulfonamides - Fatalities have occurred, although rarely, as a result of severe reactions to sulfonamides (zonisamide is a sulfonamide) including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. Such reactions may occur when a sulfonamide is readministered irrespective of the route of administration. If signs of hypersensitivity or other serious reactions occur, discontinue zonisamide immediately. Specific experience with sulfonamide-type adverse reaction to zonisamide is described below. - Serious Skin Reactions - Consideration should be given to discontinuing zonisamide capsules in patients who develop an otherwise unexplained rash. If the drug is not discontinued, patients should be observed frequently. Seven deaths from severe rash were reported in the first 11 years of marketing in Japan. All of the patients were receiving other drugs in addition to zonisamide. In post-marketing experience from Japan, a total of 49 cases of SJS or TEN have been reported, a reporting rate of 46 per million patient-years of exposure. Although this rate is greater than background, it is probably an underestimate of the true incidence because of under-reporting. There were no confirmed cases of SJS or TEN in the US, European, or Japanese development programs. - In the US and European randomized controlled trials, 6 of 269 (2.2%) zonisamide patients discontinued treatment because of rash compared to none on placebo. Across all trials during the US and European development, rash that led to discontinuation of zonisamide was reported in 1.4% of patients (12.0 events per 1000 patient-years of exposure). During Japanese development, serious rash or rash that led to study drug discontinuation was reported in 2.0% of patients (27.8 events per 1000 patient years). Rash usually occurred early in treatment, with 85% reported within 16 weeks in the US and European studies and 90% reported within two weeks in the Japanese studies. There was no apparent relationship of dose to the occurrence of rash. - Serious Hematologic Events - Two confirmed cases of aplastic anemia and one confirmed case of agranulocytosis were reported in the first 11 years of marketing in Japan, rates greater than generally accepted background rates. There were no cases of aplastic anemia and two confirmed cases of agranulocytosis in the US, European, or Japanese development programs. - There is inadequate information to assess the relationship, if any, between dose and duration of treatment and these events. - Oligohidrosis and Hyperthermia in Pediatric Patients - Oligohidrosis, sometimes resulting in heat stroke and hospitalization, is seen in association with zonisamide in pediatric patients. - During the pre-approval development program in Japan, one case of oligohidrosis was reported in 403 pediatric patients, an incidence of 1 case per 285 patient-years of exposure. While there were no cases reported in the US or European development programs, fewer than 100 pediatric patients participated in these trials. - In the first 11 years of marketing in Japan, 38 cases were reported, an estimated reporting rate of about 1 case per 10,000 patient-years of exposure. In the first year of marketing in the US, 2 cases were reported, an estimated reporting rate of about 12 cases per 10,000 patient-years of exposure. These rates are underestimates of the true incidence because of under-reporting. There has also been one report of heat stroke in an 18-year-old patient in the US. - Decreased sweating and an elevation in body temperature above normal characterized these cases. Many cases were reported after exposure to elevated environmental temperatures. Heat stroke, requiring hospitalization, was diagnosed in some cases. There have been no reported deaths. - Pediatric patients appear to be at an increased risk for zonisamide-associated oligohidrosis and hyperthermia. Patients, especially pediatric patients, treated with zonisamide capsules should be monitored closely for evidence of decreased sweating and increased body temperature, especially in warm or hot weather. Caution should be used when zonisamide is prescribed with other drugs that predispose patients to heat-related disorders; these drugs include, but are not limited to, carbonic anhydrase inhibitors and drugs with anticholinergic activity. - The practitioner should be aware that the safety and effectiveness of zonisamide in pediatric patients have not been established, and that zonisamide is not approved for use in pediatric patients. - Suicidal Behavior and Ideation - Antiepileptic drugs (AEDs), including zonisamide capsules, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. - Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. - The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. - The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed. - Table 3 shows absolute and relative risk by indication for all evaluated AEDs. - The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. - Anyone considering prescribing zonisamide capsules or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. - Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. - Metabolic Acidosis - Zonisamide causes hyperchloremic, non-anion gap, metabolic acidosis (i.e., decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis). This metabolic acidosis is caused by renal bicarbonate loss due to the inhibitory effect of zonisamide on carbonic anhydrase. - Generally, zonisamide-induced metabolic acidosis occurs early in treatment, but it can develop at any time during treatment. Metabolic acidosis generally appears to be dose-dependent and can occur at doses as low as 25 mg daily. - Conditions or therapies that predispose to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, ketogenic diet, or specific drugs) may be additive to the bicarbonate lowering effects of zonisamide. - Some manifestations of acute or chronic metabolic acidosis include hyperventilation, nonspecific symptoms such as fatigue and anorexia, or more severe sequelae including cardiac arrhythmias or stupor. Chronic, untreated, metabolic acidosis may increase the risk for nephrolithiasis or nephrocalcinosis. Nephrolithiasis has been observed in the clinical development program in 4 % of adults treated with zonisamide, has also been detected by renal ultrasound in 8 % of pediatric treated patients who had at least one ultrasound prospectively collected, and was reported as an adverse event in 3 % (4/133) of pediatric patients. - Chronic, untreated metabolic acidosis may result in osteomalacia (referred to as rickets in pediatric patients) and/or osteoporosis with an increased risk for fracture. Of potential relevance, zonisamide treatment was associated with reductions in serum phosphorus and increases in serum alkaline phosphatase, changes that may be related to metabolic acidosis and osteomalacia. - Chronic, untreated metabolic acidosis in pediatric patients may reduce growth rates. A reduction in growth rate may eventually decrease the maximal height achieved. The effect of zonisamide on growth and bone-related sequelae has not been systematically investigated. - Measurement of baseline and periodic serum bicarbonate during treatment is recommended. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing zonisamide (using dose tapering). If the decision is made to continue patients on zonisamide in the face of persistent acidosis, alkali treatment should be considered. - Serum bicarbonate was not measured in the adjunctive controlled trials of adults with epilepsy. However, serum bicarbonate was studied in three clinical trials for indications which have not been approved: a placebo-controlled trial for migraine prophylaxis in adults, a controlled trial for monotherapy in epilepsy in adults, and an open label trial for adjunctive treatment of epilepsy in pediatric patients (3 to 16 years). In adults, mean serum bicarbonate reductions ranged from approximately 2 mEq/L at daily doses of 100 mg to nearly 4 mEq/L at daily doses of 300 mg. In pediatric patients, mean serum bicarbonate reductions ranged from approximately 2 mEq/L at daily doses from above 100 mg up to 300 mg, to nearly 4 mEq/L at daily doses from above 400 mg up to 600 mg. - In two controlled studies in adults, the incidence of a persistent treatment-emergent decrease in serum bicarbonate to less than 20 mEq/L (observed at 2 or more consecutive visits or the final visit) was dose-related at relatively low zonisamide doses. In the monotherapy trial of epilepsy, the incidence of a persistent treatment-emergent decrease in serum bicarbonate was 21% for daily zonisamide doses of 25 mg or 100 mg, and was 43% at a daily dose of 300 mg. In a placebo-controlled trial for prophylaxis of migraine, the incidence of a persistent treatment-emergent decrease in serum bicarbonate was 7% for placebo, 29% for 150 mg daily, and 34% for 300 mg daily. The incidence of persistent markedly abnormally low serum bicarbonate (decrease to less than 17 mEq/L and more than 5 mEq/L) from a pretreatment value of at least 20 mEq/L in these controlled trials was 2% or less. - In the pediatric study, the incidence of persistent, treatment-emergent decreases in serum bicarbonate to levels less than 20 mEq/L was 52% at doses up to 100 mg daily, was 90% for a wide range of doses up to 600 mg daily, and generally appeared to increase with higher doses. The incidence of a persistent markedly abnormally low serum bicarbonate value was 4 % at doses up to 100 mg daily, was 18% for a wide range of doses up to 600 mg daily, and generally appeared to increase with higher doses. Some patients experienced moderately severe serum bicarbonate decrements down to a level as low as 10 mEq/L. - The relatively high frequencies of varying severities of metabolic acidosis observed in this study of pediatric patients (compared to the frequency and severity observed in various clinical trial development programs in adults) suggest that pediatric patients may be more likely to develop metabolic acidosis than adults. - Seizures on Withdrawal - As with other AEDs, abrupt withdrawal of zonisamide capsules in patients with epilepsy may precipitate increased seizure frequency or status epilepticus. Dose reduction or discontinuation of zonisamide should be done gradually. - Teratogenicity - Women of child bearing potential who are given zonisamide should be advised to use effective contraception. Zonisamide was teratogenic in mice, rats, and dogs and embryolethal in monkeys when administered during the period of organogenesis. A variety of fetal abnormalities, including cardiovascular defects, and embryo-fetal deaths occurred at maternal plasma levels similar to or lower than therapeutic levels in humans. These findings suggest that the use of zonisamide capsules during pregnancy in humans may present a significant risk to the fetus (see PRECAUTIONS, Pregnancy subsection). Zonisamide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - Cognitive/ Neuropsychiatric Adverse Events - Use of zonisamide capsules was frequently associated with central nervous system-related adverse events. The most significant of these can be classified into three general categories: 1) psychiatric symptoms, including depression and psychosis, 2) psychomotor slowing, difficulty with concentration, and speech or language problems, in particular, word-finding difficulties, and 3) somnolence or fatigue. - In placebo-controlled trials, 2.2% of patients discontinued zonisamide capsules or were hospitalized for depression compared to 0.4% of placebo patients. Among all epilepsy patients treated with zonisamide capsules, 1.4% were discontinued and 1.0% were hospitalized because of reported depression or suicide attempts. In placebo-controlled trials, 2.2% of patients discontinued zonisamide capsules or were hospitalized due to psychosis or psychosis-related symptoms compared to none of the placebo patients. Among all epilepsy patients treated with zonisamide capsules, 0.9% were discontinued and 1.4% were hospitalized because of reported psychosis or related symptoms. - Psychomotor slowing and difficulty with concentration occurred in the first month of treatment and were associated with doses above 300 mg/day. Speech and language problems tended to occur after 6 to 10 weeks of treatment and at doses above 300 mg/day. Although in most cases these events were of mild to moderate severity, they at times led to withdrawal from treatment. - Somnolence and fatigue were frequently reported CNS adverse events during clinical trials with zonisamide capsules. Although in most cases these events were of mild to moderate severity, they led to withdrawal from treatment in 0.2% of the patients enrolled in controlled trials. Somnolence and fatigue tended to occur within the first month of treatment. Somnolence and fatigue occurred most frequently at doses of 300 to 500 mg/day. Patients should be cautioned about this possibility and special care should be taken by patients if they drive, operate machinery, or perform any hazardous task. ### Precautions - General - Somnolence is commonly reported, especially at higher doses of zonisamide capsules (see WARNINGS,Cognitive/ Neuropsychiatric Adverse Events subsection). Zonisamide is metabolized by the liver and eliminated by the kidneys; caution should therefore be exercised when administering zonisamide capsules to patients with hepatic and renal dysfunction. - Kidney Stones - Among 991 patients treated during the development of zonisamide capsules, 40 patients (4.0%) with epilepsy receiving zonisamide capsules developed clinically possible or confirmed kidney stones (e.g. clinical symptomatology, sonography, etc.), a rate of 34 per 1000 patient-years of exposure (40 patients with 1168 years of exposure). Of these, 12 were symptomatic, and 28 were described as possible kidney stones based on sonographic detection. In nine patients, the diagnosis was confirmed by a passage of a stone or by a definitive sonographic finding. The rate of occurrence of kidney stones was 28.7 per 1000 patient-years of exposure in the first six months, 62.6 per 1000 patient-years of exposure between 6 and 12 months, and 24.3 per 1000 patient-years of exposure after 12 months of use. There are no normative sonographic data available for either the general population or patients with epilepsy. Although the clinical significance of the sonographic findings may not be certain, the development of nephrolithiasis may be related to metabolic acidosis. The analyzed stones were composed of calcium or urate salts. In general, increasing fluid intake and urine output can help reduce the risk of stone formation, particularly in those with predisposing risk factors. It is unknown, however, whether these measures will reduce the risk of stone formation in patients treated with zonisamide capsules. - Although not approved in pediatric patients, sonographic findings consistent with nephrolithiasis were also detected in 8 % of a subset of zonisamide treated pediatric patients who had at least one renal ultrasound prospectively performed in a clinical development program investigating open-label treatment. The incidence of kidney stone as an adverse event was 3 %. - Effect on Renal Function - In several clinical studies, zonisamide was associated with a statistically significant 8% mean increase from baseline of serum creatinine and blood urea nitrogen (BUN) compared to essentially no change in the placebo patients. The increase appeared to persist over time but was not progressive; this has been interpreted as an effect on glomerular filtration rate (GFR). There were no episodes of unexplained acute renal failure in clinical development in the US, Europe, or Japan. The decrease in GFR appeared within the first 4 weeks of treatment. In a 30-day study, the GFR returned to baseline within 2 to 3 weeks of drug discontinuation. There is no information about reversibility, after drug discontinuation, of the effects on GFR after long-term use. Zonisamide capsules should be discontinued in patients who develop acute renal failure or a clinically significant sustained increase in the creatinine/BUN concentration. Zonisamide capsules should not be used in patients with renal failure (estimated GFR <50 mL/min) as there has been insufficient experience concerning drug dosing and toxicity. - Sudden Unexplained Death in Epilepsy - During the development of zonisamide capsules, nine sudden unexplained deaths occurred among 991 patients with epilepsy receiving zonisamide capsules for whom accurate exposure data are available. This represents an incidence of 7.7 deaths per 1000 patient years. Although this rate exceeds that expected in a healthy population, it is within the range of estimates for the incidence of sudden unexplained deaths in patients with refractory epilepsy not receiving zonisamide capsules (ranging from 0.5 per 1000 patient-years for the general population of patients with epilepsy, to 2 to 5 per 1000 patient-years for patients with refractory epilepsy; higher incidences range from 9 to 15 per 1000 patient-years among surgical candidates and surgical failures). Some of the deaths could represent seizure-related deaths in which the seizure was not observed. - Status Epilepticus - Estimates of the incidence of treatment emergent status epilepticus in zonisamide capsule-treated patients are difficult because a standard definition was not employed. Nonetheless, in controlled trials, 1.1% of patients treated with zonisamide capsules had an event labeled as status epilepticus compared to none of the patients treated with placebo. Among patients treated with zonisamide capsules across all epilepsy studies (controlled and uncontrolled), 1.0% of patients had an event reported as status epilepticus. # Adverse Reactions ## Clinical Trials Experience - The most commonly observed adverse events related to treatment with zonisamide capsules (an incidence at least 4% greater than placebo) in controlled clinical trials and shown in descending order of frequency were somnolence, anorexia, dizziness, ataxia, agitation/irritability, and difficulty with memory and/or concentration. - In controlled clinical trials, 12% of patients receiving zonisamide capsules as adjunctive therapy discontinued due to an adverse event compared to 6% receiving placebo. Approximately 21% of the 1,336 patients with epilepsy who received zonisamide capsules in clinical studies discontinued treatment because of an adverse event. The adverse events most commonly associated with discontinuation were somnolence, fatigue and/or ataxia (6%), anorexia (3%), difficulty concentrating (2%), difficulty with memory, mental slowing, nausea/vomiting (2%), and weight loss (1%). Many of these adverse events were dose-related. - Table 4 lists treatment-emergent adverse events that occurred in at least 2% of patients treated with zonisamide capsules in controlled clinical trials that were numerically more common in the zonisamide capsules group. In these studies, either zonisamide capsules or placebo was added to the patient’s current AED therapy. Adverse events were usually mild or moderate in intensity. - The prescriber should be aware that these figures, obtained when zonisamide capsules were added to concurrent AED therapy, cannot be used to predict the frequency of adverse events in the course of usual medical practice when patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. An inspection of these frequencies, however, does provide the prescriber with one basis by which to estimate the relative contribution of drug and non-drug factors to the adverse event incidences in the population studied. - Zonisamide capsules have been administered to 1,598 individuals during all clinical trials, only some of which were placebo-controlled. During these trials, all events were recorded by the investigators using their own terms. To provide a useful estimate of the proportion of individuals having adverse events, similar events have been grouped into a smaller number of standardized categories using a modified COSTART dictionary. The frequencies represent the proportion of the 1,598 individuals exposed to zonisamide capsules who experienced an event on at least one occasion. All events are included except those already listed in the previous table or discussed in WARNINGS or PRECAUTIONS, trivial events, those too general to be informative, and those not reasonably associated with zonisamide capsules. - Events are further classified within each category and listed in order of decreasing frequency as follows: frequent occurring in at least 1:100 patient; infrequent occurring in 1:100 to 1:1000 patients; rare occurring in fewer than 1:1000 patients. Frequent: Accidental injury, asthenia. Infrequent: Chest pain, flank pain, malaise, allergic reaction, face edema, neck rigidity. Rare: Lupus erythematosus. Infrequent: Palpitation, tachycardia, vascular insufficiency, hypotension, hypertension, thrombophlebitis, syncope, bradycardia. Rare: Atrial fibrillation, heart failure, pulmonary embolus, ventricular extrasystoles. Frequent: Vomiting. Infrequent: Flatulence, gingivitis, gum hyperplasia, gastritis, gastroenteritis, stomatitis, cholelithiasis, glossitis, melena, rectal hemorrhage, ulcerative stomatitis, gastro-duodenal ulcer, dysphagia, gum hemorrhage. Rare: Cholangitis, hematemesis, cholecystitis, cholestatic jaundice, colitis, duodenitis, esophagitis, fecal incontinence, mouth ulceration. Infrequent: Leukopenia, anemia, immunodeficiency, lymphadenopathy. Rare: Thrombocytopenia, microcytic anemia, petechia. Infrequent: Peripheral edema, weight gain, edema, thirst, dehydration. Rare: Hypoglycemia, hyponatremia, lactic dehydrogenase increased, SGOT increased, SGPT increased. Infrequent: Leg cramps, myalgia, myasthenia, arthralgia, arthritis. Frequent: Tremor, convulsion, abnormal gait, hyperesthesia, incoordination. Infrequent: Hypertonia, twitching, abnormal dreams, vertigo, libido decreased, neuropathy, hyperkinesia, movement disorder, dysarthria, cerebrovascular accident, hypotonia, peripheral neuritis, reflexes increased. Rare: Dyskinesia, dystonia, encephalopathy, facial paralysis, hypokinesia, hyperesthesia, myoclonus, oculogyric crisis. Infrequent: Euphoria. Frequent: Pharyngitis, cough increased. Infrequent: Dyspnea. Rare: Apnea, hemoptysis. Frequent: Pruritus. Infrequent: Maculopapular rash, acne, alopecia, dry skin, sweating, eczema, urticaria, hirsutism, pustular rash, vesiculobullous rash. Frequent: Amblyopia, tinnitus. Infrequent: Conjunctivitis, parosmia, deafness, visual field defect, glaucoma. Rare: Photophobia, iritis. Infrequent: Urinary frequency, dysuria, urinary incontinence, hematuria, impotence, urinary retention, urinary urgency, amenorrhea, polyuria, nocturia. Rare: Albuminuria, enuresis, bladder pain, bladder calculus, gynecomastia, mastitis, menorrhagia. ## Postmarketing Experience - The following serious adverse events have been reported since approval and use of zonisamide worldwide.These reactions are reported voluntarily from a population of uncertain size;therefore,it is not possible to estimate their frequency or establish a causal relationship to drug exposure. - Acute pancreatitis, rhabdomyolysis,creatine phosphokinase increased. # Drug Interactions - Effects of zonisamide capsules on the pharmacokinetics of other antiepilepsy drugs (AEDs) - Zonisamide had no appreciable effect on the steady state plasma concentrations of phenytoin, carbamazepine, or valproate during clinical trials. Zonisamide did not inhibit mixed-function liver oxidase enzymes (cytochrome P450), as measured in human liver microsomal preparations, in vitro. Zonisamide is not expected to interfere with the metabolism of other drugs that are metabolized by cytochrome P450 isozymes. - Effects of other drugs on zonisamide capsules pharmacokinetics - Drugs that induce liver enzymes increase the metabolism and clearance of zonisamide and decrease its half-life. The half-life of zonisamide following a 400 mg dose in patients concurrently on enzyme-inducing AEDs such as phenytoin, carbamazepine, or phenobarbital was between 27 to 38 hours; the half-life of zonisamide in patients concurrently on the non-enzyme inducing AED, valproate, was 46 hours. Concurrent medication with drugs that either induce or inhibit CYP3A4 would be expected to alter serum concentrations of zonisamide. - Interaction with cimetidine - Zonisamide single dose pharmacokinetic parameters were not affected by cimetidine (300 mg four times a day for 12 days). - Drug Interactions with CNS Depressants - Concomitant administration of zonisamide and alcohol or other CNS depressant drugs has not been evaluated in clinical studies. Because of the potential of zonisamide to cause CNS depression, as well as other cognitive and/or neuropsychiatric adverse events, zonisamide should be used with caution if used in combination with alcohol or other CNS depressants. - Other Carbonic Anhydrase Inhibitors - Concomitant use of zonisamide, a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor (e.g., topiramate, acetazolamide or dichlorphenamide), may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. Therefore, if zonisamide is given concomitantly with another carbonic anhydrase inhibitor, the patient should be monitored for the appearance or worsening of metabolic acidosis. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Zonisamide may cause serious adverse fetal effects, based on clinical and nonclinical data. Zonisamide was teratogenic in multiple animal species. - Zonisamide treatment causes metabolic acidosis in humans. The effect of zonisamide-induced metabolic acidosis has not been studied in pregnancy; however, metabolic acidosis in pregnancy (due to other causes) may be associated with decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the fetus’ ability to tolerate labor. Pregnant patients should be monitored for metabolic acidosis and treated as in the non-pregnant state. - Newborns of mothers treated with zonisamide should be monitored for metabolic acidosis because of transfer of zonisamide to the fetus and possible occurrence of transient metabolic acidosis following birth. Transient metabolic acidosis has been reported in neonates born to mothers treated during pregnancy with a different carbonic anhydrase inhibitor. - Zonisamide was teratogenic in mice, rats, and dogs and embryolethal in monkeys when administered during the period of organogenesis. Fetal abnormalities or embryo-fetal deaths occurred in these species at zonisamide dosage and maternal plasma levels similar to or lower than therapeutic levels in humans, indicating that use of this drug in pregnancy entails a significant risk to the fetus. A variety of external, visceral, and skeletal malformations was produced in animals by prenatal exposure to zonisamide. Cardiovascular defects were prominent in both rats and dogs. - Following administration of zonisamide (10, 30, or 60 mg/kg/day) to pregnant dogs during organogenesis, increased incidences of fetal cardiovascular malformations (ventricular septal defects, cardiomegaly, various valvular and arterial anomalies) were found at doses of 30 mg/kg/day or greater. The low effect dose for malformations produced peak maternal plasma zonisamide levels (25 mcg/mL) about 0.5 times the highest plasma levels measured in patients receiving the maximum recommended human dose (MRHD) of 400 mg/day. In dogs, cardiovascular malformations were found in approximately 50% of all fetuses exposed to the high dose, which was associated with maternal plasma levels (44 mcg/mL) approximately equal to the highest levels measured in humans receiving the MRHD. Incidences of skeletal malformations were also increased at the high dose, and fetal growth retardation and increased frequencies of skeletal variations were seen at all doses in this study. The low dose produced maternal plasma levels (12 mcg/mL) about 0.25 times the highest human levels. - In cynomolgus monkeys, administration of zonisamide (10 or 20 mg/kg/day) to pregnant animals during organogenesis resulted in embryo-fetal deaths at both doses. The possibility that these deaths were due to malformations cannot be ruled out. The lowest embryolethal dose in monkeys was associated with peak maternal plasma zonisamide levels (5 mcg/mL) approximately 0.1 times the highest levels measured in patients at the MRHD. - In a mouse embryo-fetal development study, treatment of pregnant animals with zonisamide (125, 250, or 500 mg/kg/day) during the period of organogenesis resulted in increased incidences of fetal malformations (skeletal and/or craniofacial defects) at all doses tested. The low dose in this study is approximately 1.5 times the MRHD on a mg/m2 basis. In rats, increased frequencies of malformations (cardiovascular defects) and variations (persistent cords of thymic tissue, decreased skeletal ossification) were observed among the offspring of dams treated with zonisamide (20, 60, or 200 mg/kg/day) throughout organogenesis at all doses. The low effect dose is approximately 0.5 times the MRHD on a mg/m2 basis. - Perinatal death was increased among the offspring of rats treated with zonisamide (10, 30, or 60 mg/kg/day) from the latter part of gestation up to weaning at the high dose, or approximately 1.4 times the MRHD on a mg/m2 basis. The no effect level of 30 mg/kg/day is approximately 0.7 times the MRHD on a mg/m2 basis. - There are no adequate and well-controlled studies in pregnant women. Zonisamide capsules should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - To provide information regarding the effects of in utero exposure to zonisamide capsules, physicians are advised to recommend that pregnant patients taking zonisamide capsules enroll in the NAAED Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website /. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Zonisamide in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Zonisamide during labor and delivery. ### Nursing Mothers - Zonisamide is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from zonisamide, a decision should be made whether to discontinue nursing or to discontinue drug, taking into account the importance of the drug to the mother. ### Pediatric Use - The safety and effectiveness of zonisamide capsules in children under age 16 have not been established. Cases of oligohidrosis and hyperpyrexia have been reported. Zonisamide commonly causes metabolic acidosis in pediatric patients. Chronic untreated metabolic acidosis in pediatric patients may cause nephrolithiasis and/or nephrocalcinosis, osteoporosis and/or osteomalacia (potentially resulting in rickets), and may reduce growth rates. A reduction in growth rate may eventually decrease the maximal height achieved. The effect of zonisamide on growth and bone-related sequelae has not been systematically investigated. ### Geriatic Use - Single dose pharmacokinetic parameters are similar in elderly and young healthy volunteers. Clinical studies of zonisamide 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. ### Gender There is no FDA guidance on the use of Zonisamide with respect to specific gender populations. ### Race There is no FDA guidance on the use of Zonisamide with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Zonisamide in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Zonisamide in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Zonisamide in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Zonisamide in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Zonisamide in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Zonisamide in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - Experience with zonisamide capsules daily doses over 800 mg/day is limited. During zonisamide capsules clinical development, three patients ingested unknown amounts of zonisamide capsules as suicide attempts, and all three were hospitalized with CNS symptoms. One patient became comatose and developed bradycardia, hypotension, and respiratory depression; the zonisamide plasma level was 100.1 mcg/mL measured 31 hours post-ingestion. Zonisamide plasma levels fell with a half-life of 57 hours, and the patient became alert five days later. ### Management - No specific antidotes for zonisamide capsules overdosage are available. Following a suspected recent overdose, emesis should be induced or gastric lavage performed with the usual precautions to protect the airway. General supportive care is indicated, including frequent monitoring of vital signs and close observation. - Zonisamide has a long half-life. Due to the low protein binding of zonisamide (40%), renal dialysis may be effective. The effectiveness of renal dialysis as a treatment of overdose has not been formally studied. A poison control center should be contacted for information on the management of zonisamide capsules overdosage. ## Chronic Overdose There is limited information regarding Chronic Overdose of Zonisamide in the drug label. # Pharmacology ## Mechanism of Action - The precise mechanism(s) by which zonisamide exerts its antiseizure effect is unknown. Zonisamide demonstrated anticonvulsant activity in several experimental models. In animals, zonisamide was effective against tonic extension seizures induced by maximal electroshock but ineffective against clonic seizures induced by subcutaneous pentylenetetrazol. Zonisamide raised the threshold for generalized seizures in the kindled rat model and reduced the duration of cortical focal seizures induced by electrical stimulation of the visual cortex in cats. Furthermore, zonisamide suppressed both interictal spikes and the secondarily generalized seizures produced by cortical application of tungstic acid gel in rats or by cortical freezing in cats. The relevance of these models to human epilepsy is unknown. - Zonisamide may produce these effects through action at sodium and calcium channels. In vitro pharmacological studies suggest that zonisamide blocks sodium channels and reduces voltage-dependent, transient inward currents (T-type Ca2+ currents), consequently stabilizing neuronal membranes and suppressing neuronal hypersynchronization. In vitro binding studies have demonstrated that zonisamide binds to the GABA/benzodiazepine receptor ionophore complex in an allosteric fashion which does not produce changes in chloride flux. Other in vitro studies have demonstrated that zonisamide (10 to 30 mcg/mL) suppresses synaptically-driven electrical activity without affecting postsynaptic GABA or glutamate responses (cultured mouse spinal cord neurons) or neuronal or glial uptake of -GABA (rat hippocampal slices). Thus, zonisamide does not appear to potentiate the synaptic activity of GABA. In vivo microdialysis studies demonstrated that zonisamide facilitates both dopaminergic and serotonergic neurotransmission. - Zonisamide is a carbonic anhydrase inhibitor. The contribution of this pharmacological action to the therapeutic effects of zonisamide is unknown. However, as a carbonic anhydrase inhibitor, zonisamide may cause metabolic acidosis (see WARNINGS, Metabolic Acidosis subsection). ## Structure - Zonisamide capsules, USP are an antiseizure drug chemically classified as a sulfonamide and unrelated to other antiseizure agents. The active ingredient is zonisamide, 1,2- benzisoxazole-3-methanesulfonamide. The molecular formula is C8H8N2O3S with a molecular weight of 212.23. Zonisamide is a white powder, pKa = 10.2, and is soluble in methanol, ethanol, ethyl acetate and acetic acid, sparingly soluble in water, chloroform and n-hexane. - The chemical structure is: - Each capsule, for oral administration, contains 25 mg, 50 mg or 100 mg of zonisamide. In addition, each capsule contains the following inactive ingredients: colloidal silicon dioxide, microcrystalline cellulose, stearic acid and talc. - The 25 mg capsule shell contains gelatin and titanium dioxide. The 50 mg capsule shell contains black iron oxide, gelatin and titanium dioxide. The 100 mg capsule shell contains D&C yellow #10, FD&C red #40, gelatin and titanium dioxide. - The 25 mg and 50 mg capsule imprinting ink contains strong ammonia solution, black iron oxide, butyl alcohol, dehydrated alcohol, isopropyl alcohol, potassium hydroxide, propylene glycol and shellac. - The 100 mg capsule imprinting ink contains D&C yellow #10 Aluminum Lake, FD&C blue #1 Aluminum Lake, FD&C blue #2 Aluminum Lake, FD&C red #40 Aluminum Lake, n-butyl alcohol, pharmaceutical glaze, propylene glycol and synthetic black iron oxide. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Zonisamide in the drug label. ## Pharmacokinetics - Following a 200 to 400 mg oral zonisamide dose, peak plasma concentrations (range: 2 to 5 mcg/mL) in normal volunteers occur within 2 to 6 hours. In the presence of food, the time to maximum concentration is delayed, occurring at 4 to 6 hours, but food has no effect on the bioavailability of zonisamide. Zonisamide extensively binds to erythrocytes, resulting in an eight-fold higher concentration of zonisamide in red blood cells (RBC) than in plasma. The pharmacokinetics of zonisamide are dose proportional in the range of 200 to 400 mg, but the Cmax and AUC increase disproportionately at 800 mg, perhaps due to saturable binding of zonisamide to RBC. Once a stable dose is reached, steady state is achieved within 14 days. The elimination half-life of zonisamide in plasma is about 63 hours. The elimination half-life of zonisamide in RBC is approximately 105 hours. - The apparent volume of distribution (V/F) of zonisamide is about 1.45 L/kg following a 400 mg oral dose. Zonisamide, at concentrations of 1.0 to 7.0 mcg/mL, is approximately 40% bound to human plasma proteins. Protein binding of zonisamide is unaffected in the presence of therapeutic concentrations of phenytoin, phenobarbital or carbamazepine. - Metabolism and Excretion - Following oral administration of 14C-zonisamide to healthy volunteers, only zonisamide was detected in plasma. Zonisamide is excreted primarily in urine as parent drug and as the glucuronide of a metabolite. Following multiple dosing, 62% of the 14C dose was recovered in the urine, with 3% in the feces by day 10. Zonisamide undergoes acetylation to form N-acetyl zonisamide and reduction to form the open ring metabolite, 2–sulfamoylacetyl phenol (SMAP). Of the excreted dose, 35% was recovered as zonisamide, 15% as N-acetyl zonisamide, and 50% as the glucuronide of SMAP. Reduction of zonisamide to SMAP is mediated by cytochrome P450 isozyme 3A4 (CYP3A4). Zonisamide does not induce its own metabolism. Plasma clearance of zonisamide is approximately 0.30 to 0.35 mL/min/kg in patients not receiving enzyme-inducing antiepilepsy drugs (AEDs). The clearance of zonisamide is increased to 0.5 mL/min/kg in patients concurrently on enzyme-inducing AEDs. - Renal clearance is about 3.5 mL/min. The clearance of an oral dose of zonisamide from RBC is 2 mL/min. - Special Populations - Renal Insufficiency - Single 300 mg zonisamide doses were administered to three groups of volunteers. Group 1 was a healthy group with a creatinine clearance ranging from 70 to 152 mL/min. Group 2 and Group 3 had creatinine clearances ranging from 14.5 to 59 mL/min and 10 to 20 mL/min, respectively. Zonisamide renal clearance decreased with decreasing renal function (3.42, 2.50, 2.23 mL/min, respectively). Marked renal impairment (creatinine clearance < 20 mL/min) was associated with an increase in zonisamide AUC of 35%. - Hepatic Disease - The pharmacokinetics of zonisamide in patients with impaired liver function have not been studied. - Age - The pharmacokinetics of a 300 mg single dose of zonisamide was similar in young (mean age 28 years) and elderly subjects (mean age 69 years). - Gender and Race - Information on the effect of gender and race on the pharmacokinetics of zonisamide is not available. - Interactions of Zonisamide with Other Antiepilepsy Drugs (AEDs) - Concurrent medication with drugs that either induce or inhibit CYP3A4 may alter serum concentrations of zonisamide. Concomitant administration of phenytoin and carbamazepine increases zonisamide plasma clearance from 0.30 to 0.35 mL/min/kg to 0.35 to 0.5 mL/min/kg. The half-life of zonisamide is decreased to 27 hours by phenytoin, to 38 hours by phenobarbital and carbamazepine, and to 46 hours by valproate. Plasma protein binding of phenytoin and carbamazepine was not affected by zonisamide administration. - Interactions of Zonisamide with Other Carbonic Anhydrase Inhibitors - Concomitant use of zonisamide, a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor (e.g., topiramate, acetazolamide or dichlorphenamide), may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. Therefore, if zonisamide is given concomitantly with another carbonic anhydrase inhibitor, the patient should be monitored for the appearance or worsening of metabolic acidosis. ## Nonclinical Toxicology - No evidence of carcinogenicity was found in mice or rats following dietary administration of zonisamide for two years at doses of up to 80 mg/kg/day. In mice, this dose is approximately equivalent to the maximum recommended human dose (MRHD) of 400 mg/day on a mg/m2 basis. In rats, this dose is 1 to 2 times the MRHD on a mg/m2 basis. - Zonisamide was mutagenic in an in vitro chromosomal aberration assay in CHL cells. Zonisamide was not mutagenic or clastogenic in other in vitro assays (Ames, mouse lymphoma tk assay, chromosomal aberration in human lymphocytes) or in the in vivo rat bone marrow cytogenetics assay. - Rats treated with zonisamide (20, 60, or 200 mg/kg) before mating and during the initial gestation phase showed signs of reproductive toxicity (decreased corpora lutea, implantations, and live fetuses) at all doses. The low dose in this study is approximately 0.5 times the maximum recommended human dose (MRHD) on a mg/m2 basis. # Clinical Studies - The effectiveness of zonisamide capsules as adjunctive therapy (added to other antiepilepsy drugs) has been established in three multicenter, placebo-controlled, double blind, 3-month clinical trials (two domestic, one European) in 499 patients with refractory partial onset seizures with or without secondary generalization. Each patient had a history of at least four partial onset seizures per month in spite of receiving one or two antiepilepsy drugs at therapeutic concentrations. The 499 patients (209 women, 290 men) ranged in age from 13 to 68 years with a mean age of about 35 years. In the two US studies, over 80% of patients were Caucasian; 100% of patients in the European study were Caucasian. Zonisamide capsules or placebo was added to the existing therapy. The primary measure of effectiveness was median percent reduction from baseline in partial seizure frequency. The secondary measure was proportion of patients achieving a 50% or greater seizure reduction from baseline (responders). The results described below are for all partial seizures in the intent-to-treat populations. - In the first study (n = 203), all patients had a 1-month baseline observation period, then received placebo or zonisamide capsules in one of two dose escalation regimens; either 1) 100 mg/day for five weeks, 200 mg/day for one week, 300 mg/day for one week, and then 400 mg/day for five weeks; or 2) 100 mg/day for one week, followed by 200 mg/day for five weeks, then 300 mg/day for one week, then 400 mg/day for five weeks. This design allowed a 100 mg vs. placebo comparison over weeks 1 to 5, and a 200 mg vs. placebo comparison over weeks 2 to 6; the primary comparison was 400 mg (both escalation groups combined) vs. placebo over weeks 8 to 12. The total daily dose was given as twice a day dosing. Statistically significant treatment differences favoring zonisamide capsules were seen for doses of 100, 200, and 400 mg/day. - In the second (n = 152) and third (n = 138) studies, patients had a 2 to 3 month baseline, then were randomly assigned to placebo or zonisamide capsules for three months. Zonisamide capsules were introduced by administering 100 mg/day for the first week, 200 mg/day the second week, then 400 mg/day for two weeks, after which the dose (zonisamide capsules or placebo) could be adjusted as necessary to a maximum dose of 20 mg/kg/day or a maximum plasma level of 40 mcg/mL. In the second study, the total daily dose was given as twice a day dosing; in the third study, it was given as a single daily dose. The average final maintenance doses received in the studies were 530 and 430 mg/day in the second and third studies, respectively. Both studies demonstrated statistically significant differences favoring zonisamide capsules for doses of 400 to 600 mg/day, and there was no apparent difference between once daily and twice daily dosing (in different studies). Analysis of the data (first 4 weeks) during titration demonstrated statistically significant differences favoring zonisamide capsules at doses between 100 and 400 mg/day. The primary comparison in both trials was for any dose over Weeks 5 to 12. - Figure 1 presents the proportion of patients (X-axis) whose percentage reduction from baseline in the all partial seizure rate was at least as great as that indicated on the Y-axis in the second and third placebo-controlled trials. A positive value on the Y-axis indicates an improvement from baseline (i.e., a decrease in seizure rate), while a negative value indicates a worsening from baseline (i.e., an increase in seizure rate). Thus, in a display of this type, the curve for an effective treatment is shifted to the left of the curve for placebo. The proportion of patients achieving any particular level of reduction in seizure rate was consistently higher for the zonisamide capsules groups compared to the placebo groups. For example, Figure 1 indicates that approximately 27% of patients treated with zonisamide capsules experienced a 75% or greater reduction, compared to approximately 12% in the placebo groups. - No differences in efficacy based on age, sex or race, as measured by a change in seizure frequency from baseline, were detected. # How Supplied - Zonisamide capsules, USP 25 mg are available for oral administration as hard gelatin capsules with a white opaque body and a white opaque cap. “APO 25” is imprinted on each capsule in black ink. They are supplied as follows: - Bottles of 30 (NDC 60505-2545-3) - Bottles of 60 (NDC 60505-2545-6) - Bottles of 90 (NDC 60505-2545-9) - Bottles of 100 (NDC 60505-2545-1) - Bottles of 500 (NDC 60505-2545-5) - Bottles of 1000 (NDC 60505-2545-8) - Zonisamide capsules, USP 50 mg are available for oral administration as hard gelatin capsules with a white opaque body and a grey opaque cap. “APO 50” is imprinted on each capsule in black ink. They are supplied as follows: - Bottles of 30 (NDC 60505-2546-3) - Bottles of 60 (NDC 60505-2546-6) - Bottles of 90 (NDC 60505-2546-9) - Bottles of 100 (NDC 60505-2546-1) - Bottles of 500 (NDC 60505-2546-5) - Bottles of 1000 (NDC 60505-2546-8) - Zonisamide capsules, USP 100 mg are available for oral administration as hard gelatin capsules with a white opaque body and a red opaque cap. “APO 100” is imprinted on each capsule in black ink. They are supplied as follows: - Bottles of 30 (NDC 60505-2547-3) - Bottles of 60 (NDC 60505-2547-6) - Bottles of 90 (NDC 60505-2547-9) - Bottles of 100 (NDC 60505-2547-1) - Bottles of 500 (NDC 60505-2547-5) - Bottles of 1000 (NDC 60505-2547-8) - Storage - Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). - Store in a dry place. Protect from light. - Store in a tight, light-resistant container. ## Storage There is limited information regarding Zonisamide Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be informed of the availability of a Medication Guide, and they should be instructed to read the Medication Guide prior to taking zonisamide capsules. Patients should be instructed to take zonisamide capsules only as prescribed. - Patients should be advised as follows: - Zonisamide capsules may produce drowsiness, especially at higher doses. Patients should be advised not to drive a car or operate other complex machinery until they have gained experience on zonisamide capsules sufficient to determine whether it affects their performance. Because of the potential of zonisamide to cause CNS depression, as well as other cognitive and/or neuropsychiatric adverse events, zonisamide should be used with caution if used in combination with alcohol or other CNS depressants. - Patients should contact their physician immediately if a skin rash develops or seizures worsen. - Patients should contact their physician immediately if they develop signs or symptoms, such as sudden back pain, abdominal pain, and/or blood in the urine, that could indicate a kidney stone. Increasing fluid intake and urine output may reduce the risk of stone formation, particularly in those with predisposing risk factors for stones. - Patients should contact their physician immediately if a child has been taking zonisamide capsules and is not sweating as usual with or without a fever. - Because zonisamide can cause hematological complications, patients should contact their physician immediately if they develop a fever, sore throat, oral ulcers, or easy bruising. - Suicidal Thinking and Behavior - Patients, their caregivers, and families should be counseled that AEDs, including zonisamide capsules, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. - Patients should contact their physician immediately if they develop fast breathing, fatigue/tiredness, loss of appetite, or irregular heart beat or palpitations (possible manifestations of metabolic acidosis). - As with other AEDs, patients should contact their physician if they intend to become pregnant or are pregnant during zonisamide therapy. Patients should notify their physician if they intend to breast-feed or are breast-feeding an infant. - Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334. # Precautions with Alcohol - Alcohol-Zonisamide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - ZONISAMIDE ® # Look-Alike Drug Names - Zonegran® — SINEquan® # Drug Shortage Status # Price	Zonisamide 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 Zonisamide is an antiepileptic that is FDA approved for the {{{indicationType}}} of partial seizure. Common adverse reactions include pruritus, loss of appetite, ataxia, dizziness, somnolence, amblyopia, agitation, depression and disturbance in speech. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Zonisamide capsules, USP are indicated as adjunctive therapy in the treatment of partial seizures in adults with epilepsy. - Zonisamide capsules are recommended as adjunctive therapy for the treatment of partial seizures in adults. Safety and efficacy in pediatric patients below the age of 16 have not been established. Zonisamide capsules should be administered once or twice daily, using 25 mg, 50 mg or 100 mg capsules. Zonisamide capsules are given orally and can be taken with or without food. Capsules should be swallowed whole. - Adults over Age 16 - The prescriber should be aware that, because of the long half-life of zonisamide, up to two weeks may be required to achieve steady state levels upon reaching a stable dose or following dosage adjustment. Although the regimen described below is one that has been shown to be tolerated, the prescriber may wish to prolong the duration of treatment at the lower doses in order to fully assess the effects of zonisamide at steady state, noting that many of the side effects of zonisamide are more frequent at doses of 300 mg per day and above. Although there is some evidence of greater response at doses above 100 to 200 mg/day, the increase appears small and formal dose-response studies have not been conducted. - The initial dose of zonisamide capsules should be 100 mg daily. After two weeks, the dose may be increased to 200 mg/day for at least two weeks. It can be increased to 300 mg/day and 400 mg/day, with the dose stable for at least two weeks to achieve steady state at each level. Evidence from controlled trials suggests that zonisamide capsules doses of 100 to 600 mg/day are effective, but there is no suggestion of increasing response above 400 mg/day. There is little experience with doses greater than 600 mg/day. - Patients with Renal or Hepatic Disease - Because zonisamide is metabolized in the liver and excreted by the kidneys, patients with renal or hepatic disease should be treated with caution, and might require slower titration and more frequent monitoring. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Zonisamide in adult patients. ### Non–Guideline-Supported Use - Oral Zonisamide, initially at a dose of 100 mg/day. Based on tolerance, dosage was increased in 100-mg increments weekly over 3 weeks to 400 mg/day.[1] - 12 weeks of zonisamide 25 mg.[2] - Oral Zonisamide 200 to 500 mg once daily.[3] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Zonisamide in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Zonisamide in pediatric patients. ### Non–Guideline-Supported Use - Oral Zonisamide 5.8 mg/kg.[4] # Contraindications - Zonisamide capsules are contraindicated in patients who have demonstrated hypersensitivity to sulfonamides or zonisamide. # Warnings - Potentially Fatal Reactions to Sulfonamides - Fatalities have occurred, although rarely, as a result of severe reactions to sulfonamides (zonisamide is a sulfonamide) including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. Such reactions may occur when a sulfonamide is readministered irrespective of the route of administration. If signs of hypersensitivity or other serious reactions occur, discontinue zonisamide immediately. Specific experience with sulfonamide-type adverse reaction to zonisamide is described below. - Serious Skin Reactions - Consideration should be given to discontinuing zonisamide capsules in patients who develop an otherwise unexplained rash. If the drug is not discontinued, patients should be observed frequently. Seven deaths from severe rash [i.e. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)] were reported in the first 11 years of marketing in Japan. All of the patients were receiving other drugs in addition to zonisamide. In post-marketing experience from Japan, a total of 49 cases of SJS or TEN have been reported, a reporting rate of 46 per million patient-years of exposure. Although this rate is greater than background, it is probably an underestimate of the true incidence because of under-reporting. There were no confirmed cases of SJS or TEN in the US, European, or Japanese development programs. - In the US and European randomized controlled trials, 6 of 269 (2.2%) zonisamide patients discontinued treatment because of rash compared to none on placebo. Across all trials during the US and European development, rash that led to discontinuation of zonisamide was reported in 1.4% of patients (12.0 events per 1000 patient-years of exposure). During Japanese development, serious rash or rash that led to study drug discontinuation was reported in 2.0% of patients (27.8 events per 1000 patient years). Rash usually occurred early in treatment, with 85% reported within 16 weeks in the US and European studies and 90% reported within two weeks in the Japanese studies. There was no apparent relationship of dose to the occurrence of rash. - Serious Hematologic Events - Two confirmed cases of aplastic anemia and one confirmed case of agranulocytosis were reported in the first 11 years of marketing in Japan, rates greater than generally accepted background rates. There were no cases of aplastic anemia and two confirmed cases of agranulocytosis in the US, European, or Japanese development programs. - There is inadequate information to assess the relationship, if any, between dose and duration of treatment and these events. - Oligohidrosis and Hyperthermia in Pediatric Patients - Oligohidrosis, sometimes resulting in heat stroke and hospitalization, is seen in association with zonisamide in pediatric patients. - During the pre-approval development program in Japan, one case of oligohidrosis was reported in 403 pediatric patients, an incidence of 1 case per 285 patient-years of exposure. While there were no cases reported in the US or European development programs, fewer than 100 pediatric patients participated in these trials. - In the first 11 years of marketing in Japan, 38 cases were reported, an estimated reporting rate of about 1 case per 10,000 patient-years of exposure. In the first year of marketing in the US, 2 cases were reported, an estimated reporting rate of about 12 cases per 10,000 patient-years of exposure. These rates are underestimates of the true incidence because of under-reporting. There has also been one report of heat stroke in an 18-year-old patient in the US. - Decreased sweating and an elevation in body temperature above normal characterized these cases. Many cases were reported after exposure to elevated environmental temperatures. Heat stroke, requiring hospitalization, was diagnosed in some cases. There have been no reported deaths. - Pediatric patients appear to be at an increased risk for zonisamide-associated oligohidrosis and hyperthermia. Patients, especially pediatric patients, treated with zonisamide capsules should be monitored closely for evidence of decreased sweating and increased body temperature, especially in warm or hot weather. Caution should be used when zonisamide is prescribed with other drugs that predispose patients to heat-related disorders; these drugs include, but are not limited to, carbonic anhydrase inhibitors and drugs with anticholinergic activity. - The practitioner should be aware that the safety and effectiveness of zonisamide in pediatric patients have not been established, and that zonisamide is not approved for use in pediatric patients. - Suicidal Behavior and Ideation - Antiepileptic drugs (AEDs), including zonisamide capsules, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. - Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. - The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. - The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed. - Table 3 shows absolute and relative risk by indication for all evaluated AEDs. - The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. - Anyone considering prescribing zonisamide capsules or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. - Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. - Metabolic Acidosis - Zonisamide causes hyperchloremic, non-anion gap, metabolic acidosis (i.e., decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis). This metabolic acidosis is caused by renal bicarbonate loss due to the inhibitory effect of zonisamide on carbonic anhydrase. - Generally, zonisamide-induced metabolic acidosis occurs early in treatment, but it can develop at any time during treatment. Metabolic acidosis generally appears to be dose-dependent and can occur at doses as low as 25 mg daily. - Conditions or therapies that predispose to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, ketogenic diet, or specific drugs) may be additive to the bicarbonate lowering effects of zonisamide. - Some manifestations of acute or chronic metabolic acidosis include hyperventilation, nonspecific symptoms such as fatigue and anorexia, or more severe sequelae including cardiac arrhythmias or stupor. Chronic, untreated, metabolic acidosis may increase the risk for nephrolithiasis or nephrocalcinosis. Nephrolithiasis has been observed in the clinical development program in 4 % of adults treated with zonisamide, has also been detected by renal ultrasound in 8 % of pediatric treated patients who had at least one ultrasound prospectively collected, and was reported as an adverse event in 3 % (4/133) of pediatric patients. - Chronic, untreated metabolic acidosis may result in osteomalacia (referred to as rickets in pediatric patients) and/or osteoporosis with an increased risk for fracture. Of potential relevance, zonisamide treatment was associated with reductions in serum phosphorus and increases in serum alkaline phosphatase, changes that may be related to metabolic acidosis and osteomalacia. - Chronic, untreated metabolic acidosis in pediatric patients may reduce growth rates. A reduction in growth rate may eventually decrease the maximal height achieved. The effect of zonisamide on growth and bone-related sequelae has not been systematically investigated. - Measurement of baseline and periodic serum bicarbonate during treatment is recommended. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing zonisamide (using dose tapering). If the decision is made to continue patients on zonisamide in the face of persistent acidosis, alkali treatment should be considered. - Serum bicarbonate was not measured in the adjunctive controlled trials of adults with epilepsy. However, serum bicarbonate was studied in three clinical trials for indications which have not been approved: a placebo-controlled trial for migraine prophylaxis in adults, a controlled trial for monotherapy in epilepsy in adults, and an open label trial for adjunctive treatment of epilepsy in pediatric patients (3 to 16 years). In adults, mean serum bicarbonate reductions ranged from approximately 2 mEq/L at daily doses of 100 mg to nearly 4 mEq/L at daily doses of 300 mg. In pediatric patients, mean serum bicarbonate reductions ranged from approximately 2 mEq/L at daily doses from above 100 mg up to 300 mg, to nearly 4 mEq/L at daily doses from above 400 mg up to 600 mg. - In two controlled studies in adults, the incidence of a persistent treatment-emergent decrease in serum bicarbonate to less than 20 mEq/L (observed at 2 or more consecutive visits or the final visit) was dose-related at relatively low zonisamide doses. In the monotherapy trial of epilepsy, the incidence of a persistent treatment-emergent decrease in serum bicarbonate was 21% for daily zonisamide doses of 25 mg or 100 mg, and was 43% at a daily dose of 300 mg. In a placebo-controlled trial for prophylaxis of migraine, the incidence of a persistent treatment-emergent decrease in serum bicarbonate was 7% for placebo, 29% for 150 mg daily, and 34% for 300 mg daily. The incidence of persistent markedly abnormally low serum bicarbonate (decrease to less than 17 mEq/L and more than 5 mEq/L) from a pretreatment value of at least 20 mEq/L in these controlled trials was 2% or less. - In the pediatric study, the incidence of persistent, treatment-emergent decreases in serum bicarbonate to levels less than 20 mEq/L was 52% at doses up to 100 mg daily, was 90% for a wide range of doses up to 600 mg daily, and generally appeared to increase with higher doses. The incidence of a persistent markedly abnormally low serum bicarbonate value was 4 % at doses up to 100 mg daily, was 18% for a wide range of doses up to 600 mg daily, and generally appeared to increase with higher doses. Some patients experienced moderately severe serum bicarbonate decrements down to a level as low as 10 mEq/L. - The relatively high frequencies of varying severities of metabolic acidosis observed in this study of pediatric patients (compared to the frequency and severity observed in various clinical trial development programs in adults) suggest that pediatric patients may be more likely to develop metabolic acidosis than adults. - Seizures on Withdrawal - As with other AEDs, abrupt withdrawal of zonisamide capsules in patients with epilepsy may precipitate increased seizure frequency or status epilepticus. Dose reduction or discontinuation of zonisamide should be done gradually. - Teratogenicity - Women of child bearing potential who are given zonisamide should be advised to use effective contraception. Zonisamide was teratogenic in mice, rats, and dogs and embryolethal in monkeys when administered during the period of organogenesis. A variety of fetal abnormalities, including cardiovascular defects, and embryo-fetal deaths occurred at maternal plasma levels similar to or lower than therapeutic levels in humans. These findings suggest that the use of zonisamide capsules during pregnancy in humans may present a significant risk to the fetus (see PRECAUTIONS, Pregnancy subsection). Zonisamide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - Cognitive/ Neuropsychiatric Adverse Events - Use of zonisamide capsules was frequently associated with central nervous system-related adverse events. The most significant of these can be classified into three general categories: 1) psychiatric symptoms, including depression and psychosis, 2) psychomotor slowing, difficulty with concentration, and speech or language problems, in particular, word-finding difficulties, and 3) somnolence or fatigue. - In placebo-controlled trials, 2.2% of patients discontinued zonisamide capsules or were hospitalized for depression compared to 0.4% of placebo patients. Among all epilepsy patients treated with zonisamide capsules, 1.4% were discontinued and 1.0% were hospitalized because of reported depression or suicide attempts. In placebo-controlled trials, 2.2% of patients discontinued zonisamide capsules or were hospitalized due to psychosis or psychosis-related symptoms compared to none of the placebo patients. Among all epilepsy patients treated with zonisamide capsules, 0.9% were discontinued and 1.4% were hospitalized because of reported psychosis or related symptoms. - Psychomotor slowing and difficulty with concentration occurred in the first month of treatment and were associated with doses above 300 mg/day. Speech and language problems tended to occur after 6 to 10 weeks of treatment and at doses above 300 mg/day. Although in most cases these events were of mild to moderate severity, they at times led to withdrawal from treatment. - Somnolence and fatigue were frequently reported CNS adverse events during clinical trials with zonisamide capsules. Although in most cases these events were of mild to moderate severity, they led to withdrawal from treatment in 0.2% of the patients enrolled in controlled trials. Somnolence and fatigue tended to occur within the first month of treatment. Somnolence and fatigue occurred most frequently at doses of 300 to 500 mg/day. Patients should be cautioned about this possibility and special care should be taken by patients if they drive, operate machinery, or perform any hazardous task. ### Precautions - General - Somnolence is commonly reported, especially at higher doses of zonisamide capsules (see WARNINGS,Cognitive/ Neuropsychiatric Adverse Events subsection). Zonisamide is metabolized by the liver and eliminated by the kidneys; caution should therefore be exercised when administering zonisamide capsules to patients with hepatic and renal dysfunction. - Kidney Stones - Among 991 patients treated during the development of zonisamide capsules, 40 patients (4.0%) with epilepsy receiving zonisamide capsules developed clinically possible or confirmed kidney stones (e.g. clinical symptomatology, sonography, etc.), a rate of 34 per 1000 patient-years of exposure (40 patients with 1168 years of exposure). Of these, 12 were symptomatic, and 28 were described as possible kidney stones based on sonographic detection. In nine patients, the diagnosis was confirmed by a passage of a stone or by a definitive sonographic finding. The rate of occurrence of kidney stones was 28.7 per 1000 patient-years of exposure in the first six months, 62.6 per 1000 patient-years of exposure between 6 and 12 months, and 24.3 per 1000 patient-years of exposure after 12 months of use. There are no normative sonographic data available for either the general population or patients with epilepsy. Although the clinical significance of the sonographic findings may not be certain, the development of nephrolithiasis may be related to metabolic acidosis. The analyzed stones were composed of calcium or urate salts. In general, increasing fluid intake and urine output can help reduce the risk of stone formation, particularly in those with predisposing risk factors. It is unknown, however, whether these measures will reduce the risk of stone formation in patients treated with zonisamide capsules. - Although not approved in pediatric patients, sonographic findings consistent with nephrolithiasis were also detected in 8 % of a subset of zonisamide treated pediatric patients who had at least one renal ultrasound prospectively performed in a clinical development program investigating open-label treatment. The incidence of kidney stone as an adverse event was 3 %. - Effect on Renal Function - In several clinical studies, zonisamide was associated with a statistically significant 8% mean increase from baseline of serum creatinine and blood urea nitrogen (BUN) compared to essentially no change in the placebo patients. The increase appeared to persist over time but was not progressive; this has been interpreted as an effect on glomerular filtration rate (GFR). There were no episodes of unexplained acute renal failure in clinical development in the US, Europe, or Japan. The decrease in GFR appeared within the first 4 weeks of treatment. In a 30-day study, the GFR returned to baseline within 2 to 3 weeks of drug discontinuation. There is no information about reversibility, after drug discontinuation, of the effects on GFR after long-term use. Zonisamide capsules should be discontinued in patients who develop acute renal failure or a clinically significant sustained increase in the creatinine/BUN concentration. Zonisamide capsules should not be used in patients with renal failure (estimated GFR <50 mL/min) as there has been insufficient experience concerning drug dosing and toxicity. - Sudden Unexplained Death in Epilepsy - During the development of zonisamide capsules, nine sudden unexplained deaths occurred among 991 patients with epilepsy receiving zonisamide capsules for whom accurate exposure data are available. This represents an incidence of 7.7 deaths per 1000 patient years. Although this rate exceeds that expected in a healthy population, it is within the range of estimates for the incidence of sudden unexplained deaths in patients with refractory epilepsy not receiving zonisamide capsules (ranging from 0.5 per 1000 patient-years for the general population of patients with epilepsy, to 2 to 5 per 1000 patient-years for patients with refractory epilepsy; higher incidences range from 9 to 15 per 1000 patient-years among surgical candidates and surgical failures). Some of the deaths could represent seizure-related deaths in which the seizure was not observed. - Status Epilepticus - Estimates of the incidence of treatment emergent status epilepticus in zonisamide capsule-treated patients are difficult because a standard definition was not employed. Nonetheless, in controlled trials, 1.1% of patients treated with zonisamide capsules had an event labeled as status epilepticus compared to none of the patients treated with placebo. Among patients treated with zonisamide capsules across all epilepsy studies (controlled and uncontrolled), 1.0% of patients had an event reported as status epilepticus. # Adverse Reactions ## Clinical Trials Experience - The most commonly observed adverse events related to treatment with zonisamide capsules (an incidence at least 4% greater than placebo) in controlled clinical trials and shown in descending order of frequency were somnolence, anorexia, dizziness, ataxia, agitation/irritability, and difficulty with memory and/or concentration. - In controlled clinical trials, 12% of patients receiving zonisamide capsules as adjunctive therapy discontinued due to an adverse event compared to 6% receiving placebo. Approximately 21% of the 1,336 patients with epilepsy who received zonisamide capsules in clinical studies discontinued treatment because of an adverse event. The adverse events most commonly associated with discontinuation were somnolence, fatigue and/or ataxia (6%), anorexia (3%), difficulty concentrating (2%), difficulty with memory, mental slowing, nausea/vomiting (2%), and weight loss (1%). Many of these adverse events were dose-related. - Table 4 lists treatment-emergent adverse events that occurred in at least 2% of patients treated with zonisamide capsules in controlled clinical trials that were numerically more common in the zonisamide capsules group. In these studies, either zonisamide capsules or placebo was added to the patient’s current AED therapy. Adverse events were usually mild or moderate in intensity. - The prescriber should be aware that these figures, obtained when zonisamide capsules were added to concurrent AED therapy, cannot be used to predict the frequency of adverse events in the course of usual medical practice when patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. An inspection of these frequencies, however, does provide the prescriber with one basis by which to estimate the relative contribution of drug and non-drug factors to the adverse event incidences in the population studied. - Zonisamide capsules have been administered to 1,598 individuals during all clinical trials, only some of which were placebo-controlled. During these trials, all events were recorded by the investigators using their own terms. To provide a useful estimate of the proportion of individuals having adverse events, similar events have been grouped into a smaller number of standardized categories using a modified COSTART dictionary. The frequencies represent the proportion of the 1,598 individuals exposed to zonisamide capsules who experienced an event on at least one occasion. All events are included except those already listed in the previous table or discussed in WARNINGS or PRECAUTIONS, trivial events, those too general to be informative, and those not reasonably associated with zonisamide capsules. - Events are further classified within each category and listed in order of decreasing frequency as follows: frequent occurring in at least 1:100 patient; infrequent occurring in 1:100 to 1:1000 patients; rare occurring in fewer than 1:1000 patients. Frequent: Accidental injury, asthenia. Infrequent: Chest pain, flank pain, malaise, allergic reaction, face edema, neck rigidity. Rare: Lupus erythematosus. Infrequent: Palpitation, tachycardia, vascular insufficiency, hypotension, hypertension, thrombophlebitis, syncope, bradycardia. Rare: Atrial fibrillation, heart failure, pulmonary embolus, ventricular extrasystoles. Frequent: Vomiting. Infrequent: Flatulence, gingivitis, gum hyperplasia, gastritis, gastroenteritis, stomatitis, cholelithiasis, glossitis, melena, rectal hemorrhage, ulcerative stomatitis, gastro-duodenal ulcer, dysphagia, gum hemorrhage. Rare: Cholangitis, hematemesis, cholecystitis, cholestatic jaundice, colitis, duodenitis, esophagitis, fecal incontinence, mouth ulceration. Infrequent: Leukopenia, anemia, immunodeficiency, lymphadenopathy. Rare: Thrombocytopenia, microcytic anemia, petechia. Infrequent: Peripheral edema, weight gain, edema, thirst, dehydration. Rare: Hypoglycemia, hyponatremia, lactic dehydrogenase increased, SGOT increased, SGPT increased. Infrequent: Leg cramps, myalgia, myasthenia, arthralgia, arthritis. Frequent: Tremor, convulsion, abnormal gait, hyperesthesia, incoordination. Infrequent: Hypertonia, twitching, abnormal dreams, vertigo, libido decreased, neuropathy, hyperkinesia, movement disorder, dysarthria, cerebrovascular accident, hypotonia, peripheral neuritis, reflexes increased. Rare: Dyskinesia, dystonia, encephalopathy, facial paralysis, hypokinesia, hyperesthesia, myoclonus, oculogyric crisis. Infrequent: Euphoria. Frequent: Pharyngitis, cough increased. Infrequent: Dyspnea. Rare: Apnea, hemoptysis. Frequent: Pruritus. Infrequent: Maculopapular rash, acne, alopecia, dry skin, sweating, eczema, urticaria, hirsutism, pustular rash, vesiculobullous rash. Frequent: Amblyopia, tinnitus. Infrequent: Conjunctivitis, parosmia, deafness, visual field defect, glaucoma. Rare: Photophobia, iritis. Infrequent: Urinary frequency, dysuria, urinary incontinence, hematuria, impotence, urinary retention, urinary urgency, amenorrhea, polyuria, nocturia. Rare: Albuminuria, enuresis, bladder pain, bladder calculus, gynecomastia, mastitis, menorrhagia. ## Postmarketing Experience - The following serious adverse events have been reported since approval and use of zonisamide worldwide.These reactions are reported voluntarily from a population of uncertain size;therefore,it is not possible to estimate their frequency or establish a causal relationship to drug exposure. - Acute pancreatitis, rhabdomyolysis,creatine phosphokinase increased. # Drug Interactions - Effects of zonisamide capsules on the pharmacokinetics of other antiepilepsy drugs (AEDs) - Zonisamide had no appreciable effect on the steady state plasma concentrations of phenytoin, carbamazepine, or valproate during clinical trials. Zonisamide did not inhibit mixed-function liver oxidase enzymes (cytochrome P450), as measured in human liver microsomal preparations, in vitro. Zonisamide is not expected to interfere with the metabolism of other drugs that are metabolized by cytochrome P450 isozymes. - Effects of other drugs on zonisamide capsules pharmacokinetics - Drugs that induce liver enzymes increase the metabolism and clearance of zonisamide and decrease its half-life. The half-life of zonisamide following a 400 mg dose in patients concurrently on enzyme-inducing AEDs such as phenytoin, carbamazepine, or phenobarbital was between 27 to 38 hours; the half-life of zonisamide in patients concurrently on the non-enzyme inducing AED, valproate, was 46 hours. Concurrent medication with drugs that either induce or inhibit CYP3A4 would be expected to alter serum concentrations of zonisamide. - Interaction with cimetidine - Zonisamide single dose pharmacokinetic parameters were not affected by cimetidine (300 mg four times a day for 12 days). - Drug Interactions with CNS Depressants - Concomitant administration of zonisamide and alcohol or other CNS depressant drugs has not been evaluated in clinical studies. Because of the potential of zonisamide to cause CNS depression, as well as other cognitive and/or neuropsychiatric adverse events, zonisamide should be used with caution if used in combination with alcohol or other CNS depressants. - Other Carbonic Anhydrase Inhibitors - Concomitant use of zonisamide, a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor (e.g., topiramate, acetazolamide or dichlorphenamide), may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. Therefore, if zonisamide is given concomitantly with another carbonic anhydrase inhibitor, the patient should be monitored for the appearance or worsening of metabolic acidosis. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Zonisamide may cause serious adverse fetal effects, based on clinical and nonclinical data. Zonisamide was teratogenic in multiple animal species. - Zonisamide treatment causes metabolic acidosis in humans. The effect of zonisamide-induced metabolic acidosis has not been studied in pregnancy; however, metabolic acidosis in pregnancy (due to other causes) may be associated with decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the fetus’ ability to tolerate labor. Pregnant patients should be monitored for metabolic acidosis and treated as in the non-pregnant state. - Newborns of mothers treated with zonisamide should be monitored for metabolic acidosis because of transfer of zonisamide to the fetus and possible occurrence of transient metabolic acidosis following birth. Transient metabolic acidosis has been reported in neonates born to mothers treated during pregnancy with a different carbonic anhydrase inhibitor. - Zonisamide was teratogenic in mice, rats, and dogs and embryolethal in monkeys when administered during the period of organogenesis. Fetal abnormalities or embryo-fetal deaths occurred in these species at zonisamide dosage and maternal plasma levels similar to or lower than therapeutic levels in humans, indicating that use of this drug in pregnancy entails a significant risk to the fetus. A variety of external, visceral, and skeletal malformations was produced in animals by prenatal exposure to zonisamide. Cardiovascular defects were prominent in both rats and dogs. - Following administration of zonisamide (10, 30, or 60 mg/kg/day) to pregnant dogs during organogenesis, increased incidences of fetal cardiovascular malformations (ventricular septal defects, cardiomegaly, various valvular and arterial anomalies) were found at doses of 30 mg/kg/day or greater. The low effect dose for malformations produced peak maternal plasma zonisamide levels (25 mcg/mL) about 0.5 times the highest plasma levels measured in patients receiving the maximum recommended human dose (MRHD) of 400 mg/day. In dogs, cardiovascular malformations were found in approximately 50% of all fetuses exposed to the high dose, which was associated with maternal plasma levels (44 mcg/mL) approximately equal to the highest levels measured in humans receiving the MRHD. Incidences of skeletal malformations were also increased at the high dose, and fetal growth retardation and increased frequencies of skeletal variations were seen at all doses in this study. The low dose produced maternal plasma levels (12 mcg/mL) about 0.25 times the highest human levels. - In cynomolgus monkeys, administration of zonisamide (10 or 20 mg/kg/day) to pregnant animals during organogenesis resulted in embryo-fetal deaths at both doses. The possibility that these deaths were due to malformations cannot be ruled out. The lowest embryolethal dose in monkeys was associated with peak maternal plasma zonisamide levels (5 mcg/mL) approximately 0.1 times the highest levels measured in patients at the MRHD. - In a mouse embryo-fetal development study, treatment of pregnant animals with zonisamide (125, 250, or 500 mg/kg/day) during the period of organogenesis resulted in increased incidences of fetal malformations (skeletal and/or craniofacial defects) at all doses tested. The low dose in this study is approximately 1.5 times the MRHD on a mg/m2 basis. In rats, increased frequencies of malformations (cardiovascular defects) and variations (persistent cords of thymic tissue, decreased skeletal ossification) were observed among the offspring of dams treated with zonisamide (20, 60, or 200 mg/kg/day) throughout organogenesis at all doses. The low effect dose is approximately 0.5 times the MRHD on a mg/m2 basis. - Perinatal death was increased among the offspring of rats treated with zonisamide (10, 30, or 60 mg/kg/day) from the latter part of gestation up to weaning at the high dose, or approximately 1.4 times the MRHD on a mg/m2 basis. The no effect level of 30 mg/kg/day is approximately 0.7 times the MRHD on a mg/m2 basis. - There are no adequate and well-controlled studies in pregnant women. Zonisamide capsules should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - To provide information regarding the effects of in utero exposure to zonisamide capsules, physicians are advised to recommend that pregnant patients taking zonisamide capsules enroll in the NAAED Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Zonisamide in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Zonisamide during labor and delivery. ### Nursing Mothers - Zonisamide is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from zonisamide, a decision should be made whether to discontinue nursing or to discontinue drug, taking into account the importance of the drug to the mother. ### Pediatric Use - The safety and effectiveness of zonisamide capsules in children under age 16 have not been established. Cases of oligohidrosis and hyperpyrexia have been reported. Zonisamide commonly causes metabolic acidosis in pediatric patients. Chronic untreated metabolic acidosis in pediatric patients may cause nephrolithiasis and/or nephrocalcinosis, osteoporosis and/or osteomalacia (potentially resulting in rickets), and may reduce growth rates. A reduction in growth rate may eventually decrease the maximal height achieved. The effect of zonisamide on growth and bone-related sequelae has not been systematically investigated. ### Geriatic Use - Single dose pharmacokinetic parameters are similar in elderly and young healthy volunteers. Clinical studies of zonisamide 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. ### Gender There is no FDA guidance on the use of Zonisamide with respect to specific gender populations. ### Race There is no FDA guidance on the use of Zonisamide with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Zonisamide in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Zonisamide in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Zonisamide in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Zonisamide in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Zonisamide in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Zonisamide in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - Experience with zonisamide capsules daily doses over 800 mg/day is limited. During zonisamide capsules clinical development, three patients ingested unknown amounts of zonisamide capsules as suicide attempts, and all three were hospitalized with CNS symptoms. One patient became comatose and developed bradycardia, hypotension, and respiratory depression; the zonisamide plasma level was 100.1 mcg/mL measured 31 hours post-ingestion. Zonisamide plasma levels fell with a half-life of 57 hours, and the patient became alert five days later. ### Management - No specific antidotes for zonisamide capsules overdosage are available. Following a suspected recent overdose, emesis should be induced or gastric lavage performed with the usual precautions to protect the airway. General supportive care is indicated, including frequent monitoring of vital signs and close observation. - Zonisamide has a long half-life. Due to the low protein binding of zonisamide (40%), renal dialysis may be effective. The effectiveness of renal dialysis as a treatment of overdose has not been formally studied. A poison control center should be contacted for information on the management of zonisamide capsules overdosage. ## Chronic Overdose There is limited information regarding Chronic Overdose of Zonisamide in the drug label. # Pharmacology ## Mechanism of Action - The precise mechanism(s) by which zonisamide exerts its antiseizure effect is unknown. Zonisamide demonstrated anticonvulsant activity in several experimental models. In animals, zonisamide was effective against tonic extension seizures induced by maximal electroshock but ineffective against clonic seizures induced by subcutaneous pentylenetetrazol. Zonisamide raised the threshold for generalized seizures in the kindled rat model and reduced the duration of cortical focal seizures induced by electrical stimulation of the visual cortex in cats. Furthermore, zonisamide suppressed both interictal spikes and the secondarily generalized seizures produced by cortical application of tungstic acid gel in rats or by cortical freezing in cats. The relevance of these models to human epilepsy is unknown. - Zonisamide may produce these effects through action at sodium and calcium channels. In vitro pharmacological studies suggest that zonisamide blocks sodium channels and reduces voltage-dependent, transient inward currents (T-type Ca2+ currents), consequently stabilizing neuronal membranes and suppressing neuronal hypersynchronization. In vitro binding studies have demonstrated that zonisamide binds to the GABA/benzodiazepine receptor ionophore complex in an allosteric fashion which does not produce changes in chloride flux. Other in vitro studies have demonstrated that zonisamide (10 to 30 mcg/mL) suppresses synaptically-driven electrical activity without affecting postsynaptic GABA or glutamate responses (cultured mouse spinal cord neurons) or neuronal or glial uptake of [3H]-GABA (rat hippocampal slices). Thus, zonisamide does not appear to potentiate the synaptic activity of GABA. In vivo microdialysis studies demonstrated that zonisamide facilitates both dopaminergic and serotonergic neurotransmission. - Zonisamide is a carbonic anhydrase inhibitor. The contribution of this pharmacological action to the therapeutic effects of zonisamide is unknown. However, as a carbonic anhydrase inhibitor, zonisamide may cause metabolic acidosis (see WARNINGS, Metabolic Acidosis subsection). ## Structure - Zonisamide capsules, USP are an antiseizure drug chemically classified as a sulfonamide and unrelated to other antiseizure agents. The active ingredient is zonisamide, 1,2- benzisoxazole-3-methanesulfonamide. The molecular formula is C8H8N2O3S with a molecular weight of 212.23. Zonisamide is a white powder, pKa = 10.2, and is soluble in methanol, ethanol, ethyl acetate and acetic acid, sparingly soluble in water, chloroform and n-hexane. - The chemical structure is: - Each capsule, for oral administration, contains 25 mg, 50 mg or 100 mg of zonisamide. In addition, each capsule contains the following inactive ingredients: colloidal silicon dioxide, microcrystalline cellulose, stearic acid and talc. - The 25 mg capsule shell contains gelatin and titanium dioxide. The 50 mg capsule shell contains black iron oxide, gelatin and titanium dioxide. The 100 mg capsule shell contains D&C yellow #10, FD&C red #40, gelatin and titanium dioxide. - The 25 mg and 50 mg capsule imprinting ink contains strong ammonia solution, black iron oxide, butyl alcohol, dehydrated alcohol, isopropyl alcohol, potassium hydroxide, propylene glycol and shellac. - The 100 mg capsule imprinting ink contains D&C yellow #10 Aluminum Lake, FD&C blue #1 Aluminum Lake, FD&C blue #2 Aluminum Lake, FD&C red #40 Aluminum Lake, n-butyl alcohol, pharmaceutical glaze, propylene glycol and synthetic black iron oxide. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Zonisamide in the drug label. ## Pharmacokinetics - Following a 200 to 400 mg oral zonisamide dose, peak plasma concentrations (range: 2 to 5 mcg/mL) in normal volunteers occur within 2 to 6 hours. In the presence of food, the time to maximum concentration is delayed, occurring at 4 to 6 hours, but food has no effect on the bioavailability of zonisamide. Zonisamide extensively binds to erythrocytes, resulting in an eight-fold higher concentration of zonisamide in red blood cells (RBC) than in plasma. The pharmacokinetics of zonisamide are dose proportional in the range of 200 to 400 mg, but the Cmax and AUC increase disproportionately at 800 mg, perhaps due to saturable binding of zonisamide to RBC. Once a stable dose is reached, steady state is achieved within 14 days. The elimination half-life of zonisamide in plasma is about 63 hours. The elimination half-life of zonisamide in RBC is approximately 105 hours. - The apparent volume of distribution (V/F) of zonisamide is about 1.45 L/kg following a 400 mg oral dose. Zonisamide, at concentrations of 1.0 to 7.0 mcg/mL, is approximately 40% bound to human plasma proteins. Protein binding of zonisamide is unaffected in the presence of therapeutic concentrations of phenytoin, phenobarbital or carbamazepine. - Metabolism and Excretion - Following oral administration of 14C-zonisamide to healthy volunteers, only zonisamide was detected in plasma. Zonisamide is excreted primarily in urine as parent drug and as the glucuronide of a metabolite. Following multiple dosing, 62% of the 14C dose was recovered in the urine, with 3% in the feces by day 10. Zonisamide undergoes acetylation to form N-acetyl zonisamide and reduction to form the open ring metabolite, 2–sulfamoylacetyl phenol (SMAP). Of the excreted dose, 35% was recovered as zonisamide, 15% as N-acetyl zonisamide, and 50% as the glucuronide of SMAP. Reduction of zonisamide to SMAP is mediated by cytochrome P450 isozyme 3A4 (CYP3A4). Zonisamide does not induce its own metabolism. Plasma clearance of zonisamide is approximately 0.30 to 0.35 mL/min/kg in patients not receiving enzyme-inducing antiepilepsy drugs (AEDs). The clearance of zonisamide is increased to 0.5 mL/min/kg in patients concurrently on enzyme-inducing AEDs. - Renal clearance is about 3.5 mL/min. The clearance of an oral dose of zonisamide from RBC is 2 mL/min. - Special Populations - Renal Insufficiency - Single 300 mg zonisamide doses were administered to three groups of volunteers. Group 1 was a healthy group with a creatinine clearance ranging from 70 to 152 mL/min. Group 2 and Group 3 had creatinine clearances ranging from 14.5 to 59 mL/min and 10 to 20 mL/min, respectively. Zonisamide renal clearance decreased with decreasing renal function (3.42, 2.50, 2.23 mL/min, respectively). Marked renal impairment (creatinine clearance < 20 mL/min) was associated with an increase in zonisamide AUC of 35%. - Hepatic Disease - The pharmacokinetics of zonisamide in patients with impaired liver function have not been studied. - Age - The pharmacokinetics of a 300 mg single dose of zonisamide was similar in young (mean age 28 years) and elderly subjects (mean age 69 years). - Gender and Race - Information on the effect of gender and race on the pharmacokinetics of zonisamide is not available. - Interactions of Zonisamide with Other Antiepilepsy Drugs (AEDs) - Concurrent medication with drugs that either induce or inhibit CYP3A4 may alter serum concentrations of zonisamide. Concomitant administration of phenytoin and carbamazepine increases zonisamide plasma clearance from 0.30 to 0.35 mL/min/kg to 0.35 to 0.5 mL/min/kg. The half-life of zonisamide is decreased to 27 hours by phenytoin, to 38 hours by phenobarbital and carbamazepine, and to 46 hours by valproate. Plasma protein binding of phenytoin and carbamazepine was not affected by zonisamide administration. - Interactions of Zonisamide with Other Carbonic Anhydrase Inhibitors - Concomitant use of zonisamide, a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor (e.g., topiramate, acetazolamide or dichlorphenamide), may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. Therefore, if zonisamide is given concomitantly with another carbonic anhydrase inhibitor, the patient should be monitored for the appearance or worsening of metabolic acidosis. ## Nonclinical Toxicology - No evidence of carcinogenicity was found in mice or rats following dietary administration of zonisamide for two years at doses of up to 80 mg/kg/day. In mice, this dose is approximately equivalent to the maximum recommended human dose (MRHD) of 400 mg/day on a mg/m2 basis. In rats, this dose is 1 to 2 times the MRHD on a mg/m2 basis. - Zonisamide was mutagenic in an in vitro chromosomal aberration assay in CHL cells. Zonisamide was not mutagenic or clastogenic in other in vitro assays (Ames, mouse lymphoma tk assay, chromosomal aberration in human lymphocytes) or in the in vivo rat bone marrow cytogenetics assay. - Rats treated with zonisamide (20, 60, or 200 mg/kg) before mating and during the initial gestation phase showed signs of reproductive toxicity (decreased corpora lutea, implantations, and live fetuses) at all doses. The low dose in this study is approximately 0.5 times the maximum recommended human dose (MRHD) on a mg/m2 basis. # Clinical Studies - The effectiveness of zonisamide capsules as adjunctive therapy (added to other antiepilepsy drugs) has been established in three multicenter, placebo-controlled, double blind, 3-month clinical trials (two domestic, one European) in 499 patients with refractory partial onset seizures with or without secondary generalization. Each patient had a history of at least four partial onset seizures per month in spite of receiving one or two antiepilepsy drugs at therapeutic concentrations. The 499 patients (209 women, 290 men) ranged in age from 13 to 68 years with a mean age of about 35 years. In the two US studies, over 80% of patients were Caucasian; 100% of patients in the European study were Caucasian. Zonisamide capsules or placebo was added to the existing therapy. The primary measure of effectiveness was median percent reduction from baseline in partial seizure frequency. The secondary measure was proportion of patients achieving a 50% or greater seizure reduction from baseline (responders). The results described below are for all partial seizures in the intent-to-treat populations. - In the first study (n = 203), all patients had a 1-month baseline observation period, then received placebo or zonisamide capsules in one of two dose escalation regimens; either 1) 100 mg/day for five weeks, 200 mg/day for one week, 300 mg/day for one week, and then 400 mg/day for five weeks; or 2) 100 mg/day for one week, followed by 200 mg/day for five weeks, then 300 mg/day for one week, then 400 mg/day for five weeks. This design allowed a 100 mg vs. placebo comparison over weeks 1 to 5, and a 200 mg vs. placebo comparison over weeks 2 to 6; the primary comparison was 400 mg (both escalation groups combined) vs. placebo over weeks 8 to 12. The total daily dose was given as twice a day dosing. Statistically significant treatment differences favoring zonisamide capsules were seen for doses of 100, 200, and 400 mg/day. - In the second (n = 152) and third (n = 138) studies, patients had a 2 to 3 month baseline, then were randomly assigned to placebo or zonisamide capsules for three months. Zonisamide capsules were introduced by administering 100 mg/day for the first week, 200 mg/day the second week, then 400 mg/day for two weeks, after which the dose (zonisamide capsules or placebo) could be adjusted as necessary to a maximum dose of 20 mg/kg/day or a maximum plasma level of 40 mcg/mL. In the second study, the total daily dose was given as twice a day dosing; in the third study, it was given as a single daily dose. The average final maintenance doses received in the studies were 530 and 430 mg/day in the second and third studies, respectively. Both studies demonstrated statistically significant differences favoring zonisamide capsules for doses of 400 to 600 mg/day, and there was no apparent difference between once daily and twice daily dosing (in different studies). Analysis of the data (first 4 weeks) during titration demonstrated statistically significant differences favoring zonisamide capsules at doses between 100 and 400 mg/day. The primary comparison in both trials was for any dose over Weeks 5 to 12. - Figure 1 presents the proportion of patients (X-axis) whose percentage reduction from baseline in the all partial seizure rate was at least as great as that indicated on the Y-axis in the second and third placebo-controlled trials. A positive value on the Y-axis indicates an improvement from baseline (i.e., a decrease in seizure rate), while a negative value indicates a worsening from baseline (i.e., an increase in seizure rate). Thus, in a display of this type, the curve for an effective treatment is shifted to the left of the curve for placebo. The proportion of patients achieving any particular level of reduction in seizure rate was consistently higher for the zonisamide capsules groups compared to the placebo groups. For example, Figure 1 indicates that approximately 27% of patients treated with zonisamide capsules experienced a 75% or greater reduction, compared to approximately 12% in the placebo groups. - No differences in efficacy based on age, sex or race, as measured by a change in seizure frequency from baseline, were detected. # How Supplied - Zonisamide capsules, USP 25 mg are available for oral administration as hard gelatin capsules with a white opaque body and a white opaque cap. “APO 25” is imprinted on each capsule in black ink. They are supplied as follows: - Bottles of 30 (NDC 60505-2545-3) - Bottles of 60 (NDC 60505-2545-6) - Bottles of 90 (NDC 60505-2545-9) - Bottles of 100 (NDC 60505-2545-1) - Bottles of 500 (NDC 60505-2545-5) - Bottles of 1000 (NDC 60505-2545-8) - Zonisamide capsules, USP 50 mg are available for oral administration as hard gelatin capsules with a white opaque body and a grey opaque cap. “APO 50” is imprinted on each capsule in black ink. They are supplied as follows: - Bottles of 30 (NDC 60505-2546-3) - Bottles of 60 (NDC 60505-2546-6) - Bottles of 90 (NDC 60505-2546-9) - Bottles of 100 (NDC 60505-2546-1) - Bottles of 500 (NDC 60505-2546-5) - Bottles of 1000 (NDC 60505-2546-8) - Zonisamide capsules, USP 100 mg are available for oral administration as hard gelatin capsules with a white opaque body and a red opaque cap. “APO 100” is imprinted on each capsule in black ink. They are supplied as follows: - Bottles of 30 (NDC 60505-2547-3) - Bottles of 60 (NDC 60505-2547-6) - Bottles of 90 (NDC 60505-2547-9) - Bottles of 100 (NDC 60505-2547-1) - Bottles of 500 (NDC 60505-2547-5) - Bottles of 1000 (NDC 60505-2547-8) - Storage - Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). - Store in a dry place. Protect from light. - Store in a tight, light-resistant container. ## Storage There is limited information regarding Zonisamide Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be informed of the availability of a Medication Guide, and they should be instructed to read the Medication Guide prior to taking zonisamide capsules. Patients should be instructed to take zonisamide capsules only as prescribed. - Patients should be advised as follows: - Zonisamide capsules may produce drowsiness, especially at higher doses. Patients should be advised not to drive a car or operate other complex machinery until they have gained experience on zonisamide capsules sufficient to determine whether it affects their performance. Because of the potential of zonisamide to cause CNS depression, as well as other cognitive and/or neuropsychiatric adverse events, zonisamide should be used with caution if used in combination with alcohol or other CNS depressants. - Patients should contact their physician immediately if a skin rash develops or seizures worsen. - Patients should contact their physician immediately if they develop signs or symptoms, such as sudden back pain, abdominal pain, and/or blood in the urine, that could indicate a kidney stone. Increasing fluid intake and urine output may reduce the risk of stone formation, particularly in those with predisposing risk factors for stones. - Patients should contact their physician immediately if a child has been taking zonisamide capsules and is not sweating as usual with or without a fever. - Because zonisamide can cause hematological complications, patients should contact their physician immediately if they develop a fever, sore throat, oral ulcers, or easy bruising. - Suicidal Thinking and Behavior - Patients, their caregivers, and families should be counseled that AEDs, including zonisamide capsules, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. - Patients should contact their physician immediately if they develop fast breathing, fatigue/tiredness, loss of appetite, or irregular heart beat or palpitations (possible manifestations of metabolic acidosis). - As with other AEDs, patients should contact their physician if they intend to become pregnant or are pregnant during zonisamide therapy. Patients should notify their physician if they intend to breast-feed or are breast-feeding an infant. - Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334. # Precautions with Alcohol - Alcohol-Zonisamide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - ZONISAMIDE ®[6] # Look-Alike Drug Names - Zonegran® — SINEquan®[7] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Zonisamide
8d56e8f181d76495d365c1977e3d66feb4f6c34b	wikidoc	Zygomycota	Zygomycota Zygomycota, or zygote fungi, are a phylum of fungi. The name of the phylum comes from zygosporangia, resistant spherical spores formed during sexual reproduction. Approximately 600 species of zygomycetes are known. They are mostly terrestrial in habitat, living in soil or on decaying plant or animal material. Zygomycete hyphae may be coenocytic, forming septa only where gametes are formed or to wall off dead hyphae. # Reproduction A common example of a zygomycete is ] (Rhizopus stolonifer), a member of the Mucorales. It spreads over the surface of bread and other food sources, sending hyphae inward to absorb nutrients. In its asexual phase it develops bulbous black sporangia at the tips of upright hyphae, each containing hundreds of haploid spores. If the mycelia of complementary mating types are present, the fungus reproduces sexually and produces zygosporangia. Zygosporangia are typically thick-walled, highly resilient to environmental hardships, and are metabolically inert. When conditions improve, however, they germinate to produce a sporangium or vegetative hyphae. Some zygomycetes disperse their spores in a more precise manner than simply allowing them to drift aimlessly on air currents. Pilobolus, a fungus which grows on animal dung, bends its sporangiophores towards light with the help of a light sensitive pigment and then "fires" them with an explosive squirt of high-pressure cytoplasm. Sporangia can be launched as far as 2m, placing them far away from the dung and hopefully on vegetation which will be eaten by an herbivore, eventually to be deposited with dung elsewhere. Different mechanisms for forcible spore discharge have evolved among members of the zygomycete order Entomophthorales. # Phylogeny The Zygomycota are generally placed near the base of the fungal phylogenetic tree, having diverged from other fungi after chytrids. Molecular phylogenetics reveal that they form a polyphyletic group and could see a split into several new phyla. The order Glomales was removed in 2001 and elevated to Division Glomeromycota due their lack of zygospore formation, their mycorrhizal habit, and lack of DNA sequence homology. # Notes - ↑ Hibbett, D.S.; et al. (2007). "A higher level phylogenetic classification of the Fungi". Mycol. Res. 111 (5): 509–547. doi:doi:10.1016/j.mycres.2007.03.004 Check \|doi= value (help). Unknown parameter \|month= ignored (help)CS1 maint: Explicit use of et al. (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}	Zygomycota Zygomycota, or zygote fungi, are a phylum of fungi. The name of the phylum comes from zygosporangia, resistant spherical spores formed during sexual reproduction. Approximately 600 species of zygomycetes are known. They are mostly terrestrial in habitat, living in soil or on decaying plant or animal material. Zygomycete hyphae may be coenocytic, forming septa only where gametes are formed or to wall off dead hyphae. # Reproduction A common example of a zygomycete is [{black bread mold]] (Rhizopus stolonifer), a member of the Mucorales. It spreads over the surface of bread and other food sources, sending hyphae inward to absorb nutrients. In its asexual phase it develops bulbous black sporangia at the tips of upright hyphae, each containing hundreds of haploid spores. If the mycelia of complementary mating types are present, the fungus reproduces sexually and produces zygosporangia. Zygosporangia are typically thick-walled, highly resilient to environmental hardships, and are metabolically inert. When conditions improve, however, they germinate to produce a sporangium or vegetative hyphae. Some zygomycetes disperse their spores in a more precise manner than simply allowing them to drift aimlessly on air currents. Pilobolus, a fungus which grows on animal dung, bends its sporangiophores towards light with the help of a light sensitive pigment and then "fires" them with an explosive squirt of high-pressure cytoplasm. Sporangia can be launched as far as 2m, placing them far away from the dung and hopefully on vegetation which will be eaten by an herbivore, eventually to be deposited with dung elsewhere. Different mechanisms for forcible spore discharge have evolved among members of the zygomycete order Entomophthorales. # Phylogeny The Zygomycota are generally placed near the base of the fungal phylogenetic tree, having diverged from other fungi after chytrids. Molecular phylogenetics reveal that they form a polyphyletic group and could see a split into several new phyla.[1] The order Glomales was removed in 2001 and elevated to Division Glomeromycota due their lack of zygospore formation, their mycorrhizal habit, and lack of DNA sequence homology. # Notes - ↑ Hibbett, D.S.; et al. (2007). "A higher level phylogenetic classification of the Fungi". Mycol. Res. 111 (5): 509–547. doi:doi:10.1016/j.mycres.2007.03.004 Check \|doi= value (help). Unknown parameter \|month= ignored (help)CS1 maint: Explicit use of et al. (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} # External Links - Zygomycota at the Tree of Life Web Project - Zygomycetes.org de:Jochpilze eo:Zigomicetoj he:זוגניות it:Zygomycota nl:Lagere schimmels wa:Zigomicete Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Zygomycetes
85b2caf58cef5397a52cf14646bee20c05bdbbe3	wikidoc	Élan vital	Élan vital Élan vital, coined by French philosopher Henri Bergson in his 1907 book Creative Evolution, was translated in the English edition as "vital impetus", but is usually translated by his detractors as "vital force". It is a hypothetical explanation for evolution and development of organisms, which Bergson linked closely with consciousness. It was the existence of this vital force, which made people at that time believe that they were not able to synthesize organic molecules. It was believed by others that this essence (élan vital) could be harvested and embedded into an inanimate substance and activated with electricity, perhaps taking literally another of Bergson's metaphorical descriptions, the "current of life". The British biologist Julian Huxley remarked that Bergson’s élan vital is no better an explanation of life than is explaining the operation of a railway engine by its élan locomotif ("locomotive driving force"). However, Huxley himself subscribed to the notion of an élan vital as may be seen from the following excerpt: "When I was just last in New York, I went for a walk, leaving Fifth Avenue and the Business section behind me, into the crowded streets near the Bowery. And while I was there, I had a sudden feeling of relief and confidence. There was Bergson’s élan vital—there was assimilation causing life to exert as much pressure, though embodied here in the shape of men, as it has ever done in the earliest year of evolution: there was the driving force of progress" A distant precursor of Bergson can be found in the work of the pre-Christian Stoic philosopher Posidonius, who postulated a "vital force" emanated by the sun to all living creatures on the earth's surface. The concept of élan vital is very similar to Schopenhauer's concept of the will-to-live. The French philosopher Gilles Deleuze attempted to recoup the novelty of Bergson's idea in his book Bergsonism, though the term itself underwent substantial changes by Deleuze. No longer considered a mystical, elusive force acting on brute matter, as it was in the vitalist debates of the late 19th century, élan vital in Deleuze's hands denotes a substance in which the distinction between organic and inorganic matter is indiscernible, and the emergence of life undecidable. Some movie critics have likened Bergsonian theory of the élan vital as an influence on George Lucas or as a source on which he could have possibly based his ideas of The Force in his Star Wars saga. The way Obi-wan Kenobi explains The Force to Luke in the 1977 movie is particularly fitting as it is the almost heterodox vison of The Force mantained by Obi-wan's mentor Qui-Gon Jinn. ast:Élan vital de:Élan vital sk:Élan vital	Élan vital Élan vital, coined by French philosopher Henri Bergson in his 1907 book Creative Evolution, was translated in the English edition as "vital impetus", but is usually translated by his detractors as "vital force". It is a hypothetical explanation for evolution and development of organisms, which Bergson linked closely with consciousness. It was the existence of this vital force, which made people at that time believe that they were not able to synthesize organic molecules. It was believed by others that this essence (élan vital) could be harvested and embedded into an inanimate substance and activated with electricity, perhaps taking literally another of Bergson's metaphorical descriptions, the "current of life". The British biologist Julian Huxley remarked that Bergson’s élan vital is no better an explanation of life than is explaining the operation of a railway engine by its élan locomotif ("locomotive driving force"). However, Huxley himself subscribed to the notion of an élan vital as may be seen from the following excerpt: "When I was just last in New York, I went for a walk, leaving Fifth Avenue and the Business section behind me, into the crowded streets near the Bowery. And while I was there, I had a sudden feeling of relief and confidence. There was Bergson’s élan vital—there was assimilation causing life to exert as much pressure, though embodied here in the shape of men, as it has ever done in the earliest year of evolution: there was the driving force of progress" A distant precursor of Bergson can be found in the work of the pre-Christian Stoic philosopher Posidonius, who postulated a "vital force" emanated by the sun to all living creatures on the earth's surface. The concept of élan vital is very similar to Schopenhauer's concept of the will-to-live. The French philosopher Gilles Deleuze attempted to recoup the novelty of Bergson's idea in his book Bergsonism, though the term itself underwent substantial changes by Deleuze. No longer considered a mystical, elusive force acting on brute matter, as it was in the vitalist debates of the late 19th century, élan vital in Deleuze's hands denotes a substance in which the distinction between organic and inorganic matter is indiscernible, and the emergence of life undecidable. Some movie critics have likened Bergsonian theory of the élan vital as an influence on George Lucas or as a source on which he could have possibly based his ideas of The Force in his Star Wars saga. The way Obi-wan Kenobi explains The Force to Luke in the 1977 movie is particularly fitting as it is the almost heterodox vison of The Force mantained by Obi-wan's mentor Qui-Gon Jinn. ast:Élan vital de:Élan vital sk:Élan vital Template:WikiDoc Sources	https://www.wikidoc.org/index.php/%C3%89lan_vital
823edac487910dc09ce691102eee76069aa6d096	wikidoc	Pregnancy	Pregnancy # Overview Pregnancy is the carrying of one or more offspring, known as a fetus or embryo, inside the body of a female mammal such as a human. In a pregnancy, there can be multiple gestations (for example, in the case of twins or triplets). Human pregnancy is the most studied of all mammalian pregnancies, and the medical field that deals with pregnancy is called obstetrics. Childbirth usually occurs about 38 weeks from fertilization, i.e. approximately 40 weeks from the start of the last menstruation. Thus, pregnancy lasts about nine months, although the exact definition of the English word “pregnancy” is a subject of controversy. One scientific term for the state of pregnancy is gravid, and a pregnant female is sometimes referred to as a gravida. Both words are rarely used in common speech. The term embryo is used to describe the developing human during the initial weeks, and the term fetus is used from about two months of development until birth. A woman who is pregnant for the first time is known medically as a primigravida or "gravida 1", while a woman who has never been pregnant is known as "gravida 0". Similarly, the terms "para 0", "para 1" and so on are used for the number of times a woman has given birth. In many societies' medical and legal definitions, human pregnancy is somewhat arbitrarily divided into three trimester periods, as a means to simplify reference to the different stages of prenatal development. The first trimester carries the highest risk of miscarriage (natural death of embryo or fetus). During the second trimester, the development of the fetus can be more easily monitored and diagnosed. The beginning of the third trimester often approximates the point of viability, or the ability of the fetus to survive, with or without medical help, outside of the uterus. # Determining the Start of Pregnancy and Predicting Date of Birth Before pregnancy begins, a female oocyte (egg) must join with a spermatozoon in a process referred to in medicine as "fertilization", or commonly known as "conception" (though the definition of the English word "conception" is somewhat controversial). Fertilization usually occurs through the act of sexual intercourse, in which a spermatozoon penetrates and fertilizes an egg. However, the advent of artificial insemination has made it possible for women to become pregnant if pre-existing medical conditions in either the woman or the man make fertilization through sexual intercourse difficult, or if a woman chooses to become pregnant without a male partner. Though pregnancy begins at implantation, it is often convenient to date from the first day of a woman's last menstrual period, sometimes abbreviated "LMP". This is used to calculate the expected date of delivery (EDD). Traditionally a human pregnancy is considered to last approximately 40 weeks (280 days) from the LMP, or 38 weeks (266 days) from the date of fertilization. The 38 weeks of gestation is 10 lunar months, i.e. 27.3 days/lunar-month x 10 = 273 days. In the more familiar Gregorian calendar, the 40 weeks dating from the LMP is equivalent to a little more than nine months and six days. This forms the basis of Naegele's rule of approximating the EDD, although improvements to Naegele's rule have been suggested. A pregnancy is considered to have reached term between 37 and 43 weeks from the beginning of the last menstruation. Babies born before the 37 week mark are considered premature, while babies born after the 43 week mark are considered postmature. Though these are the averages, the actual length of pregnancy depends on various factors. For example, the first pregnancy tends to last longer than subsequent pregnancies. Fewer than 10% of births occur on the due date; 50% of births are within a week of the due date, and almost 90% within two weeks. The due date is typically calculated as 40 weeks from the last menstrual period. An accurate date of fertilization is important, because it is used in calculating the results of various prenatal tests (for example, in the triple test). A decision may be made to induce labor if a fetus is perceived to be overdue. Due dates are only a rough estimate, and the process of accurately dating a pregnancy is complicated by the fact that not all women have 28 day menstrual cycles, or ovulate on the 14th day following their last menstrual period. EDD may also be calculated from sonogram measurement of the fetus. This method is slightly more accurate than methods based on LMP. Confinement, the beginning of labor, begins on the day predicted by LMP 3.6% of the time and on the day predicted by sonography 4.3% of the time. The beginning of pregnancy may be detected in a number of ways, including various pregnancy tests which detect hormones generated by the newly-formed placenta. Clinical blood and urine tests can detect pregnancy soon after implantation, which is as early as 6-8 days after fertilization. Home pregnancy tests are personal urine tests, which normally cannot detect a pregnancy until at least 12-15 days after fertilization. Both clinical and home tests can only detect the state of pregnancy, and cannot detect its age. In the post-implantation phase, the blastocyst secretes a hormone named human chorionic gonadotropin which in turn, stimulates the corpus luteum in the woman's ovary to continue producing progesterone. This acts to maintain the lining of the uterus so that the embryo will continue to be nourished. The glands in the lining of the uterus will swell in response to the blastocyst, and capillaries will be stimulated to grow in that region. This allows the blastocyst to receive vital nutrients from the woman. An early sonograph can determine the age of the pregnancy fairly accurately. In practice, doctors typically express the age of a pregnancy (i.e. an "age" for an embryo) in terms of "menstrual date" based on the first day of a woman's last menstrual period, as the woman reports it. Unless a woman's recent sexual activity has been limited, the exact date of fertilization is unknown. Absent symptoms such as morning sickness, often the only visible sign of a pregnancy is an interruption of her normal monthly menstruation cycle, (i.e. a "late period"). Hence, the "menstrual date" is simply a common educated estimate for the age of a fetus, which is an average of two weeks later than the first day of the woman's last menstrual period. The term "conception date" may sometimes be used when that date is more certain, though even medical professionals can be imprecise with their use of the two distinct terms. The due date can be calculated by using Naegele's rule. # Medical signs A number of medical signs are associated with pregnancy. ### Early signs These signs typically appear, if at all, within the first few weeks after conception. Although not all of these signs are universally present, nor are all of them diagnostic by themselves, taken together they may be useful to make a presumptive diagnosis of pregnancy. - Presence of human chorionic gonadotropin (hCG) in the blood and urine, detectable by laboratory or home testing; this is the most reliable early sign of pregnancy - Missed menstrual period - Implantation bleeding, light spotting that occurs at implantation of the embryo in the uterus, in the third or fourth week after LMP - Increased basal body temperature sustained for over two weeks after ovulation - Chadwick's sign, a darkening of the cervix, vagina, and vulva - Goodell's sign, a softening of the vaginal portion of the cervix - Hegar's sign, a softening of the cervical isthmus ### Later signs - Linea nigra, a darkening of the skin in a vertical line on the abdomen, caused by hyperpigmentation resulting from hormonal changes; it usually appears around the middle of pregnancy - Steadily increasing abdominal swelling, the most visible sign of pregnancy # Symptoms Physical symptoms of pregnancy vary. Of the symptoms listed, not all will occur for every woman, and individuals may well experience different symptoms during different pregnancies. The following is a list of the most common symptoms. - Breasts may feel swollen, sore, or tender. - Pregnancy sickness may cause nausea and vomiting. It is also known as morning sickness, although it may occur at any time of the day or night. - The sense of smell may be heightened. - Cravings for and aversions to certain foods may be experienced. Food aversions may exacerbate pregnancy symptoms. - Fatigue is a common symptom in early pregnancy. It results from increased progesterone and may be compounded by increased blood volume, which can result in lower blood pressure and lower blood sugar. - Dizziness and fainting may be experienced, particularly after standing up quickly. These symptoms are caused by lower blood pressure and lower blood sugar. - Frequent mild headaches may occur, caused by increased blood circulation - Constipation is a common symptom caused by increased progesterone, which slows the activity of the large intestine. - Increased urination is caused by pressure of the growing uterus against the urinary bladder. - Emotional lability, including dysphoria, crying spells, and mood swings. These mood changes are triggered by the effect of pregnancy hormones on mood regulation in the brain. Other symptoms may be experienced specifically during the later stages, such as: - Lower backache. Balance and ease of walking may be affected. - Many women will get flatulent and gassy. - Some may have difficulty in walking and balance. - Some women may experience haemorrhoids and rectal irritation. - Some women report hair loss, others have more body or "facial" hair. - Sensitivity in teeth, higher risk for gum disease. Contact lens/spectacle prescriptions may be affected. Some women during pregnancy experience mental disturbances more severe than typical mood swings. Psychological stress during pregnancy is associated with an increase in other pregnancy symptoms. # Sexuality During Pregnancy Finally, one popular but exaggerated symptom is an increase in sexual urgency, mostly between the 5th and 8th month, when hormonal changes and physical discomfort such as nausea disappear. Some pregnant women reported a decrease in sexual interest, due to prolonged discomfort or psychological aspects such as not feeling "attractive" to pursue sexual activity, meaning that being pregnant affects their self-sense of beauty. Until the mid 20th century, it was considered a socio-moral "taboo" action for pregnant women to engage in sexual activities. However, that perception has changed today. Sex during pregnancy is a low-risk behavior except when the physician advises that sexual intercourse be avoided, which may, in some pregnancies, lead to serious pregnancy complications or health issues such as a high-risk for premature labor or a ruptured uterus. Such a decision may be based upon a history of difficulties in a previous childbirth. Some psychological research studies in the 1980s and '90s contend that it is useful for pregnant women with love partners to continue to have sexual activity. This is because studies find that those who have sex more than once a week feel less emotionally tense and more confident in the perception of their appearances. Some studies also suggest that they have less painful or quickened labors, which some physicians believe might be because sexual intercourse serves as a type of pelvic exercise. # Terminology There are likewise finer distinctions between the concepts of fertilization and the actual state of pregnancy, which starts with implantation. In a normal pregnancy, the fertilization of the egg usually will have occurred in the Fallopian tubes or in the uterus. (Often, an egg may become fertilized yet fail to become implanted in the uterus.) If the pregnancy is the result of in-vitro fertilization, the fertilization will have occurred in a Petri dish, after which pregnancy begins when one or more zygotes implant after being transferred by a physician into the woman's uterus. In the context of political debates regarding a proper definition of life, the terminology of pregnancy can be confusing. The medically and politically neutral term which remains is simply "pregnancy," though this can be problematic as it only refers indirectly to the embryo or fetus. In the context of personal treatment, bedside manner generally dictates that doctors make sparse use of clinical language like "fetus" and "embryo," and instead simply use the word "baby." # Detection The early stages of pregnancy are often discovered by using a pregnancy test, as soon as 48 hours after fertilization using sophisticated testing methods, but not until six to twelve days after fertilization using more typical methods. Pregnancy tests typically detect the presence of human chorionic gonadotropin. # Timeline of a Typical Pregnancy Pregnancy is typically broken into three periods, or trimesters, each of about three months. While there are no hard and fast rules, these distinctions are useful in describing the changes that take place over time. ## First Trimester Traditionally, doctors have measured pregnancy from a number of convenient points, including the day of last menstruation, ovulation, fertilization, implantation and chemical detection. In medicine, pregnancy is often defined as beginning when the developing embryo becomes implanted into the endometrial lining of a woman's uterus. In some cases where complications may have arisen, the fertilized egg might implant itself in the fallopian tubes or the cervix, causing an ectopic pregnancy. Most pregnant women do not have any specific signs or symptoms of implantation, although it is not uncommon to experience light bleeding at implantation. Some women will also experience cramping during their first trimester. This is usually of no concern unless there is spotting or bleeding as well. The outer layers of the embryo grow and form a placenta, for the purpose of receiving essential nutrients through the uterine wall, or endometrium. The umbilical cord in a newborn child consists of the remnants of the connection to the placenta. The developing embryo undergoes tremendous growth and changes during the process of embryonic and fetal development. Morning sickness afflicts about seventy percent of all pregnant women, typically only in the first trimester. Most miscarriages occur during this period. ## Second Trimester Months 4 through 6 of the pregnancy are called the second trimester. Most women feel more energized in this period, and begin to put on weight as the symptoms of morning sickness subside and eventually fade away. Although the fetus begins moving and takes a recognizable human shape during the first trimester, it is not until the second trimester that movement of the fetus, often referred to as "quickening", can be felt. This typically happens by the fourth month. The placenta is now fully functioning and the fetus is making insulin and urinating. The teeth are now formed inside the fetus's gums and the reproductive organs can be recognized, and can distinguish the fetus as male or female. ## Third Trimester Final weight gain takes place, and the fetus begins to move regularly. The woman's navel will sometimes become convex, "popping" out, due to her expanding abdomen. This period of her pregnancy can be uncomfortable, causing symptoms like weak bladder control and back-ache. Movement of the fetus becomes stronger and more frequent and via improved brain, eye, and muscle function the fetus is prepared for ex utero viability. The woman can feel the fetus "rolling" and it may cause pain or discomfort when it is near the woman's ribs. It is during this time that a baby born prematurely may survive. The use of modern medical intensive care technology has greatly increased the probability of premature babies living, and has pushed back the boundary of viability to much earlier dates than would be possible without assistance. In spite of these developments, premature birth remains a major threat to the fetus, and may result in ill-health in later life, even if the baby survives. # Prenatal Development and Sonograph Images Prenatal development is divided into two primary biological stages. The first is the embryonic stage, which lasts for about two months. At this point, the fetal stage begins. At the beginning of the fetal stage, the risk of miscarriage decreases sharply, all major structures including hands, feet, head, brain, and other organs are present, and they continue to grow and develop. When the fetal stage commences, a fetus is typically about 30 mm (1.2 inches) in length, and the heart can be seen beating via sonograph; the fetus bends the head, and also makes general movements and startles that involve the whole body. Brain stem activity has been detected as early as 54 days after conception, and the first measurable signs of EEG activity occur in the 12th week. Some fingerprint formation occurs from the beginning of the fetal stage. - Embryo at 4 weeks after fertilization - Fetus at 8 weeks after fertilization - Fetus at 18 weeks after fertilization - Fetus at 38 weeks after fertilization - Relative size in 1st Month (simplified illustration) - Relative size in 3rd Month (simplified illustration) - Relative size in 5th Month (simplified illustration) - Relative size in 9th Month (simplified illustration) - 7 weeks - 13 weeks - 17 weeks - 20 weeks # Food and Nutrition During Pregnancy It is important for a pregnant woman to eat a healthy diet. Unless she has a specific health problem (e.g., diabetes mellitus or edema) balancing carbohydrates, fat, and proteins; and eating a variety of foods, including dairy products and several fruits and vegetables all contribute to a healthy pregnancy. A pregnant woman may choose to consult her obstetrician for specific advice. Some specific nutritional needs for pregnancy include: Folic acid (also called folate or Vitamin B9) is strongly needed at the start of pregnancy, and even before conception. Folic acid is needed for the closing of fetus' neural tube. It thus helps prevent spina bifida, a very serious birth defect. Folates (from folia, leaf) are abundant in spinach (fresh, frozen or canned), and are also found in green vegetables, salads, melon, hummus, and eggs. In the United States and Canada, most wheat products (flour, noodles) are supplemented with folic acid. Calcium and iron are particularly needed by the rapidly growing fetus. Pregnant women should eat enough dairy products (for calcium) and red meat (for iron) if they are not lactose intolerant or vegetarian. Women who do not eat dairy or meat can obtain calcium and iron from fortified soy milk and juice, soybeans, and certain leafy greens. Care providers may prescribe iron pills if pregnant women develop iron deficiency anemia. Calcium is effective only if women also obtain enough Vitamin D. The best way to get vitamin D is to sunbathe each day for 10–15 minutes. Salmon and fatty fishes are also good sources of vitamin D. Fluoride is critical for development of teeth by increasing binding of calcium, strengthening the enamel. If water or salt does not contain fluoride, supplements are recommended during the third trimester. Many municipalities and water treatment plants add fluoride to the water. Fat from salmon, trout, tuna, herring, sardine, mackerel, and some chicken eggs contain long-chain omega-3 (n-3) fatty acids that are needed to build neuron membranes. Thus fatty fish intake during pregnancy may provide nutrition for proper brain and retina development of the fetus. However, large fish such as tuna and swordfish may contain too much toxic mercury, and one should balance risks with benefits: fish two or three times a week seems to bring enough good fat, but not too much mercury. Omega-3 fatty acids are also present in walnuts, flaxseed, and marine algae. Dangerous bacteria or parasites may contaminate foods, particularly listeria and toxoplasma, toxoplasmosis agent. To avoid those two hazards, hygiene rules should be strictly adhered to: carefully wash fruits and raw vegetables; over-cook remainders, meat and processed meat; avoid raw-milk cheeses (listeria); try to avoid contact with cat feces (toxoplasma); clean the fridge often with diluted chlorine (then rinse). # Medical Aspects of Pregnancy Diagnostic criteria are: Women who has a menstrual cycles and is sexually active, a period delayed by a few days or weeks is suggestive of pregnancy; elevated B-hcG to around 100,000 mIU/mL by 10 weeks of gestation. Prenatal medical care is of recognized value throughout the developed world. Various vitamins or supplements are recognized as beneficial during pregnancy. Prenatal multivitamins as well as folic acid and the choline available from lecithin have either government approval or published studies supporting their use. Folic acid reduces birth defects. Prenatal Choline derivable from lecithin improves the performance of rats on mental tests throughout a rat's entire life. Omega 3 fatty acids support the mental and visual development of infants and they are also beneficial postpartum. # Birth Childbirth is the process by which an infant is born. It is considered by many to be the beginning of a person's life, and age is defined relative to this event in most cultures. A woman is considered to be in labor when she begins experiencing regular uterine contractions, accompanied by changes of her cervix — primarily effacement and dilation. While childbirth is widely experienced as painful, some women do report painless labors, while others find that concentrating on the birth helps to quicken labor and lessen the sensations. Most births are successful vaginal births, but sometimes complications arise and a woman may undergo a caesarean section. While some caesarean sections are necessary, as in the case of cord prolapse, there is dispute as to whether the procedure is used too frequently. Some women choose to have a caesarean section. During the time immediately after birth, both the mother and the baby are hormonally cued to bond, the mother through the release of oxytocin, a hormone also released during breastfeeding. # Postnatal Period For topics following on from a successful pregnancy and birth, see: - Postpartum depression - Infant Formula feeding - Breastfeeding - Child development # Medical Disorders in Pregnancy Most potentially serious problems can be anticipated and treated effectively. However, problems sometimes develop suddenly and unexpectedly. Regular visits to a doctor or midwife during pregnancy make anticipation of problems possible and improve the chances of having a healthy baby. Approximately 4 million births occur in the United States each year. A significant proportion of these are complicated by one or more medical disorders. A small percentage of pregnant women and new mothers have AIDS, cancer, heart disease, lung disease, physical disabilities, diabetes and psychiatric disorders like depression. Two decades ago, many medical disorders were contra-indications to pregnancy. Advances in obstetrics, neonatology, obstetric anesthesiology, midwifery and medicine have increased the expectation that pregnancy will result in an excellent outcome for both the woman and the fetus, despite most of these conditions. Certain medications deemed harmless to the fetus may be highly necessary to the welfare and benefit of the woman, especially if she is pregnant, as some conditions are aggravated by pregnancy. A rare but possibly under-diagnosed disorder in pregnancy is Hyperemesis gravidarum, a condition in which morning sickness is constant and extreme, resulting in dehydration and malnutrition, due to frequent vomiting. A common yet under-diaganosed syndrome is "Pelvic girdle pain" (PGP). One in 35 women will experience some degree of PGP during their pregnancy. Symptoms can begin as early 12 weeks into the pregnancy. This muscloskeletal syndrome can effect any of the three pelvic joints. The female experiences a reduced tolerance for weightbearing activities ranging from being midly to severely disabled. Pregnancy must be differentiated from other causes of irregular menses and hirsutism. # Terms and Definitions ## Technical ## Euphemisms and Colloquialisms There are a number of euphemisms and colloquialisms for pregnancy, ranging from polite ("mother to be", "with child", "expecting" and "full") to crude ("up the duff" - UK, "knocked up" and "preggo" - US, and "down the well" - Australia), and even comical ("bun in the oven"). # Regional Customs In Korea, China, Japan and Vietnam, age is measured starting from conception to acknowledge that the fetus exists within the woman's body before it is born. Therefore, a newborn baby is considered to be one year old, although gestation is approximately 9 months. The ancient Mayan calendar of 276 days possibly originated from the human gestational cycle, or to indicate the world was created as slowly as a fetus develops. # Related Chapters - Abortion - Anticoagulation in pregnancy - Breastfeeding - Beginning of pregnancy controversy - Belly cast - Birth control - Birth defect - Cesarean section - Childbirth and labor - Chorionic villus sampling - Complications of pregnancy - Contraception - Couvade - Doula - Ectogenesis - False pregnancy - Father - Fertility - Fetal development - Fetal alcohol syndrome - Genetic counseling - Health care issues in pregnancy - In-vitro fertilization, also known as test-tube babies - Lamaze - Low birth weight paradox - Maternal health - Male pregnancy - Melasma - Men's role in childbirth - Mental illness accompanied with pregnancy - Midwifery - Miscarriage - Natural childbirth - Nutrition and pregnancy - Obstetrics - Parent - Pelvic girdle pain during pregnancy or postpartum - Pica (craving) - Pre-eclampsia - Pregnancy discrimination - Pregnancy over age 50 - Pregnant patients' rights - Prenatal care - Sex during pregnancy - Simulated pregnancy - Spermatozoon - Sperm donor and egg donor - Stretch marks - Surrogate mother - Taboos concerning pregnancy in many cultures - Teenage pregnancy - Twin and Multiple birth - Unassisted childbirth - Wrongful abortion - Youngest birth mothers	Pregnancy Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Pregnancy is the carrying of one or more offspring, known as a fetus or embryo, inside the body of a female mammal such as a human. In a pregnancy, there can be multiple gestations (for example, in the case of twins or triplets). Human pregnancy is the most studied of all mammalian pregnancies, and the medical field that deals with pregnancy is called obstetrics. Childbirth usually occurs about 38 weeks from fertilization, i.e. approximately 40 weeks from the start of the last menstruation. Thus, pregnancy lasts about nine months, although the exact definition of the English word “pregnancy” is a subject of controversy. One scientific term for the state of pregnancy is gravid, and a pregnant female is sometimes referred to as a gravida. Both words are rarely used in common speech. The term embryo is used to describe the developing human during the initial weeks, and the term fetus is used from about two months of development until birth. A woman who is pregnant for the first time is known medically as a primigravida or "gravida 1", while a woman who has never been pregnant is known as "gravida 0". Similarly, the terms "para 0", "para 1" and so on are used for the number of times a woman has given birth. In many societies' medical and legal definitions, human pregnancy is somewhat arbitrarily divided into three trimester periods, as a means to simplify reference to the different stages of prenatal development. The first trimester carries the highest risk of miscarriage (natural death of embryo or fetus). During the second trimester, the development of the fetus can be more easily monitored and diagnosed. The beginning of the third trimester often approximates the point of viability, or the ability of the fetus to survive, with or without medical help, outside of the uterus. # Determining the Start of Pregnancy and Predicting Date of Birth Before pregnancy begins, a female oocyte (egg) must join with a spermatozoon in a process referred to in medicine as "fertilization", or commonly known as "conception" (though the definition of the English word "conception" is somewhat controversial). Fertilization usually occurs through the act of sexual intercourse, in which a spermatozoon penetrates and fertilizes an egg. However, the advent of artificial insemination has made it possible for women to become pregnant if pre-existing medical conditions in either the woman or the man make fertilization through sexual intercourse difficult, or if a woman chooses to become pregnant without a male partner. Though pregnancy begins at implantation, it is often convenient to date from the first day of a woman's last menstrual period, sometimes abbreviated "LMP". This is used to calculate the expected date of delivery (EDD). Traditionally a human pregnancy is considered to last approximately 40 weeks (280 days) from the LMP, or 38 weeks (266 days) from the date of fertilization. The 38 weeks of gestation is 10 lunar months, i.e. 27.3 days/lunar-month x 10 = 273 days. In the more familiar Gregorian calendar, the 40 weeks dating from the LMP is equivalent to a little more than nine months and six days. This forms the basis of Naegele's rule of approximating the EDD, although improvements to Naegele's rule have been suggested.[1] A pregnancy is considered to have reached term between 37 and 43 weeks from the beginning of the last menstruation. Babies born before the 37 week mark are considered premature, while babies born after the 43 week mark are considered postmature. Though these are the averages, the actual length of pregnancy depends on various factors. For example, the first pregnancy tends to last longer than subsequent pregnancies. Fewer than 10% of births occur on the due date; 50% of births are within a week of the due date, and almost 90% within two weeks. The due date is typically calculated as 40 weeks from the last menstrual period. An accurate date of fertilization is important, because it is used in calculating the results of various prenatal tests (for example, in the triple test). A decision may be made to induce labor if a fetus is perceived to be overdue. Due dates are only a rough estimate, and the process of accurately dating a pregnancy is complicated by the fact that not all women have 28 day menstrual cycles, or ovulate on the 14th day following their last menstrual period. EDD may also be calculated from sonogram measurement of the fetus. This method is slightly more accurate than methods based on LMP.[2] Confinement, the beginning of labor, begins on the day predicted by LMP 3.6% of the time and on the day predicted by sonography 4.3% of the time.[3] The beginning of pregnancy may be detected in a number of ways, including various pregnancy tests which detect hormones generated by the newly-formed placenta. Clinical blood and urine tests can detect pregnancy soon after implantation, which is as early as 6-8 days after fertilization. Home pregnancy tests are personal urine tests, which normally cannot detect a pregnancy until at least 12-15 days after fertilization. Both clinical and home tests can only detect the state of pregnancy, and cannot detect its age. In the post-implantation phase, the blastocyst secretes a hormone named human chorionic gonadotropin which in turn, stimulates the corpus luteum in the woman's ovary to continue producing progesterone. This acts to maintain the lining of the uterus so that the embryo will continue to be nourished. The glands in the lining of the uterus will swell in response to the blastocyst, and capillaries will be stimulated to grow in that region. This allows the blastocyst to receive vital nutrients from the woman. An early sonograph can determine the age of the pregnancy fairly accurately. In practice, doctors typically express the age of a pregnancy (i.e. an "age" for an embryo) in terms of "menstrual date" based on the first day of a woman's last menstrual period, as the woman reports it. Unless a woman's recent sexual activity has been limited, the exact date of fertilization is unknown. Absent symptoms such as morning sickness, often the only visible sign of a pregnancy is an interruption of her normal monthly menstruation cycle, (i.e. a "late period"). Hence, the "menstrual date" is simply a common educated estimate for the age of a fetus, which is an average of two weeks later than the first day of the woman's last menstrual period. The term "conception date" may sometimes be used when that date is more certain, though even medical professionals can be imprecise with their use of the two distinct terms. The due date can be calculated by using Naegele's rule. # Medical signs A number of medical signs are associated with pregnancy.[4] [5] ### Early signs These signs typically appear, if at all, within the first few weeks after conception. Although not all of these signs are universally present, nor are all of them diagnostic by themselves, taken together they may be useful to make a presumptive diagnosis of pregnancy. - Presence of human chorionic gonadotropin (hCG) in the blood and urine, detectable by laboratory or home testing; this is the most reliable early sign of pregnancy - Missed menstrual period - Implantation bleeding, light spotting that occurs at implantation of the embryo in the uterus, in the third or fourth week after LMP - Increased basal body temperature sustained for over two weeks after ovulation - Chadwick's sign, a darkening of the cervix, vagina, and vulva - Goodell's sign, a softening of the vaginal portion of the cervix - Hegar's sign, a softening of the cervical isthmus ### Later signs - Linea nigra, a darkening of the skin in a vertical line on the abdomen, caused by hyperpigmentation resulting from hormonal changes; it usually appears around the middle of pregnancy - Steadily increasing abdominal swelling, the most visible sign of pregnancy # Symptoms Physical symptoms of pregnancy vary. Of the symptoms listed, not all will occur for every woman, and individuals may well experience different symptoms during different pregnancies. The following is a list of the most common symptoms.[4] - Breasts may feel swollen, sore, or tender. - Pregnancy sickness may cause nausea and vomiting. It is also known as morning sickness, although it may occur at any time of the day or night. - The sense of smell may be heightened. - Cravings for and aversions to certain foods may be experienced. Food aversions may exacerbate pregnancy symptoms. - Fatigue is a common symptom in early pregnancy. It results from increased progesterone and may be compounded by increased blood volume, which can result in lower blood pressure and lower blood sugar. - Dizziness and fainting may be experienced, particularly after standing up quickly. These symptoms are caused by lower blood pressure and lower blood sugar. - Frequent mild headaches may occur, caused by increased blood circulation - Constipation is a common symptom caused by increased progesterone, which slows the activity of the large intestine. - Increased urination is caused by pressure of the growing uterus against the urinary bladder. - Emotional lability, including dysphoria, crying spells, and mood swings. These mood changes are triggered by the effect of pregnancy hormones on mood regulation in the brain. Other symptoms may be experienced specifically during the later stages, such as: - Lower backache. Balance and ease of walking may be affected. - Many women will get flatulent and gassy. - Some may have difficulty in walking and balance. - Some women may experience haemorrhoids and rectal irritation. - Some women report hair loss, others have more body or "facial" hair. - Sensitivity in teeth, higher risk for gum disease. Contact lens/spectacle prescriptions may be affected. Some women during pregnancy experience mental disturbances more severe than typical mood swings. Psychological stress during pregnancy is associated with an increase in other pregnancy symptoms.[6] # Sexuality During Pregnancy Finally, one popular but exaggerated symptom is an increase in sexual urgency, mostly between the 5th and 8th month, when hormonal changes and physical discomfort such as nausea disappear. Some pregnant women reported a decrease in sexual interest, due to prolonged discomfort or psychological aspects such as not feeling "attractive" to pursue sexual activity, meaning that being pregnant affects their self-sense of beauty. Until the mid 20th century, it was considered a socio-moral "taboo" action for pregnant women to engage in sexual activities. However, that perception has changed today. Sex during pregnancy is a low-risk behavior except when the physician advises that sexual intercourse be avoided, which may, in some pregnancies, lead to serious pregnancy complications or health issues such as a high-risk for premature labor or a ruptured uterus. Such a decision may be based upon a history of difficulties in a previous childbirth. Some psychological research studies in the 1980s and '90s contend that it is useful for pregnant women with love partners to continue to have sexual activity. This is because studies find that those who have sex more than once a week feel less emotionally tense and more confident in the perception of their appearances. Some studies also suggest that they have less painful or quickened labors, which some physicians believe might be because sexual intercourse serves as a type of pelvic exercise. # Terminology There are likewise finer distinctions between the concepts of fertilization and the actual state of pregnancy, which starts with implantation. In a normal pregnancy, the fertilization of the egg usually will have occurred in the Fallopian tubes or in the uterus. (Often, an egg may become fertilized yet fail to become implanted in the uterus.) If the pregnancy is the result of in-vitro fertilization, the fertilization will have occurred in a Petri dish, after which pregnancy begins when one or more zygotes implant after being transferred by a physician into the woman's uterus. In the context of political debates regarding a proper definition of life, the terminology of pregnancy can be confusing. The medically and politically neutral term which remains is simply "pregnancy," though this can be problematic as it only refers indirectly to the embryo or fetus. In the context of personal treatment, bedside manner generally dictates that doctors make sparse use of clinical language like "fetus" and "embryo," and instead simply use the word "baby." # Detection The early stages of pregnancy are often discovered by using a pregnancy test, as soon as 48 hours after fertilization using sophisticated testing methods, but not until six to twelve days after fertilization using more typical methods. Pregnancy tests typically detect the presence of human chorionic gonadotropin. # Timeline of a Typical Pregnancy Pregnancy is typically broken into three periods, or trimesters, each of about three months. While there are no hard and fast rules, these distinctions are useful in describing the changes that take place over time. ## First Trimester Traditionally, doctors have measured pregnancy from a number of convenient points, including the day of last menstruation, ovulation, fertilization, implantation and chemical detection. In medicine, pregnancy is often defined as beginning when the developing embryo becomes implanted into the endometrial lining of a woman's uterus. In some cases where complications may have arisen, the fertilized egg might implant itself in the fallopian tubes or the cervix, causing an ectopic pregnancy. Most pregnant women do not have any specific signs or symptoms of implantation, although it is not uncommon to experience light bleeding at implantation. Some women will also experience cramping during their first trimester. This is usually of no concern unless there is spotting or bleeding as well. The outer layers of the embryo grow and form a placenta, for the purpose of receiving essential nutrients through the uterine wall, or endometrium. The umbilical cord in a newborn child consists of the remnants of the connection to the placenta. The developing embryo undergoes tremendous growth and changes during the process of embryonic and fetal development. Morning sickness afflicts about seventy percent of all pregnant women, typically only in the first trimester. Most miscarriages occur during this period. ## Second Trimester Months 4 through 6 of the pregnancy are called the second trimester. Most women feel more energized in this period, and begin to put on weight as the symptoms of morning sickness subside and eventually fade away. Although the fetus begins moving and takes a recognizable human shape during the first trimester, it is not until the second trimester that movement of the fetus, often referred to as "quickening", can be felt. This typically happens by the fourth month. The placenta is now fully functioning and the fetus is making insulin and urinating. The teeth are now formed inside the fetus's gums and the reproductive organs can be recognized, and can distinguish the fetus as male or female. ## Third Trimester Final weight gain takes place, and the fetus begins to move regularly. The woman's navel will sometimes become convex, "popping" out, due to her expanding abdomen. This period of her pregnancy can be uncomfortable, causing symptoms like weak bladder control and back-ache. Movement of the fetus becomes stronger and more frequent and via improved brain, eye, and muscle function the fetus is prepared for ex utero viability. The woman can feel the fetus "rolling" and it may cause pain or discomfort when it is near the woman's ribs. It is during this time that a baby born prematurely may survive. The use of modern medical intensive care technology has greatly increased the probability of premature babies living, and has pushed back the boundary of viability to much earlier dates than would be possible without assistance. In spite of these developments, premature birth remains a major threat to the fetus, and may result in ill-health in later life, even if the baby survives. # Prenatal Development and Sonograph Images Template:Seealso Prenatal development is divided into two primary biological stages. The first is the embryonic stage, which lasts for about two months. At this point, the fetal stage begins. At the beginning of the fetal stage, the risk of miscarriage decreases sharply,[7] all major structures including hands, feet, head, brain, and other organs are present, and they continue to grow and develop. When the fetal stage commences, a fetus is typically about 30 mm (1.2 inches) in length, and the heart can be seen beating via sonograph; the fetus bends the head, and also makes general movements and startles that involve the whole body.[8] Brain stem activity has been detected as early as 54 days after conception,[9] and the first measurable signs of EEG activity occur in the 12th week.[10] Some fingerprint formation occurs from the beginning of the fetal stage.[11] - Embryo at 4 weeks after fertilization[12] - Fetus at 8 weeks after fertilization[13] - Fetus at 18 weeks after fertilization[14] - Fetus at 38 weeks after fertilization[15] - Relative size in 1st Month (simplified illustration) - Relative size in 3rd Month (simplified illustration) - Relative size in 5th Month (simplified illustration) - Relative size in 9th Month (simplified illustration) - 7 weeks - 13 weeks - 17 weeks - 20 weeks # Food and Nutrition During Pregnancy It is important for a pregnant woman to eat a healthy diet. Unless she has a specific health problem (e.g., diabetes mellitus or edema) balancing carbohydrates, fat, and proteins; and eating a variety of foods, including dairy products and several fruits and vegetables all contribute to a healthy pregnancy. A pregnant woman may choose to consult her obstetrician for specific advice. Some specific nutritional needs for pregnancy include: Folic acid (also called folate or Vitamin B9) is strongly needed at the start of pregnancy, and even before conception. Folic acid is needed for the closing of fetus' neural tube. It thus helps prevent spina bifida, a very serious birth defect. Folates (from folia, leaf) are abundant in spinach (fresh, frozen or canned), and are also found in green vegetables, salads, melon, hummus, and eggs. In the United States and Canada, most wheat products (flour, noodles) are supplemented with folic acid. Calcium and iron are particularly needed by the rapidly growing fetus. Pregnant women should eat enough dairy products (for calcium) and red meat (for iron) if they are not lactose intolerant or vegetarian. Women who do not eat dairy or meat can obtain calcium and iron from fortified soy milk and juice, soybeans, and certain leafy greens. Care providers may prescribe iron pills if pregnant women develop iron deficiency anemia. Calcium is effective only if women also obtain enough Vitamin D. The best way to get vitamin D is to sunbathe each day for 10–15 minutes. Salmon and fatty fishes are also good sources of vitamin D. Fluoride is critical for development of teeth by increasing binding of calcium, strengthening the enamel. If water or salt does not contain fluoride, supplements are recommended during the third trimester. Many municipalities and water treatment plants add fluoride to the water. Fat from salmon, trout, tuna, herring, sardine, mackerel, and some chicken eggs contain long-chain omega-3 (n-3) fatty acids that are needed to build neuron membranes. Thus fatty fish intake during pregnancy may provide nutrition for proper brain and retina development of the fetus. However, large fish such as tuna and swordfish may contain too much toxic mercury, and one should balance risks with benefits: fish two or three times a week seems to bring enough good fat, but not too much mercury. Omega-3 fatty acids are also present in walnuts, flaxseed, and marine algae.[16] Dangerous bacteria or parasites may contaminate foods, particularly listeria and toxoplasma, toxoplasmosis agent. To avoid those two hazards, hygiene rules should be strictly adhered to: carefully wash fruits and raw vegetables; over-cook remainders, meat and processed meat; avoid raw-milk cheeses (listeria); try to avoid contact with cat feces (toxoplasma); clean the fridge often with diluted chlorine (then rinse). # Medical Aspects of Pregnancy Diagnostic criteria are: Women who has a menstrual cycles and is sexually active, a period delayed by a few days or weeks is suggestive of pregnancy; elevated B-hcG to around 100,000 mIU/mL by 10 weeks of gestation. Prenatal medical care is of recognized value throughout the developed world. Various vitamins or supplements are recognized as beneficial during pregnancy. Prenatal multivitamins as well as folic acid and the choline available from lecithin have either government approval or published studies supporting their use. Folic acid reduces birth defects. Prenatal Choline derivable from lecithin improves the performance of rats on mental tests throughout a rat's entire life.[17] Omega 3 fatty acids support the mental and visual development of infants and they are also beneficial postpartum.[18] # Birth Childbirth is the process by which an infant is born. It is considered by many to be the beginning of a person's life, and age is defined relative to this event in most cultures. A woman is considered to be in labor when she begins experiencing regular uterine contractions, accompanied by changes of her cervix — primarily effacement and dilation. While childbirth is widely experienced as painful, some women do report painless labors, while others find that concentrating on the birth helps to quicken labor and lessen the sensations. Most births are successful vaginal births, but sometimes complications arise and a woman may undergo a caesarean section. While some caesarean sections are necessary, as in the case of cord prolapse, there is dispute as to whether the procedure is used too frequently. Some women choose to have a caesarean section. During the time immediately after birth, both the mother and the baby are hormonally cued to bond, the mother through the release of oxytocin, a hormone also released during breastfeeding. # Postnatal Period For topics following on from a successful pregnancy and birth, see: - Postpartum depression - Infant Formula feeding - Breastfeeding - Child development # Medical Disorders in Pregnancy Most potentially serious problems can be anticipated and treated effectively. However, problems sometimes develop suddenly and unexpectedly. Regular visits to a doctor or midwife during pregnancy make anticipation of problems possible and improve the chances of having a healthy baby. Approximately 4 million births occur in the United States each year. A significant proportion of these are complicated by one or more medical disorders.[19] A small percentage of pregnant women and new mothers have AIDS, cancer, heart disease, lung disease, physical disabilities, diabetes and psychiatric disorders like depression. Two decades ago, many medical disorders were contra-indications to pregnancy. Advances in obstetrics, neonatology, obstetric anesthesiology, midwifery and medicine have increased the expectation that pregnancy will result in an excellent outcome for both the woman and the fetus, despite most of these conditions. Certain medications deemed harmless to the fetus may be highly necessary to the welfare and benefit of the woman, especially if she is pregnant, as some conditions are aggravated by pregnancy. A rare but possibly under-diagnosed disorder in pregnancy is Hyperemesis gravidarum, a condition in which morning sickness is constant and extreme, resulting in dehydration and malnutrition, due to frequent vomiting. A common yet under-diaganosed syndrome is "Pelvic girdle pain" (PGP). One in 35[20] women will experience some degree of PGP during their pregnancy. Symptoms can begin as early 12 weeks into the pregnancy. This muscloskeletal syndrome can effect any of the three pelvic joints. The female experiences a reduced tolerance for weightbearing activities ranging from being midly to severely disabled. Pregnancy must be differentiated from other causes of irregular menses and hirsutism. # Terms and Definitions ## Technical ## Euphemisms and Colloquialisms There are a number of euphemisms and colloquialisms for pregnancy, ranging from polite ("mother to be", "with child", "expecting" and "full") to crude ("up the duff" - UK, "knocked up" and "preggo" - US, and "down the well" - Australia), and even comical ("bun in the oven"). # Regional Customs In Korea, China, Japan and Vietnam, age is measured starting from conception to acknowledge that the fetus exists within the woman's body before it is born. Therefore, a newborn baby is considered to be one year old, although gestation is approximately 9 months. The ancient Mayan calendar of 276 days possibly originated from the human gestational cycle, or to indicate the world was created as slowly as a fetus develops. # Related Chapters - Abortion - Anticoagulation in pregnancy - Breastfeeding - Beginning of pregnancy controversy - Belly cast - Birth control - Birth defect - Cesarean section - Childbirth and labor - Chorionic villus sampling - Complications of pregnancy - Contraception - Couvade - Doula - Ectogenesis - False pregnancy - Father - Fertility - Fetal development - Fetal alcohol syndrome - Genetic counseling - Health care issues in pregnancy - In-vitro fertilization, also known as test-tube babies - Lamaze - Low birth weight paradox - Maternal health - Male pregnancy - Melasma - Men's role in childbirth - Mental illness accompanied with pregnancy - Midwifery - Miscarriage - Natural childbirth - Nutrition and pregnancy - Obstetrics - Parent - Pelvic girdle pain during pregnancy or postpartum - Pica (craving) - Pre-eclampsia - Pregnancy discrimination - Pregnancy over age 50 - Pregnant patients' rights - Prenatal care - Sex during pregnancy - Simulated pregnancy - Spermatozoon - Sperm donor and egg donor - Stretch marks - Surrogate mother - Taboos concerning pregnancy in many cultures - Teenage pregnancy - Twin and Multiple birth - Unassisted childbirth - Wrongful abortion - Youngest birth mothers	https://www.wikidoc.org/index.php/1st_trimester
04678afc62bd908f94a01d06998a6515ac5f4e73	wikidoc	2-Nonenal	2-Nonenal 2-Nonenal is an unsaturated aldehyde (CAS: 2463-53-8; MW: 140.22) which some research has associated with human body odor alterations during aging. In the April 2001 issue of the Journal of Investigative Dermatology, Shinichiro Haze et al published an article entitled: "2-Nonenal, Newly Found in Human Body Odor Tends to Increase with Aging". In this article they reported on their work which involved the analysis of body odor components collected, via headspace gas chromatography/mass spectrometry, from shirts worn for 3 days by subjects between the ages of 26 and 75 . They found that the concentration of many components of body odor were unaffected by age. However, they did find that the concentration of 2-nonenal tended to increase with the age of the subjects. Furthermore, they determined that that 2-nonenal is generated by the oxidative degradation of omega-7 unsaturated fatty acids, such as palmitoleic acid and vaccenic acid, found on the skin surface. They analyzed concentrations of various lipids on the skin surface by collecting samples in a gauze pad sewn into the shirts and then extracting the lipids with a hexane solvent. The article reported that concentrations of omega-10 fatty acids such as sapienic acid showed no change with age. However, concentrations of omega-7 fatty acids do increase with age. 2-Nonenal has an unpleasant greasy and grassy odor. Because of these findings, some observers have concluded that Haze's team has identified the cause of the phenomenon commonly known as "old lady smell", "old man smell" or "old person smell", an odor that is characteristically associated with the elderly. Old Person Smell also refers to a meme found in pop culture.	2-Nonenal 2-Nonenal is an unsaturated aldehyde (CAS: 2463-53-8; MW: 140.22)[1] which some research has associated with human body odor alterations during aging. In the April 2001 issue of the Journal of Investigative Dermatology, Shinichiro Haze et al published an article entitled: "2-Nonenal, Newly Found in Human Body Odor Tends to Increase with Aging". [2] In this article they reported on their work which involved the analysis of body odor components collected, via headspace gas chromatography/mass spectrometry, from shirts worn for 3 days by subjects between the ages of 26 and 75 . They found that the concentration of many components of body odor were unaffected by age. However, they did find that the concentration of 2-nonenal tended to increase with the age of the subjects. Furthermore, they determined that that 2-nonenal is generated by the oxidative degradation of omega-7 unsaturated fatty acids, such as palmitoleic acid and vaccenic acid, found on the skin surface. They analyzed concentrations of various lipids on the skin surface by collecting samples in a gauze pad sewn into the shirts and then extracting the lipids with a hexane solvent. The article reported that concentrations of omega-10 fatty acids such as sapienic acid showed no change with age. However, concentrations of omega-7 fatty acids do increase with age. 2-Nonenal has an unpleasant greasy and grassy odor. Because of these findings, some observers have concluded that Haze's team has identified the cause of the phenomenon commonly known as "old lady smell", "old man smell" or "old person smell", an odor that is characteristically associated with the elderly.[3] Old Person Smell also refers to a meme found in pop culture.	https://www.wikidoc.org/index.php/2-Nonenal
ef4810e2f0068662b09435e0e094f084f6a6363b	wikidoc	310 helix	310 helix A 310 helix is a type of secondary structure found (rarely) in proteins. # Structure The amino acids in a 310-helix are arranged in a right-handed helical structure. Each amino acid corresponds to a 120° turn in the helix (i.e., the helix has three residues per turn), and a translation of 2.0 Å (= 0.2 nm) along the helical axis. Most importantly, the N-H group of an amino acid forms a hydrogen bond with the C = O group of the amino acid three residues earlier; this repeated i + 3 → i hydrogen bonding defines a 310-helix. Similar structures include the α-helix (i + 4 → i hydrogen bonding) and the π-helix i + 5 → i hydrogen bonding). Residues in 310-helices typically adopt (φ, ψ) dihedral angles near (−49°, −26°). More generally, they adopt dihedral angles such that the ψ dihedral angle of one residue and the φ dihedral angle of the next residue sum to roughly −75°. For comparison, the sum of the dihedral angles for an α-helix is roughly −105°, whereas that for a π-helix is roughly −125°. The general formula for the rotation angle Ω per residue of any polypeptide helix with trans isomers is given by the equation 3 \cos \Omega = 1 - 4 \cos^{2} \left(\frac{\varphi + \psi}{2} \right).	310 helix Template:Downsize A 310 helix is a type of secondary structure found (rarely) in proteins. # Structure The amino acids in a 310-helix are arranged in a right-handed helical structure. Each amino acid corresponds to a 120° turn in the helix (i.e., the helix has three residues per turn), and a translation of 2.0 Å (= 0.2 nm) along the helical axis. Most importantly, the N-H group of an amino acid forms a hydrogen bond with the C = O group of the amino acid three residues earlier; this repeated i + 3 → i hydrogen bonding defines a 310-helix. Similar structures include the α-helix (i + 4 → i hydrogen bonding) and the π-helix i + 5 → i hydrogen bonding). Residues in 310-helices typically adopt (φ, ψ) dihedral angles near (−49°, −26°). More generally, they adopt dihedral angles such that the ψ dihedral angle of one residue and the φ dihedral angle of the next residue sum to roughly −75°. For comparison, the sum of the dihedral angles for an α-helix is roughly −105°, whereas that for a π-helix is roughly −125°. The general formula for the rotation angle Ω per residue of any polypeptide helix with trans isomers is given by the equation 3 \cos \Omega = 1 - 4 \cos^{2} \left(\frac{\varphi + \psi}{2} \right). </math>	https://www.wikidoc.org/index.php/310_helix
63e1a9b7ff4bb0349587ad4009919e21609f9f77	wikidoc	4-HO-DiPT	4-HO-DiPT 4-Hydroxy-di-isopropyl-tryptamine (4-HO-DiPT) is a synthetic hallucinogen. It is a close structural analogue of psilocin and classified as a tryptamine derivative. It goes by the street names "Ho-Dipped", "Tangerine", "Jitter", "Phour", and in areas of California in the Los Angeles county, "Aura". # Effects The effects of 4-HO-DiPT are broadly comparable to those of other serotonergic psychedelics such as LSD and psilocybin, but they are distinguished by their relative brevity. 4-HO-DiPT is orally active at 15-20 mg, and its effects last for 2-3 hours. Shulgin "doubt that there is another psychedelic drug, anywhere, that can match this one for speed, for intensity, for brevity, and sensitive to dose, at least one that is active orally." An idiosyncratic effect of the drug, also noted by Shulgin, is its tendency to induce tremors. Some users have reported a minor audio distortion with lower dosages. Higher dosages increase the polarity of the distortion. It is defined as being slightly lower in pitch and creating several different effects, such as pitch bend, volume distortion, and rate distortion. As with most DiPT psychedelics, music can become more dissonant and less harmonious. Users have also reported a visual distortion widely comparable to the hallucinogen LSD. # Analogues 4-Acetoxy-DIPT is metabolized to 4-HO-DIPT and can thus be regarded as a prodrug. Both drugs appear to produce the same psychoactive effects.	4-HO-DiPT 4-Hydroxy-di-isopropyl-tryptamine (4-HO-DiPT) is a synthetic hallucinogen. It is a close structural analogue of psilocin and classified as a tryptamine derivative. It goes by the street names "Ho-Dipped", "Tangerine", "Jitter", "Phour", and in areas of California in the Los Angeles county, "Aura"[citation needed]. # Effects The effects of 4-HO-DiPT are broadly comparable to those of other serotonergic psychedelics such as LSD and psilocybin, but they are distinguished by their relative brevity. 4-HO-DiPT is orally active at 15-20 mg, and its effects last for 2-3 hours. Shulgin "doubt[s] that there is another psychedelic drug, anywhere, that can match this one for speed, for intensity, for brevity, and sensitive to dose, at least one that is active orally." An idiosyncratic effect of the drug, also noted by Shulgin, is its tendency to induce tremors.[1][2][3] Some users have reported a minor audio distortion with lower dosages. Higher dosages increase the polarity of the distortion. It is defined as being slightly lower in pitch and creating several different effects, such as pitch bend, volume distortion, and rate distortion. As with most DiPT psychedelics, music can become more dissonant and less harmonious. Users have also reported a visual distortion widely comparable to the hallucinogen LSD. # Analogues 4-Acetoxy-DIPT is metabolized to 4-HO-DIPT and can thus be regarded as a prodrug[citation needed]. Both drugs appear to produce the same psychoactive effects[citation needed].	https://www.wikidoc.org/index.php/4-HO-DIPT
48c461b1a494e253680ec342d871acef6e74726b	wikidoc	Tamoxifen	Tamoxifen # 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 Tamoxifen is an antineoplastic agent, antiestrogen that is FDA approved for the treatment of metastatic breast cancer, ductal carcinoma in situ (DCIS), adjuvant treatment of breast cancer,. There is a Black Box Warning for this drug as shown here. Common adverse reactions include menopausal flushing, irregular periods, vaginal discharge. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Tamoxifen citrate tablets are indicated for the treatment of node-positive breast cancer in women following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation. In some tamoxifen adjuvant studies, most of the benefit to date has been in the subgroup with four or more positive axillary nodes. - Tamoxifen citrate tablets are indicated for the treatment of axillary node-negative breast cancer in women following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation. - The \|estrogen and progesterone receptor values may help to predict whether adjuvant tamoxifen therapy is likely to be beneficial. - Tamoxifen reduces the occurrence of contralateral breast cancer in patients receiving adjuvant tamoxifen therapy for breast cancer. - Dosing Information - For patients with breast cancer, the recommended daily dose is 20 to 40 mg. Dosages greater than 20 mg per day should be given in divided doses (morning and evening). - In three single agent adjuvant studies in women, one 10 mg tamoxifen citrate tablet was administered two (ECOG and NATO) or three (Toronto) times a day for two years. In the NSABP B-14 adjuvant study in women with node-negative breast cancer, one 10 mg tamoxifen citrate tablet was given twice a day for at least 5 years. Results of the B-14 study suggest that continuation of therapy beyond five years does not provide additional benefit . In the EBCTCG 1995 overview, the reduction in recurrence and mortality was greater in those studies that used tamoxifen for about 5 years than in those that used tamoxifen for a shorter period of therapy. There was no indication that doses greater than 20 mg per day were more effective. Current data from clinical trials support 5 years of adjuvant tamoxifen therapy for patients with breast cancer. - Tamoxifen citrate tablets are indicated to reduce the incidence of breast cancer in women at high risk for breast cancer. This effect was shown in a study of 5 years planned duration with a median follow-up of 4.2 years. Twenty-five percent of the participants received drug for 5 years. The longer-term effects are not known. In this study, there was no impact of tamoxifen on overall or breast cancer-related mortality . - Tamoxifen citrate tablets are indicated only for high-risk women. “High risk” is defined as women at least 35 years of age with a 5 year predicted risk of breast cancer ≥ 1.67%, as calculated by the Gail Model. - Examples of combinations of factors predicting a 5 year risk ≥ 1.67% are: - Age 35 or older and any of the following combination of factors: - One first degree relative with a history of breast cancer, 2 or more benign biopsies, and a history of a breast biopsy showing atypical hyperplasia; or - At least 2 first degree relatives with a history of breast cancer, and a personal history of at least 1 breast biopsy; or - LCIS - Age 40 or older and any of the following combination of factors: - One first degree relative with a history of breast cancer, 2 or more benign biopsies, age at first live birth 25 or older, and age at menarche 11 or younger; or - At least 2 first degree relatives with a history of breast cancer, and age at first live birth 19 or younger; or - One first degree relative with a history of breast cancer, and a personal history of a breast biopsy showing atypical hyperplasia. - Age 45 or older and any of the following combination of factors: - At least 2 first degree relatives with a history of breast cancer and age at first live birth 24 or younger; or - One first degree relative with a history of breast cancer with a personal history of a benign breast biopsy, age at menarche 11 or less and age at first live birth 20 or more. - Age 50 or older and any of the following combination of factors: - At least 2 first degree relatives with a history of breast cancer; or - History of 1 breast biopsy showing atypical hyperplasia, and age at first live birth 30 or older and age at menarche 11 or less; or - History of at least 2 breast biopsies with a history of atypical hyperplasia, and age at first live birth 30 or more. - Age 55 or older and any of the following combination of factors: - One first degree relative with a history of breast cancer with a personal history of a benign breast biopsy, and age at menarche 11 or less; or - History of at least 2 breast biopsies with a history of atypical hyperplasia, and age at first live birth 20 or older. - Age 60 or older and: - Five-year predicted risk of breast cancer ≥ 1.67%, as calculated by the Gail Model. - For women whose risk factors are not described in the above examples, the Gail Model is necessary to estimate absolute breast cancer risk. Health Care Professionals can obtain a Gail Model Risk Assessment Tool by dialing 1-888-838-2872. - There are insufficient data available regarding the effect of tamoxifen on breast cancer incidence in women with inherited mutations (BRCA1, BRCA2) to be able to make specific recommendations on the effectiveness of tamoxifen in these patients. - After an assessment of the risk of developing breast cancer, the decision regarding therapy with tamoxifen for the reduction in breast cancer incidence should be based upon an individual assessment of the benefits and risks of tamoxifen therapy. In the NSABP P-1 trial, tamoxifen treatment lowered the risk of developing breast cancer during the follow-up period of the trial, but did not eliminate breast cancer risk. - Dosing Information - The recommended dose is tamoxifen 20 mg daily for 5 years. There are no data to support the use of tamoxifen other than for 5 years. - In women with DCIS, following breast surgery and radiation, tamoxifen citrate tablets are indicated to reduce the risk of invasive breast cancer . The decision regarding therapy with tamoxifen for the reduction in breast cancer incidence should be based upon an individual assessment of the benefits and risks of tamoxifen therapy. - Current data from clinical trials support 5 years of adjuvant tamoxifen therapy for patients with breast cancer. - Dosing Information - The recommended dose is tamoxifen 20 mg daily for 5 years. ### Metastatic breast cancer - Tamoxifen citrate tablets are effective in the treatment of metastatic breast cancer in women and men. In premenopausal women with metastatic breast cancer, tamoxifen is an alternative to oophorectomy or ovarian irradiation. Available evidence indicates that patients whose tumors are estrogen receptor positive are more likely to benefit from tamoxifen therapy. - Dosing Information - 20-40 mg ORALLY daily ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Tamoxifen in adult patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Tamoxifen in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - There is limited information regarding FDA-Labeled Use of Tamoxifen in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Tamoxifen in pediatric patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Tamoxifen in pediatric patients. # Contraindications - Tamoxifen is contraindicated in patients with known hypersensitivity to the drug or any of its ingredients. - Reduction in Breast Cancer Incidence in High Risk Women and Women with DCIS: - Tamoxifen is contraindicated in women who require concomitant coumarin-type anticoagulant therapy or in women with a history of deep vein thrombosis or pulmonary embolus. # Warnings Effects in Metastatic Breast Cancer Patients - As with other additive hormonal therapy (estrogens and androgens), hypercalcemia has been reported in some breast cancer patients with bone metastases within a few weeks of starting treatment with tamoxifen. If hypercalcemia does occur, appropriate measures should be taken and, if severe, tamoxifen should be discontinued. Effects on the Uterus-Endometrial Cancer and Uterine Sarcoma - An increased incidence of uterine malignancies has been reported in association with tamoxifen treatment. The underlying mechanism is unknown, but may be related to the estrogen-like effect of tamoxifen. Most uterine malignancies seen in association with tamoxifen are classified as adenocarcinoma of the endometrium. However, rare uterine sarcomas, including malignant mixed mullerian tumors (MMMT), have also been reported. Uterine sarcoma is generally associated with a higher FIGO stage (III/IV) at diagnosis, poorer prognosis, and shorter survival. Uterine sarcoma has been reported to occur more frequently among long-term users (≥ 2 years) of tamoxifen than non-users. Some of the uterine malignancies (endometrial carcinoma or uterine sarcoma) have been fatal. - In the NSABP P-1 trial, among participants randomized to tamoxifen there was a statistically significant increase in the incidence of endometrial cancer (33 cases of invasive endometrial cancer, compared to 14 cases among participants randomized to placebo (RR = 2.48, 95% CI: 1.27 to 4.92). The 33 cases in participants receiving tamoxifen were FIGO Stage I, including 20 IA, 12 IB, and 1 IC endometrial adenocarcinomas. In participants randomized to placebo, 13 were FIGO Stage I (8 IA and 5 IB) and 1 was FIGO Stage IV. Five women on tamoxifen and 1 on placebo received postoperative radiation therapy in addition to surgery. This increase was primarily observed among women at least 50 years of age at the time of randomization (26 cases of invasive endometrial cancer, compared to 6 cases among participants randomized to placebo (RR = 4.50, 95% CI: 1.78 to 13.16). Among women ≤ 49 years of age at the time of randomization there were 7 cases of invasive endometrial cancer, compared to 8 cases among participants randomized to placebo (RR = 0.94, 95% CI: 0.28 to 2.89). If age at the time of diagnosis is considered, there were 4 cases of endometrial cancer among participants ≤ 49 randomized to tamoxifen compared to 2 among participants randomized to placebo (RR = 2.21, 95% CI: 0.4 to 12.0). For women ≥ 50 at the time of diagnosis, there were 29 cases among participants randomized to tamoxifen compared to 12 among women on placebo (RR = 2.5, 95% CI: 1.3 to 4.9). The risk ratios were similar in the two groups, although fewer events occurred in younger women. Most (29 of 33 cases in the tamoxifen group) endometrial cancers were diagnosed in symptomatic women, although 5 of 33 cases in the tamoxifen group occurred in asymptomatic women. Among women receiving tamoxifen the events appeared between 1 and 61 months (average = 32 months) from the start of treatment. - In an updated review of long-term data (median length of total follow-up is 6.9 years, including blinded follow-up) on 8,306 women with an intact uterus at randomization in the NSABP P-1 risk reduction trial, the incidence of both adenocarcinomas and rare uterine sarcomas was increased in women taking tamoxifen. During blinded follow-up, there were 36 cases of FIGO Stage I endometrial adenocarcinoma (22 were FIGO Stage IA, 13 IB, and 1 IC) in women receiving tamoxifen and 15 cases in women receiving placebo . Of the patients receiving tamoxifen who developed endometrial cancer, one with Stage IA and 4 with Stage IB cancers received radiation therapy. In the placebo group, one patient with FIGO Stage IB cancer received radiation therapy and the patient with FIGO Stage IVB cancer received chemotherapy and hormonal therapy. During total follow-up, endometrial adenocarcinoma was reported in 53 women randomized to tamoxifen (30 cases of FIGO Stage IA, 20 were Stage IB, 1 was Stage IC, and 2 were Stage IIIC), and 17 women randomized to placebo (9 cases were FIGO Stage IA, 6 were Stage IB, 1 was Stage IIIC, and 1 was Stage IVB) (incidence per 1,000 women-years of 2.20 and 0.71, respectively). Some patients received postoperative radiation therapy in addition to surgery. Uterine sarcomas were reported in 4 women randomized to tamoxifen (1 was FIGO IA, 1 was FIGO IB, 1 was FIGO IIA, and 1 was FIGO IIIC) and 1 patient randomized to placebo (FIGO 1A); incidence per 1,000 women-years of 0.17 and 0.04, respectively. Of the patients randomized to tamoxifen, the FIGO IA and IB cases were a MMMT and sarcoma, respectively; the FIGO II was a MMMT; and the FIGO III was a sarcoma; and the 1 patient randomized to placebo had a MMMT. A similar increased incidence in endometrial adenocarcinoma and uterine sarcoma was observed among women receiving tamoxifen in 5 other NSABP clinical trials. - Any patient receiving or who has previously received tamoxifen who reports vaginal bleeding should be promptly evaluated. Patients receiving or who have previously received tamoxifen should have annual gynecological examinations and they should promptly inform their physicians if they experience any abnormal gynecological symptoms, e.g., menstrual irregularities, abnormal vaginal bleeding, changes in vaginal discharge, or pelvic pain or pressure. - In the P-1 trial, endometrial sampling did not alter the endometrial cancer detection rate compared to women who did not undergo endometrial sampling (0.6% with sampling, 0.5% without sampling) for women with an intact uterus. There are no data to suggest that routine endometrial sampling in asymptomatic women taking tamoxifen to reduce the incidence of breast cancer would be beneficial. Non-Malignant Effects on the Uterus - An increased incidence of endometrial changes including hyperplasia and polyps has been reported in association with tamoxifen treatment. The incidence and pattern of this increase suggest that the underlying mechanism is related to the estrogenic properties of tamoxifen. - There have been a few reports of endometriosis and uterine fibroids in women receiving tamoxifen. The underlying mechanism may be due to the partial estrogenic effect of tamoxifen. Ovarian cysts have also been observed in a small number of premenopausal patients with advanced breast cancer who have been treated with tamoxifen. - Tamoxifen has been reported to cause menstrual irregularity or amenorrhea. Thromboembolic Effects of Tamoxifen - There is evidence of an increased incidence of thromboembolic events, including deep-vein thrombosis and pulmonary embolism, during tamoxifen therapy. When tamoxifen is coadministered with chemotherapy, there may be a further increase in the incidence of thromboembolic events. For treatment of breast cancer, the risks and benefits of tamoxifen should be carefully considered in women with a history of thromboembolic events. In a small substudy (N = 81) of the NSABP-1 trial, there appeared to be no benefit to screening women for Factor V Leiden and Prothrombin mutations G20210A as a means to identify those who may not be appropriate candidates for tamoxifen therapy. - Data from the NSABP P-1 trial show that participants receiving tamoxifen without a history of pulmonary emboli (PE) had a statistically significant increase in pulmonary emboli (18 tamoxifen, 6 placebo; RR = 3.01, 95% CI: 1.15 to 9.27). Three of the pulmonary emboli, all in the tamoxifen arm, were fatal. Eighty-seven percent of the cases of pulmonary embolism occurred in women at least 50 years of age at randomization. Among women receiving tamoxifen, the events appeared between 2 and 60 months (average = 27 months) from the start of treatment. - In this same population, a non-statistically significant increase in deep-vein thrombosis (DVT) was seen in the tamoxifen group (30-tamoxifen, 19-placebo; RR = 1.59, 95% CI: 0.86 to 2.98). The same increase in relative risk was seen in women ≤ 49 and in women ≥ 50, although fewer events occurred in younger women. Women with thromboembolic events were at risk for a second related event (7 out of 25 women on placebo, 5 out of 48 women on tamoxifen) and were at risk for complications of the event and its treatment (0/25 on placebo, 4/48 on tamoxifen). Among women receiving tamoxifen, deep-vein thrombosis events occurred between 2 and 57 months (average = 19 months) from the start of treatment. - There was a non-statistically significant increase in stroke among patients randomized to tamoxifen (24 placebo; 34 tamoxifen; RR = 1.42, 95% CI: 0.82 to 2.51). Six of the 24 strokes in the placebo group were considered hemorrhagic in origin and 10 of the 34 strokes in the tamoxifen group were categorized as hemorrhagic. Seventeen of the 34 strokes in the tamoxifen group were considered occlusive and 7 were considered to be of unknown etiology. Fourteen of the 24 strokes on the placebo arm were reported to be occlusive and 4 of unknown etiology. Among these strokes 3 strokes in the placebo group and 4 strokes in the tamoxifen group were fatal. Eighty-eight percent of the strokes occurred in women at least 50 years of age at the time of randomization. Among women receiving tamoxifen, the events occurred between 1 and 63 months (average = 30 months) from the start of treatment. Effects on the Liver: Liver Cancer - In the Swedish trial using adjuvant tamoxifen 40 mg/day for 2 to 5 years, 3 cases of liver cancer have been reported in the tamoxifen-treated group vs. 1 case in the observation group . In other clinical trials evaluating tamoxifen, no cases of liver cancer have been reported to date. - One case of liver cancer was reported in NSABP P-1 in a participant randomized to tamoxifen. Effects on the Liver: Non-Malignant Effects - Tamoxifen has been associated with changes in liver enzyme levels, and on rare occasions, a spectrum of more severe liver abnormalities including fatty liver, cholestasis, hepatitis and hepatic necrosis. A few of these serious cases included fatalities. In most reported cases the relationship to tamoxifen is uncertain. However, some positive rechallenges and dechallenges have been reported. - In the NSABP P-1 trial, few grade 3 to 4 changes in liver function (SGOT, SGPT, bilirubin, alkaline phosphatase) were observed (10 on placebo and 6 on tamoxifen). Serum lipids were not systematically collected. Other Cancers - A number of second primary tumors, occurring at sites other than the endometrium, have been reported following the treatment of breast cancer with tamoxifen in clinical trials. Data from the NSABP B-14 and P-1 studies show no increase in other (non-uterine) cancers among patients receiving tamoxifen. Whether an increased risk for other (non-uterine) cancers is associated with tamoxifen is still uncertain and continues to be evaluated. Effects on the Eye - Ocular disturbances, including corneal changes, decrement in color vision perception, retinal vein thrombosis, and retinopathy have been reported in patients receiving tamoxifen. An increased incidence of cataracts and the need for cataract surgery have been reported in patients receiving tamoxifen. - In the NSABP P-1 trial, an increased risk of borderline significance of developing cataracts among those women without cataracts at baseline (540 tamoxifen; 483 placebo; RR = 1.13, 95% CI: 1.00 to 1.28) was observed. Among these same women, tamoxifen was associated with an increased risk of having cataract surgery (101 tamoxifen; 63 placebo; RR = 1.62, 95% CI: 1.18 to 2.22). Among all women on the trial (with or without cataracts at baseline), tamoxifen was associated with an increased risk of having cataract surgery (201 tamoxifen; 129 placebo; RR = 1.58, 95% CI: 1.26 to 1.97). Eye examinations were not required during the study. No other conclusions regarding non-cataract ophthalmic events can be made. ### Precautions General - Decreases in platelet counts, usually to 50,000 to 100,000/mm3, infrequently lower, have been occasionally reported in patients taking tamoxifen for breast cancer. In patients with significant thrombocytopenia, rare hemorrhagic episodes have occurred, but it is uncertain if these episodes are due to tamoxifen therapy. Leukopenia has been observed, sometimes in association with anemia and/or thrombocytopenia. There have been rare reports of neutropenia and pancytopenia in patients receiving tamoxifen; this can sometimes be severe. - In the NSABP P-1 trial, 6 women on tamoxifen and 2 on placebo experienced grade 3 to 4 drops in platelet counts (≤ 50,000/mm3). Information for Patients - Patients should be instructed to read the Medication Guide supplied as required by law when tamoxifen is dispensed. The complete text of the Medication Guide is reprinted at the end of this document. Reduction in Invasive Breast Cancer and DCIS in Women With DCIS - Women with DCIS treated with lumpectomy and radiation therapy who are considering tamoxifen to reduce the incidence of a second breast cancer event should assess the risks and benefits of therapy, since treatment with tamoxifen decreased the incidence of invasive breast cancer, but has not been shown to affect survival . Reduction in Breast Cancer Incidence in High Risk Women - Women who are at high risk for breast cancer can consider taking tamoxifen therapy to reduce the incidence of breast cancer. Whether the benefits of treatment are considered to outweigh the risks depends on a woman’s personal health history and on how she weighs the benefits and risks. Tamoxifen therapy to reduce the incidence of breast cancer may therefore not be appropriate for all women at high risk for breast cancer. Women who are considering tamoxifen therapy should consult their health care professional for an assessment of the potential benefits and risks prior to starting therapy for reduction in breast cancer incidence . Women should understand that tamoxifen reduces the incidence of breast cancer, but may not eliminate risk. Tamoxifen decreased the incidence of small estrogen receptor positive tumors, but did not alter the incidence of estrogen receptor negative tumors or larger tumors. In women with breast cancer who are at high risk of developing a second breast cancer, treatment with about 5 years of tamoxifen reduced the annual incidence rate of a second breast cancer by approximately 50%. - Women who are pregnant or who plan to become pregnant should not take tamoxifen to reduce their risk of breast cancer. Effective nonhormonal contraception must be used by all premenopausal women taking tamoxifen and for approximately two months after discontinuing therapy if they are sexually active. Tamoxifen does not cause infertility, even in the presence of menstrual irregularity. For sexually active women of child-bearing potential, tamoxifen therapy should be initiated during menstruation. In women with menstrual irregularity, a negative B-HCG immediately prior to the initiation of therapy is sufficient - Two European trials of tamoxifen to reduce the risk of breast cancer were conducted and showed no difference in the number of breast cancer cases between the tamoxifen and placebo arms. These studies had trial designs that differed from that of NSABP P-1, were smaller than NSABP P-1, and enrolled women at a lower risk for breast cancer than those in P-1. Monitoring During Tamoxifen Therapy - Women taking or having previously taken tamoxifen should be instructed to seek prompt medical attention for new breast lumps, vaginal bleeding, gynecologic symptoms (menstrual irregularities, changes in vaginal discharge, or pelvic pain or pressure), symptoms of leg swelling or tenderness, unexplained shortness of breath, or changes in vision. Women should inform all care providers, regardless of the reason for evaluation, that they take tamoxifen. - Women taking tamoxifen to reduce the incidence of breast cancer should have a breast examination, a mammogram, and a gynecologic examination prior to the initiation of therapy. These studies should be repeated at regular intervals while on therapy, in keeping with good medical practice. Women taking tamoxifen as adjuvant breast cancer therapy should follow the same monitoring procedures as for women taking tamoxifen for the reduction in the incidence of breast cancer. Women taking tamoxifen as treatment for metastatic breast cancer should review this monitoring plan with their care provider and select the appropriate modalities and schedule of evaluation. Laboratory Tests - Periodic complete blood counts, including platelet counts, and periodic liver function tests should be obtained. - During the ATAC trial, more patients receiving anastrozole were reported to have an elevated serum cholesterol compared to patients receiving tamoxifen (9% versus 3.5%, respectively). Drug/Laboratory Testing Interactions - During postmarketing surveillance, T4 elevations were reported for a few postmenopausal patients which may be explained by increases in thyroid-binding globulin. These elevations were not accompanied by clinical hyperthyroidism. - Variations in the karyopyknotic index on vaginal smears and various degrees of estrogen effect on Pap smears have been infrequently seen in postmenopausal patients given tamoxifen. - In the postmarketing experience with tamoxifen, infrequent cases of hyperlipidemias have been reported. Periodic monitoring of plasma triglycerides and cholesterol may be indicated in patients with preexisting hyperlipidemias. # Adverse Reactions ## Clinical Trials Experience - Adverse reactions to tamoxifen are relatively mild and rarely severe enough to require discontinuation of treatment in breast cancer patients. - Continued clinical studies have resulted in further information which better indicates the incidence of adverse reactions with tamoxifen as compared to placebo. Metastatic Breast Cancer - Increased bone and tumor pain and, also, local disease flare have occurred, which are sometimes associated with a good tumor response. Patients with increased bone pain may require additional analgesics. Patients with soft tissue disease may have sudden increases in the size of preexisting lesions, sometimes associated with marked erythema within and surrounding the lesions and/or the development of new lesions. When they occur, the bone pain or disease flare are seen shortly after starting tamoxifen and generally subside rapidly. - In patients treated with tamoxifen for metastatic breast cancer, the most frequent adverse reaction to tamoxifen is hot flashes. - Other adverse reactions which are seen infrequently are hypercalcemia, peripheral edema, distaste for food, pruritus vulvae, depression, dizziness, lightheadedness, headache, hair thinning and/or partial hair loss, and vaginal dryness. Premenopausal Women - The following table summarizes the incidence of adverse reactions reported at a frequency of 2% or greater from clinical trials (Ingle, Pritchard, Buchanan) which compared tamoxifen therapy to ovarian ablation in premenopausal patients with metastatic breast cancer. Male Breast Cancer - Tamoxifen is well tolerated in males with breast cancer. Reports from the literature and case reports suggest that the safety profile of tamoxifen in males is similar to that seen in women. Loss of libido and impotence have resulted in discontinuation of tamoxifen therapy in male patients. Also, in oligospermic males treated with tamoxifen, LH, FSH, testosterone and estrogen levels were elevated. No significant clinical changes were reported. Adjuvant Breast Cancer - In the NSABP B-14 study, women with axillary node-negative breast cancer were randomized to 5 years of tamoxifen 20 mg/day or placebo following primary surgery. The reported adverse effects are tabulated below (mean follow-up of approximately 6.8 years) showing adverse events more common on tamoxifen than on placebo. The incidence of hot flashes (64% vs. 48%), vaginal discharge (30% vs. 15%), and irregular menses (25% vs. 19%) were higher with tamoxifen compared with placebo. All other adverse effects occurred with similar frequency in the 2 treatment groups, with the exception of thrombotic events; a higher incidence was seen in tamoxifen-treated patients (through 5 years, 1.7% vs. 0.4%). Two of the patients treated with tamoxifen who had thrombotic events died. - In the Eastern Cooperative Oncology Group (ECOG) adjuvant breast cancer trial, tamoxifen or placebo was administered for 2 years to women following mastectomy. When compared to placebo, tamoxifen showed a significantly higher incidence of hot flashes (19% vs. 8% for placebo). The incidence of all other adverse reactions was similar in the 2 treatment groups with the exception of thrombocytopenia where the incidence for tamoxifen was 10% vs. 3% for placebo, an observation of borderline statistical significance. - In other adjuvant studies, Toronto and Tamoxifen Adjuvant Trial Organization (NATO), women received either tamoxifen or no therapy. In the Toronto study, hot flashes were observed in 29% of patients for tamoxifen vs. 1% in the untreated group. In the NATO trial, hot flashes and vaginal bleeding were reported in 2.8% and 2.0% of women, respectively, for tamoxifen vs. 0.2% for each in the untreated group. - Anastrozole Adjuvant Trial – Study of Anastrozole Compared to Tamoxifen for Adjuvant Treatment of Early Breast Cancer . - At a median follow-up of 33 months, the combination of anastrozole and tamoxifen did not demonstrate any efficacy benefit when compared to tamoxifen therapy given alone in all patients as well as in the hormone receptor positive subpopulation. This treatment arm was discontinued from the trial. The median duration of adjuvant treatment for safety evaluation was 59.8 months and 59.6 months for patients receiving anastrozole 1 mg and tamoxifen 20 mg, respectively. - Adverse events occurring with an incidence of at least 5% in either treatment group during treatment or within 14 days of the end of treatment are presented in the following table. - Certain adverse events and combinations of adverse events were prospectively specified for analysis, based on the known pharmacologic properties and side effect profiles of the two drugs (see the following table). - Patients receiving anastrozole had an increase in joint disorders (including arthritis, arthrosis and arthralgia) compared with patients receiving tamoxifen. Patients receiving anastrozole had an increase in the incidence of all fractures (specifically fractures of spine, hip and wrist) compared with patients receiving tamoxifen . Patients receiving anastrozole had a decrease in hot flashes, vaginal bleeding, vaginal discharge, endometrial cancer, venous thromboembolic events and ischemic cerebrovascular events compared with patients receiving tamoxifen. - Patients receiving tamoxifen had a decrease in hypercholesterolemia compared to patients receiving anastrozole . Angina pectoris was reported in 71 (2.3%) patients in the anastrozole arm and 51 (1.6%) patients in the tamoxifen arm; myocardial infarction was reported in 37 (1.2%) patients in the anastrozole arm and in 34 (1.1%) patients in the tamoxifen arm. - Results from the adjuvant trial bone substudy, at 12 and 24 months demonstrated that patients receiving anastozole had a mean decrease in both lumbar spine and total hip bone mineral density (BMD) compared to baseline. Patients receiving tamoxifen had a mean increase in both lumbar spine and total hip BMD compared to baseline. Ductal Carcinoma in Situ (DCIS) - The type and frequency of adverse events in the NSABP B-24 trial were consistent with those observed in the other adjuvant trials conducted with tamoxifen. Reduction in Breast Cancer Incidence in High Risk Women - In the NSABP P-1 trial, there was an increase in five serious adverse effects in the tamoxifen group: endometrial cancer (33 cases in the tamoxifen group vs. 14 in the placebo group); pulmonary embolism (18 cases in the tamoxifen group vs. 6 in the placebo group); deep-vein thrombosis (30 cases in the tamoxifen group vs. 19 in the placebo group); stroke (34 cases in the tamoxifen group vs. 24 in the placebo group); cataract formation (540 cases in the tamoxifen group vs. 483 in the placebo group) and cataract surgery (101 cases in the tamoxifen group vs. 63 in the placebo group) . - The following table presents the adverse events observed in NSABP P-1 by treatment arm. Only adverse events more common on tamoxifen than placebo are shown. - In the NSABP P-1 trial, 15.0% and 9.7% of participants receiving tamoxifen and placebo therapy, respectively withdrew from the trial for medical reasons. The following are the medical reasons for withdrawing from tamoxifen and placebo therapy, respectively: hot flashes (3.1% vs. 1.5%) and vaginal discharge (0.5% vs. 0.1%). - In the NSABP P-1 trial, 8.7% and 9.6% of participants receiving tamoxifen and placebo therapy, respectively withdrew for non-medical reasons. - On the NSABP P-1 trial, hot flashes of any severity occurred in 68% of women on placebo and in 80% of women on tamoxifen. Severe hot flashes occurred in 28% of women on placebo and 45% of women on tamoxifen. Vaginal discharge occurred in 35% and 55% of women on placebo and tamoxifen respectively; and was severe in 4.5% and 12.3% respectively. There was no difference in the incidence of vaginal bleeding between treatment arms. Pediatric Patients McCune-Albright Syndrome - Mean uterine volume increased after 6 months of treatment and doubled at the end of the one-year study. A causal relationship has not been established; however, as an increase in the incidence of endometrial adenocarcinoma and uterine sarcoma has been noted in adults treated with tamoxifen , continued monitoring of McCune-Albright patients treated with tamoxifen for long-term effects is recommended. The safety and efficacy of tamoxifen for girls aged 2 to 10 years with McCune-Albright syndrome and precocious puberty have not been studied beyond 1 year of treatment. The long-term effects of tamoxifen therapy in girls have not been established. ## Postmarketing Experience - Less frequently reported adverse reactions are vaginal bleeding, vaginal discharge, menstrual irregularities, skin rash and headaches. Usually these have not been of sufficient severity to require dosage reduction or discontinuation of treatment. Very rare reports of erythema multiforme, Stevens-Johnson syndrome, bullous pemphigoid, interstitial pneumonitis, and rare reports of hypersensitivity reactions including angioedema have been reported with tamoxifen therapy. In some of these cases, the time to onset was more than one year. Rarely, elevation of serum triglyceride levels, in some cases with pancreatitis, may be associated with the use of tamoxifen . # Drug Interactions - When tamoxifen is used in combination with coumarin-type anticoagulants, a significant increase in anticoagulant effect may occur. Where such coadministration exists, careful monitoring of the patient's prothrombin time is recommended. - In the NSABP P-1 trial, women who required coumarin-type anticoagulants for any reason were ineligible for participation in the trial . - There is an increased risk of thromboembolic events occurring when cytotoxic agents are used in combination with tamoxifen. - Tamoxifen reduced letrozole plasma concentrations by 37%. The effect of tamoxifen on metabolism and excretion of other antineoplastic drugs, such as cyclophosphamide and other drugs that require mixed function oxidases for activation, is not known. Tamoxifen and N-desmethyl tamoxifen plasma concentrations have been shown to be reduced when coadministered with rifampin or aminoglutethimide. Induction of CYP3A4-mediated metabolism is considered to be the mechanism by which these reductions occur; other CYP3A4 inducing agents have not been studied to confirm this effect. - One patient receiving tamoxifen with concomitant phenobarbital exhibited a steady-state serum level of tamoxifen lower than that observed for other patients (i.e., 26 ng/mL vs. mean value of 122 ng/mL). However, the clinical significance of this finding is not known. Rifampin induced the metabolism of tamoxifen and significantly reduced the plasma concentrations of tamoxifen in 10 patients. Aminoglutethimide reduces tamoxifen and N-desmethyl tamoxifen plasma concentrations. Medroxyprogesterone reduces plasma concentrations of N-desmethyl, but not tamoxifen. - Concomitant bromocriptine therapy has been shown to elevate serum tamoxifen and N-desmethyl tamoxifen. - Based on clinical and pharmacokinetic results from the anastrozole adjuvant trial, tamoxifen should not be administered with anastrozole. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D Pregnancy Category D - Tamoxifen may cause fetal harm when administered to a pregnant woman. Women should be advised not to become pregnant while taking tamoxifen or within 2 months of discontinuing tamoxifen and should use barrier or nonhormonal contraceptive measures if sexually active. Tamoxifen does not cause infertility, even in the presence of menstrual irregularity. Effects on reproductive functions are expected from the antiestrogenic properties of the drug. In reproductive studies in rats at dose levels equal to or below the human dose, nonteratogenic developmental skeletal changes were seen and were found reversible. In addition, in fertility studies in rats and in teratology studies in rabbits using doses at or below those used in humans, a lower incidence of embryo implantation and a higher incidence of fetal death or retarded in utero growth were observed, with slower learning behavior in some rat pups when compared to historical controls. Several pregnant marmosets were dosed with 10 mg/kg/day (about 2 fold the daily maximum recommended human dose on a mg/m2 basis) during organogenesis or in the last half of pregnancy. No deformations were seen and, although the dose was high enough to terminate pregnancy in some animals, those that did maintain pregnancy showed no evidence of teratogenic malformations. - In rodent models of fetal reproductive tract development, tamoxifen (at doses 0.002 to 2.4 fold the daily maximum recommended human dose on a mg/m2 basis) caused changes in both sexes that are similar to those caused by estradiol, ethynylestradiol and diethylstilbestrol. Although the clinical relevance of these changes is unknown, some of these changes, especially vaginal adenosis, are similar to those seen in young women who were exposed to diethylstilbestrol in utero and who have a 1 in 1,000 risk of developing clear-cell adenocarcinoma of the vagina or cervix. To date, in utero exposure to tamoxifen has not been shown to cause vaginal adenosis, or clear-cell adenocarcinoma of the vagina or cervix, in young women. However, only a small number of young women have been exposed to tamoxifen in utero, and a smaller number have been followed long enough (to age 15 to 20) to determine whether vaginal or cervical neoplasia could occur as a result of this exposure. - There are no adequate and well-controlled trials of tamoxifen in pregnant women. There have been a small number of reports of vaginal bleeding, spontaneous abortions, birth defects, and fetal deaths in pregnant women. If this drug is used during pregnancy, or the patient becomes pregnant while taking this drug, or within approximately two months after discontinuing therapy, the patient should be apprised of the potential risks to the fetus including the potential long-term risk of a DES-like syndrome. Reduction in Breast Cancer Incidence in High Risk Women Pregnancy Category D - For sexually active women of child-bearing potential, tamoxifen therapy should be initiated during menstruation. In women with menstrual irregularity, a negative B-HCG immediately prior to the initiation of therapy is sufficient Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category - There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tamoxifen in women who are pregnant. ### Labor and Delivery - There is no FDA guidance on use of Tamoxifen during labor and delivery. ### Nursing Mothers - Tamoxifen has been reported to inhibit lactation. Two placebo-controlled studies in over 150 women have shown that tamoxifen significantly inhibits early postpartum milk production. In both studies tamoxifen was administered within 24 hours of delivery for between 5 and 18 days. The effect of tamoxifen on established milk production is not known. - There are no data that address whether tamoxifen is excreted into human milk. If excreted, there are no data regarding the effects of tamoxifen in breast milk on the breastfed infant or breastfed animals. However, direct neonatal exposure of tamoxifen to mice and rats (not via breast milk) produced 1) reproductive tract lesions in female rodents (similar to those seen in humans after intrauterine exposure to diethylstilbestrol) and 2) functional defects of the reproductive tract in male rodents such as testicular atrophy and arrest of spermatogenesis. - It is not known if tamoxifen is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from tamoxifen, women taking tamoxifen should not breast feed. Reduction in Breast Cancer Incidence in High Risk Women With DCIS - It is not known if tamoxifen is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from tamoxifen, women taking tamoxifen should not breast feed. ### Pediatric Use - The safety and efficacy of tamoxifen for girls aged 2 to 10 years with McCune-Albright syndrome and precocious puberty have not been studied beyond one year of treatment. The long-term effects of tamoxifen therapy for girls have not been established. In adults treated with tamoxifen, an increase in incidence of uterine malignancies, stroke and pulmonary embolism has been noted. ### Geriatic Use - In the NSABP P-1 trial, the percentage of women at least 65 years of age was 16%. Women at least 70 years of age accounted for 6% of the participants. A reduction in breast cancer incidence was seen among participants in each of the subsets. A total of 28 and 10 invasive breast cancers were seen among participants 65 and older in the placebo and tamoxifen groups, respectively. Across all other outcomes, the results in this subset reflect the results observed in the subset of women at least 50 years of age. No overall differences in tolerability were observed between older and younger patients. - In the NSABP B-24 trial, the percentage of women at least 65 years of age was 23%. Women at least 70 years of age accounted for 10% of participants. A total of 14 and 12 invasive breast cancers were seen among participants 65 and older in the placebo and tamoxifen groups, respectively. This subset is too small to reach any conclusions on efficacy. Across all other endpoints, the results in this subset were comparable to those of younger women enrolled in this trial. No overall differences in tolerability were observed between older and younger patients. ### Gender - There is no FDA guidance on the use of Tamoxifen with respect to specific gender populations. ### Race - There is no FDA guidance on the use of Tamoxifen with respect to specific racial populations. ### Renal Impairment - There is no FDA guidance on the use of Tamoxifen in patients with renal impairment. ### Hepatic Impairment - There is no FDA guidance on the use of Tamoxifen in patients with hepatic impairment. ### Females of Reproductive Potential and Males - There is no FDA guidance on the use of Tamoxifen in women of reproductive potentials and males. ### Immunocompromised Patients - There is no FDA guidance one the use of Tamoxifen in patients who are immunocompromised. # Administration and Monitoring ### Administration - For patients with breast cancer, the recommended daily dose is 20 to 40 mg. Dosages greater than 20 mg per day should be given in divided doses (morning and evening). - In three single agent adjuvant studies in women, one 10 mg tamoxifen citrate tablet was administered two (ECOG and NATO) or three (Toronto) times a day for two years. In the NSABP B-14 adjuvant study in women with node-negative breast cancer, one 10 mg tamoxifen citrate tablet was given twice a day for at least 5 years. Results of the B-14 study suggest that continuation of therapy beyond five years does not provide additional benefit. In the EBCTCG 1995 overview, the reduction in recurrence and mortality was greater in those studies that used tamoxifen for about 5 years than in those that used tamoxifen for a shorter period of therapy. There was no indication that doses greater than 20 mg per day were more effective. Current data from clinical trials support 5 years of adjuvant tamoxifen therapy for patients with breast cancer. Ductal Carcinoma in Situ (DCIS) - The recommended dose is tamoxifen 20 mg daily for 5 years. Reduction in Breast Cancer Incidence in High Risk Women - The recommended dose is tamoxifen 20 mg daily for 5 years. There are no data to support the use of tamoxifen other than for 5 years. ### Monitoring - There is limited information regarding Monitoring of Tamoxifen in the drug label. # IV Compatibility - There is limited information regarding IV Compatibility of Tamoxifen in the drug label. # Overdosage - Signs observed at the highest doses following studies to determine LD50 in animals were respiratory difficulties and convulsions. - Acute overdosage in humans has not been reported. In a study of advanced metastatic cancer patients which specifically determined the maximum tolerated dose of tamoxifen in evaluating the use of very high doses to reverse multidrug resistance, acute neurotoxicity manifested by tremor, hyperreflexia, unsteady gait and dizziness were noted. These symptoms occurred within 3 to 5 days of beginning tamoxifen and cleared within 2 to 5 days after stopping therapy. No permanent neurologic toxicity was noted. One patient experienced a seizure several days after tamoxifen was discontinued and neurotoxic symptoms had resolved. The causal relationship of the seizure to tamoxifen therapy is unknown. Doses given in these patients were all greater than 400 mg/m2 loading dose, followed by maintenance doses of 150 mg/m2 of tamoxifen given twice a day. - In the same study, prolongation of the QT interval on the electrocardiogram was noted when patients were given doses higher than 250 mg/m2 loading dose, followed by maintenance doses of 80 mg/m2 of tamoxifen given twice a day. For a woman with a body surface area of 1.5 m2 the minimal loading dose and maintenance doses given at which neurological symptoms and QT changes occurred were at least 6 fold higher in respect to the maximum recommended dose. - No specific treatment for overdosage is known; treatment must be symptomatic. # Pharmacology ## Mechanism of Action - Tamoxifen citrate is a nonsteroidal agent that has demonstrated potent antiestrogenic properties in animal test systems. The antiestrogenic effects may be related to its ability to compete with estrogen for binding sites in target tissues such as breast. Tamoxifen inhibits the induction of rat mammary carcinoma induced by dimethylbenzanthracene (DMBA) and causes the regression of already established DMBA-induced tumors. In this rat model, tamoxifen appears to exert its antitumor effects by binding the estrogen receptors. - In cytosols derived from human breast adenocarcinomas, tamoxifen competes with estradiol for estrogen receptor protein. ## Structure - Tamoxifen citrate tablets USP, a nonsteroidal antiestrogen, are for oral administration. Each tablet contains 10 mg or 20 mg tamoxifen (equivalent to 15.2 mg or 30.4 mg, respectively, of tamoxifen citrate). - Each tablet contains the following inactive ingredients: croscarmellose sodium, hypromellose, lactose (monohydrate), magnesium stearate, polyethylene glycol 400, povidone, corn starch, and titanium dioxide. - Chemically, tamoxifen is the trans-isomer of a triphenylethylene derivative. The chemical name is (Z)2-(4-(1,2-diphenyl-1-butenyl)phenoxy)- N,N-dimethylethanamine 2-hydroxy-1,2,3- propanetricarboxylate (1:1). The structural formula, empirical formula, and molecular weight are as follows: - C32H37NO8 M.W. 563.62 - Tamoxifen citrate has a pKa’ of 8.85, the equilibrium solubility in water at 37°C is 0.5 mg/mL and in 0.02 N HCl at 37°C, it is 0.2 mg/mL. ## Pharmacodynamics - There is limited information regarding Pharmacodynamics of Tamoxifen in the drug label. ## Pharmacokinetics Absorption and Distribution - Following a single oral dose of 20 mg tamoxifen, an average peak plasma concentration of 40 ng/mL (range 35 to 45 ng/mL) occurred approximately 5 hours after dosing. The decline in plasma concentrations of tamoxifen is biphasic with a terminal elimination half-life of about 5 to 7 days. The average peak plasma concentration of N-desmethyl tamoxifen is 15 ng/mL (range 10 to 20 ng/mL). Chronic administration of 10 mg tamoxifen given twice daily for 3 months to patients results in average steady-state plasma concentrations of 120 ng/mL (range 67 to 183 ng/mL) for tamoxifen and 336 ng/mL (range 148 to 654 ng/mL) for N-desmethyl tamoxifen. The average steady-state plasma concentrations of tamoxifen and N-desmethyl tamoxifen after administration of 20 mg tamoxifen once daily for 3 months are 122 ng/mL (range 71 to 183 ng/mL) and 353 ng/mL (range 152 to 706 ng/mL), respectively. After initiation of therapy, steady-state concentrations for tamoxifen are achieved in about 4 weeks and steady-state concentrations for N-desmethyl tamoxifen are achieved in about 8 weeks, suggesting a half-life of approximately 14 days for this metabolite. In a steady-state, crossover study of 10 mg tamoxifen citrate tablets given twice a day vs. a 20 mg tamoxifen citrate tablet given once daily, the 20 mg tamoxifen citrate tablet was bioequivalent to the 10 mg tamoxifen citrate tablets. Metabolism - Tamoxifen is extensively metabolized after oral administration. N-desmethyl tamoxifen is the major metabolite found in patients’ plasma. The biological activity of N-desmethyl tamoxifen appears to be similar to that of tamoxifen. 4-Hydroxytamoxifen and a side chain primary alcohol derivative of tamoxifen have been identified as minor metabolites in plasma. Tamoxifen is a substrate of cytochrome P-450 3A, 2C9 and 2D6, and an inhibitor of P-glycoprotein. Excretion - Studies in women receiving 20 mg of 14C tamoxifen have shown that approximately 65% of the administered dose was excreted from the body over a period of 2 weeks with fecal excretion as the primary route of elimination. The drug is excreted mainly as polar conjugates, with unchanged drug and unconjugated metabolites accounting for less than 30% of the total fecal radioactivity. Special Populations - The effects of age, gender and race on the pharmacokinetics of tamoxifen have not been determined. The effects of reduced liver function on the metabolism and pharmacokinetics of tamoxifen have not been determined. Pediatric Patients - The pharmacokinetics of tamoxifen and N-desmethyl tamoxifen were characterized using a population pharmacokinetic analysis with sparse samples per patient obtained from 27 female pediatric patients aged 2 to 10 years enrolled in a study designed to evaluate the safety, efficacy, and pharmacokinetics of tamoxifen in treating McCune-Albright syndrome. Rich data from two tamoxifen citrate pharmacokinetic trials in which 59 postmenopausal women with breast cancer completed the studies were included in the analysis to determine the structural pharmacokinetic model for tamoxifen. A one-compartment model provided the best fit to the data. - In pediatric patients, an average steady-state peak plasma concentration (Css, max) and AUC were of 187 ng/mL and 4,110 ng hr/mL, respectively, and Css, max occurred approximately 8 hours after dosing. Clearance (CL/F) as body weight adjusted in female pediatric patients was approximately 2.3 fold higher than in female breast cancer patients. In the youngest cohort of female pediatric patients (2 to 6 year olds), CL/F was 2.6 fold higher; in the oldest cohort (7 to 10.9 year olds) CL/F was approximately 1.9 fold higher. Exposure to N-desmethyl tamoxifen was comparable between the pediatric and adult patients. The safety and efficacy of tamoxifen for girls aged 2 to 10 years with McCune-Albright syndrome and precocious puberty have not been studied beyond one year of treatment. The long-term effects of tamoxifen therapy in girls have not been established. In adults treated with tamoxifen an increase in incidence of uterine malignancies, stroke and pulmonary embolism has been noted . Drug-Drug Interactions - In vitro studies showed that erythromycin, cyclosporin, nifedipine and diltiazem competitively inhibited formation of N-desmethyl tamoxifen with apparent K1 of 20, 1, 45 and 30 µM, respectively. The clinical significance of these in vitro studies is unknown. - Tamoxifen reduced the plasma concentration of letrozole by 37% when these drugs were coadministered. Rifampin, a cytochrome P-450 3A4 inducer reduced tamoxifen AUC and Cmax by 86% and 55%, respectively. Aminoglutethimide reduces tamoxifen and N-desmethyl tamoxifen plasma concentrations. Medroxyprogesterone reduces plasma concentrations of N-desmethyl, but not tamoxifen. - In the anastrozole adjuvant trial, coadministration of anastrozole and tamoxifen in breast cancer patients reduced anastrozole plasma concentration by 27% compared to those achieved with anastrozole alone; however, the coadministration did not affect the pharmacokinetics of tamoxifen or N-desmethyltamoxifen . Tamoxifen should not be coadministered with anastrozole. ## Nonclinical Toxicology Carcinogenesis - A conventional carcinogenesis study in rats at doses of 5, 20, and 35 mg/kg/day (about one, three and seven-fold the daily maximum recommended human dose on a mg/m2 basis) administered by oral gavage for up to 2 years revealed a significant increase in hepatocellular carcinoma at all doses. The incidence of these tumors was significantly greater among rats administered 20 or 35 mg/kg/day (69%) compared to those administered 5 mg/kg/day (14%). In a separate study, rats were administered tamoxifen at 45 mg/kg/day (about nine-fold the daily maximum recommended human dose on a mg/m2 basis); hepatocellular neoplasia was exhibited at 3 to 6 months. - Granulosa cell ovarian tumors and interstitial cell testicular tumors were observed in 2 separate mouse studies. The mice were administered the trans and racemic forms of tamoxifen for 13 to 15 months at doses of 5, 20, and 50 mg/kg/day (about one-half, two, and five-fold the daily recommended human dose on a mg/m2 basis). Mutagenesis - No genotoxic potential was found in a conventional battery of in vivo and in vitro tests with pro- and eukaryotic test systems with drug metabolizing systems. However, increased levels of DNA adducts were observed by 32P post-labeling in DNA from rat liver and cultured human lymphocytes. Tamoxifen also has been found to increase levels of micronucleus formation in vitro in human lymphoblastoid cell line (MCL-5). Based on these findings, tamoxifen is genotoxic in rodent and human MCL-5 cells. Impairment of Fertility - Tamoxifen produced impairment of fertility and conception in female rats at doses of 0.04 mg/kg/day (about 0.01 fold the daily maximum recommended human dose on a mg/m2 basis) when dosed for two weeks prior to mating through day 7 of pregnancy. At this dose, fertility and reproductive indices were markedly reduced with total fetal mortality. Fetal mortality was also increased at doses of 0.16 mg/kg/day (about 0.03 fold the daily maximum recommended human dose on a mg/m2 basis) when female rats were dosed from days 7 to 17 of pregnancy. Tamoxifen produced abortion, premature delivery and fetal death in rabbits administered doses equal to or greater than 0.125 mg/kg/day (about 0.05 fold the daily maximum recommended human dose on a mg/m2 basis). There were no teratogenic changes in either rats or rabbits. # Clinical Studies Metastatic Breast Cancer Premenopausal women (tamoxifen vs. ablation) - Three prospective, randomized studies (Ingle, Pritchard, Buchanan) compared tamoxifen to ovarian ablation (oophorectomy or ovarian irradiation) in premenopausal women with advanced breast cancer. Although the objective response rate, time to treatment failure, and survival were similar with both treatments, the limited patient accrual prevented a demonstration of equivalence. In an overview analysis of survival data from the 3 studies, the hazard ratio for death (tamoxifen/ovarian ablation) was 1.00 with two-sided 95% confidence intervals of 0.73 to 1.37. Elevated serum and plasma estrogens have been observed in premenopausal women receiving tamoxifen, but the data from the randomized studies do not suggest an adverse effect of this increase. A limited number of premenopausal patients with disease progression during tamoxifen therapy responded to subsequent ovarian ablation. Male breast cancer - Published results from 122 patients (119 evaluable) and case reports in 16 patients (13 evaluable) treated with tamoxifen have shown that tamoxifen is effective for the palliative treatment of male breast cancer. Sixty-six of these 132 evaluable patients responded to tamoxifen which constitutes a 50% objective response rate. Adjuvant Breast Cancer Overview - The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) conducted worldwide overviews of systemic adjuvant therapy for early breast cancer in 1985, 1990, and again in 1995. In 1998, 10 year outcome data were reported for 36,689 women in 55 randomized trials of adjuvant tamoxifen using doses of 20 to 40 mg/day for 1 to 5+ years. Twenty-five percent of patients received 1 year or less of trial treatment, 52% received 2 years, and 23% received about 5 years. Forty-eight percent of tumors were estrogen receptor (ER) positive (> 10 fmol/mg), 21% were ER poor (< 10 fmol/l), and 31% were ER unknown. Among 29,441 patients with ER positive or unknown breast cancer, 58% were entered into trials comparing tamoxifen to no adjuvant therapy and 42% were entered into trials comparing tamoxifen in combination with chemotherapy vs. the same chemotherapy alone. Among these patients, 54% had node positive disease and 46% had node negative disease. - Among women with ER positive or unknown breast cancer and positive nodes who received about 5 years of treatment, overall survival at 10 years was 61.4% for tamoxifen vs. 50.5% for control (logrank 2p < 0.00001). The recurrence-free rate at 10 years was 59.7% for tamoxifen vs. 44.5% for control (logrank 2p < 0.00001). Among women with ER positive or unknown breast cancer and negative nodes who received about 5 years of treatment, overall survival at 10 years was 78.9% for tamoxifen vs. 73.3% for control (logrank 2p < 0.00001). The recurrence-free rate at 10 years was 79.2% for tamoxifen vs. 64.3% for control (logrank 2p < 0.00001). - The effect of the scheduled duration of tamoxifen may be described as follows. In women with ER positive or unknown breast cancer receiving 1 year or less, 2 years or about 5 years of tamoxifen, the proportional reductions in mortality were 12%, 17% and 26%, respectively (trend significant at 2p < 0.003). The corresponding reductions in breast cancer recurrence were 21%, 29% and 47% (trend significant at 2p < 0.00001). - Benefit is less clear for women with ER poor breast cancer in whom the proportional reduction in recurrence was 10% (2p = 0.007) for all durations taken together, or 9% (2p = 0.02) if contralateral breast cancers are excluded. The corresponding reduction in mortality was 6% (NS). The effects of about 5 years of tamoxifen on recurrence and mortality were similar regardless of age and concurrent chemotherapy. There was no indication that doses greater than 20 mg per day were more effective. Anastrozole adjuvant ATAC trial – study of anastrozole compared to tamoxifen for adjuvant treatment of early breast cancer - An anastrozole adjuvant trial was conducted in 9,366 postmenopausal women with operable breast cancer who were randomized to receive adjuvant treatment with either anastrozole 1 mg daily, tamoxifen 20 mg daily, or a combination of these two treatments for 5 years or until recurrence of the disease. At a median follow-up of 33 months, the combination of anastrozole and tamoxifen did not demonstrate any efficacy benefit when compared with tamoxifen therapy alone in all patients as well as in the hormone receptor-positive subpopulation. This treatment arm was discontinued from the trial. - Patients in the two monotherapy arms of the ATAC trial were treated for a median of 60 months (5 years) and followed for a median of 68 months. Disease-free survival in the intent-to-treat population was statistically significantly improved in the anastrozole arm compared to the tamoxifen arm. Node positive – individual studies - Two studies (Hubay and NSABP B-09) demonstrated an improved disease-free survival following radical or modified radical mastectomy in postmenopausal women or women 50 years of age or older with surgically curable breast cancer with positive axillary nodes when tamoxifen was added to adjuvant cytotoxic chemotherapy. In the Hubay study, tamoxifen was added to "low-dose" CMF (cyclophosphamide, methotrexate and fluorouracil). In the NSABP B-09 study, tamoxifen was added to melphalan and fluorouracil (F). - In the Hubay study, patients with a positive (more than 3 fmol) estrogen receptor were more likely to benefit. In the NSABP B-09 study in women age 50 to 59 years, only women with both estrogen and progesterone receptor levels 10 fmol or greater clearly benefited, while there was a nonstatistically significant trend toward adverse effect in women with both estrogen and progesterone receptor levels less than 10 fmol. In women age 60 to 70 years, there was a trend toward a beneficial effect of tamoxifen without any clear relationship to estrogen or progesterone receptor status. - Three prospective studies (ECOG-1178, Toronto, NATO) using tamoxifen adjuvantly as a single agent demonstrated an improved disease-free survival following total mastectomy and axillary dissection for postmenopausal women with positive axillary nodes compared to placebo/no treatment controls. The NATO study also demonstrated an overall survival benefit. Node negative – individual studies - NSABP B-14, a prospective, double-blind, randomized study, compared tamoxifen to placebo in women with axillary node-negative, estrogen-receptor positive (≥ 10 fmol/mg cytosol protein) breast cancer (as adjuvant therapy, following total mastectomy and axillary dissection, or segmental resection, axillary dissection, and breast radiation). After five years of treatment, there was a significant improvement in disease-free survival in women receiving tamoxifen. This benefit was apparent both in women under age 50 and in women at or beyond age 50. - One additional randomized study (NATO) demonstrated improved disease-free survival for tamoxifen compared to no adjuvant therapy following total mastectomy and axillary dissection in postmenopausal women with axillary node-negative breast cancer. In this study, the benefits of tamoxifen appeared to be independent of estrogen receptor status. Duration of therapy - In the EBCTCG 1995 overview, the reduction in recurrence and mortality was greater in those studies that used tamoxifen for about 5 years than in those that used tamoxifen for a shorter period of therapy. - In the NSABP B-14 trial, in which patients were randomized to tamoxifen 20 mg/day for 5 years vs. placebo and were disease-free at the end of this 5 year period were offered rerandomization to an additional 5 years of tamoxifen or placebo. With 4 years of follow-up after this rerandomization, 92% of the women that received 5 years of tamoxifen were alive and disease-free, compared to 86% of the women scheduled to receive 10 years of tamoxifen (p = 0.003). Overall survivals were 96% and 94%, respectively (p = 0.08). Results of the B-14 study suggest that continuation of therapy beyond 5 years does not provide additional benefit. - A Scottish trial of 5 years of tamoxifen vs. indefinite treatment found a disease-free survival of 70% in the five-year group and 61% in the indefinite group, with 6.2 years median follow-up (HR = 1.27, 95% CI: 0.87 to 1.85). - In a large randomized trial conducted by the Swedish Breast Cancer Cooperative Group of adjuvant tamoxifen 40 mg/day for 2 or 5 years, overall survival at 10 years was estimated to be 80% in the patients in the 5 year tamoxifen group, compared with 74% among corresponding patients in the 2 year treatment group (p = 0.03). Disease-free survival at 10 years was 73% in the 5 year group and 67% in the 2 year group (p = 0.009). Compared with 2 years of tamoxifen treatment, 5 years of treatment resulted in a slightly greater reduction in the incidence of contralateral breast cancer at 10 years, but this difference was not statistically significant. Contralateral breast cancer - The incidence of contralateral breast cancer is reduced in breast cancer patients (premenopausal and postmenopausal) receiving tamoxifen compared to placebo. Data on contralateral breast cancer are available from 32,422 out of 36,689 patients in the 1995 overview analysis of the Early Breast Cancer Trialists Collaborative Group (EBCTCG). In clinical trials with tamoxifen of 1 year or less, 2 years, and about 5 years duration, the proportional reductions in the incidence rate of contralateral breast cancer among women receiving tamoxifen were 13% (NS), 26% (2p = 0.004) and 47% (2p < 0.00001), with a significant trend favoring longer tamoxifen duration (2p = 0.008). The proportional reductions in the incidence of contralateral breast cancer were independent of age and ER status of the primary tumor. Treatment with about 5 years of tamoxifen reduced the annual incidence rate of contralateral breast cancer from 7.6 per 1,000 patients in the control group compared with 3.9 per 1,000 patients in the tamoxifen group. - In a large randomized trial in Sweden (the Stockholm Trial) of adjuvant tamoxifen 40 mg/day for 2 to 5 years, the incidence of second primary breast tumors was reduced 40% (p < 0.008) on tamoxifen compared to control. In the NSABP B-14 trial in which patients were randomized to tamoxifen 20 mg/day for 5 years vs. placebo, the incidence of second primary breast cancers was also significantly reduced (p < 0.01). In NSABP B-14, the annual rate of contralateral breast cancer was 8.0 per 1,000 patients in the placebo group compared with 5.0 per 1,000 patients in the tamoxifen group, at 10 years after first randomization. Ductal Carcinoma in Situ - NSABP B-24, a double-blind, randomized trial included women with ductal carcinoma in situ (DCIS). This trial compared the addition of tamoxifen or placebo to treatment with lumpectomy and radiation therapy for women with DCIS. The primary objective was to determine whether 5 years of tamoxifen therapy (20 mg/day) would reduce the incidence of invasive breast cancer in the ipsilateral (the same) or contralateral (the opposite) breast. - In this trial 1,804 women were randomized to receive either tamoxifen or placebo for 5 years: 902 women were randomized to tamoxifen citrate 10 mg tablets twice a day and 902 women were randomized to placebo. As of December 31, 1998, follow-up data were available for 1,798 women and the median duration of follow-up was 74 months. - The tamoxifen and placebo groups were well balanced for baseline demographic and prognostic factors. Over 80% of the tumors were less than or equal to 1 cm in their maximum dimension, were not palpable, and were detected by mammography alone. Over 60% of the study population was postmenopausal. In 16% of patients, the margin of the resected specimen was reported as being positive after surgery. Approximately half of the tumors were reported to contain comedo necrosis. - For the primary endpoint, the incidence of invasive breast cancer was reduced by 43% among women assigned to tamoxifen (44 cases-tamoxifen, 74 cases-placebo; p = 0.004; relative risk (RR) = 0.57, 95% CI: 0.39 to 0.84). No data are available regarding the ER status of the invasive cancers. The stage distribution of the invasive cancers at diagnosis was similar to that reported annually in the SEER data base. - Results are shown in Table 1. For each endpoint the following results are presented: the number of events and rate per 1,000 women per year for the placebo and tamoxifen groups; and the relative risk (RR) and its associated 95% confidence interval (CI) between tamoxifen and placebo. Relative risks less than 1.0 indicate a benefit of tamoxifen therapy. The limits of the confidence intervals can be used to assess the statistical significance of the benefits of tamoxifen therapy. If the upper limit of the CI is less than 1.0, then a statistically significant benefit exists. - Survival was similar in the placebo and tamoxifen groups. At 5 years from study entry, survival was 97% for both groups. Reduction in Breast Cancer Incidence in High Risk Women - The Breast Cancer Prevention Trial (BCPT, NSABP P-1) was a double-blind, randomized, placebo-controlled trial with a primary objective to determine whether 5 years of tamoxifen therapy (20 mg/day) would reduce the incidence of invasive breast cancer in women at high risk for the disease . Secondary objectives included an evaluation of the incidence of ischemic heart disease; the effects on the incidence of bone fractures; and other events that might be associated with the use of tamoxifen, including: endometrial cancer, pulmonary embolus, deep-vein thrombosis, stroke, and cataract formation and surgery . - The Gail Model was used to calculate predicted breast cancer risk for women who were less than 60 years of age and did not have lobular carcinoma in situ (LCIS). The following risk factors were used: age; number of first-degree female relatives with breast cancer; previous breast biopsies; presence or absence of atypical hyperplasia; nulliparity; age at first live birth; and age at menarche. A 5 year predicted risk of breast cancer of ≥ 1.67% was required for entry into the trial. - In this trial, 13,388 women of at least 35 years of age were randomized to receive either tamoxifen or placebo for five years. The median duration of treatment was 3.5 years. As of January 31, 1998, follow-up data is available for 13,114 women. Twenty-seven percent of women randomized to placebo (1,782) and 24% of women randomized to tamoxifen (1,596) completed 5 years of therapy. The demographic characteristics of women on the trial with follow-up data are shown in Table 2. - Results are shown in Table 3. After a median follow-up of 4.2 years, the incidence of invasive breast cancer was reduced by 44% among women assigned to tamoxifen (86 cases-tamoxifen, 156 cases-placebo; p < 0.00001; relative risk (RR) = 0.56, 95% CI: 0.43 to 0.72). A reduction in the incidence of breast cancer was seen in each prospectively specified age group (≤ 49, 50 to 59, ≥ 60), in women with or without LCIS, and in each of the absolute risk levels specified in Table 3. A non-significant decrease in the incidence of ductal carcinoma in situ (DCIS) was seen (23 tamoxifen, 35 placebo; RR = 0.66, 95% CI: 0.39 to 1.11). - There was no statistically significant difference in the number of myocardial infarctions, severe angina, or acute ischemic cardiac events between the two groups (61 tamoxifen, 59 placebo; RR = 1.04, 95% CI: 0.73 to 1.49). - No overall difference in mortality (53 deaths in tamoxifen group vs. 65 deaths in placebo group) was present. No difference in breast cancer-related mortality was observed (4 deaths in tamoxifen group vs. 5 deaths in placebo group). - Although there was a non-significant reduction in the number of hip fractures (9 on tamoxifen, 20 on placebo) in the tamoxifen group, the number of wrist fractures was similar in the two treatment groups (69 on tamoxifen, 74 on placebo). A subgroup analysis of the P-1 trial, suggests a difference in effect in bone mineral density (BMD) related to menopausal status in patients receiving tamoxifen. In postmenopausal women there was no evidence of bone loss of the lumbar spine and hip. Conversely, tamoxifen was associated with significant bone loss of the lumbar spine and hip in premenopausal women. - The risks of tamoxifen therapy include endometrial cancer, DVT, PE, stroke, cataract formation, and cataract surgery (see Table 3). In the NSABP P-1 trial, 33 cases of endometrial cancer were observed in the tamoxifen group vs. 14 in the placebo group (RR = 2.48, 95% CI: 1.27 to 4.92). Deep-vein thrombosis was observed in 30 women receiving tamoxifen vs. 19 in women receiving placebo (RR = 1.59, 95% CI: 0.86 to 2.98). Eighteen cases of pulmonary embolism were observed in the tamoxifen group vs. 6 in the placebo group (RR = 3.01, 95% CI: 1.15 to 9.27). There were 34 strokes on the tamoxifen arm and 24 on the placebo arm (RR = 1.42, 95% CI: 0.82 to 2.51). Cataract formation in women without cataracts at baseline was observed in 540 women taking tamoxifen vs. 483 women receiving placebo (RR = 1.13, 95% CI: 1.00 to 1.28). Cataract surgery (with or without cataracts at baseline) was performed in 201 women taking tamoxifen vs. 129 women receiving placebo (RR = 1.51, 95% CI: 1.21 to 1.89) . - Table 3 summarizes the major outcomes of the NSABP P-1 trial. For each endpoint, the following results are presented: the number of events and rate per 1,000 women per year for the placebo and tamoxifen groups; and the relative risk (RR) and its associated 95% confidence interval (CI) between tamoxifen and placebo. Relative risks less than 1.0 indicate a benefit of tamoxifen therapy. The limits of the confidence intervals can be used to assess the statistical significance of the benefits or risks of tamoxifen therapy. If the upper limit of the CI is less than 1.0, then a statistically significant benefit exists. - For most participants, multiple risk factors would have been required for eligibility. This table considers risk factors individually, regardless of other co-existing risk factors, for women who developed breast cancer. The 5 year predicted absolute breast cancer risk accounts for multiple risk factors in an individual and should provide the best estimate of individual benefit . - Table 4 describes the characteristics of the breast cancers in the NSABP P-1 trial and includes tumor size, nodal status, ER status. Tamoxifen decreased the incidence of small estrogen receptor positive tumors, but did not alter the incidence of estrogen receptor negative tumors or larger tumors. - Interim results from 2 trials in addition to the NSABP P-1 trial examining the effects of tamoxifen in reducing breast cancer incidence have been reported. - The first was the Italian Tamoxifen Prevention trial. In this trial women between the ages of 35 and 70, who had had a total hysterectomy, were randomized to receive 20 mg tamoxifen or matching placebo for 5 years. The primary endpoints were occurrence of, and death from, invasive breast cancer. Women without any specific risk factors for breast cancer were to be entered. Between 1992 and 1997, 5,408 women were randomized. Hormone Replacement Therapy (HRT) was used in 14% of participants. The trial closed in 1997 due to the large number of dropouts during the first year of treatment (26%). After 46 months of follow-up there were 22 breast cancers in women on placebo and 19 in women on tamoxifen. Although no decrease in breast cancer incidence was observed, there was a trend for reduction in breast cancer among women receiving protocol therapy for at least 1 year (19 placebo, 11 tamoxifen). The small numbers of participants along with the low level of risk in this otherwise healthy group precluded an adequate assessment of the effect of tamoxifen in reducing the incidence of breast cancer. - The second trial, the Royal Marsden Trial (RMT) was reported as an interim analysis. The RMT was begun in 1986 as a feasibility study of whether larger scale trials could be mounted. The trial was subsequently extended to a pilot trial to accrue additional participants to further assess the safety of tamoxifen. Twenty-four hundred and seventy-one women were entered between 1986 and 1996; they were selected on the basis of a family history of breast cancer. HRT was used in 40% of participants. In this trial, with a 70 month median follow-up, 34 and 36 breast cancers (8 noninvasive, 4 on each arm) were observed among women on tamoxifen and placebo, respectively. Patients in this trial were younger than those in the NSABP P-1 trial and may have been more likely to develop ER (-) tumors, which are unlikely to be reduced in number by tamoxifen therapy. Although women were selected on the basis of family history and were thought to have a high risk of breast cancer, few events occurred, reducing the statistical power of the study. These factors are potential reasons why the RMT may not have provided an adequate assessment of the effectiveness of tamoxifen in reducing the incidence of breast cancer. - In these trials, an increased number of cases of deep-vein thrombosis, pulmonary embolus, stroke, and endometrial cancer were observed on the tamoxifen arm compared to the placebo arm. The frequency of events was consistent with the safety data observed in the NSABP P-1 trial. McCune-Albright Syndrome - A single, uncontrolled multicenter trial of tamoxifen 20 mg once a day was conducted in a heterogenous group of girls with McCune-Albright syndrome and precocious puberty manifested by physical signs of pubertal development, episodes of vaginal bleeding and/or advanced bone age (bone age of at least 12 months beyond chronological age). Twenty-eight female pediatric patients, aged 2 to 10 years, were treated for up to 12 months. Effect of treatment on frequency of vaginal bleeding, bone age advancement, and linear growth rate was assessed relative to prestudy baseline. Tamoxifen treatment was associated with a 50% reduction in frequency of vaginal bleeding episodes by patient or family report (mean annualized frequency of 3.56 episodes at baseline and 1.73 episodes on-treatment). Among the patients who reported vaginal bleeding during the prestudy period, 62% (13 out of 21 patients) reported no bleeding for a 6 month period and 33% (7 out of 21 patients) reported no vaginal bleeding for the duration of the trial. Not all patients improved on treatment and a few patients not reporting vaginal bleeding in the 6 months prior to enrollment reported menses on treatment. Tamoxifen therapy was associated with a reduction in mean rate of increase of bone age. Individual responses with regard to bone age advancement were highly heterogeneous. Linear growth rate was reduced during the course of tamoxifen treatment in a majority of patients (mean change of 1.68 cm/year relative to baseline; change from 7.47 cm/year at baseline to 5.79 cm/year on study). This change was not uniformly seen across all stages of bone maturity; all recorded response failures occurred in patients with bone ages less than 7 years at screening. - Mean uterine volume increased after 6 months of treatment and doubled at the end of the one-year study. A causal relationship has not been established; however, as an increase in the incidence of endometrial adenocarcinoma and uterine sarcoma has been noted in adults treated with tamoxifen , continued monitoring of McCune-Albright patients treated with tamoxifen for long-term uterine effects is recommended. The safety and efficacy of tamoxifen for girls aged 2 to 10 years with McCune-Albright syndrome and precocious puberty have not been studied beyond one year of treatment. The long-term effects of tamoxifen therapy in girls have not been established. # How Supplied - Tamoxifen citrate tablets USP, 10 mg (base) are white, round, biconvex, film-coated, unscored tablets debossed “93” and “784” and are supplied in bottles of 30, 50, 60, 90 and 100. ## Storage - Store at 20° to 25°C (68° to 77°F) . - Dispense in a well-closed, light-resistant container as defined in the USP, with a child-resistant closure (as required). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information # Precautions with Alcohol - Alcohol-Tamoxifen interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names Nolvadex, Soltamox. # Look-Alike Drug Names There is limited information regarding Tamoxifen Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Tamoxifen Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Deepika Beereddy, MBBS [2];Aparna Vuppala, M.B.B.S. [3] # 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 Tamoxifen is an antineoplastic agent, antiestrogen that is FDA approved for the treatment of metastatic breast cancer, ductal carcinoma in situ (DCIS), adjuvant treatment of breast cancer,. There is a Black Box Warning for this drug as shown here. Common adverse reactions include menopausal flushing, irregular periods, vaginal discharge. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Tamoxifen citrate tablets are indicated for the treatment of node-positive breast cancer in women following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation. In some tamoxifen adjuvant studies, most of the benefit to date has been in the subgroup with four or more positive axillary nodes. - Tamoxifen citrate tablets are indicated for the treatment of axillary node-negative breast cancer in women following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation. - The \|estrogen and progesterone receptor values may help to predict whether adjuvant tamoxifen therapy is likely to be beneficial. - Tamoxifen reduces the occurrence of contralateral breast cancer in patients receiving adjuvant tamoxifen therapy for breast cancer. - Dosing Information - For patients with breast cancer, the recommended daily dose is 20 to 40 mg. Dosages greater than 20 mg per day should be given in divided doses (morning and evening). - In three single agent adjuvant studies in women, one 10 mg tamoxifen citrate tablet was administered two (ECOG and NATO) or three (Toronto) times a day for two years. In the NSABP B-14 adjuvant study in women with node-negative breast cancer, one 10 mg tamoxifen citrate tablet was given twice a day for at least 5 years. Results of the B-14 study suggest that continuation of therapy beyond five years does not provide additional benefit . In the EBCTCG 1995 overview, the reduction in recurrence and mortality was greater in those studies that used tamoxifen for about 5 years than in those that used tamoxifen for a shorter period of therapy. There was no indication that doses greater than 20 mg per day were more effective. Current data from clinical trials support 5 years of adjuvant tamoxifen therapy for patients with breast cancer. - Tamoxifen citrate tablets are indicated to reduce the incidence of breast cancer in women at high risk for breast cancer. This effect was shown in a study of 5 years planned duration with a median follow-up of 4.2 years. Twenty-five percent of the participants received drug for 5 years. The longer-term effects are not known. In this study, there was no impact of tamoxifen on overall or breast cancer-related mortality . - Tamoxifen citrate tablets are indicated only for high-risk women. “High risk” is defined as women at least 35 years of age with a 5 year predicted risk of breast cancer ≥ 1.67%, as calculated by the Gail Model. - Examples of combinations of factors predicting a 5 year risk ≥ 1.67% are: - Age 35 or older and any of the following combination of factors: - One first degree relative with a history of breast cancer, 2 or more benign biopsies, and a history of a breast biopsy showing atypical hyperplasia; or - At least 2 first degree relatives with a history of breast cancer, and a personal history of at least 1 breast biopsy; or - LCIS - Age 40 or older and any of the following combination of factors: - One first degree relative with a history of breast cancer, 2 or more benign biopsies, age at first live birth 25 or older, and age at menarche 11 or younger; or - At least 2 first degree relatives with a history of breast cancer, and age at first live birth 19 or younger; or - One first degree relative with a history of breast cancer, and a personal history of a breast biopsy showing atypical hyperplasia. - Age 45 or older and any of the following combination of factors: - At least 2 first degree relatives with a history of breast cancer and age at first live birth 24 or younger; or - One first degree relative with a history of breast cancer with a personal history of a benign breast biopsy, age at menarche 11 or less and age at first live birth 20 or more. - Age 50 or older and any of the following combination of factors: - At least 2 first degree relatives with a history of breast cancer; or - History of 1 breast biopsy showing atypical hyperplasia, and age at first live birth 30 or older and age at menarche 11 or less; or - History of at least 2 breast biopsies with a history of atypical hyperplasia, and age at first live birth 30 or more. - Age 55 or older and any of the following combination of factors: - One first degree relative with a history of breast cancer with a personal history of a benign breast biopsy, and age at menarche 11 or less; or - History of at least 2 breast biopsies with a history of atypical hyperplasia, and age at first live birth 20 or older. - Age 60 or older and: - Five-year predicted risk of breast cancer ≥ 1.67%, as calculated by the Gail Model. - For women whose risk factors are not described in the above examples, the Gail Model is necessary to estimate absolute breast cancer risk. Health Care Professionals can obtain a Gail Model Risk Assessment Tool by dialing 1-888-838-2872. - There are insufficient data available regarding the effect of tamoxifen on breast cancer incidence in women with inherited mutations (BRCA1, BRCA2) to be able to make specific recommendations on the effectiveness of tamoxifen in these patients. - After an assessment of the risk of developing breast cancer, the decision regarding therapy with tamoxifen for the reduction in breast cancer incidence should be based upon an individual assessment of the benefits and risks of tamoxifen therapy. In the NSABP P-1 trial, tamoxifen treatment lowered the risk of developing breast cancer during the follow-up period of the trial, but did not eliminate breast cancer risk. - Dosing Information - The recommended dose is tamoxifen 20 mg daily for 5 years. There are no data to support the use of tamoxifen other than for 5 years. - In women with DCIS, following breast surgery and radiation, tamoxifen citrate tablets are indicated to reduce the risk of invasive breast cancer . The decision regarding therapy with tamoxifen for the reduction in breast cancer incidence should be based upon an individual assessment of the benefits and risks of tamoxifen therapy. - Current data from clinical trials support 5 years of adjuvant tamoxifen therapy for patients with breast cancer. - Dosing Information - The recommended dose is tamoxifen 20 mg daily for 5 years. ### Metastatic breast cancer - Tamoxifen citrate tablets are effective in the treatment of metastatic breast cancer in women and men. In premenopausal women with metastatic breast cancer, tamoxifen is an alternative to oophorectomy or ovarian irradiation. Available evidence indicates that patients whose tumors are estrogen receptor positive are more likely to benefit from tamoxifen therapy. - Dosing Information - 20-40 mg ORALLY daily ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Tamoxifen in adult patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Tamoxifen in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - There is limited information regarding FDA-Labeled Use of Tamoxifen in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Tamoxifen in pediatric patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Tamoxifen in pediatric patients. # Contraindications - Tamoxifen is contraindicated in patients with known hypersensitivity to the drug or any of its ingredients. - Reduction in Breast Cancer Incidence in High Risk Women and Women with DCIS: - Tamoxifen is contraindicated in women who require concomitant coumarin-type anticoagulant therapy or in women with a history of deep vein thrombosis or pulmonary embolus. # Warnings Effects in Metastatic Breast Cancer Patients - As with other additive hormonal therapy (estrogens and androgens), hypercalcemia has been reported in some breast cancer patients with bone metastases within a few weeks of starting treatment with tamoxifen. If hypercalcemia does occur, appropriate measures should be taken and, if severe, tamoxifen should be discontinued. Effects on the Uterus-Endometrial Cancer and Uterine Sarcoma - An increased incidence of uterine malignancies has been reported in association with tamoxifen treatment. The underlying mechanism is unknown, but may be related to the estrogen-like effect of tamoxifen. Most uterine malignancies seen in association with tamoxifen are classified as adenocarcinoma of the endometrium. However, rare uterine sarcomas, including malignant mixed mullerian tumors (MMMT), have also been reported. Uterine sarcoma is generally associated with a higher FIGO stage (III/IV) at diagnosis, poorer prognosis, and shorter survival. Uterine sarcoma has been reported to occur more frequently among long-term users (≥ 2 years) of tamoxifen than non-users. Some of the uterine malignancies (endometrial carcinoma or uterine sarcoma) have been fatal. - In the NSABP P-1 trial, among participants randomized to tamoxifen there was a statistically significant increase in the incidence of endometrial cancer (33 cases of invasive endometrial cancer, compared to 14 cases among participants randomized to placebo (RR = 2.48, 95% CI: 1.27 to 4.92). The 33 cases in participants receiving tamoxifen were FIGO Stage I, including 20 IA, 12 IB, and 1 IC endometrial adenocarcinomas. In participants randomized to placebo, 13 were FIGO Stage I (8 IA and 5 IB) and 1 was FIGO Stage IV. Five women on tamoxifen and 1 on placebo received postoperative radiation therapy in addition to surgery. This increase was primarily observed among women at least 50 years of age at the time of randomization (26 cases of invasive endometrial cancer, compared to 6 cases among participants randomized to placebo (RR = 4.50, 95% CI: 1.78 to 13.16). Among women ≤ 49 years of age at the time of randomization there were 7 cases of invasive endometrial cancer, compared to 8 cases among participants randomized to placebo (RR = 0.94, 95% CI: 0.28 to 2.89). If age at the time of diagnosis is considered, there were 4 cases of endometrial cancer among participants ≤ 49 randomized to tamoxifen compared to 2 among participants randomized to placebo (RR = 2.21, 95% CI: 0.4 to 12.0). For women ≥ 50 at the time of diagnosis, there were 29 cases among participants randomized to tamoxifen compared to 12 among women on placebo (RR = 2.5, 95% CI: 1.3 to 4.9). The risk ratios were similar in the two groups, although fewer events occurred in younger women. Most (29 of 33 cases in the tamoxifen group) endometrial cancers were diagnosed in symptomatic women, although 5 of 33 cases in the tamoxifen group occurred in asymptomatic women. Among women receiving tamoxifen the events appeared between 1 and 61 months (average = 32 months) from the start of treatment. - In an updated review of long-term data (median length of total follow-up is 6.9 years, including blinded follow-up) on 8,306 women with an intact uterus at randomization in the NSABP P-1 risk reduction trial, the incidence of both adenocarcinomas and rare uterine sarcomas was increased in women taking tamoxifen. During blinded follow-up, there were 36 cases of FIGO Stage I endometrial adenocarcinoma (22 were FIGO Stage IA, 13 IB, and 1 IC) in women receiving tamoxifen and 15 cases in women receiving placebo [14 were FIGO Stage I (9 IA and 5 IB), and 1 case was FIGO Stage IV]. Of the patients receiving tamoxifen who developed endometrial cancer, one with Stage IA and 4 with Stage IB cancers received radiation therapy. In the placebo group, one patient with FIGO Stage IB cancer received radiation therapy and the patient with FIGO Stage IVB cancer received chemotherapy and hormonal therapy. During total follow-up, endometrial adenocarcinoma was reported in 53 women randomized to tamoxifen (30 cases of FIGO Stage IA, 20 were Stage IB, 1 was Stage IC, and 2 were Stage IIIC), and 17 women randomized to placebo (9 cases were FIGO Stage IA, 6 were Stage IB, 1 was Stage IIIC, and 1 was Stage IVB) (incidence per 1,000 women-years of 2.20 and 0.71, respectively). Some patients received postoperative radiation therapy in addition to surgery. Uterine sarcomas were reported in 4 women randomized to tamoxifen (1 was FIGO IA, 1 was FIGO IB, 1 was FIGO IIA, and 1 was FIGO IIIC) and 1 patient randomized to placebo (FIGO 1A); incidence per 1,000 women-years of 0.17 and 0.04, respectively. Of the patients randomized to tamoxifen, the FIGO IA and IB cases were a MMMT and sarcoma, respectively; the FIGO II was a MMMT; and the FIGO III was a sarcoma; and the 1 patient randomized to placebo had a MMMT. A similar increased incidence in endometrial adenocarcinoma and uterine sarcoma was observed among women receiving tamoxifen in 5 other NSABP clinical trials. - Any patient receiving or who has previously received tamoxifen who reports vaginal bleeding should be promptly evaluated. Patients receiving or who have previously received tamoxifen should have annual gynecological examinations and they should promptly inform their physicians if they experience any abnormal gynecological symptoms, e.g., menstrual irregularities, abnormal vaginal bleeding, changes in vaginal discharge, or pelvic pain or pressure. - In the P-1 trial, endometrial sampling did not alter the endometrial cancer detection rate compared to women who did not undergo endometrial sampling (0.6% with sampling, 0.5% without sampling) for women with an intact uterus. There are no data to suggest that routine endometrial sampling in asymptomatic women taking tamoxifen to reduce the incidence of breast cancer would be beneficial. Non-Malignant Effects on the Uterus - An increased incidence of endometrial changes including hyperplasia and polyps has been reported in association with tamoxifen treatment. The incidence and pattern of this increase suggest that the underlying mechanism is related to the estrogenic properties of tamoxifen. - There have been a few reports of endometriosis and uterine fibroids in women receiving tamoxifen. The underlying mechanism may be due to the partial estrogenic effect of tamoxifen. Ovarian cysts have also been observed in a small number of premenopausal patients with advanced breast cancer who have been treated with tamoxifen. - Tamoxifen has been reported to cause menstrual irregularity or amenorrhea. Thromboembolic Effects of Tamoxifen - There is evidence of an increased incidence of thromboembolic events, including deep-vein thrombosis and pulmonary embolism, during tamoxifen therapy. When tamoxifen is coadministered with chemotherapy, there may be a further increase in the incidence of thromboembolic events. For treatment of breast cancer, the risks and benefits of tamoxifen should be carefully considered in women with a history of thromboembolic events. In a small substudy (N = 81) of the NSABP-1 trial, there appeared to be no benefit to screening women for Factor V Leiden and Prothrombin mutations G20210A as a means to identify those who may not be appropriate candidates for tamoxifen therapy. - Data from the NSABP P-1 trial show that participants receiving tamoxifen without a history of pulmonary emboli (PE) had a statistically significant increase in pulmonary emboli (18 tamoxifen, 6 placebo; RR = 3.01, 95% CI: 1.15 to 9.27). Three of the pulmonary emboli, all in the tamoxifen arm, were fatal. Eighty-seven percent of the cases of pulmonary embolism occurred in women at least 50 years of age at randomization. Among women receiving tamoxifen, the events appeared between 2 and 60 months (average = 27 months) from the start of treatment. - In this same population, a non-statistically significant increase in deep-vein thrombosis (DVT) was seen in the tamoxifen group (30-tamoxifen, 19-placebo; RR = 1.59, 95% CI: 0.86 to 2.98). The same increase in relative risk was seen in women ≤ 49 and in women ≥ 50, although fewer events occurred in younger women. Women with thromboembolic events were at risk for a second related event (7 out of 25 women on placebo, 5 out of 48 women on tamoxifen) and were at risk for complications of the event and its treatment (0/25 on placebo, 4/48 on tamoxifen). Among women receiving tamoxifen, deep-vein thrombosis events occurred between 2 and 57 months (average = 19 months) from the start of treatment. - There was a non-statistically significant increase in stroke among patients randomized to tamoxifen (24 placebo; 34 tamoxifen; RR = 1.42, 95% CI: 0.82 to 2.51). Six of the 24 strokes in the placebo group were considered hemorrhagic in origin and 10 of the 34 strokes in the tamoxifen group were categorized as hemorrhagic. Seventeen of the 34 strokes in the tamoxifen group were considered occlusive and 7 were considered to be of unknown etiology. Fourteen of the 24 strokes on the placebo arm were reported to be occlusive and 4 of unknown etiology. Among these strokes 3 strokes in the placebo group and 4 strokes in the tamoxifen group were fatal. Eighty-eight percent of the strokes occurred in women at least 50 years of age at the time of randomization. Among women receiving tamoxifen, the events occurred between 1 and 63 months (average = 30 months) from the start of treatment. Effects on the Liver: Liver Cancer - In the Swedish trial using adjuvant tamoxifen 40 mg/day for 2 to 5 years, 3 cases of liver cancer have been reported in the tamoxifen-treated group vs. 1 case in the observation group . In other clinical trials evaluating tamoxifen, no cases of liver cancer have been reported to date. - One case of liver cancer was reported in NSABP P-1 in a participant randomized to tamoxifen. Effects on the Liver: Non-Malignant Effects - Tamoxifen has been associated with changes in liver enzyme levels, and on rare occasions, a spectrum of more severe liver abnormalities including fatty liver, cholestasis, hepatitis and hepatic necrosis. A few of these serious cases included fatalities. In most reported cases the relationship to tamoxifen is uncertain. However, some positive rechallenges and dechallenges have been reported. - In the NSABP P-1 trial, few grade 3 to 4 changes in liver function (SGOT, SGPT, bilirubin, alkaline phosphatase) were observed (10 on placebo and 6 on tamoxifen). Serum lipids were not systematically collected. Other Cancers - A number of second primary tumors, occurring at sites other than the endometrium, have been reported following the treatment of breast cancer with tamoxifen in clinical trials. Data from the NSABP B-14 and P-1 studies show no increase in other (non-uterine) cancers among patients receiving tamoxifen. Whether an increased risk for other (non-uterine) cancers is associated with tamoxifen is still uncertain and continues to be evaluated. Effects on the Eye - Ocular disturbances, including corneal changes, decrement in color vision perception, retinal vein thrombosis, and retinopathy have been reported in patients receiving tamoxifen. An increased incidence of cataracts and the need for cataract surgery have been reported in patients receiving tamoxifen. - In the NSABP P-1 trial, an increased risk of borderline significance of developing cataracts among those women without cataracts at baseline (540 tamoxifen; 483 placebo; RR = 1.13, 95% CI: 1.00 to 1.28) was observed. Among these same women, tamoxifen was associated with an increased risk of having cataract surgery (101 tamoxifen; 63 placebo; RR = 1.62, 95% CI: 1.18 to 2.22). Among all women on the trial (with or without cataracts at baseline), tamoxifen was associated with an increased risk of having cataract surgery (201 tamoxifen; 129 placebo; RR = 1.58, 95% CI: 1.26 to 1.97). Eye examinations were not required during the study. No other conclusions regarding non-cataract ophthalmic events can be made. ### Precautions General - Decreases in platelet counts, usually to 50,000 to 100,000/mm3, infrequently lower, have been occasionally reported in patients taking tamoxifen for breast cancer. In patients with significant thrombocytopenia, rare hemorrhagic episodes have occurred, but it is uncertain if these episodes are due to tamoxifen therapy. Leukopenia has been observed, sometimes in association with anemia and/or thrombocytopenia. There have been rare reports of neutropenia and pancytopenia in patients receiving tamoxifen; this can sometimes be severe. - In the NSABP P-1 trial, 6 women on tamoxifen and 2 on placebo experienced grade 3 to 4 drops in platelet counts (≤ 50,000/mm3). Information for Patients - Patients should be instructed to read the Medication Guide supplied as required by law when tamoxifen is dispensed. The complete text of the Medication Guide is reprinted at the end of this document. Reduction in Invasive Breast Cancer and DCIS in Women With DCIS - Women with DCIS treated with lumpectomy and radiation therapy who are considering tamoxifen to reduce the incidence of a second breast cancer event should assess the risks and benefits of therapy, since treatment with tamoxifen decreased the incidence of invasive breast cancer, but has not been shown to affect survival . Reduction in Breast Cancer Incidence in High Risk Women - Women who are at high risk for breast cancer can consider taking tamoxifen therapy to reduce the incidence of breast cancer. Whether the benefits of treatment are considered to outweigh the risks depends on a woman’s personal health history and on how she weighs the benefits and risks. Tamoxifen therapy to reduce the incidence of breast cancer may therefore not be appropriate for all women at high risk for breast cancer. Women who are considering tamoxifen therapy should consult their health care professional for an assessment of the potential benefits and risks prior to starting therapy for reduction in breast cancer incidence . Women should understand that tamoxifen reduces the incidence of breast cancer, but may not eliminate risk. Tamoxifen decreased the incidence of small estrogen receptor positive tumors, but did not alter the incidence of estrogen receptor negative tumors or larger tumors. In women with breast cancer who are at high risk of developing a second breast cancer, treatment with about 5 years of tamoxifen reduced the annual incidence rate of a second breast cancer by approximately 50%. - Women who are pregnant or who plan to become pregnant should not take tamoxifen to reduce their risk of breast cancer. Effective nonhormonal contraception must be used by all premenopausal women taking tamoxifen and for approximately two months after discontinuing therapy if they are sexually active. Tamoxifen does not cause infertility, even in the presence of menstrual irregularity. For sexually active women of child-bearing potential, tamoxifen therapy should be initiated during menstruation. In women with menstrual irregularity, a negative B-HCG immediately prior to the initiation of therapy is sufficient - Two European trials of tamoxifen to reduce the risk of breast cancer were conducted and showed no difference in the number of breast cancer cases between the tamoxifen and placebo arms. These studies had trial designs that differed from that of NSABP P-1, were smaller than NSABP P-1, and enrolled women at a lower risk for breast cancer than those in P-1. Monitoring During Tamoxifen Therapy - Women taking or having previously taken tamoxifen should be instructed to seek prompt medical attention for new breast lumps, vaginal bleeding, gynecologic symptoms (menstrual irregularities, changes in vaginal discharge, or pelvic pain or pressure), symptoms of leg swelling or tenderness, unexplained shortness of breath, or changes in vision. Women should inform all care providers, regardless of the reason for evaluation, that they take tamoxifen. - Women taking tamoxifen to reduce the incidence of breast cancer should have a breast examination, a mammogram, and a gynecologic examination prior to the initiation of therapy. These studies should be repeated at regular intervals while on therapy, in keeping with good medical practice. Women taking tamoxifen as adjuvant breast cancer therapy should follow the same monitoring procedures as for women taking tamoxifen for the reduction in the incidence of breast cancer. Women taking tamoxifen as treatment for metastatic breast cancer should review this monitoring plan with their care provider and select the appropriate modalities and schedule of evaluation. Laboratory Tests - Periodic complete blood counts, including platelet counts, and periodic liver function tests should be obtained. - During the ATAC trial, more patients receiving anastrozole were reported to have an elevated serum cholesterol compared to patients receiving tamoxifen (9% versus 3.5%, respectively). Drug/Laboratory Testing Interactions - During postmarketing surveillance, T4 elevations were reported for a few postmenopausal patients which may be explained by increases in thyroid-binding globulin. These elevations were not accompanied by clinical hyperthyroidism. - Variations in the karyopyknotic index on vaginal smears and various degrees of estrogen effect on Pap smears have been infrequently seen in postmenopausal patients given tamoxifen. - In the postmarketing experience with tamoxifen, infrequent cases of hyperlipidemias have been reported. Periodic monitoring of plasma triglycerides and cholesterol may be indicated in patients with preexisting hyperlipidemias. # Adverse Reactions ## Clinical Trials Experience - Adverse reactions to tamoxifen are relatively mild and rarely severe enough to require discontinuation of treatment in breast cancer patients. - Continued clinical studies have resulted in further information which better indicates the incidence of adverse reactions with tamoxifen as compared to placebo. Metastatic Breast Cancer - Increased bone and tumor pain and, also, local disease flare have occurred, which are sometimes associated with a good tumor response. Patients with increased bone pain may require additional analgesics. Patients with soft tissue disease may have sudden increases in the size of preexisting lesions, sometimes associated with marked erythema within and surrounding the lesions and/or the development of new lesions. When they occur, the bone pain or disease flare are seen shortly after starting tamoxifen and generally subside rapidly. - In patients treated with tamoxifen for metastatic breast cancer, the most frequent adverse reaction to tamoxifen is hot flashes. - Other adverse reactions which are seen infrequently are hypercalcemia, peripheral edema, distaste for food, pruritus vulvae, depression, dizziness, lightheadedness, headache, hair thinning and/or partial hair loss, and vaginal dryness. Premenopausal Women - The following table summarizes the incidence of adverse reactions reported at a frequency of 2% or greater from clinical trials (Ingle, Pritchard, Buchanan) which compared tamoxifen therapy to ovarian ablation in premenopausal patients with metastatic breast cancer. Male Breast Cancer - Tamoxifen is well tolerated in males with breast cancer. Reports from the literature and case reports suggest that the safety profile of tamoxifen in males is similar to that seen in women. Loss of libido and impotence have resulted in discontinuation of tamoxifen therapy in male patients. Also, in oligospermic males treated with tamoxifen, LH, FSH, testosterone and estrogen levels were elevated. No significant clinical changes were reported. Adjuvant Breast Cancer - In the NSABP B-14 study, women with axillary node-negative breast cancer were randomized to 5 years of tamoxifen 20 mg/day or placebo following primary surgery. The reported adverse effects are tabulated below (mean follow-up of approximately 6.8 years) showing adverse events more common on tamoxifen than on placebo. The incidence of hot flashes (64% vs. 48%), vaginal discharge (30% vs. 15%), and irregular menses (25% vs. 19%) were higher with tamoxifen compared with placebo. All other adverse effects occurred with similar frequency in the 2 treatment groups, with the exception of thrombotic events; a higher incidence was seen in tamoxifen-treated patients (through 5 years, 1.7% vs. 0.4%). Two of the patients treated with tamoxifen who had thrombotic events died. - In the Eastern Cooperative Oncology Group (ECOG) adjuvant breast cancer trial, tamoxifen or placebo was administered for 2 years to women following mastectomy. When compared to placebo, tamoxifen showed a significantly higher incidence of hot flashes (19% vs. 8% for placebo). The incidence of all other adverse reactions was similar in the 2 treatment groups with the exception of thrombocytopenia where the incidence for tamoxifen was 10% vs. 3% for placebo, an observation of borderline statistical significance. - In other adjuvant studies, Toronto and Tamoxifen Adjuvant Trial Organization (NATO), women received either tamoxifen or no therapy. In the Toronto study, hot flashes were observed in 29% of patients for tamoxifen vs. 1% in the untreated group. In the NATO trial, hot flashes and vaginal bleeding were reported in 2.8% and 2.0% of women, respectively, for tamoxifen vs. 0.2% for each in the untreated group. - Anastrozole Adjuvant Trial – Study of Anastrozole Compared to Tamoxifen for Adjuvant Treatment of Early Breast Cancer . - At a median follow-up of 33 months, the combination of anastrozole and tamoxifen did not demonstrate any efficacy benefit when compared to tamoxifen therapy given alone in all patients as well as in the hormone receptor positive subpopulation. This treatment arm was discontinued from the trial. The median duration of adjuvant treatment for safety evaluation was 59.8 months and 59.6 months for patients receiving anastrozole 1 mg and tamoxifen 20 mg, respectively. - Adverse events occurring with an incidence of at least 5% in either treatment group during treatment or within 14 days of the end of treatment are presented in the following table. - Certain adverse events and combinations of adverse events were prospectively specified for analysis, based on the known pharmacologic properties and side effect profiles of the two drugs (see the following table). - Patients receiving anastrozole had an increase in joint disorders (including arthritis, arthrosis and arthralgia) compared with patients receiving tamoxifen. Patients receiving anastrozole had an increase in the incidence of all fractures (specifically fractures of spine, hip and wrist) [315 (10%)] compared with patients receiving tamoxifen [209 (7%)]. Patients receiving anastrozole had a decrease in hot flashes, vaginal bleeding, vaginal discharge, endometrial cancer, venous thromboembolic events and ischemic cerebrovascular events compared with patients receiving tamoxifen. - Patients receiving tamoxifen had a decrease in hypercholesterolemia [108 (3.5%)] compared to patients receiving anastrozole [278 (9%)]. Angina pectoris was reported in 71 (2.3%) patients in the anastrozole arm and 51 (1.6%) patients in the tamoxifen arm; myocardial infarction was reported in 37 (1.2%) patients in the anastrozole arm and in 34 (1.1%) patients in the tamoxifen arm. - Results from the adjuvant trial bone substudy, at 12 and 24 months demonstrated that patients receiving anastozole had a mean decrease in both lumbar spine and total hip bone mineral density (BMD) compared to baseline. Patients receiving tamoxifen had a mean increase in both lumbar spine and total hip BMD compared to baseline. Ductal Carcinoma in Situ (DCIS) - The type and frequency of adverse events in the NSABP B-24 trial were consistent with those observed in the other adjuvant trials conducted with tamoxifen. Reduction in Breast Cancer Incidence in High Risk Women - In the NSABP P-1 trial, there was an increase in five serious adverse effects in the tamoxifen group: endometrial cancer (33 cases in the tamoxifen group vs. 14 in the placebo group); pulmonary embolism (18 cases in the tamoxifen group vs. 6 in the placebo group); deep-vein thrombosis (30 cases in the tamoxifen group vs. 19 in the placebo group); stroke (34 cases in the tamoxifen group vs. 24 in the placebo group); cataract formation (540 cases in the tamoxifen group vs. 483 in the placebo group) and cataract surgery (101 cases in the tamoxifen group vs. 63 in the placebo group) . - The following table presents the adverse events observed in NSABP P-1 by treatment arm. Only adverse events more common on tamoxifen than placebo are shown. - In the NSABP P-1 trial, 15.0% and 9.7% of participants receiving tamoxifen and placebo therapy, respectively withdrew from the trial for medical reasons. The following are the medical reasons for withdrawing from tamoxifen and placebo therapy, respectively: hot flashes (3.1% vs. 1.5%) and vaginal discharge (0.5% vs. 0.1%). - In the NSABP P-1 trial, 8.7% and 9.6% of participants receiving tamoxifen and placebo therapy, respectively withdrew for non-medical reasons. - On the NSABP P-1 trial, hot flashes of any severity occurred in 68% of women on placebo and in 80% of women on tamoxifen. Severe hot flashes occurred in 28% of women on placebo and 45% of women on tamoxifen. Vaginal discharge occurred in 35% and 55% of women on placebo and tamoxifen respectively; and was severe in 4.5% and 12.3% respectively. There was no difference in the incidence of vaginal bleeding between treatment arms. Pediatric Patients McCune-Albright Syndrome - Mean uterine volume increased after 6 months of treatment and doubled at the end of the one-year study. A causal relationship has not been established; however, as an increase in the incidence of endometrial adenocarcinoma and uterine sarcoma has been noted in adults treated with tamoxifen , continued monitoring of McCune-Albright patients treated with tamoxifen for long-term effects is recommended. The safety and efficacy of tamoxifen for girls aged 2 to 10 years with McCune-Albright syndrome and precocious puberty have not been studied beyond 1 year of treatment. The long-term effects of tamoxifen therapy in girls have not been established. ## Postmarketing Experience - Less frequently reported adverse reactions are vaginal bleeding, vaginal discharge, menstrual irregularities, skin rash and headaches. Usually these have not been of sufficient severity to require dosage reduction or discontinuation of treatment. Very rare reports of erythema multiforme, Stevens-Johnson syndrome, bullous pemphigoid, interstitial pneumonitis, and rare reports of hypersensitivity reactions including angioedema have been reported with tamoxifen therapy. In some of these cases, the time to onset was more than one year. Rarely, elevation of serum triglyceride levels, in some cases with pancreatitis, may be associated with the use of tamoxifen . # Drug Interactions - When tamoxifen is used in combination with coumarin-type anticoagulants, a significant increase in anticoagulant effect may occur. Where such coadministration exists, careful monitoring of the patient's prothrombin time is recommended. - In the NSABP P-1 trial, women who required coumarin-type anticoagulants for any reason were ineligible for participation in the trial . - There is an increased risk of thromboembolic events occurring when cytotoxic agents are used in combination with tamoxifen. - Tamoxifen reduced letrozole plasma concentrations by 37%. The effect of tamoxifen on metabolism and excretion of other antineoplastic drugs, such as cyclophosphamide and other drugs that require mixed function oxidases for activation, is not known. Tamoxifen and N-desmethyl tamoxifen plasma concentrations have been shown to be reduced when coadministered with rifampin or aminoglutethimide. Induction of CYP3A4-mediated metabolism is considered to be the mechanism by which these reductions occur; other CYP3A4 inducing agents have not been studied to confirm this effect. - One patient receiving tamoxifen with concomitant phenobarbital exhibited a steady-state serum level of tamoxifen lower than that observed for other patients (i.e., 26 ng/mL vs. mean value of 122 ng/mL). However, the clinical significance of this finding is not known. Rifampin induced the metabolism of tamoxifen and significantly reduced the plasma concentrations of tamoxifen in 10 patients. Aminoglutethimide reduces tamoxifen and N-desmethyl tamoxifen plasma concentrations. Medroxyprogesterone reduces plasma concentrations of N-desmethyl, but not tamoxifen. - Concomitant bromocriptine therapy has been shown to elevate serum tamoxifen and N-desmethyl tamoxifen. - Based on clinical and pharmacokinetic results from the anastrozole adjuvant trial, tamoxifen should not be administered with anastrozole. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D Pregnancy Category D - Tamoxifen may cause fetal harm when administered to a pregnant woman. Women should be advised not to become pregnant while taking tamoxifen or within 2 months of discontinuing tamoxifen and should use barrier or nonhormonal contraceptive measures if sexually active. Tamoxifen does not cause infertility, even in the presence of menstrual irregularity. Effects on reproductive functions are expected from the antiestrogenic properties of the drug. In reproductive studies in rats at dose levels equal to or below the human dose, nonteratogenic developmental skeletal changes were seen and were found reversible. In addition, in fertility studies in rats and in teratology studies in rabbits using doses at or below those used in humans, a lower incidence of embryo implantation and a higher incidence of fetal death or retarded in utero growth were observed, with slower learning behavior in some rat pups when compared to historical controls. Several pregnant marmosets were dosed with 10 mg/kg/day (about 2 fold the daily maximum recommended human dose on a mg/m2 basis) during organogenesis or in the last half of pregnancy. No deformations were seen and, although the dose was high enough to terminate pregnancy in some animals, those that did maintain pregnancy showed no evidence of teratogenic malformations. - In rodent models of fetal reproductive tract development, tamoxifen (at doses 0.002 to 2.4 fold the daily maximum recommended human dose on a mg/m2 basis) caused changes in both sexes that are similar to those caused by estradiol, ethynylestradiol and diethylstilbestrol. Although the clinical relevance of these changes is unknown, some of these changes, especially vaginal adenosis, are similar to those seen in young women who were exposed to diethylstilbestrol in utero and who have a 1 in 1,000 risk of developing clear-cell adenocarcinoma of the vagina or cervix. To date, in utero exposure to tamoxifen has not been shown to cause vaginal adenosis, or clear-cell adenocarcinoma of the vagina or cervix, in young women. However, only a small number of young women have been exposed to tamoxifen in utero, and a smaller number have been followed long enough (to age 15 to 20) to determine whether vaginal or cervical neoplasia could occur as a result of this exposure. - There are no adequate and well-controlled trials of tamoxifen in pregnant women. There have been a small number of reports of vaginal bleeding, spontaneous abortions, birth defects, and fetal deaths in pregnant women. If this drug is used during pregnancy, or the patient becomes pregnant while taking this drug, or within approximately two months after discontinuing therapy, the patient should be apprised of the potential risks to the fetus including the potential long-term risk of a DES-like syndrome. Reduction in Breast Cancer Incidence in High Risk Women Pregnancy Category D - For sexually active women of child-bearing potential, tamoxifen therapy should be initiated during menstruation. In women with menstrual irregularity, a negative B-HCG immediately prior to the initiation of therapy is sufficient Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category - There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tamoxifen in women who are pregnant. ### Labor and Delivery - There is no FDA guidance on use of Tamoxifen during labor and delivery. ### Nursing Mothers - Tamoxifen has been reported to inhibit lactation. Two placebo-controlled studies in over 150 women have shown that tamoxifen significantly inhibits early postpartum milk production. In both studies tamoxifen was administered within 24 hours of delivery for between 5 and 18 days. The effect of tamoxifen on established milk production is not known. - There are no data that address whether tamoxifen is excreted into human milk. If excreted, there are no data regarding the effects of tamoxifen in breast milk on the breastfed infant or breastfed animals. However, direct neonatal exposure of tamoxifen to mice and rats (not via breast milk) produced 1) reproductive tract lesions in female rodents (similar to those seen in humans after intrauterine exposure to diethylstilbestrol) and 2) functional defects of the reproductive tract in male rodents such as testicular atrophy and arrest of spermatogenesis. - It is not known if tamoxifen is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from tamoxifen, women taking tamoxifen should not breast feed. Reduction in Breast Cancer Incidence in High Risk Women With DCIS - It is not known if tamoxifen is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from tamoxifen, women taking tamoxifen should not breast feed. ### Pediatric Use - The safety and efficacy of tamoxifen for girls aged 2 to 10 years with McCune-Albright syndrome and precocious puberty have not been studied beyond one year of treatment. The long-term effects of tamoxifen therapy for girls have not been established. In adults treated with tamoxifen, an increase in incidence of uterine malignancies, stroke and pulmonary embolism has been noted. ### Geriatic Use - In the NSABP P-1 trial, the percentage of women at least 65 years of age was 16%. Women at least 70 years of age accounted for 6% of the participants. A reduction in breast cancer incidence was seen among participants in each of the subsets. A total of 28 and 10 invasive breast cancers were seen among participants 65 and older in the placebo and tamoxifen groups, respectively. Across all other outcomes, the results in this subset reflect the results observed in the subset of women at least 50 years of age. No overall differences in tolerability were observed between older and younger patients. - In the NSABP B-24 trial, the percentage of women at least 65 years of age was 23%. Women at least 70 years of age accounted for 10% of participants. A total of 14 and 12 invasive breast cancers were seen among participants 65 and older in the placebo and tamoxifen groups, respectively. This subset is too small to reach any conclusions on efficacy. Across all other endpoints, the results in this subset were comparable to those of younger women enrolled in this trial. No overall differences in tolerability were observed between older and younger patients. ### Gender - There is no FDA guidance on the use of Tamoxifen with respect to specific gender populations. ### Race - There is no FDA guidance on the use of Tamoxifen with respect to specific racial populations. ### Renal Impairment - There is no FDA guidance on the use of Tamoxifen in patients with renal impairment. ### Hepatic Impairment - There is no FDA guidance on the use of Tamoxifen in patients with hepatic impairment. ### Females of Reproductive Potential and Males - There is no FDA guidance on the use of Tamoxifen in women of reproductive potentials and males. ### Immunocompromised Patients - There is no FDA guidance one the use of Tamoxifen in patients who are immunocompromised. # Administration and Monitoring ### Administration - For patients with breast cancer, the recommended daily dose is 20 to 40 mg. Dosages greater than 20 mg per day should be given in divided doses (morning and evening). - In three single agent adjuvant studies in women, one 10 mg tamoxifen citrate tablet was administered two (ECOG and NATO) or three (Toronto) times a day for two years. In the NSABP B-14 adjuvant study in women with node-negative breast cancer, one 10 mg tamoxifen citrate tablet was given twice a day for at least 5 years. Results of the B-14 study suggest that continuation of therapy beyond five years does not provide additional benefit. In the EBCTCG 1995 overview, the reduction in recurrence and mortality was greater in those studies that used tamoxifen for about 5 years than in those that used tamoxifen for a shorter period of therapy. There was no indication that doses greater than 20 mg per day were more effective. Current data from clinical trials support 5 years of adjuvant tamoxifen therapy for patients with breast cancer. Ductal Carcinoma in Situ (DCIS) - The recommended dose is tamoxifen 20 mg daily for 5 years. Reduction in Breast Cancer Incidence in High Risk Women - The recommended dose is tamoxifen 20 mg daily for 5 years. There are no data to support the use of tamoxifen other than for 5 years. ### Monitoring - There is limited information regarding Monitoring of Tamoxifen in the drug label. # IV Compatibility - There is limited information regarding IV Compatibility of Tamoxifen in the drug label. # Overdosage - Signs observed at the highest doses following studies to determine LD50 in animals were respiratory difficulties and convulsions. - Acute overdosage in humans has not been reported. In a study of advanced metastatic cancer patients which specifically determined the maximum tolerated dose of tamoxifen in evaluating the use of very high doses to reverse multidrug resistance, acute neurotoxicity manifested by tremor, hyperreflexia, unsteady gait and dizziness were noted. These symptoms occurred within 3 to 5 days of beginning tamoxifen and cleared within 2 to 5 days after stopping therapy. No permanent neurologic toxicity was noted. One patient experienced a seizure several days after tamoxifen was discontinued and neurotoxic symptoms had resolved. The causal relationship of the seizure to tamoxifen therapy is unknown. Doses given in these patients were all greater than 400 mg/m2 loading dose, followed by maintenance doses of 150 mg/m2 of tamoxifen given twice a day. - In the same study, prolongation of the QT interval on the electrocardiogram was noted when patients were given doses higher than 250 mg/m2 loading dose, followed by maintenance doses of 80 mg/m2 of tamoxifen given twice a day. For a woman with a body surface area of 1.5 m2 the minimal loading dose and maintenance doses given at which neurological symptoms and QT changes occurred were at least 6 fold higher in respect to the maximum recommended dose. - No specific treatment for overdosage is known; treatment must be symptomatic. # Pharmacology ## Mechanism of Action - Tamoxifen citrate is a nonsteroidal agent that has demonstrated potent antiestrogenic properties in animal test systems. The antiestrogenic effects may be related to its ability to compete with estrogen for binding sites in target tissues such as breast. Tamoxifen inhibits the induction of rat mammary carcinoma induced by dimethylbenzanthracene (DMBA) and causes the regression of already established DMBA-induced tumors. In this rat model, tamoxifen appears to exert its antitumor effects by binding the estrogen receptors. - In cytosols derived from human breast adenocarcinomas, tamoxifen competes with estradiol for estrogen receptor protein. ## Structure - Tamoxifen citrate tablets USP, a nonsteroidal antiestrogen, are for oral administration. Each tablet contains 10 mg or 20 mg tamoxifen (equivalent to 15.2 mg or 30.4 mg, respectively, of tamoxifen citrate). - Each tablet contains the following inactive ingredients: croscarmellose sodium, hypromellose, lactose (monohydrate), magnesium stearate, polyethylene glycol 400, povidone, corn starch, and titanium dioxide. - Chemically, tamoxifen is the trans-isomer of a triphenylethylene derivative. The chemical name is (Z)2-(4-(1,2-diphenyl-1-butenyl)phenoxy)- N,N-dimethylethanamine 2-hydroxy-1,2,3- propanetricarboxylate (1:1). The structural formula, empirical formula, and molecular weight are as follows: - C32H37NO8 M.W. 563.62 - Tamoxifen citrate has a pKa’ of 8.85, the equilibrium solubility in water at 37°C is 0.5 mg/mL and in 0.02 N HCl at 37°C, it is 0.2 mg/mL. ## Pharmacodynamics - There is limited information regarding Pharmacodynamics of Tamoxifen in the drug label. ## Pharmacokinetics Absorption and Distribution - Following a single oral dose of 20 mg tamoxifen, an average peak plasma concentration of 40 ng/mL (range 35 to 45 ng/mL) occurred approximately 5 hours after dosing. The decline in plasma concentrations of tamoxifen is biphasic with a terminal elimination half-life of about 5 to 7 days. The average peak plasma concentration of N-desmethyl tamoxifen is 15 ng/mL (range 10 to 20 ng/mL). Chronic administration of 10 mg tamoxifen given twice daily for 3 months to patients results in average steady-state plasma concentrations of 120 ng/mL (range 67 to 183 ng/mL) for tamoxifen and 336 ng/mL (range 148 to 654 ng/mL) for N-desmethyl tamoxifen. The average steady-state plasma concentrations of tamoxifen and N-desmethyl tamoxifen after administration of 20 mg tamoxifen once daily for 3 months are 122 ng/mL (range 71 to 183 ng/mL) and 353 ng/mL (range 152 to 706 ng/mL), respectively. After initiation of therapy, steady-state concentrations for tamoxifen are achieved in about 4 weeks and steady-state concentrations for N-desmethyl tamoxifen are achieved in about 8 weeks, suggesting a half-life of approximately 14 days for this metabolite. In a steady-state, crossover study of 10 mg tamoxifen citrate tablets given twice a day vs. a 20 mg tamoxifen citrate tablet given once daily, the 20 mg tamoxifen citrate tablet was bioequivalent to the 10 mg tamoxifen citrate tablets. Metabolism - Tamoxifen is extensively metabolized after oral administration. N-desmethyl tamoxifen is the major metabolite found in patients’ plasma. The biological activity of N-desmethyl tamoxifen appears to be similar to that of tamoxifen. 4-Hydroxytamoxifen and a side chain primary alcohol derivative of tamoxifen have been identified as minor metabolites in plasma. Tamoxifen is a substrate of cytochrome P-450 3A, 2C9 and 2D6, and an inhibitor of P-glycoprotein. Excretion - Studies in women receiving 20 mg of 14C tamoxifen have shown that approximately 65% of the administered dose was excreted from the body over a period of 2 weeks with fecal excretion as the primary route of elimination. The drug is excreted mainly as polar conjugates, with unchanged drug and unconjugated metabolites accounting for less than 30% of the total fecal radioactivity. Special Populations - The effects of age, gender and race on the pharmacokinetics of tamoxifen have not been determined. The effects of reduced liver function on the metabolism and pharmacokinetics of tamoxifen have not been determined. Pediatric Patients - The pharmacokinetics of tamoxifen and N-desmethyl tamoxifen were characterized using a population pharmacokinetic analysis with sparse samples per patient obtained from 27 female pediatric patients aged 2 to 10 years enrolled in a study designed to evaluate the safety, efficacy, and pharmacokinetics of tamoxifen in treating McCune-Albright syndrome. Rich data from two tamoxifen citrate pharmacokinetic trials in which 59 postmenopausal women with breast cancer completed the studies were included in the analysis to determine the structural pharmacokinetic model for tamoxifen. A one-compartment model provided the best fit to the data. - In pediatric patients, an average steady-state peak plasma concentration (Css, max) and AUC were of 187 ng/mL and 4,110 ng hr/mL, respectively, and Css, max occurred approximately 8 hours after dosing. Clearance (CL/F) as body weight adjusted in female pediatric patients was approximately 2.3 fold higher than in female breast cancer patients. In the youngest cohort of female pediatric patients (2 to 6 year olds), CL/F was 2.6 fold higher; in the oldest cohort (7 to 10.9 year olds) CL/F was approximately 1.9 fold higher. Exposure to N-desmethyl tamoxifen was comparable between the pediatric and adult patients. The safety and efficacy of tamoxifen for girls aged 2 to 10 years with McCune-Albright syndrome and precocious puberty have not been studied beyond one year of treatment. The long-term effects of tamoxifen therapy in girls have not been established. In adults treated with tamoxifen an increase in incidence of uterine malignancies, stroke and pulmonary embolism has been noted . Drug-Drug Interactions - In vitro studies showed that erythromycin, cyclosporin, nifedipine and diltiazem competitively inhibited formation of N-desmethyl tamoxifen with apparent K1 of 20, 1, 45 and 30 µM, respectively. The clinical significance of these in vitro studies is unknown. - Tamoxifen reduced the plasma concentration of letrozole by 37% when these drugs were coadministered. Rifampin, a cytochrome P-450 3A4 inducer reduced tamoxifen AUC and Cmax by 86% and 55%, respectively. Aminoglutethimide reduces tamoxifen and N-desmethyl tamoxifen plasma concentrations. Medroxyprogesterone reduces plasma concentrations of N-desmethyl, but not tamoxifen. - In the anastrozole adjuvant trial, coadministration of anastrozole and tamoxifen in breast cancer patients reduced anastrozole plasma concentration by 27% compared to those achieved with anastrozole alone; however, the coadministration did not affect the pharmacokinetics of tamoxifen or N-desmethyltamoxifen . Tamoxifen should not be coadministered with anastrozole. ## Nonclinical Toxicology Carcinogenesis - A conventional carcinogenesis study in rats at doses of 5, 20, and 35 mg/kg/day (about one, three and seven-fold the daily maximum recommended human dose on a mg/m2 basis) administered by oral gavage for up to 2 years revealed a significant increase in hepatocellular carcinoma at all doses. The incidence of these tumors was significantly greater among rats administered 20 or 35 mg/kg/day (69%) compared to those administered 5 mg/kg/day (14%). In a separate study, rats were administered tamoxifen at 45 mg/kg/day (about nine-fold the daily maximum recommended human dose on a mg/m2 basis); hepatocellular neoplasia was exhibited at 3 to 6 months. - Granulosa cell ovarian tumors and interstitial cell testicular tumors were observed in 2 separate mouse studies. The mice were administered the trans and racemic forms of tamoxifen for 13 to 15 months at doses of 5, 20, and 50 mg/kg/day (about one-half, two, and five-fold the daily recommended human dose on a mg/m2 basis). Mutagenesis - No genotoxic potential was found in a conventional battery of in vivo and in vitro tests with pro- and eukaryotic test systems with drug metabolizing systems. However, increased levels of DNA adducts were observed by 32P post-labeling in DNA from rat liver and cultured human lymphocytes. Tamoxifen also has been found to increase levels of micronucleus formation in vitro in human lymphoblastoid cell line (MCL-5). Based on these findings, tamoxifen is genotoxic in rodent and human MCL-5 cells. Impairment of Fertility - Tamoxifen produced impairment of fertility and conception in female rats at doses of 0.04 mg/kg/day (about 0.01 fold the daily maximum recommended human dose on a mg/m2 basis) when dosed for two weeks prior to mating through day 7 of pregnancy. At this dose, fertility and reproductive indices were markedly reduced with total fetal mortality. Fetal mortality was also increased at doses of 0.16 mg/kg/day (about 0.03 fold the daily maximum recommended human dose on a mg/m2 basis) when female rats were dosed from days 7 to 17 of pregnancy. Tamoxifen produced abortion, premature delivery and fetal death in rabbits administered doses equal to or greater than 0.125 mg/kg/day (about 0.05 fold the daily maximum recommended human dose on a mg/m2 basis). There were no teratogenic changes in either rats or rabbits. # Clinical Studies Metastatic Breast Cancer Premenopausal women (tamoxifen vs. ablation) - Three prospective, randomized studies (Ingle, Pritchard, Buchanan) compared tamoxifen to ovarian ablation (oophorectomy or ovarian irradiation) in premenopausal women with advanced breast cancer. Although the objective response rate, time to treatment failure, and survival were similar with both treatments, the limited patient accrual prevented a demonstration of equivalence. In an overview analysis of survival data from the 3 studies, the hazard ratio for death (tamoxifen/ovarian ablation) was 1.00 with two-sided 95% confidence intervals of 0.73 to 1.37. Elevated serum and plasma estrogens have been observed in premenopausal women receiving tamoxifen, but the data from the randomized studies do not suggest an adverse effect of this increase. A limited number of premenopausal patients with disease progression during tamoxifen therapy responded to subsequent ovarian ablation. Male breast cancer - Published results from 122 patients (119 evaluable) and case reports in 16 patients (13 evaluable) treated with tamoxifen have shown that tamoxifen is effective for the palliative treatment of male breast cancer. Sixty-six of these 132 evaluable patients responded to tamoxifen which constitutes a 50% objective response rate. Adjuvant Breast Cancer Overview - The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) conducted worldwide overviews of systemic adjuvant therapy for early breast cancer in 1985, 1990, and again in 1995. In 1998, 10 year outcome data were reported for 36,689 women in 55 randomized trials of adjuvant tamoxifen using doses of 20 to 40 mg/day for 1 to 5+ years. Twenty-five percent of patients received 1 year or less of trial treatment, 52% received 2 years, and 23% received about 5 years. Forty-eight percent of tumors were estrogen receptor (ER) positive (> 10 fmol/mg), 21% were ER poor (< 10 fmol/l), and 31% were ER unknown. Among 29,441 patients with ER positive or unknown breast cancer, 58% were entered into trials comparing tamoxifen to no adjuvant therapy and 42% were entered into trials comparing tamoxifen in combination with chemotherapy vs. the same chemotherapy alone. Among these patients, 54% had node positive disease and 46% had node negative disease. - Among women with ER positive or unknown breast cancer and positive nodes who received about 5 years of treatment, overall survival at 10 years was 61.4% for tamoxifen vs. 50.5% for control (logrank 2p < 0.00001). The recurrence-free rate at 10 years was 59.7% for tamoxifen vs. 44.5% for control (logrank 2p < 0.00001). Among women with ER positive or unknown breast cancer and negative nodes who received about 5 years of treatment, overall survival at 10 years was 78.9% for tamoxifen vs. 73.3% for control (logrank 2p < 0.00001). The recurrence-free rate at 10 years was 79.2% for tamoxifen vs. 64.3% for control (logrank 2p < 0.00001). - The effect of the scheduled duration of tamoxifen may be described as follows. In women with ER positive or unknown breast cancer receiving 1 year or less, 2 years or about 5 years of tamoxifen, the proportional reductions in mortality were 12%, 17% and 26%, respectively (trend significant at 2p < 0.003). The corresponding reductions in breast cancer recurrence were 21%, 29% and 47% (trend significant at 2p < 0.00001). - Benefit is less clear for women with ER poor breast cancer in whom the proportional reduction in recurrence was 10% (2p = 0.007) for all durations taken together, or 9% (2p = 0.02) if contralateral breast cancers are excluded. The corresponding reduction in mortality was 6% (NS). The effects of about 5 years of tamoxifen on recurrence and mortality were similar regardless of age and concurrent chemotherapy. There was no indication that doses greater than 20 mg per day were more effective. Anastrozole adjuvant ATAC trial – study of anastrozole compared to tamoxifen for adjuvant treatment of early breast cancer - An anastrozole adjuvant trial was conducted in 9,366 postmenopausal women with operable breast cancer who were randomized to receive adjuvant treatment with either anastrozole 1 mg daily, tamoxifen 20 mg daily, or a combination of these two treatments for 5 years or until recurrence of the disease. At a median follow-up of 33 months, the combination of anastrozole and tamoxifen did not demonstrate any efficacy benefit when compared with tamoxifen therapy alone in all patients as well as in the hormone receptor-positive subpopulation. This treatment arm was discontinued from the trial. - Patients in the two monotherapy arms of the ATAC trial were treated for a median of 60 months (5 years) and followed for a median of 68 months. Disease-free survival in the intent-to-treat population was statistically significantly improved [Hazard Ratio (HR) = 0.87, 95% CI: 0.78, 0.97, p = 0.0127] in the anastrozole arm compared to the tamoxifen arm. Node positive – individual studies - Two studies (Hubay and NSABP B-09) demonstrated an improved disease-free survival following radical or modified radical mastectomy in postmenopausal women or women 50 years of age or older with surgically curable breast cancer with positive axillary nodes when tamoxifen was added to adjuvant cytotoxic chemotherapy. In the Hubay study, tamoxifen was added to "low-dose" CMF (cyclophosphamide, methotrexate and fluorouracil). In the NSABP B-09 study, tamoxifen was added to melphalan [L-phenylalanine mustard (P)] and fluorouracil (F). - In the Hubay study, patients with a positive (more than 3 fmol) estrogen receptor were more likely to benefit. In the NSABP B-09 study in women age 50 to 59 years, only women with both estrogen and progesterone receptor levels 10 fmol or greater clearly benefited, while there was a nonstatistically significant trend toward adverse effect in women with both estrogen and progesterone receptor levels less than 10 fmol. In women age 60 to 70 years, there was a trend toward a beneficial effect of tamoxifen without any clear relationship to estrogen or progesterone receptor status. - Three prospective studies (ECOG-1178, Toronto, NATO) using tamoxifen adjuvantly as a single agent demonstrated an improved disease-free survival following total mastectomy and axillary dissection for postmenopausal women with positive axillary nodes compared to placebo/no treatment controls. The NATO study also demonstrated an overall survival benefit. Node negative – individual studies - NSABP B-14, a prospective, double-blind, randomized study, compared tamoxifen to placebo in women with axillary node-negative, estrogen-receptor positive (≥ 10 fmol/mg cytosol protein) breast cancer (as adjuvant therapy, following total mastectomy and axillary dissection, or segmental resection, axillary dissection, and breast radiation). After five years of treatment, there was a significant improvement in disease-free survival in women receiving tamoxifen. This benefit was apparent both in women under age 50 and in women at or beyond age 50. - One additional randomized study (NATO) demonstrated improved disease-free survival for tamoxifen compared to no adjuvant therapy following total mastectomy and axillary dissection in postmenopausal women with axillary node-negative breast cancer. In this study, the benefits of tamoxifen appeared to be independent of estrogen receptor status. Duration of therapy - In the EBCTCG 1995 overview, the reduction in recurrence and mortality was greater in those studies that used tamoxifen for about 5 years than in those that used tamoxifen for a shorter period of therapy. - In the NSABP B-14 trial, in which patients were randomized to tamoxifen 20 mg/day for 5 years vs. placebo and were disease-free at the end of this 5 year period were offered rerandomization to an additional 5 years of tamoxifen or placebo. With 4 years of follow-up after this rerandomization, 92% of the women that received 5 years of tamoxifen were alive and disease-free, compared to 86% of the women scheduled to receive 10 years of tamoxifen (p = 0.003). Overall survivals were 96% and 94%, respectively (p = 0.08). Results of the B-14 study suggest that continuation of therapy beyond 5 years does not provide additional benefit. - A Scottish trial of 5 years of tamoxifen vs. indefinite treatment found a disease-free survival of 70% in the five-year group and 61% in the indefinite group, with 6.2 years median follow-up (HR = 1.27, 95% CI: 0.87 to 1.85). - In a large randomized trial conducted by the Swedish Breast Cancer Cooperative Group of adjuvant tamoxifen 40 mg/day for 2 or 5 years, overall survival at 10 years was estimated to be 80% in the patients in the 5 year tamoxifen group, compared with 74% among corresponding patients in the 2 year treatment group (p = 0.03). Disease-free survival at 10 years was 73% in the 5 year group and 67% in the 2 year group (p = 0.009). Compared with 2 years of tamoxifen treatment, 5 years of treatment resulted in a slightly greater reduction in the incidence of contralateral breast cancer at 10 years, but this difference was not statistically significant. Contralateral breast cancer - The incidence of contralateral breast cancer is reduced in breast cancer patients (premenopausal and postmenopausal) receiving tamoxifen compared to placebo. Data on contralateral breast cancer are available from 32,422 out of 36,689 patients in the 1995 overview analysis of the Early Breast Cancer Trialists Collaborative Group (EBCTCG). In clinical trials with tamoxifen of 1 year or less, 2 years, and about 5 years duration, the proportional reductions in the incidence rate of contralateral breast cancer among women receiving tamoxifen were 13% (NS), 26% (2p = 0.004) and 47% (2p < 0.00001), with a significant trend favoring longer tamoxifen duration (2p = 0.008). The proportional reductions in the incidence of contralateral breast cancer were independent of age and ER status of the primary tumor. Treatment with about 5 years of tamoxifen reduced the annual incidence rate of contralateral breast cancer from 7.6 per 1,000 patients in the control group compared with 3.9 per 1,000 patients in the tamoxifen group. - In a large randomized trial in Sweden (the Stockholm Trial) of adjuvant tamoxifen 40 mg/day for 2 to 5 years, the incidence of second primary breast tumors was reduced 40% (p < 0.008) on tamoxifen compared to control. In the NSABP B-14 trial in which patients were randomized to tamoxifen 20 mg/day for 5 years vs. placebo, the incidence of second primary breast cancers was also significantly reduced (p < 0.01). In NSABP B-14, the annual rate of contralateral breast cancer was 8.0 per 1,000 patients in the placebo group compared with 5.0 per 1,000 patients in the tamoxifen group, at 10 years after first randomization. Ductal Carcinoma in Situ - NSABP B-24, a double-blind, randomized trial included women with ductal carcinoma in situ (DCIS). This trial compared the addition of tamoxifen or placebo to treatment with lumpectomy and radiation therapy for women with DCIS. The primary objective was to determine whether 5 years of tamoxifen therapy (20 mg/day) would reduce the incidence of invasive breast cancer in the ipsilateral (the same) or contralateral (the opposite) breast. - In this trial 1,804 women were randomized to receive either tamoxifen or placebo for 5 years: 902 women were randomized to tamoxifen citrate 10 mg tablets twice a day and 902 women were randomized to placebo. As of December 31, 1998, follow-up data were available for 1,798 women and the median duration of follow-up was 74 months. - The tamoxifen and placebo groups were well balanced for baseline demographic and prognostic factors. Over 80% of the tumors were less than or equal to 1 cm in their maximum dimension, were not palpable, and were detected by mammography alone. Over 60% of the study population was postmenopausal. In 16% of patients, the margin of the resected specimen was reported as being positive after surgery. Approximately half of the tumors were reported to contain comedo necrosis. - For the primary endpoint, the incidence of invasive breast cancer was reduced by 43% among women assigned to tamoxifen (44 cases-tamoxifen, 74 cases-placebo; p = 0.004; relative risk (RR) = 0.57, 95% CI: 0.39 to 0.84). No data are available regarding the ER status of the invasive cancers. The stage distribution of the invasive cancers at diagnosis was similar to that reported annually in the SEER data base. - Results are shown in Table 1. For each endpoint the following results are presented: the number of events and rate per 1,000 women per year for the placebo and tamoxifen groups; and the relative risk (RR) and its associated 95% confidence interval (CI) between tamoxifen and placebo. Relative risks less than 1.0 indicate a benefit of tamoxifen therapy. The limits of the confidence intervals can be used to assess the statistical significance of the benefits of tamoxifen therapy. If the upper limit of the CI is less than 1.0, then a statistically significant benefit exists. - Survival was similar in the placebo and tamoxifen groups. At 5 years from study entry, survival was 97% for both groups. Reduction in Breast Cancer Incidence in High Risk Women - The Breast Cancer Prevention Trial (BCPT, NSABP P-1) was a double-blind, randomized, placebo-controlled trial with a primary objective to determine whether 5 years of tamoxifen therapy (20 mg/day) would reduce the incidence of invasive breast cancer in women at high risk for the disease . Secondary objectives included an evaluation of the incidence of ischemic heart disease; the effects on the incidence of bone fractures; and other events that might be associated with the use of tamoxifen, including: endometrial cancer, pulmonary embolus, deep-vein thrombosis, stroke, and cataract formation and surgery . - The Gail Model was used to calculate predicted breast cancer risk for women who were less than 60 years of age and did not have lobular carcinoma in situ (LCIS). The following risk factors were used: age; number of first-degree female relatives with breast cancer; previous breast biopsies; presence or absence of atypical hyperplasia; nulliparity; age at first live birth; and age at menarche. A 5 year predicted risk of breast cancer of ≥ 1.67% was required for entry into the trial. - In this trial, 13,388 women of at least 35 years of age were randomized to receive either tamoxifen or placebo for five years. The median duration of treatment was 3.5 years. As of January 31, 1998, follow-up data is available for 13,114 women. Twenty-seven percent of women randomized to placebo (1,782) and 24% of women randomized to tamoxifen (1,596) completed 5 years of therapy. The demographic characteristics of women on the trial with follow-up data are shown in Table 2. - Results are shown in Table 3. After a median follow-up of 4.2 years, the incidence of invasive breast cancer was reduced by 44% among women assigned to tamoxifen (86 cases-tamoxifen, 156 cases-placebo; p < 0.00001; relative risk (RR) = 0.56, 95% CI: 0.43 to 0.72). A reduction in the incidence of breast cancer was seen in each prospectively specified age group (≤ 49, 50 to 59, ≥ 60), in women with or without LCIS, and in each of the absolute risk levels specified in Table 3. A non-significant decrease in the incidence of ductal carcinoma in situ (DCIS) was seen (23 tamoxifen, 35 placebo; RR = 0.66, 95% CI: 0.39 to 1.11). - There was no statistically significant difference in the number of myocardial infarctions, severe angina, or acute ischemic cardiac events between the two groups (61 tamoxifen, 59 placebo; RR = 1.04, 95% CI: 0.73 to 1.49). - No overall difference in mortality (53 deaths in tamoxifen group vs. 65 deaths in placebo group) was present. No difference in breast cancer-related mortality was observed (4 deaths in tamoxifen group vs. 5 deaths in placebo group). - Although there was a non-significant reduction in the number of hip fractures (9 on tamoxifen, 20 on placebo) in the tamoxifen group, the number of wrist fractures was similar in the two treatment groups (69 on tamoxifen, 74 on placebo). A subgroup analysis of the P-1 trial, suggests a difference in effect in bone mineral density (BMD) related to menopausal status in patients receiving tamoxifen. In postmenopausal women there was no evidence of bone loss of the lumbar spine and hip. Conversely, tamoxifen was associated with significant bone loss of the lumbar spine and hip in premenopausal women. - The risks of tamoxifen therapy include endometrial cancer, DVT, PE, stroke, cataract formation, and cataract surgery (see Table 3). In the NSABP P-1 trial, 33 cases of endometrial cancer were observed in the tamoxifen group vs. 14 in the placebo group (RR = 2.48, 95% CI: 1.27 to 4.92). Deep-vein thrombosis was observed in 30 women receiving tamoxifen vs. 19 in women receiving placebo (RR = 1.59, 95% CI: 0.86 to 2.98). Eighteen cases of pulmonary embolism were observed in the tamoxifen group vs. 6 in the placebo group (RR = 3.01, 95% CI: 1.15 to 9.27). There were 34 strokes on the tamoxifen arm and 24 on the placebo arm (RR = 1.42, 95% CI: 0.82 to 2.51). Cataract formation in women without cataracts at baseline was observed in 540 women taking tamoxifen vs. 483 women receiving placebo (RR = 1.13, 95% CI: 1.00 to 1.28). Cataract surgery (with or without cataracts at baseline) was performed in 201 women taking tamoxifen vs. 129 women receiving placebo (RR = 1.51, 95% CI: 1.21 to 1.89) . - Table 3 summarizes the major outcomes of the NSABP P-1 trial. For each endpoint, the following results are presented: the number of events and rate per 1,000 women per year for the placebo and tamoxifen groups; and the relative risk (RR) and its associated 95% confidence interval (CI) between tamoxifen and placebo. Relative risks less than 1.0 indicate a benefit of tamoxifen therapy. The limits of the confidence intervals can be used to assess the statistical significance of the benefits or risks of tamoxifen therapy. If the upper limit of the CI is less than 1.0, then a statistically significant benefit exists. - For most participants, multiple risk factors would have been required for eligibility. This table considers risk factors individually, regardless of other co-existing risk factors, for women who developed breast cancer. The 5 year predicted absolute breast cancer risk accounts for multiple risk factors in an individual and should provide the best estimate of individual benefit . - Table 4 describes the characteristics of the breast cancers in the NSABP P-1 trial and includes tumor size, nodal status, ER status. Tamoxifen decreased the incidence of small estrogen receptor positive tumors, but did not alter the incidence of estrogen receptor negative tumors or larger tumors. - Interim results from 2 trials in addition to the NSABP P-1 trial examining the effects of tamoxifen in reducing breast cancer incidence have been reported. - The first was the Italian Tamoxifen Prevention trial. In this trial women between the ages of 35 and 70, who had had a total hysterectomy, were randomized to receive 20 mg tamoxifen or matching placebo for 5 years. The primary endpoints were occurrence of, and death from, invasive breast cancer. Women without any specific risk factors for breast cancer were to be entered. Between 1992 and 1997, 5,408 women were randomized. Hormone Replacement Therapy (HRT) was used in 14% of participants. The trial closed in 1997 due to the large number of dropouts during the first year of treatment (26%). After 46 months of follow-up there were 22 breast cancers in women on placebo and 19 in women on tamoxifen. Although no decrease in breast cancer incidence was observed, there was a trend for reduction in breast cancer among women receiving protocol therapy for at least 1 year (19 placebo, 11 tamoxifen). The small numbers of participants along with the low level of risk in this otherwise healthy group precluded an adequate assessment of the effect of tamoxifen in reducing the incidence of breast cancer. - The second trial, the Royal Marsden Trial (RMT) was reported as an interim analysis. The RMT was begun in 1986 as a feasibility study of whether larger scale trials could be mounted. The trial was subsequently extended to a pilot trial to accrue additional participants to further assess the safety of tamoxifen. Twenty-four hundred and seventy-one women were entered between 1986 and 1996; they were selected on the basis of a family history of breast cancer. HRT was used in 40% of participants. In this trial, with a 70 month median follow-up, 34 and 36 breast cancers (8 noninvasive, 4 on each arm) were observed among women on tamoxifen and placebo, respectively. Patients in this trial were younger than those in the NSABP P-1 trial and may have been more likely to develop ER (-) tumors, which are unlikely to be reduced in number by tamoxifen therapy. Although women were selected on the basis of family history and were thought to have a high risk of breast cancer, few events occurred, reducing the statistical power of the study. These factors are potential reasons why the RMT may not have provided an adequate assessment of the effectiveness of tamoxifen in reducing the incidence of breast cancer. - In these trials, an increased number of cases of deep-vein thrombosis, pulmonary embolus, stroke, and endometrial cancer were observed on the tamoxifen arm compared to the placebo arm. The frequency of events was consistent with the safety data observed in the NSABP P-1 trial. McCune-Albright Syndrome - A single, uncontrolled multicenter trial of tamoxifen 20 mg once a day was conducted in a heterogenous group of girls with McCune-Albright syndrome and precocious puberty manifested by physical signs of pubertal development, episodes of vaginal bleeding and/or advanced bone age (bone age of at least 12 months beyond chronological age). Twenty-eight female pediatric patients, aged 2 to 10 years, were treated for up to 12 months. Effect of treatment on frequency of vaginal bleeding, bone age advancement, and linear growth rate was assessed relative to prestudy baseline. Tamoxifen treatment was associated with a 50% reduction in frequency of vaginal bleeding episodes by patient or family report (mean annualized frequency of 3.56 episodes at baseline and 1.73 episodes on-treatment). Among the patients who reported vaginal bleeding during the prestudy period, 62% (13 out of 21 patients) reported no bleeding for a 6 month period and 33% (7 out of 21 patients) reported no vaginal bleeding for the duration of the trial. Not all patients improved on treatment and a few patients not reporting vaginal bleeding in the 6 months prior to enrollment reported menses on treatment. Tamoxifen therapy was associated with a reduction in mean rate of increase of bone age. Individual responses with regard to bone age advancement were highly heterogeneous. Linear growth rate was reduced during the course of tamoxifen treatment in a majority of patients (mean change of 1.68 cm/year relative to baseline; change from 7.47 cm/year at baseline to 5.79 cm/year on study). This change was not uniformly seen across all stages of bone maturity; all recorded response failures occurred in patients with bone ages less than 7 years at screening. - Mean uterine volume increased after 6 months of treatment and doubled at the end of the one-year study. A causal relationship has not been established; however, as an increase in the incidence of endometrial adenocarcinoma and uterine sarcoma has been noted in adults treated with tamoxifen , continued monitoring of McCune-Albright patients treated with tamoxifen for long-term uterine effects is recommended. The safety and efficacy of tamoxifen for girls aged 2 to 10 years with McCune-Albright syndrome and precocious puberty have not been studied beyond one year of treatment. The long-term effects of tamoxifen therapy in girls have not been established. # How Supplied - Tamoxifen citrate tablets USP, 10 mg (base) are white, round, biconvex, film-coated, unscored tablets debossed “93” and “784” and are supplied in bottles of 30, 50, 60, 90 and 100. ## Storage - Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. - Dispense in a well-closed, light-resistant container as defined in the USP, with a child-resistant closure (as required). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information # Precautions with Alcohol - Alcohol-Tamoxifen interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names Nolvadex, Soltamox. # Look-Alike Drug Names There is limited information regarding Tamoxifen Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/4-hydroxytamoxifen
aba91cec195050349a87639a1fdc1e9c581fbeb4	wikidoc	Karyotype	Karyotype # Overview A karyotype is the characteristic chromosome complement of an eukaryote species. The preparation and study of karyotypes is part of cytogenetics. In normal diploid organisms, autosomal chromosomes are present in two identical copies. There may, or may not, be sex chromosomes. Polyploid cells have multiple copies of chromosomes and haploid cells have single copies. The study of whole sets of chromosomes is sometimes known as karyology. The chromosomes are depicted (by rearranging a microphotograph) in a standard format known as a karyogram or idiogram: in pairs, ordered by size and position of centromere for chromosomes of the same size. The study of karyotypes is made possible by staining: usually a suitable dye is applied after cells have been arrested during cell division by a solution of colchicine. Sometimes observations may be made on non-dividing (interphase) cells. The sex of an unborn fetus can be determined by observation of interphase cells (see amniotic centesis and Barr body). Most (but not all) species have a standard karyotype. The normal human karyotypes contain 22 pairs of autosomal chromosomes and one pair of sex chromosomes. Normal karyotypes for women contain two X chromosomes and are denoted 46,XX; men have both an X and a Y chromosome denoted 46,XY. However, some individuals have other karyotypes with added or missing chromosomes, and in all such cases there are developmental abnormalities as a consequence. Karyotypes can be used for many purposes. They may be used to study chromosomal aberrations, to study cellular function, to study taxonomic relationships, or to gather information about past evolutionary events. # Observations on karyotypes Six different characteristics of karyotypes are usually observed and compared: - differences in absolute sizes of chromosomes. Chromosomes can vary in absolute size by as much as twenty-fold between genera of the same family: Lotus tenuis and Vicia faba (legumes), both have six pairs of chromosomes (n=6) yet V. faba chromosomes are many times larger. This feature probably reflects different amounts of DNA duplication. - differences in the position of centromeres. This is brought about by translocations. - differences in relative size of chromosomes can only be caused by segmental interchange of unequal lengths. - differences in basic number of chromosomes may occur due to successive unequal translocations which finally remove all the essential genetic material from a chromosome, permitting its loss without penalty to the organism (the dislocation hypothesis). Humans have one pair fewer chromosomes than the great apes, but the genes have been mostly translocated (added) to other chromosomes. - differences in number and position of satellites, which (when they occur) are small bodies attached to a chromosome by a thin thread. - differences in degree and distribution of heterochromatic regions. Heterochromatin stains darker than euchromatin, indicating tighter packing, and mainly consists of genetically inactive repetitive DNA sequences. A full account of a karyotype may therefore include the number, type, shape and banding of the chromosomes, as well as other cytogenetic information. Variation is often found: - between the two sexes - between the germ-line and soma (between gametes and the rest of the body) - between members of a population (chromosome polymorphism) - geographical variation between races - mosaics or otherwise abnormal individuals. ### Historical note Levitsky seems to have been the first to define the karyotype as the phenotypic appearance of the somatic chromosomes, in contrast to their genic contents. The subsequent history of the concept can be followed in the works of Darlington and White. Investigation into the human karyotype took many years to settle the most basic question: how many chromosomes does a normal diploid human cell contain? In 1912, Hans von Winiwarter reported 47 chromosomes in spermatogonia and 48 in oogonia, concluding an XX/XO sex determination mechanism. Painter in 1922 was not certain whether the diploid number of man was 46 or 48, at first favoring 46. He revised his opinion later from 46 to 48, and he correctly insisted on man having an XX/XY system. Considering their techniques, these results were quite remarkable. New techniques were needed to definitively solve the problem: - Using cells in culture - Pretreating cells in a hypotonic solution, which swells them and spreads the chromosomes - Arresting mitosis in metaphase by a solution of colchicine - Squashing the preparation on the slide forcing the chromosomes into a single plane - Cutting up a photomicrograph and arranging the result into an indisputable karyogram. It took until the mid 1950s until it became generally accepted that the karyotype of man included only 46 chromosomes. Rather interestingly, the great apes have 48 chromosomes. # Diversity and evolution of karyotypes Although the replication and transcription of DNA is highly standardized in eukaryotes, the same cannot be said for their karyotypes, which are highly variable between species in chromosome number and in detailed organization despite being constructed out of the same macromolecules. In some cases there is even significant variation within species. This variation provides the basis for a range of studies in what might be called evolutionary cytology. ### Changes during development Instead of the usual gene repression, some organisms go in for large-scale elimination of heterochromatin, or other kinds of visible adjustment to the karyotype. - Chromosome elimination. In some species, as in many sciarid flies, entire chromosomes are eliminated during development. - Chromatin diminution (founding father: Theodor Boveri). In this process, found in some copepods and roundworms such as Ascaris suum, portions of the chromosomes are cast away in particular cells. This process is a carefully organised genome rearrangement where new telomeres are constructed and certain heterochromatin regions are lost. In A. suum, all the somatic cell precursors undergo chromatin diminution. - X-inactivation. The inactivation of one X chromosome takes place during the early development of mammals (see Barr body and dosage compensation). In placental mammals, the inactivation is random as between the two Xs; but in marsupials it is always the paternal X which is inactivated. ### Number of chromosomes in a set A spectacular example of variability between closely related species is the muntjac, which was investigated by Kurt Benirschke and his colleague Doris Wurster. The diploid number of the Chinese muntjac, Muntiacus reevesi, was found to be 46, all telocentric. When they looked at the karyotype of the closely related Indian muntjac, Muntiacus muntjak, they were astonished to find it had female = 6, male = 7 chromosomes. The number of chromosomes in the karyotype between (relatively) unrelated species is hugely variable. The low record is held by the nematode Parascaris univalens, where the haploid n = 1; the high record would be somewhere amongst the ferns, with the Adder's Tongue Fern Ophioglossum ahead with an average of 1262 chromosomes. Top score for animals might be the shortnose sturgeon Acipenser brevirostrum at a mere 372 chromosomes. The existence of supernumerary or B chromosomes means that chromosome number can vary even within one interbreeding population; and aneuploids are another example, though in this case they would not be regarded as normal members of the population. ### Ploidy: the number of sets in a karyotype - Polyploidy, where there are more than two sets of homologous chromosomes in the cells, occurs mainly in plants. It has been of major significance in plant evolution according to Stebbins. The proportion of flowering plants which are polyploid was estimated by Stebbins to be 30-35%, but in grasses the average is much higher, about 70%. Polyploidy in lower plants (ferns, horsetails and psilotales) is also common, and some species of ferns have reached levels of polyploidy far in excess of the highest levels known in flowering plants.Polyploidy in animals is much less common, but it has been significant in some groups. - Haplo-diploidy, where one sex is diploid, and the other haploid. It is a common arrangement in the Hymenoptera, and in some other groups. - Endopolyploidy occurs when in adult differentiated tissues the cells have ceased to divide by mitosis, but the nuclei contain more than the original somatic number of chromosomes. In the endocycle (endomitosis or endoreduplication) chromosomes in a 'resting' nucleus undergo reduplication, the daughter chromosomes separating from each other inside an intact nuclear membrane. In many instances, endopolyploid nuclei contain tens of thousands of chromosomes (which cannot be exactly counted). The cells do not always contain exact multiples (powers of two), which is why the simple definition 'an increase in the number of chromosome sets caused by replication without cell division' is not quite accurate.This process (especially studied in insects and some higher plants such as maize) may be a developmental strategy for increasing the productivity of tissues which are highly active in biosynthesis. The phenomenon occurs sporadically throughout the eukaryote kingdom from protozoa to man; it is diverse and complex, and serves differentiation and morphogenesis in many ways. - See palaeopolyploidy for the investigation of ancient karyotype duplications. ### Species trees The detailed study of chromosome banding in insects with polytene chromosomes can reveal relationships between closely related species: the classic example is the study of chromosome banding in Hawaiian drosophilids by Hampton Carson. In about 6,500 square miles, the Hawaiian islands have the most diverse collection of drosophilid flies in the world, living from rainforests to subalpine meadows. These roughly 800 Hawaiian drosophilid species are usually assigned to two genera Drosophila and Scaptomyza in the family Drosophilidae. The polytene banding of the 'picture wing' group, the best-studied group of Hawaiian drosophilids, enabled Carson to work out the evolutionary tree long before genome analysis was practicable. In a sense, gene arrangements are visible in the banding patterns of each chromosome. Chromosome rearrangements, especially inversions, make it possible to see which species are closely related. The results are clear. The inversions, when plotted in tree form (and independent of all other information), show a clear "flow" of species from older to newer islands. There are also cases of colonization back to older islands, and skipping of islands, but these are much less frequent. Using K-Ar dating, the present islands date from 0.4 million years ago (mya) (Mauna Kea) to 10mya (Necker). The oldest member of the Hawaiian archipelago still above the sea is Kure Atoll, which can be dated to 30 mya. The archipelago itself (produced by the Pacific plate moving over a hot spot) has existed for far longer, at least into the Cretaceous. Previous islands now beneath the sea (guyots) form the All of the native Drosophila and Scaptomyza species in Hawaii have apparently descended from a single ancestral species that colonized the islands, probably 20 million years ago. The subsequent adaptive radiation was spurred by a lack of competition and a wide variety of niches. Although it would be possible for a single gravid female to colonise an island, it is more likely to have been a group from the same species. There are other animals and plants on the Hawaiian archipelago which have undergone similar, if less spectacular, adaptive radiations. ### Overview Although much is known about karyotypes at the descriptive level, and it is clear that changes in karyotype organization has had effects on the evolutionary course of many species, it is quite unclear what the general significance might be. # Depiction of karyotypes ### Types of banding Cytogenetics employs several techniques to visualize different aspects of chromosomes: - G-banding is obtained with Giemsa stain following digestion of chromosomes with trypsin. It yields a series of lightly and darkly stained bands - the dark regions tend to be heterochromatic, late-replicating and AT rich. The light regions tend to be euchromatic, early-replicating and GC rich. This method will normally produce 300-400 bands in a normal, human genome. - R-banding is the reverse of G-banding (the R stands for "reverse"). The dark regions are euchromatic (guanine-cytosine rich regions) and the bright regions are heterochromatic (thymine-adenine rich regions). - C-banding: Giemsa binds to constitutive heterochromatin, so it stains centromeres. - Q-banding is a fluorescent pattern obtained using quinacrine for staining. The pattern of bands is very similar to that seen in G-banding. - T-banding: visualize telomeres. ### Classic karyotype cytogenetics In the "classic" (depicted) karyotype, a dye, often Giemsa (G-banding), less frequently Quinacrine, is used to stain bands on the chromosomes. Giemsa is specific for the phosphate groups of DNA. Quinacrine binds to the adenine-thymine-rich regions. Each chromosome has a characteristic banding pattern that helps to identify them; both chromosomes in a pair will have the same banding pattern. Karyotypes are arranged with the short arm of the chromosome on top, and the long arm on the bottom. Some karyotypes call the short and long arms p and q, respectively. In addition, the differently stained regions and sub-regions are given numerical designations from proximal to distal on the chromosome arms. For example, Cri du chat syndrome involves a deletion on the short arm of chromosome 5. It is written as 46,XX,5p-. The critical region for this syndrome is deletion of 15.2, which is written as 46,XX,del(5)(p15.2). ### Spectral karyotype (SKY technique) Spectral karyotyping is a molecular cytogenetic technique used to simultaneously visualize all the pairs of chromosomes in an organism in different colors. Fluorescently-labeled probes for each chromosome are made by labeling chromosome-specific DNA with different fluorophores. Because there are a limited number of spectrally-distinct fluorophores, a combinatorial labeling method is used to generate many different colors. Spectral differences generated by combinatorial labeling are captured and analyzed by using an interferometer attached to a fluorescence microscope. Image processing software then assigns a pseudo color to each spectrally different combination, allowing the visualization of the individually colored chromosomes. This technique is used to identify structural chromosome aberrations in cancer cells and other disease conditions when Giemsa banding or other techniques are not accurate enough. ### Digital Karyotyping Digital Karyotyping is a technique used to quantify the DNA copy number on a genomic scale. Short sequences of DNA from specific loci all over the genome are isolated and enumerated. # Chromosome abnormalities Chromosome abnormalities can be numerical, as in the presence of extra or missing chromosomes, or structural, as in translocations, inversions, large-scale deletions or duplications. Numerical abnormalities, also known as aneuploidy, often occur as a result of nondisjunction during meiosis in the formation of a gamete; trisomies, in which three copies of a chromosome are present instead of the usual two, are common numerical abnormalities. Structural abnormalities often arise from errors in homologous recombination. Both types of abnormalities can occur in gametes and therefore will be present in all cells of an affected person's body, or they can occur during mitosis and give rise to a genetic mosaic individual who has some normal and some abnormal cells. Chromosomal abnormalities that lead to disease in humans include: - Turner syndrome results from a single X chromosome (45, X or 45, X0). - Klinefelter syndrome, the most common male chromosomal disease, otherwise known as 47, XXY is caused by an extra X chromosome. - Edwards syndrome is caused by trisomy (three copies) of chromosome 18. - Down syndrome, a common chromosomal disease, is caused by trisomy of chromosome 21. - Patau syndrome is caused by trisomy of chromosome 13. - Also documented are trisomy 8, trisomy 9 and trisomy 16, although they generally do not survive to birth. Some disorders arise from loss of just a piece of one chromosome, including - Cri du chat (cry of the cat), from a truncated short arm on chromosome 5. The name comes from the babies' distinctive cry, caused by abnormal formation of the larynx. - 1p36 Deletion syndrome, from the loss of part of the short arm of chromosome 1. - Angelman syndrome – 50% of cases have a segment of the long arm of chromosome 15 missing. Chromosomal abnormalities can also occur in cancerous cells of an otherwise genetically normal individual; one well-documented example is the Philadelphia chromosome, a translocation mutation commonly associated with chronic myelogenous leukemia and less often with acute lymphoblastic leukemia. # Diagnostic Findings Images courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology - A t(9;22)(q34;q11) (Philadelphia chromosome) lymphoblast karyotype. This karyotype is from the bone marrow of a 28-year-old man with ALL. Material from the long arm (q) of chromosome 22 is translocated to the long arm of chromosome 9 (arrows). This translocation is found in approximately 20 to 25 percent of adults and approximately 2 percent of children with ALL. It is associated with a poor prognosis. (Giemsa-trypsin banding) - Acute myelogenous leukemia, AML, ANLL, M2 (FAB), karyotype; t(8;21) is specific for M2 ANLL involving possible oncogens c-mos or c-myc. - Acute myelogenous leukemia, Myelodysplastic syndrome, karyotype; Monosomy 7 or -7 is associated with bad prognosis and increased sepsis due to poor granulocyte function. - Acute Promyelocytic Leukemia, AML, M3 (FAB); t(15;17) is consistently associated with APL resulting in a fusion gene for PML and RAR-alpha which accounts for response to retinoid therapy. RAR is retinoic acid receptor. - Acute myeloblastic leukemia with maturation (AML-M2) associated with A t(8;21) chromosome abnormality G-banded Wright-Giemsa stained partial karyotype showing the 8;21 chromosome translocation. The abnormal chromosomes are on the right, with breakpoints designated by arrowheads. - B-cell chronic lymphocytic leukemia: Trisomy for chromosome 12 Karyotype of a lymphocyte from a patient with B CLL showing an extra copy of chromosome 12. (G-banded, Wright-Giemsa stained) - Lymph node: Burkitt's lymphoma, NonHodgkin's Lymphoma, NHL, karyotype; t(8;14) seen in Burkitt's lymphoma or L3 ALL results in a fusion protein of c-myc oncogene (8) and the Ig heavy chain gene in 14. - Chronic Lymphocytic Leukemia: 13q-chromosome abnormality karyotype of a lymphocyte from a patient with newly diagnosed B CLL. There is a clonal abnormality involving partial deletion of the long arm of chromosome 13 at bands q13q22. (G-banded, Wright-Giemsa stained) - Chronic myelogenous leukemia, in transition, blast crisis, karyotype; Ph1 t(9;22), +8, i(17) are additional karyotypic changes from Ph chromosome indicating multistep in transformation to acute leukemia. - Chronic Myeloid Leukemia: Philadelphia Chromosome. Partial karyotype of a myeloid cell from the bone marrow of a patient with CML showing the typical t(9;22) translocation. (G-banded, Wright-Giemsa stained) - Down syndrome G karyotype - Down syndrome karyotype - Lymph node: Evolved B cell NonHodgkin's lymphoma, NHL; t(8;14) and t(14;18), appears in 75% of follicular NHL, juxtaposing the bcl-2 (band 18q21) proto-oncogene with Ig (band 14q32) heavy chain gene (resulting in deregulation of bcl-2 (inhibits apoptosis) - Hyperdiploid lymphoblast karyotype This bone marrow karyotype is from a 5-year-old female with ALL. There is hyperdiploidy with 55 chromosomes. Hyperdiploidy with greater than 50 chromosomes is found in approximately 25 percent of children with ALL and is associated with a good prognosis. (Giemsa-trypsin banding) - Hypergranular acute promyelocytic leukemia (AML-M3) G-banded Wright-Giemsa stained partial karyotype showing the 15;17 chromosome translocation. The breakpoints on the abnormal chromosomes are designated by arrowheads. - Karyotype of normal female. - Karyotype of normal male. - Karyotype R bands composite - Lymphoblast karyotype from a patient with mixed phenotype acute leukemia (Bilineal). A karyotype from bone marrow cells of the patient whose blood smear is depicted in figure 146. There is a translocation of material from the long arm of chromosome 4 to the long arm of chromosome 11, t(4;11) (q21;q23). This translocation is found in less than 5 percent of cases of childhood ALL. It is associated with markedly elevated leukocyte counts and poor prognosis. Approximately 20 percent of patients are less than 1 month of age at diagnosis (congenital leukemia). - Myelodysplastic syndrome (MDS), Agnogenic myeloid metaplasia, myelofibrosis, karyotype; Trisomy 8 or +8 is most common karyotype abnormality in MDS, and acute nonlymphocytic leukemias. - Myelodysplastic syndrome, MDS. Refractory anemia (RA), karyotype, 5q- syndrome; 5q- abnormality per se is not a bad prognostic marker but results in a refractory anemia called 5q- syndrome. - Myelodysplastic syndrome, MDS. Refractory anemia (RA), karyotype, 5q- syndrome; 5q- abnormality per se is not a bad prognostic marker but results in a refractory anemia called 5q- syndrome. - Normal female karyotype. - Normal karyotype. - Philadelphia chromosome in Chronic Myelogenous Leukemia (CML); Ph, t(9;22) results in a fusion mRNA of 210 kd called bcr/abl which inhibits cellular apoptosis and increase granulocytes in Chronic Myelogenous Leukemia (CML). - T-prolymphocytic leukemia. Portion of a karyotype of a lymphocyte from the specimen shown in B showing an inv(14)(q11q32) abnormality. (G banded, Wright-Giemsa stained) - Trisomy 13 karyotype.jpg - Trisomy 18 karyotype.jpg - Turner's karyotype. - Turner's karyotype 46x 150x.	Karyotype Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview A karyotype is the characteristic chromosome complement of an eukaryote species.[1][2] The preparation and study of karyotypes is part of cytogenetics. In normal diploid organisms, autosomal chromosomes are present in two identical copies. There may, or may not, be sex chromosomes. Polyploid cells have multiple copies of chromosomes and haploid cells have single copies. The study of whole sets of chromosomes is sometimes known as karyology. The chromosomes are depicted (by rearranging a microphotograph) in a standard format known as a karyogram or idiogram: in pairs, ordered by size and position of centromere for chromosomes of the same size. The study of karyotypes is made possible by staining: usually a suitable dye is applied after cells have been arrested during cell division by a solution of colchicine.[3] Sometimes observations may be made on non-dividing (interphase) cells. The sex of an unborn fetus can be determined by observation of interphase cells (see amniotic centesis and Barr body). Most (but not all) species have a standard karyotype. The normal human karyotypes contain 22 pairs of autosomal chromosomes and one pair of sex chromosomes. Normal karyotypes for women contain two X chromosomes and are denoted 46,XX; men have both an X and a Y chromosome denoted 46,XY. However, some individuals have other karyotypes with added or missing chromosomes, and in all such cases there are developmental abnormalities as a consequence. Karyotypes can be used for many purposes. They may be used to study chromosomal aberrations, to study cellular function, to study taxonomic relationships, or to gather information about past evolutionary events. # Observations on karyotypes Six different characteristics of karyotypes are usually observed and compared:[4] - differences in absolute sizes of chromosomes. Chromosomes can vary in absolute size by as much as twenty-fold between genera of the same family: Lotus tenuis and Vicia faba (legumes), both have six pairs of chromosomes (n=6) yet V. faba chromosomes are many times larger. This feature probably reflects different amounts of DNA duplication. - differences in the position of centromeres. This is brought about by translocations. - differences in relative size of chromosomes can only be caused by segmental interchange of unequal lengths. - differences in basic number of chromosomes may occur due to successive unequal translocations which finally remove all the essential genetic material from a chromosome, permitting its loss without penalty to the organism (the dislocation hypothesis). Humans have one pair fewer chromosomes than the great apes, but the genes have been mostly translocated (added) to other chromosomes. - differences in number and position of satellites, which (when they occur) are small bodies attached to a chromosome by a thin thread. - differences in degree and distribution of heterochromatic regions. Heterochromatin stains darker than euchromatin, indicating tighter packing, and mainly consists of genetically inactive repetitive DNA sequences. A full account of a karyotype may therefore include the number, type, shape and banding of the chromosomes, as well as other cytogenetic information. Variation is often found: - between the two sexes - between the germ-line and soma (between gametes and the rest of the body) - between members of a population (chromosome polymorphism) - geographical variation between races - mosaics or otherwise abnormal individuals.[5] ### Historical note Levitsky seems to have been the first to define the karyotype as the phenotypic appearance of the somatic chromosomes, in contrast to their genic contents.[6][7] The subsequent history of the concept can be followed in the works of Darlington[8] and White.[9][10] Investigation into the human karyotype took many years to settle the most basic question: how many chromosomes does a normal diploid human cell contain?[11] In 1912, Hans von Winiwarter reported 47 chromosomes in spermatogonia and 48 in oogonia, concluding an XX/XO sex determination mechanism.[12] Painter in 1922 was not certain whether the diploid number of man was 46 or 48, at first favoring 46.[13] He revised his opinion later from 46 to 48, and he correctly insisted on man having an XX/XY system.[14] Considering their techniques, these results were quite remarkable. New techniques were needed to definitively solve the problem: - Using cells in culture - Pretreating cells in a hypotonic solution, which swells them and spreads the chromosomes - Arresting mitosis in metaphase by a solution of colchicine - Squashing the preparation on the slide forcing the chromosomes into a single plane - Cutting up a photomicrograph and arranging the result into an indisputable karyogram. It took until the mid 1950s until it became generally accepted that the karyotype of man included only 46 chromosomes.[15][16] Rather interestingly, the great apes have 48 chromosomes. # Diversity and evolution of karyotypes Although the replication and transcription of DNA is highly standardized in eukaryotes, the same cannot be said for their karyotypes, which are highly variable between species in chromosome number and in detailed organization despite being constructed out of the same macromolecules. In some cases there is even significant variation within species. This variation provides the basis for a range of studies in what might be called evolutionary cytology. ### Changes during development Instead of the usual gene repression, some organisms go in for large-scale elimination of heterochromatin, or other kinds of visible adjustment to the karyotype. - Chromosome elimination. In some species, as in many sciarid flies, entire chromosomes are eliminated during development.[17] - Chromatin diminution (founding father: Theodor Boveri). In this process, found in some copepods and roundworms such as Ascaris suum, portions of the chromosomes are cast away in particular cells. This process is a carefully organised genome rearrangement where new telomeres are constructed and certain heterochromatin regions are lost.[18][19] In A. suum, all the somatic cell precursors undergo chromatin diminution.[20] - X-inactivation. The inactivation of one X chromosome takes place during the early development of mammals (see Barr body and dosage compensation). In placental mammals, the inactivation is random as between the two Xs; but in marsupials it is always the paternal X which is inactivated. ### Number of chromosomes in a set A spectacular example of variability between closely related species is the muntjac, which was investigated by Kurt Benirschke and his colleague Doris Wurster. The diploid number of the Chinese muntjac, Muntiacus reevesi, was found to be 46, all telocentric. When they looked at the karyotype of the closely related Indian muntjac, Muntiacus muntjak, they were astonished to find it had female = 6, male = 7 chromosomes.[21] The number of chromosomes in the karyotype between (relatively) unrelated species is hugely variable. The low record is held by the nematode Parascaris univalens, where the haploid n = 1; the high record would be somewhere amongst the ferns, with the Adder's Tongue Fern Ophioglossum ahead with an average of 1262 chromosomes.[23] Top score for animals might be the shortnose sturgeon Acipenser brevirostrum at a mere 372 chromosomes.[24] The existence of supernumerary or B chromosomes means that chromosome number can vary even within one interbreeding population; and aneuploids are another example, though in this case they would not be regarded as normal members of the population. ### Ploidy: the number of sets in a karyotype - Polyploidy, where there are more than two sets of homologous chromosomes in the cells, occurs mainly in plants. It has been of major significance in plant evolution according to Stebbins.[25][26][27][28] The proportion of flowering plants which are polyploid was estimated by Stebbins to be 30-35%, but in grasses the average is much higher, about 70%.[29] Polyploidy in lower plants (ferns, horsetails and psilotales) is also common, and some species of ferns have reached levels of polyploidy far in excess of the highest levels known in flowering plants.Polyploidy in animals is much less common, but it has been significant in some groups.[30] - Haplo-diploidy, where one sex is diploid, and the other haploid. It is a common arrangement in the Hymenoptera, and in some other groups. - Endopolyploidy occurs when in adult differentiated tissues the cells have ceased to divide by mitosis, but the nuclei contain more than the original somatic number of chromosomes.[31] In the endocycle (endomitosis or endoreduplication) chromosomes in a 'resting' nucleus undergo reduplication, the daughter chromosomes separating from each other inside an intact nuclear membrane.[32] In many instances, endopolyploid nuclei contain tens of thousands of chromosomes (which cannot be exactly counted). The cells do not always contain exact multiples (powers of two), which is why the simple definition 'an increase in the number of chromosome sets caused by replication without cell division' is not quite accurate.This process (especially studied in insects and some higher plants such as maize) may be a developmental strategy for increasing the productivity of tissues which are highly active in biosynthesis.[33] The phenomenon occurs sporadically throughout the eukaryote kingdom from protozoa to man; it is diverse and complex, and serves differentiation and morphogenesis in many ways.[34] - See palaeopolyploidy for the investigation of ancient karyotype duplications. ### Species trees The detailed study of chromosome banding in insects with polytene chromosomes can reveal relationships between closely related species: the classic example is the study of chromosome banding in Hawaiian drosophilids by Hampton Carson. In about 6,500 square miles, the Hawaiian islands have the most diverse collection of drosophilid flies in the world, living from rainforests to subalpine meadows. These roughly 800 Hawaiian drosophilid species are usually assigned to two genera Drosophila and Scaptomyza in the family Drosophilidae. The polytene banding of the 'picture wing' group, the best-studied group of Hawaiian drosophilids, enabled Carson to work out the evolutionary tree long before genome analysis was practicable. In a sense, gene arrangements are visible in the banding patterns of each chromosome. Chromosome rearrangements, especially inversions, make it possible to see which species are closely related. The results are clear. The inversions, when plotted in tree form (and independent of all other information), show a clear "flow" of species from older to newer islands. There are also cases of colonization back to older islands, and skipping of islands, but these are much less frequent. Using K-Ar dating, the present islands date from 0.4 million years ago (mya) (Mauna Kea) to 10mya (Necker). The oldest member of the Hawaiian archipelago still above the sea is Kure Atoll, which can be dated to 30 mya. The archipelago itself (produced by the Pacific plate moving over a hot spot) has existed for far longer, at least into the Cretaceous. Previous islands now beneath the sea (guyots) form the [[Emperor Seamount Chain.[35] All of the native Drosophila and Scaptomyza species in Hawaii have apparently descended from a single ancestral species that colonized the islands, probably 20 million years ago. The subsequent adaptive radiation was spurred by a lack of competition and a wide variety of niches. Although it would be possible for a single gravid female to colonise an island, it is more likely to have been a group from the same species.[36][37][38][39] There are other animals and plants on the Hawaiian archipelago which have undergone similar, if less spectacular, adaptive radiations.[40][41] ### Overview Although much is known about karyotypes at the descriptive level, and it is clear that changes in karyotype organization has had effects on the evolutionary course of many species, it is quite unclear what the general significance might be. # Depiction of karyotypes ### Types of banding Cytogenetics employs several techniques to visualize different aspects of chromosomes:[43] - G-banding is obtained with Giemsa stain following digestion of chromosomes with trypsin. It yields a series of lightly and darkly stained bands - the dark regions tend to be heterochromatic, late-replicating and AT rich. The light regions tend to be euchromatic, early-replicating and GC rich. This method will normally produce 300-400 bands in a normal, human genome. - R-banding is the reverse of G-banding (the R stands for "reverse"). The dark regions are euchromatic (guanine-cytosine rich regions) and the bright regions are heterochromatic (thymine-adenine rich regions). - C-banding: Giemsa binds to constitutive heterochromatin, so it stains centromeres. - Q-banding is a fluorescent pattern obtained using quinacrine for staining. The pattern of bands is very similar to that seen in G-banding. - T-banding: visualize telomeres. ### Classic karyotype cytogenetics In the "classic" (depicted) karyotype, a dye, often Giemsa (G-banding), less frequently Quinacrine, is used to stain bands on the chromosomes. Giemsa is specific for the phosphate groups of DNA. Quinacrine binds to the adenine-thymine-rich regions. Each chromosome has a characteristic banding pattern that helps to identify them; both chromosomes in a pair will have the same banding pattern. Karyotypes are arranged with the short arm of the chromosome on top, and the long arm on the bottom. Some karyotypes call the short and long arms p and q, respectively. In addition, the differently stained regions and sub-regions are given numerical designations from proximal to distal on the chromosome arms. For example, Cri du chat syndrome involves a deletion on the short arm of chromosome 5. It is written as 46,XX,5p-. The critical region for this syndrome is deletion of 15.2, which is written as 46,XX,del(5)(p15.2).[44] ### Spectral karyotype (SKY technique) Spectral karyotyping is a molecular cytogenetic technique used to simultaneously visualize all the pairs of chromosomes in an organism in different colors. Fluorescently-labeled probes for each chromosome are made by labeling chromosome-specific DNA with different fluorophores. Because there are a limited number of spectrally-distinct fluorophores, a combinatorial labeling method is used to generate many different colors. Spectral differences generated by combinatorial labeling are captured and analyzed by using an interferometer attached to a fluorescence microscope. Image processing software then assigns a pseudo color to each spectrally different combination, allowing the visualization of the individually colored chromosomes.[45] This technique is used to identify structural chromosome aberrations in cancer cells and other disease conditions when Giemsa banding or other techniques are not accurate enough. ### Digital Karyotyping Digital Karyotyping is a technique used to quantify the DNA copy number on a genomic scale. Short sequences of DNA from specific loci all over the genome are isolated and enumerated. [46] # Chromosome abnormalities Chromosome abnormalities can be numerical, as in the presence of extra or missing chromosomes, or structural, as in translocations, inversions, large-scale deletions or duplications. Numerical abnormalities, also known as aneuploidy, often occur as a result of nondisjunction during meiosis in the formation of a gamete; trisomies, in which three copies of a chromosome are present instead of the usual two, are common numerical abnormalities. Structural abnormalities often arise from errors in homologous recombination. Both types of abnormalities can occur in gametes and therefore will be present in all cells of an affected person's body, or they can occur during mitosis and give rise to a genetic mosaic individual who has some normal and some abnormal cells. Chromosomal abnormalities that lead to disease in humans include: - Turner syndrome results from a single X chromosome (45, X or 45, X0). - Klinefelter syndrome, the most common male chromosomal disease, otherwise known as 47, XXY is caused by an extra X chromosome. - Edwards syndrome is caused by trisomy (three copies) of chromosome 18. - Down syndrome, a common chromosomal disease, is caused by trisomy of chromosome 21. - Patau syndrome is caused by trisomy of chromosome 13. - Also documented are trisomy 8, trisomy 9 and trisomy 16, although they generally do not survive to birth. Some disorders arise from loss of just a piece of one chromosome, including - Cri du chat (cry of the cat), from a truncated short arm on chromosome 5. The name comes from the babies' distinctive cry, caused by abnormal formation of the larynx. - 1p36 Deletion syndrome, from the loss of part of the short arm of chromosome 1. - Angelman syndrome – 50% of cases have a segment of the long arm of chromosome 15 missing. Chromosomal abnormalities can also occur in cancerous cells of an otherwise genetically normal individual; one well-documented example is the Philadelphia chromosome, a translocation mutation commonly associated with chronic myelogenous leukemia and less often with acute lymphoblastic leukemia. # Diagnostic Findings Images courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology - A t(9;22)(q34;q11) (Philadelphia chromosome) lymphoblast karyotype. This karyotype is from the bone marrow of a 28-year-old man with ALL. Material from the long arm (q) of chromosome 22 is translocated to the long arm of chromosome 9 (arrows). This translocation is found in approximately 20 to 25 percent of adults and approximately 2 percent of children with ALL. It is associated with a poor prognosis. (Giemsa-trypsin banding) - Acute myelogenous leukemia, AML, ANLL, M2 (FAB), karyotype; t(8;21) is specific for M2 ANLL involving possible oncogens c-mos or c-myc. - Acute myelogenous leukemia, Myelodysplastic syndrome, karyotype; Monosomy 7 or -7 is associated with bad prognosis and increased sepsis due to poor granulocyte function. - Acute Promyelocytic Leukemia, AML, M3 (FAB); t(15;17) is consistently associated with APL resulting in a fusion gene for PML and RAR-alpha which accounts for response to retinoid therapy. RAR is retinoic acid receptor. - Acute myeloblastic leukemia with maturation (AML-M2) associated with A t(8;21) chromosome abnormality G-banded Wright-Giemsa stained partial karyotype showing the 8;21 chromosome translocation. The abnormal chromosomes are on the right, with breakpoints designated by arrowheads. - B-cell chronic lymphocytic leukemia: Trisomy for chromosome 12 Karyotype of a lymphocyte from a patient with B CLL showing an extra copy of chromosome 12. (G-banded, Wright-Giemsa stained) - Lymph node: Burkitt's lymphoma, NonHodgkin's Lymphoma, NHL, karyotype; t(8;14) seen in Burkitt's lymphoma or L3 ALL results in a fusion protein of c-myc oncogene (8) and the Ig heavy chain gene in 14. - Chronic Lymphocytic Leukemia: 13q-chromosome abnormality karyotype of a lymphocyte from a patient with newly diagnosed B CLL. There is a clonal abnormality involving partial deletion of the long arm of chromosome 13 at bands q13q22. (G-banded, Wright-Giemsa stained) - Chronic myelogenous leukemia, in transition, blast crisis, karyotype; Ph1 t(9;22), +8, i(17) are additional karyotypic changes from Ph chromosome indicating multistep in transformation to acute leukemia. - Chronic Myeloid Leukemia: Philadelphia Chromosome. Partial karyotype of a myeloid cell from the bone marrow of a patient with CML showing the typical t(9;22) translocation. (G-banded, Wright-Giemsa stained) - Down syndrome G karyotype - Down syndrome karyotype - Lymph node: Evolved B cell NonHodgkin's lymphoma, NHL; t(8;14) and t(14;18), appears in 75% of follicular NHL, juxtaposing the bcl-2 (band 18q21) proto-oncogene with Ig (band 14q32) heavy chain gene (resulting in deregulation of bcl-2 (inhibits apoptosis) - Hyperdiploid lymphoblast karyotype This bone marrow karyotype is from a 5-year-old female with ALL. There is hyperdiploidy with 55 chromosomes. Hyperdiploidy with greater than 50 chromosomes is found in approximately 25 percent of children with ALL and is associated with a good prognosis. (Giemsa-trypsin banding) - Hypergranular acute promyelocytic leukemia (AML-M3) G-banded Wright-Giemsa stained partial karyotype showing the 15;17 chromosome translocation. The breakpoints on the abnormal chromosomes are designated by arrowheads. - Karyotype of normal female. - Karyotype of normal male. - Karyotype R bands composite - Lymphoblast karyotype from a patient with mixed phenotype acute leukemia (Bilineal). A karyotype from bone marrow cells of the patient whose blood smear is depicted in figure 146. There is a translocation of material from the long arm of chromosome 4 to the long arm of chromosome 11, t(4;11) (q21;q23). This translocation is found in less than 5 percent of cases of childhood ALL. It is associated with markedly elevated leukocyte counts and poor prognosis. Approximately 20 percent of patients are less than 1 month of age at diagnosis (congenital leukemia). - Myelodysplastic syndrome (MDS), Agnogenic myeloid metaplasia, myelofibrosis, karyotype; Trisomy 8 or +8 is most common karyotype abnormality in MDS, and acute nonlymphocytic leukemias. - Myelodysplastic syndrome, MDS. Refractory anemia (RA), karyotype, 5q- syndrome; 5q- abnormality per se is not a bad prognostic marker but results in a refractory anemia called 5q- syndrome. - Myelodysplastic syndrome, MDS. Refractory anemia (RA), karyotype, 5q- syndrome; 5q- abnormality per se is not a bad prognostic marker but results in a refractory anemia called 5q- syndrome. - Normal female karyotype. - Normal karyotype. - Philadelphia chromosome in Chronic Myelogenous Leukemia (CML); Ph, t(9;22) results in a fusion mRNA of 210 kd called bcr/abl which inhibits cellular apoptosis and increase granulocytes in Chronic Myelogenous Leukemia (CML). - T-prolymphocytic leukemia. Portion of a karyotype of a lymphocyte from the specimen shown in B showing an inv(14)(q11q32) abnormality. (G banded, Wright-Giemsa stained) - Trisomy 13 karyotype.jpg - Trisomy 18 karyotype.jpg - Turner's karyotype. - Turner's karyotype 46x 150x.	https://www.wikidoc.org/index.php/46,XX
dabc8ff46d96448d144da0362ec0c1b4da05eb2e	wikidoc	49, XXXXX	49, XXXXX # Overview XXXXX syndrome (also called pentasomy X or 49,XXXXX) is the presence of three additional X chromosomes. Diagnosis is done by karyotyping. Approximately 25 females have been described in medical literature worldwide with this extremely rare condition. The condition was first described in 1963. # Effects ## Physical traits XXXXX syndrome is associated with microcephaly (undersized head), micrognathia (undersized jaw), and round face. The ears are generally low-set and malformed. Eyes are upslanting and show palpebral fissures, hypertelorism, and strabismus. Usually the nose is shaped with a broad and depressed nasal bridge and epicanthus, with the mouth having a cleft palate, highly arched palate, dental abnormalities, and thick, furrowed, and everted lips. The neck is webbed, much like the underarms of a woman with Turner's Syndrome. The hands and feet are small with overlapping toes, camptodactyly, clinodactyly, talipes equinovarus, and metatarsus varus. Scoliosis generally affects the spine and hypotonia affects the muscles. ## Internal organs The heart is usually affected by patent ductus arteriosus, atrial septal defect, ventricular septal defect, and aortic dextroposition. There is abnormal lobulation of the lungs and neonatal asphyxia. The ovaries are abnormally shaped with a small uterus and kidney hypoplasia. ## Growth and development XXXXX syndrome causes mental, growth, and motor retardation. There is occasional delayed puberty. Behavior and performance is affected by Opisthotonoid posture. The 'rule of thumb' states that there will be a 10 to 15 IQ point decrease for each extra X chromosome. Thus, the average IQ would be between 55 and 70..	49, XXXXX Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] } # Overview XXXXX syndrome (also called pentasomy X or 49,XXXXX) is the presence of three additional X chromosomes. Diagnosis is done by karyotyping. Approximately 25 females have been described in medical literature worldwide with this extremely rare condition. The condition was first described in 1963. # Effects ## Physical traits XXXXX syndrome is associated with microcephaly (undersized head), micrognathia (undersized jaw), and round face. The ears are generally low-set and malformed. Eyes are upslanting and show palpebral fissures, hypertelorism, and strabismus. Usually the nose is shaped with a broad and depressed nasal bridge and epicanthus, with the mouth having a cleft palate, highly arched palate, dental abnormalities, and thick, furrowed, and everted lips. The neck is webbed, much like the underarms of a woman with Turner's Syndrome. The hands and feet are small with overlapping toes, camptodactyly, clinodactyly, talipes equinovarus, and metatarsus varus. Scoliosis generally affects the spine and hypotonia affects the muscles. ## Internal organs The heart is usually affected by patent ductus arteriosus, atrial septal defect, ventricular septal defect, and aortic dextroposition. There is abnormal lobulation of the lungs and neonatal asphyxia. The ovaries are abnormally shaped with a small uterus and kidney hypoplasia. ## Growth and development XXXXX syndrome causes mental, growth, and motor retardation. There is occasional delayed puberty. Behavior and performance is affected by Opisthotonoid posture. The 'rule of thumb' states that there will be a 10 to 15 IQ point decrease for each extra X chromosome. Thus, the average IQ would be between 55 and 70.[1].	https://www.wikidoc.org/index.php/49,_XXXXX
d44bba8b61b9c9d3abfe4aad8f34c54e238f0811	wikidoc	Serotonin	Serotonin Serotonin (Template:PronEng) (5-hydroxytryptamine, or 5-HT) is a monoamine neurotransmitter synthesized in serotonergic neurons in the central nervous system (CNS) and enterochromaffin cells in the gastrointestinal tract of animals including humans. Serotonin is also found in many mushrooms and plants, including fruits and vegetables. # Function In the central nervous system, serotonin is believed to play an important role as a neurotransmitter, in the inhibition of anger, aggression, body temperature, mood, sleep, vomiting, sexuality, and appetite. In addition, serotonin is also a peripheral signal mediator. For instance, serotonin is found extensively in the human gastrointestinal tract (about 90%), and the major storage place is platelets in the blood stream. ## Neurotransmission As with all neurotransmitters, the effects of 5-HT on the human mood and state of mind, and its role in consciousness, are very difficult to ascertain. ### Gross anatomy The neurons of the raphe nuclei are the principal source of 5-HT release in the brain. The raphe nuclei are neurons grouped into about nine pairs and distributed along the entire length of the brainstem, centered around the reticular formation. Axons from the neurons of the raphe nuclei form a neurotransmitter system, reaching large areas of the brain. Axons of neurons in the caudal dorsal raphe nucleus terminate in e.g.: - Deep cerebellar nuclei - Cerebellar cortex - Spinal cord On the other hand, axons of neurons in the rostral dorsal raphe nucleus terminate in e.g.: - Thalamus - Striatum - Hypothalamus - Nucleus accumbens - Neocortex - Cingulate gyrus - Cingulum - Hippocampus - Amygdala Thus, activation of this serotonin system has effects on large areas of the brain, which explains the effects of therapeutic modulation of it. ### Microanatomy 5-HT is thought to be released from serotonergic varicosities into the extra neuronal space, in other words from swellings (varicosities) along the axon, rather than from synaptic terminal buttons (in the manner of classical neurotransmission). From here it is free to diffuse over a relatively large region of space (>20µm) and activate 5-HT receptors located on the dendrites, cell bodies and presynaptic terminals of adjacent neurons. 5-HT receptors are the receptors for serotonin. They are located on the cell membrane of nerve cells and other cell types in animals and mediate the effects of serotonin as the endogenous ligand and of a broad range of pharmaceutical and hallucinogenic drugs. With the exception of the 5-HT3 receptor, a ligand gated ion channel, all other 5-HT receptors are G protein coupled seven transmembrane (or heptahelical) receptors that activate an intracellular second messenger cascade. Genetic variations in alleles which code for serotonin receptors are now known to have a significant impact on the likelihood of the appearance of certain psychological disorders and problems. For instance, a mutation in the allele which codes for the 5-HT2A receptor appears to double the risk of suicide for those with that genotype. . However, evidence for this has yet to be replicated satisfactorily, and doubts over the validity of this finding have been raised. It is very unlikely that one individual gene could be responsible for increased suicides. It is more probable that a number of genes combine with environmental factors to affect behaviour in this way. Serotonergic action is terminated primarily via uptake of 5-HT from the synapse. This is through the specific monoamine transporter for 5-HT, 5-HT reuptake transporter, on the presynaptic neuron. Various agents can inhibit 5-HT reuptake including MDMA (ecstasy), amphetamine, cocaine, dextromethorphan (an antitussive), tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). ## Other functions Recent research suggests that serotonin plays an important role in liver regeneration and acts as a mitogen (induces cell division) throughout the body. # Pathology If neurons of the brainstem that make serotonin — serotonergic neurons — are abnormal in infants, there is a risk of sudden infant death syndrome (SIDS). Low levels of serotonin may also be associated with intense religious experiences. It has also been discovered that serial killers consistently have low levels of serotonin. This is possibly a result of the aggressive and angry behaviors also associated with low levels of serotonin). Recent research conducted at Rockefeller University shows that in both patients who suffer from depression and in mice that model that disease, levels of the p11 protein are decreased. This protein is related to serotonin transmission within the brain. # Synthesis In the body, serotonin is synthesized from the amino acid tryptophan by a short metabolic pathway consisting of two enzymes: tryptophan hydroxylase (TPH) and amino acid decarboxylase (DDC). The TPH-mediated reaction is the rate-limiting step in the pathway. TPH has been shown to exist in two forms: TPH1, found in several tissues, and TPH2, which is a brain-specific isoform. There is evidence that genetic polymorphisms in both these subtypes influence susceptibility to anxiety and depression. There is also evidence that ovarian hormones can affect the expression of TPH in various species, suggesting a possible mechanism for postpartum depression and premenstrual stress syndrome. Serotonin taken orally does not pass into the serotonergic pathways of the central nervous system because it does not cross the blood-brain barrier. However, tryptophan and its metabolite 5-hydroxytryptophan (5-HTP), from which serotonin is synthesized, can and do cross the blood-brain barrier. These agents are available as dietary supplements and may be effective serotonergic agents. One product of serotonin breakdown is 5-Hydroxyindoleacetic acid (5 HIAA), which is excreted in the urine. Serotonin and 5 HIAA are sometimes produced in excess amounts by certain tumors or cancers, and levels of these substances may be measured in the urine to test for these tumors. # Serotonergic drugs Several classes of drugs target the 5-HT system including some antidepressants, antipsychotics, anxiolytics, antiemetics, and antimigraine drugs as well as the psychedelic drugs and empathogens. # Psychoactive drugs The psychedelic drugs psilocin/psilocybin, DMT, mescaline, and LSD mimick the action of serotonin at 5-HT2A receptors. The empathogen MDMA (ecstasy) releases serotonin from synaptic vesicles of neurons. ## Antidepressants The MAOIs prevent the breakdown of monoamine neurotransmitters (including serotonin), and therefore increase concentrations of the neurotransmitter in the brain. MAOI therapy is associated with many adverse drug reactions, and patients are at risk of hypertensive emergency triggered by foods with high tyramine content and certain drugs. Some drugs inhibit this re-uptake of serotonin, again making it stay in the synapse longer. The tricyclic antidepressants (TCAs) inhibit the re-uptake of both serotonin and norepinephrine. The newer selective serotonin re-uptake inhibitors (SSRIs) have fewer (though still numerous) side-effects and fewer interactions with other drugs. Like many centrally active drugs, prolonged use of SSRIs may not be effective for increasing levels of serotonin as homeostasis may reverse the effects of SSRIs via negative feedback, tolerance or downregulation. ## Antiemetics 5-HT3 antagonists such as ondansetron, granisetron, and tropisetron are important antiemetic agents. They are particularly important in treating the nausea and vomiting that occur during anticancer chemotherapy using cytotoxic drugs. Another application is in treatment of post-operative nausea and vomiting. Applications to the treatment of depression and other mental and psychological conditions have also been investigated with some positive results. ## Serotonin syndrome Extremely high levels of serotonin can have toxic and potentially fatal effects, causing a condition known as serotonin syndrome. In practice, such toxic levels are essentially impossible to reach through an overdose of a single anti-depressant drug, but require a combination of serotonergic agents, such as an SSRI with an MAOI. The intensity of the symptoms of serotonin syndrome vary over a wide spectrum, and the milder forms are seen even at non-toxic levels. For example, recreational doses of MDMA (ecstasy) will generally cause such symptoms but only rarely lead to true toxicity. ## Chronic diseases resulting from serotonin 5-HT2B overstimulation In blood, serotonin stored in platelets is active wherever platelets bind, as a vasoconstictor to stop bleeding, and also as a fibrocyte mitotic, to aid healing. Because of these effects, overdoses of serotonin, or serotonin agonist drugs, may cause acute or chronic pulmonary hypertension from pulmonary vasoconstriction, or else syndromes of retroperitoneal fibrosis or cardiac valve fibrosis (endocardial fibrosis) from overstimulation of serotonic growth receptors on fibrocytes. Serotonin itself may cause a syndrome of cardiac fibrosis when it is eaten in large quantities in the diet (the Matoki banana of East Africa) or when it is over-secreted by certain mid-gut carcinoid tumors. The valvular fibrosis in such cases is typically on the right side of the heart, since excess serotonin in the serum outside platelets is metabolized in the lungs, and does not reach the left circulation. Serotonergic agonist drugs in overdose in experimental animals not only cause acute (and sometimes fatal) pulmonary hypertension, but there is epidemiologic evidence that chronic use of certain of these drugs produce a chronic pulmonary hypertensive syndrome in humans, also. Some serotinergic agonist drugs also cause fibrosis anywhere in the body, particularly the syndrome of retroperitoneal fibrosis, as well as right-sided cardiac valve fibrosis. In the past, three groups of serotonergic drugs have been epidemiolgically linked with these syndromes. They are the serotonergic vasoconstrictive anti-migraine drugs (ergotamine and methysergide), the serotonergic appetite suppressant drugs (fenfluramine, chlorphentermine, and aminorex), and certain anti-parkinsonian dopaminergic agonists, which also stimulate serotonergic 5-HT2B receptors. These include (pergolide and cabergoline, but not the more specific lisuride). A number of these drugs have recently been withdrawn from the market after groups taking them showed a statistical increase of one or more off the side effects described. Because neither the amino acid L-tryptophan nor the SSRI-class antidepressants raise blood serotonin levels, they are not under suspicion to cause the syndromes described. However, since 5-hydroxytryptophan (5-HTP) does raise blood serotonin levels, it is under some of the same scrutiny as actively serotonergic drugs. # In unicellular organisms Serotonin is used by a variety of single-cell organisms for various purposes. Selective serotonin re-uptake inhibitors (SSRIs) have been found to be toxic to algae. The gastrointestinal parasite Entamoeba histolytica secretes serotonin, causing a sustained secretory diarrhea in some patients. Patients infected with Entamoeba histolytica have been found to have highly elevated serum serotonin levels which returned to normal following resolution of the infection.Entamoeba histolytica also responds to the presence of serotonin by becoming more virulent. # In plants Serotonin is found in mushrooms and plants, including fruits and vegetables. The highest values of 25–400 mg/kg have been found in nuts of the walnut (Juglans) and hickory (Carya) genuses. Serotonin concentrations of 3–30 mg/kg have been found in plantain, pineapple, banana, kiwifruit, plums, and tomatoes. Moderate levels from 0.1–3 mg/kg have been found in a wide range of tested vegetables. Serotonin is one compound of the poison contained in the stinging hairs of the stinging nettle (Urtica dioica). It should be noted that serotonin, unlike its precursors 5-HTP and tryptophan, does not cross the blood–brain barrier. Several plants contain serotonin together with a family of related tryptamines that are methylated at the amino (NH2) and hydroxy (OH) groups, are N-oxides, or miss the OH group. Examples are plants from the Anadenanthera genus that are used in the hallucinogenic yopo snuff. # In animals Serotonin as a neurotransmitter is found in all animals, including insects. Several toad venoms, as well as that of the Brazilian Wandering Spider and stingray, contain serotonin and related tryptamines. # History Isolated and named in 1948 by Maurice M. Rapport, Arda Green, and Irvine Page of the Cleveland Clinic, the name serotonin is something of a misnomer and reflects the circumstances of the compound's discovery. It was initially identified as a vasoconstrictor substance in blood serum – hence serotonin, a serum agent affecting vascular tone. This agent was later chemically identified as 5-hydroxytryptamine (5-HT) by Rapport, and, as the broad range of physiological roles were elucidated, 5-HT became the preferred name in the pharmacological field.	Serotonin Template:Chembox new Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Serotonin (Template:PronEng) (5-hydroxytryptamine, or 5-HT) is a monoamine neurotransmitter synthesized in serotonergic neurons in the central nervous system (CNS) and enterochromaffin cells in the gastrointestinal tract of animals including humans. Serotonin is also found in many mushrooms and plants, including fruits and vegetables. # Function In the central nervous system, serotonin is believed to play an important role as a neurotransmitter, in the inhibition of anger, aggression, body temperature, mood, sleep, vomiting, sexuality, and appetite. In addition, serotonin is also a peripheral signal mediator. For instance, serotonin is found extensively in the human gastrointestinal tract (about 90%),[1] and the major storage place is platelets in the blood stream. ## Neurotransmission As with all neurotransmitters, the effects of 5-HT on the human mood and state of mind, and its role in consciousness, are very difficult to ascertain. ### Gross anatomy The neurons of the raphe nuclei are the principal source of 5-HT release in the brain.[2] The raphe nuclei are neurons grouped into about nine pairs and distributed along the entire length of the brainstem, centered around the reticular formation. [3] Axons from the neurons of the raphe nuclei form a neurotransmitter system, reaching large areas of the brain. Axons of neurons in the caudal dorsal raphe nucleus terminate in e.g.: - Deep cerebellar nuclei - Cerebellar cortex - Spinal cord On the other hand, axons of neurons in the rostral dorsal raphe nucleus terminate in e.g.: - Thalamus - Striatum - Hypothalamus - Nucleus accumbens - Neocortex - Cingulate gyrus - Cingulum - Hippocampus - Amygdala Thus, activation of this serotonin system has effects on large areas of the brain, which explains the effects of therapeutic modulation of it. ### Microanatomy 5-HT is thought to be released from serotonergic varicosities into the extra neuronal space, in other words from swellings (varicosities) along the axon, rather than from synaptic terminal buttons (in the manner of classical neurotransmission). From here it is free to diffuse over a relatively large region of space (>20µm) and activate 5-HT receptors located on the dendrites, cell bodies and presynaptic terminals of adjacent neurons. 5-HT receptors are the receptors for serotonin. They are located on the cell membrane of nerve cells and other cell types in animals and mediate the effects of serotonin as the endogenous ligand and of a broad range of pharmaceutical and hallucinogenic drugs. With the exception of the 5-HT3 receptor, a ligand gated ion channel, all other 5-HT receptors are G protein coupled seven transmembrane (or heptahelical) receptors that activate an intracellular second messenger cascade. Genetic variations in alleles which code for serotonin receptors are now known to have a significant impact on the likelihood of the appearance of certain psychological disorders and problems. For instance, a mutation in the allele which codes for the 5-HT2A receptor appears to double the risk of suicide for those with that genotype. [2]. However, evidence for this has yet to be replicated satisfactorily, and doubts over the validity of this finding have been raised. It is very unlikely that one individual gene could be responsible for increased suicides. It is more probable that a number of genes combine with environmental factors to affect behaviour in this way. Serotonergic action is terminated primarily via uptake of 5-HT from the synapse. This is through the specific monoamine transporter for 5-HT, 5-HT reuptake transporter, on the presynaptic neuron. Various agents can inhibit 5-HT reuptake including MDMA (ecstasy), amphetamine, cocaine, dextromethorphan (an antitussive), tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). ## Other functions Recent research suggests that serotonin plays an important role in liver regeneration and acts as a mitogen (induces cell division) throughout the body.[4] # Pathology If neurons of the brainstem that make serotonin — serotonergic neurons — are abnormal in infants, there is a risk of sudden infant death syndrome (SIDS).[5][6] Low levels of serotonin may also be associated with intense religious experiences.[7] It has also been discovered that serial killers consistently have low levels of serotonin. This is possibly a result of the aggressive and angry behaviors also associated with low levels of serotonin). Recent research conducted at Rockefeller University shows that in both patients who suffer from depression and in mice that model that disease, levels of the p11 protein are decreased. This protein is related to serotonin transmission within the brain.[8] # Synthesis In the body, serotonin is synthesized from the amino acid tryptophan by a short metabolic pathway consisting of two enzymes: tryptophan hydroxylase (TPH) and amino acid decarboxylase (DDC). The TPH-mediated reaction is the rate-limiting step in the pathway. TPH has been shown to exist in two forms: TPH1, found in several tissues, and TPH2, which is a brain-specific isoform. There is evidence that genetic polymorphisms in both these subtypes influence susceptibility to anxiety and depression. There is also evidence that ovarian hormones can affect the expression of TPH in various species, suggesting a possible mechanism for postpartum depression and premenstrual stress syndrome. Serotonin taken orally does not pass into the serotonergic pathways of the central nervous system because it does not cross the blood-brain barrier. However, tryptophan and its metabolite 5-hydroxytryptophan (5-HTP), from which serotonin is synthesized, can and do cross the blood-brain barrier. These agents are available as dietary supplements and may be effective serotonergic agents. One product of serotonin breakdown is 5-Hydroxyindoleacetic acid (5 HIAA), which is excreted in the urine. Serotonin and 5 HIAA are sometimes produced in excess amounts by certain tumors or cancers, and levels of these substances may be measured in the urine to test for these tumors. # Serotonergic drugs Several classes of drugs target the 5-HT system including some antidepressants, antipsychotics, anxiolytics, antiemetics, and antimigraine drugs as well as the psychedelic drugs and empathogens. # Psychoactive drugs The psychedelic drugs psilocin/psilocybin, DMT, mescaline, and LSD mimick the action of serotonin at 5-HT2A receptors. The empathogen MDMA (ecstasy) releases serotonin from synaptic vesicles of neurons. ## Antidepressants The MAOIs prevent the breakdown of monoamine neurotransmitters (including serotonin), and therefore increase concentrations of the neurotransmitter in the brain. MAOI therapy is associated with many adverse drug reactions, and patients are at risk of hypertensive emergency triggered by foods with high tyramine content and certain drugs. Some drugs inhibit this re-uptake of serotonin, again making it stay in the synapse longer. The tricyclic antidepressants (TCAs) inhibit the re-uptake of both serotonin and norepinephrine. The newer selective serotonin re-uptake inhibitors (SSRIs) have fewer (though still numerous) side-effects and fewer interactions with other drugs. Like many centrally active drugs, prolonged use of SSRIs may not be effective for increasing levels of serotonin as homeostasis may reverse the effects of SSRIs via negative feedback, tolerance or downregulation. ## Antiemetics 5-HT3 antagonists such as ondansetron, granisetron, and tropisetron are important antiemetic agents. They are particularly important in treating the nausea and vomiting that occur during anticancer chemotherapy using cytotoxic drugs. Another application is in treatment of post-operative nausea and vomiting. Applications to the treatment of depression and other mental and psychological conditions have also been investigated with some positive results. ## Serotonin syndrome Extremely high levels of serotonin can have toxic and potentially fatal effects, causing a condition known as serotonin syndrome. In practice, such toxic levels are essentially impossible to reach through an overdose of a single anti-depressant drug, but require a combination of serotonergic agents, such as an SSRI with an MAOI.[9] The intensity of the symptoms of serotonin syndrome vary over a wide spectrum, and the milder forms are seen even at non-toxic levels.[10] For example, recreational doses of MDMA (ecstasy) will generally cause such symptoms but only rarely lead to true toxicity. ## Chronic diseases resulting from serotonin 5-HT2B overstimulation In blood, serotonin stored in platelets is active wherever platelets bind, as a vasoconstictor to stop bleeding, and also as a fibrocyte mitotic, to aid healing. Because of these effects, overdoses of serotonin, or serotonin agonist drugs, may cause acute or chronic pulmonary hypertension from pulmonary vasoconstriction, or else syndromes of retroperitoneal fibrosis or cardiac valve fibrosis (endocardial fibrosis) from overstimulation of serotonic growth receptors on fibrocytes. Serotonin itself may cause a syndrome of cardiac fibrosis when it is eaten in large quantities in the diet (the Matoki banana of East Africa) or when it is over-secreted by certain mid-gut carcinoid tumors. The valvular fibrosis in such cases is typically on the right side of the heart, since excess serotonin in the serum outside platelets is metabolized in the lungs, and does not reach the left circulation. Serotonergic agonist drugs in overdose in experimental animals not only cause acute (and sometimes fatal) pulmonary hypertension, but there is epidemiologic evidence that chronic use of certain of these drugs produce a chronic pulmonary hypertensive syndrome in humans, also. Some serotinergic agonist drugs also cause fibrosis anywhere in the body, particularly the syndrome of retroperitoneal fibrosis, as well as right-sided cardiac valve fibrosis. In the past, three groups of serotonergic drugs have been epidemiolgically linked with these syndromes. They are the serotonergic vasoconstrictive anti-migraine drugs (ergotamine and methysergide), the serotonergic appetite suppressant drugs (fenfluramine, chlorphentermine, and aminorex), and certain anti-parkinsonian dopaminergic agonists, which also stimulate serotonergic 5-HT2B receptors. These include (pergolide and cabergoline, but not the more specific lisuride). A number of these drugs have recently been withdrawn from the market after groups taking them showed a statistical increase of one or more off the side effects described. Because neither the amino acid L-tryptophan nor the SSRI-class antidepressants raise blood serotonin levels, they are not under suspicion to cause the syndromes described. However, since 5-hydroxytryptophan (5-HTP) does raise blood serotonin levels, it is under some of the same scrutiny as actively serotonergic drugs. # In unicellular organisms Serotonin is used by a variety of single-cell organisms for various purposes. Selective serotonin re-uptake inhibitors (SSRIs) have been found to be toxic to algae.[11] The gastrointestinal parasite Entamoeba histolytica secretes serotonin, causing a sustained secretory diarrhea in some patients.[12][13] Patients infected with Entamoeba histolytica have been found to have highly elevated serum serotonin levels which returned to normal following resolution of the infection.[14]Entamoeba histolytica also responds to the presence of serotonin by becoming more virulent.[15] # In plants Serotonin is found in mushrooms and plants, including fruits and vegetables. The highest values of 25–400 mg/kg have been found in nuts of the walnut (Juglans) and hickory (Carya) genuses. Serotonin concentrations of 3–30 mg/kg have been found in plantain, pineapple, banana, kiwifruit, plums, and tomatoes. Moderate levels from 0.1–3 mg/kg have been found in a wide range of tested vegetables.[16] Serotonin is one compound of the poison contained in the stinging hairs of the stinging nettle (Urtica dioica). It should be noted that serotonin, unlike its precursors 5-HTP and tryptophan, does not cross the blood–brain barrier. Several plants contain serotonin together with a family of related tryptamines that are methylated at the amino (NH2) and hydroxy (OH) groups, are N-oxides, or miss the OH group. Examples are plants from the Anadenanthera genus that are used in the hallucinogenic yopo snuff. # In animals Serotonin as a neurotransmitter is found in all animals, including insects. Several toad venoms, as well as that of the Brazilian Wandering Spider and stingray, contain serotonin and related tryptamines. # History Isolated and named in 1948 by Maurice M. Rapport, Arda Green, and Irvine Page of the Cleveland Clinic,[17] the name serotonin is something of a misnomer and reflects the circumstances of the compound's discovery. It was initially identified as a vasoconstrictor substance in blood serum – hence serotonin, a serum agent affecting vascular tone. This agent was later chemically identified as 5-hydroxytryptamine (5-HT) by Rapport, and, as the broad range of physiological roles were elucidated, 5-HT became the preferred name in the pharmacological field.	https://www.wikidoc.org/index.php/5-HT
fc111e71a7c60d3603160d80a743c977c783694b	wikidoc	5-MeO-AET	5-MeO-AET 5-MeO-α-ET is a tryptamine that produces psychedelic, entactogenic, and stimulant effects. # Chemistry 5-MeO-α-ET is short for 5-methoxy-alpha-ethyltryptamine. The full name of the chemical is 1-(5-methoxy-1H-indol-3-yl)butan-2-amine. 5-MeO-α-ET is a tryptamine, which belong to a larger family of compounds known as indolethylamines. 5-MeO-α-ET is closely related to the compounds 5-MeO-AMT and α-ET. # Dosage 5-MeO-α-ET, when used recreationally, is usually taken orally at dosages of 50-75 mg. # Effects 5-MeO-α-ET produces entactogenic and stimulant effects that can last 4-6 hours. However, little information exists on the psychopharmacological of this compound, thus considerable variation with regard to dosage and effects can be expected. # Dangers There have been no reported deaths or hospitalizations from 5-MeO-α-ET, but its safety profile is unknown. # Legality 5-MeO-α-ET is unscheduled and uncontrolled in the United States, but possession and sales of 5-MeO-α-ET could be prosecuted under the Federal Analog Act because of its structural similarities to α-ET and α-MT.	5-MeO-AET 5-MeO-α-ET is a tryptamine that produces psychedelic, entactogenic, and stimulant effects. # Chemistry 5-MeO-α-ET is short for 5-methoxy-alpha-ethyltryptamine. The full name of the chemical is 1-(5-methoxy-1H-indol-3-yl)butan-2-amine. 5-MeO-α-ET is a tryptamine, which belong to a larger family of compounds known as indolethylamines. 5-MeO-α-ET is closely related to the compounds 5-MeO-AMT and α-ET. # Dosage 5-MeO-α-ET, when used recreationally, is usually taken orally at dosages of 50-75 mg. # Effects 5-MeO-α-ET produces entactogenic and stimulant effects that can last 4-6 hours. However, little information exists on the psychopharmacological of this compound, thus considerable variation with regard to dosage and effects can be expected. # Dangers There have been no reported deaths or hospitalizations from 5-MeO-α-ET, but its safety profile is unknown. # Legality 5-MeO-α-ET is unscheduled and uncontrolled in the United States, but possession and sales of 5-MeO-α-ET could be prosecuted under the Federal Analog Act because of its structural similarities to α-ET and α-MT. # External links - 5-MeO-α-ET information from www.bluelight.ru Template:Tryptamines	https://www.wikidoc.org/index.php/5-MeO-AET
a0ab9e088abe10fca5a9d9e4a441f0df0756731a	wikidoc	5-MeO-AMT	5-MeO-AMT 5-MeO-AMT (5-methoxy-α-methyltryptamine) is a psychedelic drug. It is soluble in alcohol. It is one of the most potent tryptamines; that is, a very small amount is needed to achieve intense effects. # Pharmacology The sympathomimetic effects may in turn be caused by 5-MeO-AMT's structural similarity to the amphetamines. As noted by Alexander Shulgin, the alpha-methylated tryptamines can be looked at as the tryptamine homologues of the amphetamines (alpha-methylated phenethylamines). # Recreational usage It is supposedly sold in 4mg tablets by the street name Alpha-O and taken as a recreational drug. Since the DEA arrests of the makers of a huge percentage of the United States' LSD in 2000, 5-MeO-AMT may have occasionally been sold under the guise of LSD in liquid, sugar cube, or blotter form. Although this idea may be because the DEA has released reports of finding it on sugar cubes, and blotters, "LSD Style". The most common route of administration for 5-MeO-AMT is orally, however anecdotal reports have stated less common methods such as snorting or smoking. Intravenous (IV) and intramuscular (IM) routes are rarely, if ever, used outside research settings due to the high potency, powerful effects and quicker onset. # Effects The effects of 5-MeO-AMT occur at very low oral dosages, in the 4-7mg range for most users. Inexperienced hallucinogen users should take caution and begin with a light dose, 2-7mg. Erowid lists the following effects: ### Positive - Increased energy - Improved mood heading into euphoria at higher doses - Increased sociability, gregariousness - Increased giggling and laughing - Increased sense of creative thinking - Increased pleasure from sense of touch - Intensification in sexual / erotic experiences for some users ### Neutral - Light headedness - Brightening of colors - Visuals including motion, waves, breathing walls, etc (usually at doses over 4-5mg) - Increased attention on details - Auditory distortions or hallucinations (usually at higher doses) ### Negative - Headache - Body fatigue - Stress and extreme fatigue from long duration of effects. - Nausea, diarrhea - Vomiting at high doses - Difficulty sleeping or resting for 12-24 hours after ingestion. - Paranoia, irritability, anxiety (increasing with dose). - Delusional, aggressive, or dissociated behaviour at very high doses (20+mg) # Dangers When users take more "hits" of 5-MeO-AMT than is normal, possibly thinking it is the relatively safer LSD, they may overdose. Overdosing can also occur at dosages in the normal (for most users) range, as low as 8 mg. This has led to at least a few hospitalizations and possibly more than one death. It is likely that the overdose potential of the compound is due to its sympathomimetic effects, as the side effects noted in overdose cases include cardiac arrhythmia and seizure. It also seems that oral consumption is safer than insufflation. # Legality According to the US Department of Justice, 5-MeO-AMT is illegal for human consumption. It is an analog of 5-MeO-DIPT and alpha-methyltryptamine (AMT), which are Schedule I drugs under the Controlled Substances Act. According to 21 U.S.C. § 813, “a controlled substance analog(ue) shall, to the extent intended for human consumption, be treated, for the purposes of any Federal law as a controlled substance in Schedule I.” Thus, authorities can prosecute drug offenses involving 5-MeO-AMT in the same manner as offenses involving 5-MeO-DIPT and AMT. (See 21 U.S.C.§ 802(32) for the definition of a controlled substance analog(ue).) # Additional Images - 5-MeO-AMT blotters. 5-MeO-AMT blotters.	5-MeO-AMT 5-MeO-AMT (5-methoxy-α-methyltryptamine) is a psychedelic drug. It is soluble in alcohol. It is one of the most potent tryptamines; that is, a very small amount is needed to achieve intense effects. # Pharmacology The sympathomimetic effects may in turn be caused by 5-MeO-AMT's structural similarity to the amphetamines. As noted by Alexander Shulgin, the alpha-methylated tryptamines can be looked at as the tryptamine homologues of the amphetamines (alpha-methylated phenethylamines). # Recreational usage It is supposedly sold in 4mg tablets by the street name Alpha-O and taken as a recreational drug. Since the DEA arrests of the makers of a huge percentage of the United States' LSD in 2000, 5-MeO-AMT may have occasionally been sold under the guise of LSD in liquid, sugar cube, or blotter form. Although this idea may be because the DEA has released reports of finding it on sugar cubes, and blotters, "LSD Style".[1][2] The most common route of administration for 5-MeO-AMT is orally, however anecdotal reports have stated less common methods such as snorting or smoking. Intravenous (IV) and intramuscular (IM) routes are rarely, if ever, used outside research settings due to the high potency, powerful effects and quicker onset. # Effects The effects of 5-MeO-AMT occur at very low oral dosages, in the 4-7mg range for most users. Inexperienced hallucinogen users should take caution and begin with a light dose, 2-7mg. Erowid lists the following effects:[3] ### Positive - Increased energy - Improved mood heading into euphoria at higher doses - Increased sociability, gregariousness - Increased giggling and laughing - Increased sense of creative thinking - Increased pleasure from sense of touch - Intensification in sexual / erotic experiences for some users ### Neutral - Light headedness - Brightening of colors - Visuals including motion, waves, breathing walls, etc (usually at doses over 4-5mg) - Increased attention on details - Auditory distortions or hallucinations (usually at higher doses) ### Negative - Headache - Body fatigue - Stress and extreme fatigue from long duration of effects. - Nausea, diarrhea - Vomiting at high doses - Difficulty sleeping or resting for 12-24 hours after ingestion. - Paranoia, irritability, anxiety (increasing with dose). - Delusional, aggressive, or dissociated behaviour at very high doses (20+mg) # Dangers When users take more "hits" of 5-MeO-AMT than is normal, possibly thinking it is the relatively safer LSD, they may overdose. Overdosing can also occur at dosages in the normal (for most users) range, as low as 8 mg. This has led to at least a few hospitalizations and possibly more than one death.[4] It is likely that the overdose potential of the compound is due to its sympathomimetic effects, as the side effects noted in overdose cases include cardiac arrhythmia and seizure. It also seems that oral consumption is safer than insufflation. # Legality According to the US Department of Justice, 5-MeO-AMT is illegal for human consumption. It is an analog of 5-MeO-DIPT and alpha-methyltryptamine (AMT), which are Schedule I drugs under the Controlled Substances Act. According to 21 U.S.C. § 813, “a controlled substance analog(ue) shall, to the extent intended for human consumption, be treated, for the purposes of any Federal law as a controlled substance in Schedule I.” Thus, authorities can prosecute drug offenses involving 5-MeO-AMT in the same manner as offenses involving 5-MeO-DIPT and AMT. (See 21 U.S.C.§ 802(32) for the definition of a controlled substance analog(ue).)[5] # Additional Images - 5-MeO-AMT blotters. 5-MeO-AMT blotters.	https://www.wikidoc.org/index.php/5-MeO-AMT
4f3cd8d834402b138e20166815a9c84ddb95b383	wikidoc	5-MeO-DMT	5-MeO-DMT 5-MeO-DMT is a very powerful psychedelic tryptamine. It is found in a wide variety of plant and toad species, and like its close relatives DMT and bufotenin (5-OH-DMT), it has been used as an entheogen by South American shamans for thousands of years. 5-MeO-DMT is sometimes referred to as "Businessman's Trip" due to its short duration. # Chemistry 5-MeO-DMT was first synthesized in 1936, and in 1959 it was isolated as one of the psychoactive ingredients of Anadenanthera peregrina seeds used in preparing Yopo snuff. It was once believed to be a major player in the psychoactive effects of the snuff. However, recent tests confirm that bufotenin is the main active psychoactive ingredient of Yopo and that DMT and 5-MeO-DMT are present in quantities too small to elicit much effects. It occurs in many organisms that contain bufotenin(e) (5-hydroxy-DMT), and is the O-methyl analogue of that compound. # History Traditionally 5-MeO-DMT has been used in psychedelic snuff made from Virola bark resin, and may be a trace constituent of ayahuasca when plants such as Diplopterys cabrerana are used as an admixture. 5-MeO-DMT is also found in the venom of the Colorado River Toad (Bufo alvarius), although there is no direct evidence this was used as a hallucinogen until recent times. # Use and effects When used as a drug in its purified form, 5-MeO-DMT is smoked, insufflated, or injected and is active at a dose of as little as 2 mg. 5-MeO-DMT is also active orally, when taken with an monoamine oxidase inhibitor, but according to numerous reports, the combination with MAOI is extremely unpleasant and has a strong body-load. According to the researcher Jonathan Ott, 5-MeO-DMT is active orally with doses over 30 mg without aid of a MAOI. The onset of effects occurs in seconds after smoking/injecting, or minutes after insufflating, and the experience is sometimes described as similar to a near-death experience. Peak effects last for approximately 5-10 minutes, when smoked. When insufflated, the peak effects are considerably less intense, but last for 15-25 minutes on average. Although similar in many respects to its close relatives DMT and bufotenin (5-OH-DMT), the effects are typically not as visual. Some users report experiencing no visual effects from it even at very high doses. Some report the effects to be unpleasant causing nausea and the feeling of being "sat on by an elephant". Erowid lists the following effects for smoked 5-MeO-DMT: ### Positive - immersive experiences - powerful "rushing" sensation - radical perspective shifting - profound life-changing spiritual experiences - some people experience erotic / sensual enhancement - occasional euphoria - internal visions (actual visual effects not as common) - journey into mind ### Neutral - short duration - change in perception of time - experience of "the void" - lack of memory of experience - muscle jerking, twitching, abnormal vocalizations - unconsciousness / nonresponsiveness lasting 5-20 minutes - dissociation ### Negative - overly-intense experiences - nausea - sense of pressure in the body - hard on the lungs to smoke - difficulty integrating experiences - fear, terror and panic - dysphoria (bad feelings) - fast onset and intensity can lead to problems if not prepared (dropped pipe, knocking things over, falling & hitting head, etc) # Legality ## International Law ### Denmark As of December 1, 2004, 5-MeO-DMT is legally restricted to "medical or scientific purposes". See EMCDDA. (Thanks Vman and Ali) ### Germany Schedule I / Highest level of control, unable to be prescribed, manufactured, or possessed as of Sep, 1999. (listed as dimethylazan) (see Deutsche BtMG or ) ### Greece 5-MeO-DMT became a controlled substance in Greece on Feb 18, 2003 . ### New Zealand 5-MeO-DMT is Schedule I (Class A) in New Zealand. ### Sweden Controlled in Sweden as of Oct 1, 2004 (see notisum.se) ### Switzerland 5-MeO-DMT is Schedule I in Switzerland. ## US State Law ### Nebraska Schedule I (Reference) ### S. Dakota Schedule I : 5-methoxy-N, N-Dimethyltryptamine. Feb 2003	5-MeO-DMT 5-MeO-DMT is a very powerful psychedelic tryptamine. It is found in a wide variety of plant and toad species, and like its close relatives DMT and bufotenin (5-OH-DMT), it has been used as an entheogen by South American shamans for thousands of years. 5-MeO-DMT is sometimes referred to as "Businessman's Trip" due to its short duration.[citation needed] # Chemistry 5-MeO-DMT was first synthesized in 1936, and in 1959 it was isolated as one of the psychoactive ingredients of Anadenanthera peregrina seeds used in preparing Yopo snuff. It was once believed to be a major player in the psychoactive effects of the snuff. However, recent tests confirm that bufotenin is the main active psychoactive ingredient of Yopo and that DMT and 5-MeO-DMT are present in quantities too small to elicit much effects.[1] It occurs in many organisms that contain bufotenin(e) (5-hydroxy-DMT), and is the O-methyl analogue of that compound. # History Traditionally 5-MeO-DMT has been used in psychedelic snuff made from Virola bark resin, and may be a trace constituent of ayahuasca when plants such as Diplopterys cabrerana are used as an admixture. 5-MeO-DMT is also found in the venom of the Colorado River Toad (Bufo alvarius), although there is no direct evidence this was used as a hallucinogen until recent times. # Use and effects Template:SectOR When used as a drug in its purified form, 5-MeO-DMT is smoked, insufflated, or injected and is active at a dose of as little as 2 mg. 5-MeO-DMT is also active orally, when taken with an monoamine oxidase inhibitor, but according to numerous reports, the combination with MAOI is extremely unpleasant and has a strong body-load. According to the researcher Jonathan Ott, 5-MeO-DMT is active orally with doses over 30 mg without aid of a MAOI. The onset of effects occurs in seconds after smoking/injecting, or minutes after insufflating, and the experience is sometimes described as similar to a near-death experience. Peak effects last for approximately 5-10 minutes, when smoked. When insufflated, the peak effects are considerably less intense, but last for 15-25 minutes on average. Although similar in many respects to its close relatives DMT and bufotenin (5-OH-DMT), the effects are typically not as visual. Some users report experiencing no visual effects from it even at very high doses.[2] Some report the effects to be unpleasant causing nausea and the feeling of being "sat on by an elephant".[3] Erowid lists the following effects for smoked 5-MeO-DMT:[2] ### Positive - immersive experiences - powerful "rushing" sensation - radical perspective shifting - profound life-changing spiritual experiences - some people experience erotic / sensual enhancement - occasional euphoria - internal visions (actual visual effects not as common) - journey into mind ### Neutral - short duration - change in perception of time - experience of "the void" - lack of memory of experience - muscle jerking, twitching, abnormal vocalizations - unconsciousness / nonresponsiveness lasting 5-20 minutes - dissociation ### Negative - overly-intense experiences - nausea[3] - sense of pressure in the body[3] - hard on the lungs to smoke - difficulty integrating experiences - fear, terror and panic - dysphoria (bad feelings) - fast onset and intensity can lead to problems if not prepared (dropped pipe, knocking things over, falling & hitting head, etc) # Legality ## International Law ### Denmark As of December 1, 2004, 5-MeO-DMT is legally restricted to "medical or scientific purposes". See EMCDDA. (Thanks Vman and Ali) ### Germany Schedule I / Highest level of control, unable to be prescribed, manufactured, or possessed as of Sep, 1999. (listed as [2-(5-Methoxyindol-3-yl)ethyl]dimethylazan) (see Deutsche BtMG or http://www.silicium-sensei.de/projecte/drugs/news/news.html) ### Greece 5-MeO-DMT became a controlled substance in Greece on Feb 18, 2003 [EU Legal Database]. ### New Zealand 5-MeO-DMT is Schedule I (Class A) in New Zealand. ### Sweden Controlled in Sweden as of Oct 1, 2004 (see notisum.se) ### Switzerland 5-MeO-DMT is Schedule I in Switzerland. [unconfirmed] ## US State Law ### Nebraska Schedule I (Reference) ### S. Dakota Schedule I : 5-methoxy-N, N-Dimethyltryptamine. Feb 2003	https://www.wikidoc.org/index.php/5-MeO-DMT
d4726a3fd26be6c32c782aa5dfff8d0ad7f4c282	wikidoc	5-MeO-DPT	5-MeO-DPT 5-MeO-DPT (also known as 5-methoxy-N,N-Dipropyltryptamine), is a hallucinogenic and entheogenic drug. # Chemistry The full chemical name is N--N-propylpropan-1-amine. It is classified as a tryptamine derivative. # Effects Little is known about the subjective effects of 5-MeO-DPT, but the nature of the compound probably comparable to psilocybin/psilocin, or DPT, which are also psychedelic tryptamines/indoles. However, the duration of the above mentioned drugs vary considerably. # Dosage 5-MeO-DPT is orally active, with 6-10 mg represents a fully effective dosage for most users. Effects begin within an hour, and usually last 4-6 hours.	5-MeO-DPT 5-MeO-DPT (also known as 5-methoxy-N,N-Dipropyltryptamine), is a hallucinogenic and entheogenic drug. # Chemistry The full chemical name is N-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N-propylpropan-1-amine. It is classified as a tryptamine derivative. # Effects Little is known about the subjective effects of 5-MeO-DPT, but the nature of the compound probably comparable to psilocybin/psilocin, or DPT, which are also psychedelic tryptamines/indoles. However, the duration of the above mentioned drugs vary considerably. # Dosage 5-MeO-DPT is orally active, with 6-10 mg represents a fully effective dosage for most users. Effects begin within an hour, and usually last 4-6 hours. # External links - 5-MeO-DET TiHKAL Entry on Erowid, mentioning 5-MeO-DPT Template:Tryptamines Template:Hallucinogen-stub Template:WikiDoc Sources	https://www.wikidoc.org/index.php/5-MeO-DPT
392f29487a41525e84663b44f010a32cee747e32	wikidoc	Acid-fast	Acid-fast Synonyms and keywords: AFB, AFB stain # Overview Acid-fastness is a physical property of some bacteria referring to their resistance to decolorization by acids during staining procedures. Acid-fast organisms are difficult to characterize using standard microbiological techniques (e.g. Gram staining), though they can be stained using concentrated dyes, particularly when the staining process is combined with heat. Once stained, these organisms resist the dilute acid and/or ethanol-based de-colorization procedures common in many staining protocols—hence the name acid-fast. The high mycolic acid content of certain bacterial cell walls, like those of Mycobacterium, is responsible for the staining pattern of poor absorption followed by high retention. The most common staining technique used to identify acid-fast bacteria is the Ziehl-Neelsen stain, in which the bacteria are stained bright red and stand out clearly against a blue background. Acid-fast bacteria can also be visualized by fluorescence microscopy using specific fluorescent dyes (auramine-rhodamine stain, for example). Some bacteria may also be partially acid-fast. Only a few types of bacteria are acid-fast, notably members of the Mycobacterium. Most are rod-shaped, termed acid-fast bacilli (AFB), but other forms also occur. Medically the most important AFB is Mycobacterium tuberculosis. Genera like Nocardia and Corynebacterium are also notable examples.	Acid-fast Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Synonyms and keywords: AFB, AFB stain # Overview Acid-fastness is a physical property of some bacteria referring to their resistance to decolorization by acids during staining procedures.[1][2] Acid-fast organisms are difficult to characterize using standard microbiological techniques (e.g. Gram staining), though they can be stained using concentrated dyes, particularly when the staining process is combined with heat. Once stained, these organisms resist the dilute acid and/or ethanol-based de-colorization procedures common in many staining protocols—hence the name acid-fast.[2] The high mycolic acid content of certain bacterial cell walls, like those of Mycobacterium, is responsible for the staining pattern of poor absorption followed by high retention. The most common staining technique used to identify acid-fast bacteria is the Ziehl-Neelsen stain, in which the bacteria are stained bright red and stand out clearly against a blue background. Acid-fast bacteria can also be visualized by fluorescence microscopy using specific fluorescent dyes (auramine-rhodamine stain, for example).[3] Some bacteria may also be partially acid-fast. Only a few types of bacteria are acid-fast, notably members of the Mycobacterium. Most are rod-shaped, termed acid-fast bacilli (AFB), but other forms also occur. Medically the most important AFB is Mycobacterium tuberculosis. Genera like Nocardia and Corynebacterium are also notable examples.	https://www.wikidoc.org/index.php/AFB
f4e820162f1d911ded45f10842e76ba792930bb5	wikidoc	APACHE II	APACHE II # Overview APACHE II ("Acute Physiology and Chronic Health Evaluation II") is a severity of disease classification system (Knaus et al., 1985), one of several ICU scoring systems. After admission of a patient to an intensive care unit, an integer score from 0 to 71 is computed based on several measurements; higher scores imply a more severe disease and a higher risk of death. # Application APACHE II was designed to measure the severity of disease for adult patients admitted to Intensive care units. The lower age is not specified in the original article, but a good limit is to use Apache II only for patients age 15 or older. This scoring systems is used in many ways: - Some procedures and some medicine is only given to patients with certain APACHE II score - APACHE II score can be used to describe the morbidity of a patient when comparing the outcome with other patients. - Predicted mortalities are averaged for groups of patients in order to specify the group's morbidity. Even though newer scoring systems, like SAPS II have replaced APACHE II in many places, APACHE II continues to be used extensively because so much documentation is based on it. # Calculation The point score is calculated from 12 routine physiological measurements (such as blood pressure, body temperature, heart rate etc.) during the first 24 hours after admission, information about previous health status and some information obtained at admission (such as age). The calculation method is optimized for paper schemas. The resulting point score should always be interpreted in relation to the illness of the patient. After the initial score has been determined within 24 hours of admission, no new score can be calculated during the hospital stay. If a patient is discharged from the ICU and readmitted, a new APACHE II score can be calculated. The appendix of the document that originally described the APACHE II score, makes an attempt to describe how to calculate a predicted death rate for a patient. In order to make this calculation of predicted mortality precise, the principal diagnosis leading to ICU admission was added as a category weight: the predicted mortality is computed based on the patient's APACHE II score and their prinicipal diagnosis at admission. # APACHE III A method to compute a refined score known as APACHE III was published in 1992.	APACHE II Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview APACHE II ("Acute Physiology and Chronic Health Evaluation II") is a severity of disease classification system (Knaus et al., 1985), one of several ICU scoring systems. After admission of a patient to an intensive care unit, an integer score from 0 to 71 is computed based on several measurements; higher scores imply a more severe disease and a higher risk of death. # Application APACHE II was designed to measure the severity of disease for adult patients admitted to Intensive care units. The lower age is not specified in the original article, but a good limit is to use Apache II only for patients age 15 or older. This scoring systems is used in many ways: - Some procedures and some medicine is only given to patients with certain APACHE II score - APACHE II score can be used to describe the morbidity of a patient when comparing the outcome with other patients. - Predicted mortalities are averaged for groups of patients in order to specify the group's morbidity. Even though newer scoring systems, like SAPS II have replaced APACHE II in many places, APACHE II continues to be used extensively because so much documentation is based on it. # Calculation The point score is calculated from 12 routine physiological measurements (such as blood pressure, body temperature, heart rate etc.) during the first 24 hours after admission, information about previous health status and some information obtained at admission (such as age). The calculation method is optimized for paper schemas. The resulting point score should always be interpreted in relation to the illness of the patient. After the initial score has been determined within 24 hours of admission, no new score can be calculated during the hospital stay. If a patient is discharged from the ICU and readmitted, a new APACHE II score can be calculated. The appendix of the document that originally described the APACHE II score, makes an attempt to describe how to calculate a predicted death rate for a patient. In order to make this calculation of predicted mortality precise, the principal diagnosis leading to ICU admission was added as a category weight: the predicted mortality is computed based on the patient's APACHE II score and their prinicipal diagnosis at admission. # APACHE III A method to compute a refined score known as APACHE III was published in 1992.	https://www.wikidoc.org/index.php/APACHE_II
9f58450e93c9275ba27c2dc11909c4ad79437b03	wikidoc	Aprataxin	Aprataxin Aprataxin is a protein that in humans is encoded by the APTX gene. This gene encodes a member of the histidine triad (HIT) superfamily, some of which have nucleotide-binding and diadenosine polyphosphate hydrolase activities. The encoded protein may play a role in single-stranded DNA repair. Mutations in this gene have been associated with ataxia-ocular apraxia. Multiple transcript variants encoding distinct isoforms have been identified for this gene, however, the full length nature of some variants has not been determined. # Function Aprataxin removes AMP from DNA ends following abortive ligation attempts by DNA Ligase IV during non-homologous end joining, thereby permitting subsequent attempts at ligation. # DNA strand breaks Ataxia oculomotor apraxia-1 is a neurological disorder caused by mutations in the APTX gene that encodes aprataxin. The neurological disorder appears to be caused by the gradual accumulation of unrepaired DNA strand breaks resulting from abortive DNA ligation events. # Premature aging Aptx−/− mutant mice have been generated, but they lack an obvious phenotype. Another mouse model was generated in which a mutation of superoxide dismutase I (SOD1) is expressed in an Aptx−/− mouse. The SOD1 mutation causes a reduction in transcription recovery following oxidative stress. These mice showed accelerated cellular senescence. This study also demonstrated a protective role of Aptx in vivo and suggested that the loss of Aptx function results in progressive accumulation of DNA breaks in the nervous system, triggering hallmarks of systemic premature aging (see DNA damage theory of aging). # Interactions Aprataxin has been shown to interact with: - PARP1, - P53, - XRCC1, and - XRCC4.	Aprataxin Aprataxin is a protein that in humans is encoded by the APTX gene.[1][2][3] This gene encodes a member of the histidine triad (HIT) superfamily, some of which have nucleotide-binding and diadenosine polyphosphate hydrolase activities. The encoded protein may play a role in single-stranded DNA repair. Mutations in this gene have been associated with ataxia-ocular apraxia. Multiple transcript variants encoding distinct isoforms have been identified for this gene, however, the full length nature of some variants has not been determined.[3] # Function Aprataxin removes AMP from DNA ends following abortive ligation attempts by DNA Ligase IV during non-homologous end joining, thereby permitting subsequent attempts at ligation.[4][5] # DNA strand breaks Ataxia oculomotor apraxia-1 is a neurological disorder caused by mutations in the APTX gene that encodes aprataxin.[6] The neurological disorder appears to be caused by the gradual accumulation of unrepaired DNA strand breaks resulting from abortive DNA ligation events.[6] # Premature aging Aptx−/− mutant mice have been generated, but they lack an obvious phenotype.[6] Another mouse model was generated in which a mutation of superoxide dismutase I (SOD1) is expressed in an Aptx−/− mouse.[7] The SOD1 mutation causes a reduction in transcription recovery following oxidative stress. These mice showed accelerated cellular senescence. This study also demonstrated a protective role of Aptx in vivo and suggested that the loss of Aptx function results in progressive accumulation of DNA breaks in the nervous system, triggering hallmarks of systemic premature aging [7] (see DNA damage theory of aging). # Interactions Aprataxin has been shown to interact with: - PARP1,[8][9] - P53,[9] - XRCC1,[8][9] and - XRCC4.[10]	https://www.wikidoc.org/index.php/APTX
5398adb7d057ecf610888099de718201537a3513	wikidoc	APTX 4869	APTX 4869 APTX 4869 is a fictional poison in the anime and manga Case Closed. The toxin is a derivative of an experimental immortality formula, adapted by Sherry to function as an untraceable, lethal poison. APTX is an abbreviation of "Apoptoxin," and, as the name implies, it involves the activation of uncontrolled apoptosis which causes death by the destruction of cells. In addition, it can also activate telomerase. The poison is designed to be untraceable in its victims. However, in very rare cases, it causes the apoptosis of non-neural cells only and the apoptosis would stabilise at some point, causing the victim's apparent age to be decreased. Conan Edogawa, the series' protagonist, is such a victim; later Shiho Miyano, who chooses to attempt suicide by using her own drug, was added to the very short list of people not killed by APTX-4869. Throughout the series there are several instances in which the APTX was temporarily neutralized and Shinichi and Ai/Shiho were returned to their actual age forms. The main ingredient for this reversal is a component found in Chinese ginseng root schnaps, which Ai has already incorporated in a prototype - and as yet non-permanent - antidote for the APTX. It is to note that in the instances where Shinichi or Ai changed back, the recipient was suffering from a common cold while the component was ingested, indicating that the immune system somehow has to be taxed for the antidote to work. th:APTX 4869	APTX 4869 APTX 4869 is a fictional poison in the anime and manga Case Closed. The toxin is a derivative of an experimental immortality formula, adapted by Sherry to function as an untraceable, lethal poison. APTX is an abbreviation of "Apoptoxin," and, as the name implies, it involves the activation of uncontrolled apoptosis which causes death by the destruction of cells. In addition, it can also activate telomerase. The poison is designed to be untraceable in its victims. However, in very rare cases, it causes the apoptosis of non-neural cells only and the apoptosis would stabilise at some point, causing the victim's apparent age to be decreased. Conan Edogawa, the series' protagonist, is such a victim; later Shiho Miyano, who chooses to attempt suicide by using her own drug, was added to the very short list of people not killed by APTX-4869. Throughout the series there are several instances in which the APTX was temporarily neutralized and Shinichi and Ai/Shiho were returned to their actual age forms. The main ingredient for this reversal is a component found in Chinese ginseng root schnaps, which Ai has already incorporated in a prototype - and as yet non-permanent - antidote for the APTX. It is to note that in the instances where Shinichi or Ai changed back, the recipient was suffering from a common cold while the component was ingested, indicating that the immune system somehow has to be taxed for the antidote to work. Template:Anime-stub th:APTX 4869 Template:WikiDoc Sources	https://www.wikidoc.org/index.php/APTX_4869
365d60e0672e676fb7c71fcbb51566447c3fa766	wikidoc	ASA score	ASA score ASA stands for American Society of Anesthesiologists. In 1963 the ASA adopted a five category physical status classification system for assessing a patient before surgery. A sixth category was later added. These are: - A normal healthy patient. - A patient with mild systemic disease. - A patient with severe systemic disease. - A patient with severe systemic disease that is a constant threat to life. - A moribund patient who is not expected to survive without the operation. - A declared brain-dead patient whose organs are being removed for donor purposes. If the surgery is an emergency, the physical status score is followed by “E” (for emergency) for example “3E”. Category 5 is always an emergency so should not be written without "E". The category 6E probably does not exist. The original definition of emergency in 1940, when ASA classification was first designed, was "a surgical procedure which, in the surgeon's opinion, should be performed without delay". This gives an opportunity to the surgeon to manipulate the schedule of surgery for personal convenience. An emergency is now "defined as existing when delay in treatment of the patient would lead to a significant increase in the threat to life or body part. If it is correct then severe pain due to broken bones, ureteric stone or parturition is not emergency. These definitions appear in each annual edition of the ASA Relative Value Guide. There is no additional information that can be helpful to further define these categories. # Limitations and proposed modifications Different authors give different versions of this ASA definition. It is because this classification is vague and far from perfect. Many authors try to explain it on the basis of 'functional limitation' or 'anxiety' of patient which are not mentioned in the actual definition. Often different anesthesia providers assign different scores to the same patient. For example, heart attack (myocardial infarction), though grave, is a 'local' problem and is not a 'systemic' disease, so a patient with recent (or old) heart attack, in the absence of any other systemic disease, does not truly fit in any category of the ASA classification, yet having poor post-surgery survival rates. Other severe heart, liver, lung or kidney diseases, although they greatly affect physical status of patient and outcome of surgery, cannot be labelled as “systemic disease” (which means a generalized disorder of the whole body like hypertension or diabetes mellitus). Local diseases can also change physical status but not be mentioned in ASA classification. This scoring system assumes that age of the patient has no relation to physical fitness, which is not true. Neonates and very old people, even in the absence of any systemic disease, tolerate anesthesia and surgery badly in comparison to young adults. Similarly this classification ignores patients with malignancy (cancer). This scoring system could not be improved to a more elaborated and scientific form, probably because it is often used for price reimbursement. Some anesthetists now propose that like an 'E' modifier for emergency, a 'P' modifier for pregnancy should be added to the ASA score. # Uses While anesthesia providers use this scale to indicate the patient's overall physical health or "sickness" preoperatively, it is regarded by hospitals, law firms, accrediting boards and other health care groups as a scale to predict risk, and thus decide if a patient should have – or should have had – an operation.To predict operative risk, age and obesity of the patient, the nature and severity of the operative procedure, selection of anesthetic techniques, the competency of the surgical team (surgeon, anesthesia providers and assisting staff), duration of surgery or anesthesia, availability of equipment, medicine, blood, implants and especially the level of post-operative care etc. are often far more important than simple ASA score. # History In 1940-41, ASA asked a committee of three physicians (Meyer Saklad, M.D., Emery Rovenstine, M.D., and Ivan Taylor, M.D.) to study, examine, experiment and devise a system for the collection and tabulation of statistical data in anesthesia which could be applicable under any circumstances. This effort was the first by any medical specialty to stratify risk for its patients. While their mission was to determine predictors for operative risk, they quickly dismissed this task as being impossible to devise. They state: "In attempting to standardize and define what has heretofore been considered 'Operative Risk', it was found that the term … could not be used. It was felt that for the purposes of the anesthesia record and for any future evaluation of anesthetic agents or surgical procedures, it would be best to classify and grade the patient in relation to his physical status only." The scale they proposed addressed the patient's preoperative state only, not the surgical procedure or other factors that could influence surgical outcome. They hoped anesthesiologists from all parts of the country would adopt their "common terminology," making statistical comparisons of morbidity and mortality possible by comparing outcomes to "the operative procedure and the patient's preoperative condition". They described a six-point scale, ranging from a healthy patient (class 1) to one with an extreme systemic disorder that is an imminent threat to life (class4). The first four points of their scale roughly correspond to today's ASA classes 1-4, which were first published in 1963. The original authors included two classes that encompassed emergencies which otherwise would have been coded in either the first two classes (class 5) or the second two (class 6). By the time of the 1963 publication of the present classification, two modifications were made. First, previous classes 5 and 6 were removed and a new class 5 was added for moribund patients not expected to survive 24 hours, with or without surgery. Second, separate classes for emergencies were eliminated in lieu of the "E" modifier of the other classes. The sixth class is now used for declared brain-dead organ donors. Saklad gave examples of each class of patient in an attempt to encourage uniformity. Unfortunately, the ASA did not later describe each category with examples of patients and thus actually increased confusion.	ASA score ASA stands for American Society of Anesthesiologists. In 1963 the ASA adopted a five category physical status classification system for assessing a patient before surgery. A sixth category was later added. These are: - A normal healthy patient. - A patient with mild systemic disease. - A patient with severe systemic disease. - A patient with severe systemic disease that is a constant threat to life. - A moribund patient who is not expected to survive without the operation. - A declared brain-dead patient whose organs are being removed for donor purposes. If the surgery is an emergency, the physical status score is followed by “E” (for emergency) for example “3E”. Category 5 is always an emergency so should not be written without "E". The category 6E probably does not exist. The original definition of emergency in 1940, when ASA classification was first designed, was "a surgical procedure which, in the surgeon's opinion, should be performed without delay"[1]. This gives an opportunity to the surgeon to manipulate the schedule of surgery for personal convenience. An emergency is now "defined as existing when delay in treatment of the patient would lead to a significant increase in the threat to life or body part[2]. If it is correct then severe pain due to broken bones, ureteric stone or parturition is not emergency. These definitions appear in each annual edition of the ASA Relative Value Guide. There is no additional information that can be helpful to further define these categories.[3] # Limitations and proposed modifications Different authors give different versions of this ASA definition.[4] It is because this classification is vague and far from perfect. Many authors try to explain it on the basis of 'functional limitation' or 'anxiety' of patient which are not mentioned in the actual definition. Often different anesthesia providers assign different scores to the same patient.[5][6][7][8] For example, heart attack (myocardial infarction), though grave, is a 'local' problem and is not a 'systemic' disease, so a patient with recent (or old) heart attack, in the absence of any other systemic disease, does not truly fit in any category of the ASA classification, yet having poor post-surgery survival rates. Other severe heart, liver, lung or kidney diseases, although they greatly affect physical status of patient and outcome of surgery, cannot be labelled as “systemic disease” (which means a generalized disorder of the whole body like hypertension or diabetes mellitus). Local diseases can also change physical status but not be mentioned in ASA classification. This scoring system assumes that age of the patient has no relation to physical fitness, which is not true. Neonates and very old people, even in the absence of any systemic disease, tolerate anesthesia and surgery badly in comparison to young adults. Similarly this classification ignores patients with malignancy (cancer). This scoring system could not be improved to a more elaborated and scientific form, probably because it is often used for price reimbursement. Some anesthetists now propose that like an 'E' modifier for emergency, a 'P' modifier for pregnancy should be added to the ASA score.[9] # Uses While anesthesia providers use this scale to indicate the patient's overall physical health or "sickness" preoperatively, it is regarded by hospitals, law firms, accrediting boards and other health care groups as a scale to predict risk[10], and thus decide if a patient should have – or should have had – an operation.[11]To predict operative risk, age and obesity of the patient, the nature and severity of the operative procedure, selection of anesthetic techniques, the competency of the surgical team (surgeon, anesthesia providers and assisting staff), duration of surgery or anesthesia, availability of equipment, medicine, blood, implants and especially the level of post-operative care etc. are often far more important than simple ASA score. # History In 1940-41, ASA asked a committee of three physicians (Meyer Saklad, M.D., Emery Rovenstine, M.D., and Ivan Taylor, M.D.) to study, examine, experiment and devise a system for the collection and tabulation of statistical data in anesthesia which could be applicable under any circumstances.[1] This effort was the first by any medical specialty to stratify risk for its patients.[12] While their mission was to determine predictors for operative risk, they quickly dismissed this task as being impossible to devise. They state: "In attempting to standardize and define what has heretofore been considered 'Operative Risk', it was found that the term … could not be used. It was felt that for the purposes of the anesthesia record and for any future evaluation of anesthetic agents or surgical procedures, it would be best to classify and grade the patient in relation to his physical status only."[11] The scale they proposed addressed the patient's preoperative state only, not the surgical procedure or other factors that could influence surgical outcome. They hoped anesthesiologists from all parts of the country would adopt their "common terminology," making statistical comparisons of morbidity and mortality possible by comparing outcomes to "the operative procedure and the patient's preoperative condition".[1][13] They described a six-point scale, ranging from a healthy patient (class 1) to one with an extreme systemic disorder that is an imminent threat to life (class4). The first four points of their scale roughly correspond to today's ASA classes 1-4, which were first published in 1963.[5] The original authors included two classes that encompassed emergencies which otherwise would have been coded in either the first two classes (class 5) or the second two (class 6). By the time of the 1963 publication of the present classification, two modifications were made. First, previous classes 5 and 6 were removed and a new class 5 was added for moribund patients not expected to survive 24 hours, with or without surgery. Second, separate classes for emergencies were eliminated in lieu of the "E" modifier of the other classes.[14][13] The sixth class is now used for declared brain-dead organ donors. Saklad gave examples of each class of patient in an attempt to encourage uniformity. Unfortunately, the ASA did not later describe each category with examples of patients and thus actually increased confusion.	https://www.wikidoc.org/index.php/ASA_score
621c65e6f1caa91a1f1b888f49ce134e1dd0ac3e	wikidoc	Abatacept	Abatacept # 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 Abatacept is an immune modulator that is FDA approved for the {{{indicationType}}} of adult rheumatoid arthritis (RA), juvenile idiopathic arthritis. Common adverse reactions include headache, upper respiratory tract infection, nasopharyngitis, and nausea. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - ORENCIA® is indicated for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active rheumatoid arthritis. ORENCIA may be used as monotherapy or concomitantly with disease-modifying antirheumatic drugs (DMARDs) other than tumor necrosis factor (TNF) antagonists. - Intravenous Dosing Regimen - ORENCIA intravenous should be administered as a 30-minute intravenous infusion utilizing the weight range-based dosing specified in Table 1. Following the initial intravenous administration, an intravenous infusion should be given at 2 and 4 weeks after the first infusion and every 4 weeks thereafter. - Subcutaneous Dosing Regimen - ORENCIA 125 mg should be administered by subcutaneous injection once weekly and may be initiated with or without an intravenous loading dose. For patients initiating therapy with an intravenous loading dose, ORENCIA should be initiated with a single intravenous infusion (as per body weight categories listed in Table 1), followed by the first 125 mg subcutaneous injection administered within a day of the intravenous infusion. - Patients transitioning from ORENCIA intravenous therapy to subcutaneous administration should administer the first subcutaneous dose instead of the next scheduled intravenous dose. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Abatacept in adult patients. ### Non–Guideline-Supported Use - Dosing Information - Abatacept approximately 10 mg/kg as an IV infusion on days 1, 15, and 29, and every 4 weeks thereafter. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Dosing Information - ORENCIA is indicated for reducing signs and symptoms in pediatric patients 6 years of age and older with moderately to severely active polyarticular juvenile idiopathic arthritis. ORENCIA may be used as monotherapy or concomitantly with methotrexate (MTX). - The recommended dose of ORENCIA for patients 6 to 17 years of age with juvenile idiopathic arthritis who weigh less than 75 kg is 10 mg/kg intravenously calculated based on the patient’s body weight at each administration. Pediatric patients weighing 75 kg or more should be administered ORENCIA following the adult intravenous dosing regimen, not to exceed a maximum dose of 1000 mg. ORENCIA should be administered as a 30-minute intravenous infusion. Following the initial administration, ORENCIA should be given at 2 and 4 weeks after the first infusion and every 4 weeks thereafter. Any unused portions in the vials must be immediately discarded. - The safety and efficacy of subcutaneous ORENCIA injection has not been studied in patients under 18 years of age. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Abatacept in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Abatacept in pediatric patients. # Contraindications None # Warnings ### Precautions - Concomitant Use with TNF Antagonists - In controlled clinical trials in patients with adult RA, patients receiving concomitant intravenous ORENCIA and TNF antagonist therapy experienced more infections (63%) and serious infections (4.4%) compared to patients treated with only TNF antagonists (43% and 0.8%, respectively). These trials failed to demonstrate an important enhancement of efficacy with concomitant administration of ORENCIA with TNF antagonist; therefore, concurrent therapy with ORENCIA and a TNF antagonist is not recommended. While transitioning from TNF antagonist therapy to ORENCIA therapy, patients should be monitored for signs of infection. - Hypersensitivity - In controlled, double-blind and open-label clinical trials, the occurrence of anaphylaxis and anaphylactoid reactions was rare (<0.1%) and was only observed in patients dosed with intravenous ORENCIA. Other reactions potentially associated with drug hypersensitivity, such as hypotension, urticaria, and dyspnea that occurred within 24 hours of ORENCIA infusion, were uncommon (<1%). Of the 190 patients with juvenile idiopathic arthritis treated with ORENCIA in clinical trials, there was one case of a hypersensitivity reaction (0.5%). Appropriate medical support measures for the treatment of hypersensitivity reactions should be available for immediate use in the event of a reaction. Anaphylaxis or anaphylactoid reactions can occur after the first infusion and can be life threatening. In postmarketing experience, a case of fatal anaphylaxis following the first infusion of ORENCIA has been reported. If an anaphylactic or other serious allergic reaction occurs, administration of ORENCIA should be stopped immediately with appropriate therapy instituted, and the use of ORENCIA should be permanently discontinued. - Infections - Serious infections, including sepsis and pneumonia, have been reported in patients receiving ORENCIA. Some of these infections have been fatal. Many of the serious infections have occurred in patients on concomitant immunosuppressive therapy which in addition to their underlying disease, could further predispose them to infection. Physicians should exercise caution when considering the use of ORENCIA in patients with a history of recurrent infections, underlying conditions which may predispose them to infections, or chronic, latent, or localized infections. Patients who develop a new infection while undergoing treatment with ORENCIA should be monitored closely. Administration of ORENCIA should be discontinued if a patient develops a serious infection. A higher rate of serious infections has been observed in adult RA patients treated with concurrent TNF antagonists and ORENCIA. - Prior to initiating immunomodulatory therapies, including ORENCIA, patients should be screened for latent tuberculosis infection with a tuberculin skin test. ORENCIA has not been studied in patients with a positive tuberculosis screen, and the safety of ORENCIA in individuals with latent tuberculosis infection is unknown. Patients testing positive in tuberculosis screening should be treated by standard medical practice prior to therapy with ORENCIA. - Antirheumatic therapies have been associated with hepatitis B reactivation. Therefore, screening for viral hepatitis should be performed in accordance with published guidelines before starting therapy with ORENCIA. In clinical studies with ORENCIA, patients who screened positive for hepatitis were excluded from study. - Immunizations - Live vaccines should not be given concurrently with ORENCIA or within 3 months of its discontinuation. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving ORENCIA. The efficacy of vaccination in patients receiving ORENCIA is not known. Based on its mechanism of action, ORENCIA may blunt the effectiveness of some immunizations. - It is recommended that patients with juvenile idiopathic arthritis be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating ORENCIA therapy. - Use in Patients with Chronic Obstructive Pulmonary Disease (COPD) - Adult COPD patients treated with ORENCIA developed adverse events more frequently than those treated with placebo, including COPD exacerbations, cough, rhonchi, and dyspnea. Use of ORENCIA in patients with RA and COPD should be undertaken with caution and such patients should be monitored for worsening of their respiratory status. - Immunosuppression - The possibility exists for drugs inhibiting T cell activation, including ORENCIA, to affect host defenses against infections and malignancies since T cells mediate cellular immune responses. The impact of treatment with ORENCIA on the development and course of malignancies is not fully understood. In clinical trials in patients with adult RA, a higher rate of infections was seen in ORENCIA-treated patients compared to placebo. # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not predict the rates observed in a broader patient population in clinical practice. - The data described herein reflect exposure to ORENCIA administered intravenously in patients with active RA in placebo-controlled studies (1955 patients with ORENCIA, 989 with placebo). The studies had either a double-blind, placebo-controlled period of 6 months (258 patients with ORENCIA, 133 with placebo) or 1 year (1697 patients with ORENCIA, 856 with placebo). A subset of these patients received concomitant biologic DMARD therapy, such as a TNF blocking agent (204 patients with ORENCIA, 134 with placebo). - The majority of patients in RA clinical studies received one or more of the following concomitant medications with ORENCIA: methotrexate, nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, TNF blocking agents, azathioprine, chloroquine, gold, hydroxychloroquine, leflunomide, sulfasalazine, and anakinra. - The most serious adverse reactions were serious infections and malignancies. - The most commonly reported adverse events (occurring in ≥10% of patients treated with ORENCIA) were headache, upper respiratory tract infection, nasopharyngitis, and nausea. - The adverse events most frequently resulting in clinical intervention (interruption or discontinuation of ORENCIA) were due to infection. The most frequently reported infections resulting in dose interruption were upper respiratory tract infection (1.0%), bronchitis (0.7%), and herpes zoster (0.7%). The most frequent infections resulting in discontinuation were pneumonia (0.2%), localized infection (0.2%), and bronchitis (0.1%). - Infections - In the placebo-controlled trials, infections were reported in 54% of ORENCIA-treated patients and 48% of placebo-treated patients. The most commonly reported infections (reported in 5%-13% of patients) were upper respiratory tract infection, nasopharyngitis, sinusitis, urinary tract infection, influenza, and bronchitis. Other infections reported in fewer than 5% of patients at a higher frequency (>0.5%) with ORENCIA compared to placebo, were rhinitis, herpes simplex, and pneumonia. - Serious infections were reported in 3.0% of patients treated with ORENCIA and 1.9% of patients treated with placebo. The most common (0.2%-0.5%) serious infections reported with ORENCIA were pneumonia, cellulitis, urinary tract infection, bronchitis, diverticulitis, and acute pyelonephritis. - Malignancies - In the placebo-controlled portions of the clinical trials (1955 patients treated with ORENCIA for a median of 12 months), the overall frequencies of malignancies were similar in the ORENCIA- and placebo-treated patients (1.3% and 1.1%, respectively). However, more cases of lung cancer were observed in ORENCIA-treated patients (4, 0.2%) than placebo-treated patients (0). In the cumulative ORENCIA clinical trials (placebo-controlled and uncontrolled, open-label) a total of 8 cases of lung cancer (0.21 cases per 100 patient-years) and 4 lymphomas (0.10 cases per 100 patient-years) were observed in 2688 patients (3827 patient-years). The rate observed for lymphoma is approximately 3.5-fold higher than expected in an age- and gender-matched general population based on the National Cancer Institute's Surveillance, Epidemiology, and End Results Database. Patients with RA, particularly those with highly active disease, are at a higher risk for the development of lymphoma. Other malignancies included skin, breast, bile duct, bladder, cervical, endometrial, lymphoma, melanoma, myelodysplastic syndrome, ovarian, prostate, renal, thyroid, and uterine cancers. The potential role of ORENCIA in the development of malignancies in humans is unknown. - Infusion-Related Reactions and Hypersensitivity Reactions - Acute infusion-related events (adverse reactions occurring within 1 hour of the start of the infusion) in Studies III, IV, and V were more common in the ORENCIA-treated patients than the placebo patients (9% for ORENCIA, 6% for placebo). The most frequently reported events (1%-2%) were dizziness, headache, and hypertension. - Acute infusion-related events that were reported in >0.1% and ≤1% of patients treated with ORENCIA included cardiopulmonary symptoms, such as hypotension, increased blood pressure, and dyspnea; other symptoms included nausea, flushing, urticaria, cough, hypersensitivity, pruritus, rash, and wheezing. Most of these reactions were mild (68%) to moderate (28%). Fewer than 1% of ORENCIA-treated patients discontinued due to an acute infusion-related event. In controlled trials, 6 ORENCIA-treated patients compared to 2 placebo-treated patients discontinued study treatment due to acute infusion-related events. - Anaphylaxis was observed in patients dosed with ORENCIA administered intravenously in controlled and open-label clinical trials, and the occurrence was rare (<0.1%). Other reactions potentially associated with drug hypersensitivity, such as hypotension, urticaria, and dyspnea that occurred within 24 hours of ORENCIA infusion, were uncommon (<1%). Appropriate medical support measures for the treatment of hypersensitivity reactions should be available for immediate use in the event of a reaction. - Adverse Reactions in Patients with COPD - In Study V, there were 37 patients with chronic obstructive pulmonary disease (COPD) who were treated with ORENCIA and 17 COPD patients who were treated with placebo. The COPD patients treated with ORENCIA developed adverse events more frequently than those treated with placebo (97% vs 88%, respectively). Respiratory disorders occurred more frequently in ORENCIA-treated patients compared to placebo-treated patients (43% vs 24%, respectively) including COPD exacerbation, cough, rhonchi, and dyspnea. A greater percentage of ORENCIA-treated patients developed a serious adverse event compared to placebo-treated patients (27% vs 6%), including COPD exacerbation (3 of 37 patients ) and pneumonia (1 of 37 patients ). - Other Adverse Reactions - Adverse events occurring in 3% or more of patients and at least 1% more frequently in ORENCIA-treated patients during placebo-controlled RA studies are summarized in Table 2. - Immunogenicity - Antibodies directed against the entire abatacept molecule or to the CTLA-4 portion of abatacept were assessed by ELISA assays in RA patients for up to 2 years following repeated treatment with ORENCIA. Thirty-four of 1993 (1.7%) patients developed binding antibodies to the entire abatacept molecule or to the CTLA-4 portion of abatacept. Because trough levels of abatacept can interfere with assay results, a subset analysis was performed. In this analysis it was observed that 9 of 154 (5.8%) patients that had discontinued treatment with ORENCIA for over 56 days developed antibodies. - Samples with confirmed binding activity to CTLA-4 were assessed for the presence of neutralizing antibodies in a cell-based luciferase reporter assay. Six of 9 (67%) evaluable patients were shown to possess neutralizing antibodies. However, the development of neutralizing antibodies may be underreported due to lack of assay sensitivity. - No correlation of antibody development to clinical response or adverse events was observed. - The data reflect the percentage of patients whose test results were positive for antibodies to abatacept in specific assays. The observed incidence of antibody (including neutralizing antibody) positivity in an assay is highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to abatacept with the incidence of antibodies to other products may be misleading. - Clinical Experience in Methotrexate-Naive Patients - Study VI was an active-controlled clinical trial in methotrexate-naive patients. The safety experience in these patients was consistent with Studies I-V. - Because clinical trials are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not predict the rates observed in a broader patient population in clinical practice. - Study SC-1 was a randomized, double-blind, double-dummy, non-inferiority study that compared the efficacy and safety of abatacept administered subcutaneously (SC) and intravenously (IV) in 1457 subjects with rheumatoid arthritis, receiving background methotrexate, and experiencing an inadequate response to methotrexate (MTX-IR). The safety experience and immunogenicity for ORENCIA administered subcutaneously was consistent with intravenous Studies I-VI. Due to the route of administration, injection site reactions and immunogenicity were evaluated in Study SC-1 and two other smaller studies discussed in the sections below. - Injection Site Reactions in Adult RA Patients Treated with Subcutaneous ORENCIA - Study SC-1 compared the safety of abatacept including injection site reactions following subcutaneous or intravenous administration. The overall frequency of injection site reactions was 2.6% (19/736) and 2.5% (18/721) for the subcutaneous abatacept group and the intravenous abatacept group (subcutaneous placebo), respectively. All these injection site reactions (including hematoma, pruritus, and erythema) were mild (83%) to moderate (17%) in severity, and none necessitated drug discontinuation. - Immunogenicity in Adult RA Patients Treated with Subcutaneous ORENCIA - Study SC-1 compared the immunogenicity to abatacept following subcutaneous or intravenous administration. The overall immunogenicity frequency to abatacept was 1.1% (8/725) and 2.3% (16/710) for the subcutaneous and intravenous groups, respectively. The rate is consistent with previous experience, and there was no correlation of immunogenicity with effects on pharmacokinetics, safety, or efficacy. - Immunogenicity and Safety of Subcutaneous ORENCIA Administration as Monotherapy without an Intravenous Loading Dose - Study SC-2 was conducted to determine the effect of monotherapy use of ORENCIA on immunogenicity following subcutaneous administration without an intravenous load in 100 RA patients, who had not previously received abatacept or other CTLA4Ig, who received either subcutaneous ORENCIA plus methotrexate (n=51) or subcutaneous ORENCIA monotherapy (n=49). No patients in either group developed anti-product antibodies after 4 months of treatment. The safety observed in this study was consistent with that observed in the other subcutaneous studies. - Immunogenicity and Safety of Subcutaneous ORENCIA upon Withdrawal (Three Months) and Restart of Treatment - Study SC-3 in the subcutaneous program was conducted to investigate the effect of withdrawal (three months) and restart of ORENCIA subcutaneous treatment on immunogenicity in RA patients treated concomitantly with methotrexate. One hundred sixty-seven patients were enrolled in the first 3-month treatment period and responders (n=120) were randomized to either subcutaneous ORENCIA or placebo for the second 3-month period (withdrawal period). Patients from this period then received open-label ORENCIA treatment in the final 3-month period of the study (period 3). At the end of the withdrawal period, 0/38 patients who continued to receive subcutaneous ORENCIA developed anti-product antibodies compared to 7/73 (9.6%) of patients who had subcutaneous ORENCIA withdrawn during this period. Half of the patients receiving subcutaneous placebo during the withdrawal period received a single intravenous infusion of ORENCIA at the start of period 3 and half received intravenous placebo. At the end of period 3, when all patients again received subcutaneous ORENCIA, the immunogenicity rates were 1/38 (2.6%) in the group receiving subcutaneous ORENCIA throughout, and 2/73 (2.7%) in the group that had received placebo during the withdrawal period. Upon reinitiating therapy, there were no injection reactions and no differences in response to therapy in patients who were withdrawn from subcutaneous therapy for up to 3 months relative to those who remained on subcutaneous therapy, whether therapy was reintroduced with or without an intravenous loading dose. The safety observed in this study was consistent with that observed in the other studies. - 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. - In general, the adverse events in pediatric patients were similar in frequency and type to those seen in adult patients. - ORENCIA has been studied in 190 pediatric patients, 6 to 17 years of age, with polyarticular juvenile idiopathic arthritis. Overall frequency of adverse events in the 4-month, lead-in, open-label period of the study was 70%; infections occurred at a frequency of 36%. The most common infections were upper respiratory tract infection and nasopharyngitis. The infections resolved without sequelae, and the types of infections were consistent with those commonly seen in outpatient pediatric populations. Other events that occurred at a prevalence of at least 5% were headache, nausea, diarrhea, cough, pyrexia, and abdominal pain. - A total of 6 serious adverse events (acute lymphocytic leukemia, ovarian cyst, varicella infection, disease flare , and joint wear) were reported during the initial 4 months of treatment with ORENCIA. - Of the 190 patients with juvenile idiopathic arthritis treated with ORENCIA in clinical trials, there was one case of a hypersensitivity reaction (0.5%). During Periods A, B, and C, acute infusion-related reactions occurred at a frequency of 4%, 2%, and 3%, respectively, and were consistent with the types of events reported in adults. - Upon continued treatment in the open-label extension period, the types of adverse events were similar in frequency and type to those seen in adult patients, except for a single patient diagnosed with multiple sclerosis while on open-label treatment. - Immunogenicity - Antibodies directed against the entire abatacept molecule or to the CTLA-4 portion of abatacept were assessed by ELISA assays in patients with juvenile idiopathic arthritis following repeated treatment with ORENCIA throughout the open-label period. For patients who were withdrawn from therapy for up to 6 months during the double-blind period, the rate of antibody formation to the CTLA-4 portion of the molecule was 41% (22/54), while for those who remained on therapy the rate was 13% (7/54). Twenty of these patients had samples that could be tested for antibodies with neutralizing activity; of these, 8 (40%) patients were shown to possess neutralizing antibodies. - The presence of antibodies was generally transient and titers were low. The presence of antibodies was not associated with adverse events, changes in efficacy, or an effect on serum concentrations of abatacept. For patients who were withdrawn from ORENCIA during the double-blind period for up to 6 months, no serious acute infusion-related events were observed upon re-initiation of ORENCIA therapy. ## Postmarketing Experience - Adverse reactions have been reported during the postapproval use of ORENCIA. 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 ORENCIA. Based on the postmarketing experience in adult RA patients, the following adverse reaction has been identified during postapproval use with ORENCIA. - Vasculitis (including cutaneous vasculitis and leukocytoclastic vasculitis) # Drug Interactions - TNF Antagonists - Concurrent administration of a TNF antagonist with ORENCIA has been associated with an increased risk of serious infections and no significant additional efficacy over use of the TNF antagonists alone. Concurrent therapy with ORENCIA and TNF antagonists is not recommended. - Other Biologic RA Therapy - There is insufficient experience to assess the safety and efficacy of ORENCIA administered concurrently with other biologic RA therapy, such as anakinra, and therefore such use is not recommended. - Blood Glucose Testing - Parenteral drug products containing maltose can interfere with the readings of blood glucose monitors that use test strips with glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ). The GDH-PQQ based glucose monitoring systems may react with the maltose present in ORENCIA for intravenous administration, resulting in falsely elevated blood glucose readings on the day of infusion. When receiving ORENCIA through intravenous administration, patients that require blood glucose monitoring should be advised to consider methods that do not react with maltose, such as those based on glucose dehydrogenase nicotine adenine dinucleotide (GDH-NAD), glucose oxidase, or glucose hexokinase test methods. - ORENCIA for subcutaneous administration does not contain maltose; therefore, patients do not need to alter their glucose monitoring. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - There are no adequate and well-controlled studies of ORENCIA use in pregnant women. Abatacept has been shown to cross the placenta in animals, and in animal reproduction studies alterations in immune function occurred. ORENCIA should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. - Abatacept was not teratogenic when administered to pregnant mice at doses up to 300 mg/kg and in pregnant rats and rabbits at doses up to 200 mg/kg daily representing approximately 29 times the exposure associated with the maximum recommended human dose (MRHD) of 10 mg/kg based on AUC (area under the time-concentration curve). - Abatacept administered to female rats every three days during early gestation and throughout the lactation period, produced no adverse effects in offspring at doses up to 45 mg/kg, representing 3 times the exposure associated with the MRHD of 10 mg/kg based on AUC. However, at 200 mg/kg, 11 times the MRHD exposure, alterations in immune function were observed consisting of a 9-fold increase in T-cell dependent antibody response in female pups and thyroid inflammation in one female pup. It is not known whether these findings indicate a risk for development of autoimmune diseases in humans exposed in utero to abatacept. However, exposure to abatacept in the juvenile rat, which may be more representative of the fetal immune system state in the human, resulted in immune system abnormalities including inflammation of the thyroid and pancreas. - Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to ORENCIA, a pregnancy registry has been established. Healthcare professionals are encouraged to register patients and pregnant women are encouraged to enroll themselves by calling 1-877-311-8972. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Abatacept in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Abatacept during labor and delivery. ### Nursing Mothers - It is not known whether ORENCIA is excreted into human milk or absorbed systemically after ingestion by a nursing infant. However, abatacept was excreted in rat milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ORENCIA, 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 - Intravenous ORENCIA is indicated for reducing signs and symptoms in pediatric patients with moderately to severely active polyarticular juvenile idiopathic arthritis ages 6 years and older. ORENCIA may be used as monotherapy or concomitantly with methotrexate. - Studies in juvenile rats exposed to ORENCIA prior to immune system maturity have shown immune system abnormalities including an increase in the incidence of infections leading to death as well as inflammation of the thyroid and pancreas. Studies in adult mice and monkeys have not demonstrated similar findings. As the immune system of the rat is undeveloped in the first few weeks after birth, the relevance of these results to humans greater than 6 years of age (where the immune system is largely developed) is unknown. - ORENCIA is not recommended for use in patients below the age of 6 years. - The safety and effectiveness of ORENCIA in pediatric patients below 6 years of age have not been established. The safety and efficacy of ORENCIA in pediatric patients for uses other than juvenile idiopathic arthritis have not been established. - The safety and efficacy of subcutaneous ORENCIA has not been studied in patients under 18 years of age. ### Geriatic Use - A total of 323 patients 65 years of age and older, including 53 patients 75 years and older, received ORENCIA in clinical studies. No overall differences in safety or effectiveness were observed between these patients and younger patients, but these numbers are too low to rule out differences. The frequency of serious infection and malignancy among ORENCIA-treated patients over age 65 was higher than for those under age 65. Because there is a higher incidence of infections and malignancies in the elderly population in general, caution should be used when treating the elderly. ### Gender There is no FDA guidance on the use of Abatacept with respect to specific gender populations. ### Race There is no FDA guidance on the use of Abatacept with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Abatacept in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Abatacept in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Abatacept in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Abatacept in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous - Subcutaneous ### Monitoring - While transitioning from TNF antagonist therapy to ORENCIA therapy, patients should be monitored for signs of infection. # IV Compatibility There is limited information regarding IV Compatibility of Abatacept in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - Doses up to 50 mg/kg have been administered intravenously without apparent toxic effect. ### Management - In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment instituted. ## Chronic Overdose There is limited information regarding Chronic Overdose of Abatacept in the drug label. # Pharmacology ## Mechanism of Action - Abatacept, a selective costimulation modulator, inhibits T cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. This interaction provides a costimulatory signal necessary for full activation of T lymphocytes. Activated T lymphocytes are implicated in the pathogenesis of RA and are found in the synovium of patients with RA. - In vitro, abatacept decreases T cell proliferation and inhibits the production of the cytokines TNF alpha (TNFα), interferon-γ, and interleukin-2. In a rat collagen-induced arthritis model, abatacept suppresses inflammation, decreases anti-collagen antibody production, and reduces antigen specific production of interferon-γ. The relationship of these biological response markers to the mechanisms by which ORENCIA exerts its effects in RA is unknown. ## Structure - ORENCIA® (abatacept) is a soluble fusion protein that consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to the modified Fc (hinge, CH2, and CH3 domains) portion of human immunoglobulin G1 (IgG1). Abatacept is produced by recombinant DNA technology in a mammalian cell expression system. The apparent molecular weight of abatacept is 92 kilodaltons. - ORENCIA lyophilized powder for intravenous infusion is supplied as a sterile, white, preservative-free, lyophilized powder for intravenous administration. Following reconstitution of the lyophilized powder with 10 mL of Sterile Water for Injection, USP, the solution of ORENCIA is clear, colorless to pale yellow, with a pH range of 7.2 to 7.8. Each single-use vial of ORENCIA provides 250 mg abatacept, maltose (500 mg), monobasic sodium phosphate (17.2 mg), and sodium chloride (14.6 mg) for administration. - ORENCIA solution for subcutaneous administration is supplied as a sterile, preservative-free, clear, colorless to pale-yellow solution with a pH of 6.8 to 7.4. Each single dose of subcutaneous injection provides 125 mg abatacept, dibasic sodium phosphate anhydrous (0.838 mg), monobasic sodium phosphate monohydrate (0.286 mg), poloxamer 188 (8 mg), sucrose (170 mg), and quantity sufficient to 1 mL with water for injection. Unlike the intravenous formulation, ORENCIA solution for subcutaneous administration contains no maltose. ## Pharmacodynamics - In clinical trials with ORENCIA at doses approximating 10 mg/kg, decreases were observed in serum levels of soluble interleukin-2 receptor (sIL-2R), interleukin-6 (IL-6), rheumatoid factor (RF), C-reactive protein (CRP), matrix metalloproteinase-3 (MMP3), and TNFα. The relationship of these biological response markers to the mechanisms by which ORENCIA exerts its effects in RA is unknown. ## Pharmacokinetics - Healthy Adults and Adult RA - Intravenous Administration - The pharmacokinetics of abatacept were studied in healthy adult subjects after a single 10 mg/kg intravenous infusion and in RA patients after multiple 10 mg/kg intravenous infusions (see Table 3). - The pharmacokinetics of abatacept in RA patients and healthy subjects appeared to be comparable. In RA patients, after multiple intravenous infusions, the pharmacokinetics of abatacept showed proportional increases of Cmax and AUC over the dose range of 2 mg/kg to 10 mg/kg. At 10 mg/kg, serum concentration appeared to reach a steady-state by day 60 with a mean (range) trough concentration of 24 mcg/mL (1 to 66 mcg/mL). No systemic accumulation of abatacept occurred upon continued repeated treatment with 10 mg/kg at monthly intervals in RA patients. - Population pharmacokinetic analyses in RA patients revealed that there was a trend toward higher clearance of abatacept with increasing body weight. Age and gender (when corrected for body weight) did not affect clearance. Concomitant methotrexate, NSAIDs, corticosteroids, and TNF blocking agents did not influence abatacept clearance. - No formal studies were conducted to examine the effects of either renal or hepatic impairment on the pharmacokinetics of abatacept. - Juvenile Idiopathic Arthritis - In patients 6 to 17 years of age, the mean (range) steady-state serum peak and trough concentrations of abatacept were 217 mcg/mL (57 to 700 mcg/mL) and 11.9 mcg/mL (0.15 to 44.6 mcg/mL). Population pharmacokinetic analyses of the serum concentration data showed that clearance of abatacept increased with baseline body weight. The estimated mean (range) clearance of abatacept in the juvenile idiopathic arthritis patients was 0.4 mL/h/kg (0.20 to 1.12 mL/h/kg). After accounting for the effect of body weight, the clearance of abatacept was not related to age and gender. Concomitant methotrexate, corticosteroids, and NSAIDs were also shown not to influence abatacept clearance. - Adult RA - Subcutaneous Administration - Abatacept exhibited linear pharmacokinetics following subcutaneous administration. The mean (range) for Cmin and Cmax at steady state observed after 85 days of treatment was 32.5 mcg/mL (6.6 to 113.8 mcg/mL) and 48.1 mcg/mL (9.8 to 132.4 mcg/mL), respectively. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. Mean estimates for systemic clearance (0.28 mL/h/kg), volume of distribution (0.11 L/kg), and terminal half-life (14.3 days) were comparable between subcutaneous and intravenous administration. - Study SC-2 was conducted to determine the effect of monotherapy use of ORENCIA on immunogenicity following subcutaneous administration without an intravenous load. When the intravenous loading dose was not administered, a mean trough concentration of 12.6 mcg/mL was achieved after 2 weeks of dosing. - Consistent with the intravenous data, population pharmacokinetic analyses for subcutaneous abatacept in RA patients revealed that there was a trend toward higher clearance of abatacept with increasing body weight. Age and gender (when corrected for body weight) did not affect apparent clearance. Concomitant medication, such as methotrexate, corticosteroids, and NSAIDs, did not influence abatacept apparent clearance. ## Nonclinical Toxicology - In a mouse carcinogenicity study, weekly subcutaneous injections of 20, 65, or 200 mg/kg of abatacept administered for up to 84 weeks in males and 88 weeks in females were associated with increases in the incidence of malignant lymphomas (all doses) and mammary gland tumors (intermediate- and high-dose in females). The mice from this study were infected with murine leukemia virus and mouse mammary tumor virus. These viruses are associated with an increased incidence of lymphomas and mammary gland tumors, respectively, in immunosuppressed mice. The doses used in these studies produced exposures 0.8, 2.0, and 3.0 times higher, respectively, than the exposure associated with the maximum recommended human dose (MRHD) of 10 mg/kg based on AUC (area under the time-concentration curve). The relevance of these findings to the clinical use of ORENCIA is unknown. - In a one-year toxicity study in cynomolgus monkeys, abatacept was administered intravenously once weekly at doses up to 50 mg/kg (producing 9 times the MRHD exposure based on AUC). Abatacept was not associated with any significant drug-related toxicity. Reversible pharmacological effects consisted of minimal transient decreases in serum IgG and minimal to severe lymphoid depletion of germinal centers in the spleen and/or lymph nodes. No evidence of lymphomas or preneoplastic morphologic changes was observed, despite the presence of a virus (lymphocryptovirus) known to cause these lesions in immunosuppressed monkeys within the time frame of this study. The relevance of these findings to the clinical use of ORENCIA is unknown. - No mutagenic potential of abatacept was observed in the in vitro bacterial reverse mutation (Ames) or Chinese hamster ovary/hypoxanthine guanine phosphoribosyl-transferase (CHO/HGPRT) forward point mutation assays with or without metabolic activation, and no chromosomal aberrations were observed in human lymphocytes treated with abatacept with or without metabolic activation. - Abatacept had no adverse effects on male or female fertility in rats at doses up to 200 mg/kg every three days (11 times the MRHD exposure based on AUC). - A juvenile animal study was conducted in rats dosed with abatacept from 4 to 94 days of age in which an increase in the incidence of infections leading to death occurred at all doses compared with controls. Altered T-cell subsets including increased T-helper cells and reduced T-regulatory cells were observed. In addition, inhibition of T-cell-dependent antibody responses (TDAR) was observed. Upon following these animals into adulthood, lymphocytic inflammation of the thyroid and pancreatic islets was observed. - In studies of adult mice and monkeys, inhibition of TDAR was apparent. However, infection and mortality, altered T-helper cells, and inflammation of thyroid and pancreas were not observed. # Clinical Studies - The efficacy and safety of ORENCIA for intravenous administration were assessed in six randomized, double-blind, controlled studies (five placebo-controlled and one active-controlled) in patients ≥18 years of age with active RA diagnosed according to American College of Rheumatology (ACR) criteria. Studies I, II, III, IV, and VI required patients to have at least 12 tender and 10 swollen joints at randomization. Study V did not require any specific number of tender or swollen joints. ORENCIA or placebo treatment was given intravenously at weeks 0, 2, and 4 and then every 4 weeks thereafter in intravenous Studies I, II, III, IV, and VI. The safety and efficacy of ORENCIA for subcutaneous administration were assessed in Study SC-1, which was a randomized, double-blind, double-dummy, non-inferiority study that compared abatacept administered subcutaneously and intravenously in 1457 subjects with rheumatoid arthritis (RA), receiving background methotrexate (MTX), and experiencing an inadequate response to methotrexate (MTX-IR). - Study I evaluated ORENCIA as monotherapy in 122 patients with active RA who had failed at least one non-biologic DMARD or etanercept. In Study II and Study III, the efficacy and safety of ORENCIA were assessed in patients with an inadequate response to methotrexate and who were continued on their stable dose of methotrexate. In Study IV, the efficacy and safety of ORENCIA were assessed in patients with an inadequate response to a TNF blocking agent, with the TNF blocking agent discontinued prior to randomization; other DMARDs were permitted. Study V primarily assessed safety in patients with active RA requiring additional intervention in spite of current therapy with DMARDs; all DMARDs used at enrollment were continued. Patients in Study V were not excluded for comorbid medical conditions. In Study VI, the efficacy and safety of ORENCIA were assessed in methotrexate-naive patients with RA of less than 2 years disease duration. In Study VI, patients previously naive to methotrexate were randomized to receive ORENCIA plus methotrexate or methotrexate plus placebo. In Study SC-1, the goal was to demonstrate the efficacy and safety of ORENCIA subcutaneous relative to ORENCIA intravenous administration in subjects with moderate to severely active RA and experiencing inadequate response to methotrexate, using a non-inferiority study design. - Study I patients were randomized to receive one of three doses of ORENCIA (0.5, 2, or 10 mg/kg) or placebo ending at week 8. Study II patients were randomized to receive ORENCIA 2 or 10 mg/kg or placebo for 12 months. Study III, IV, V, and VI patients were randomized to receive a dose of ORENCIA based on weight range or placebo for 12 months (Studies III, V, and VI) or 6 months (Study IV). The dose of ORENCIA was 500 mg for patients weighing less than 60 kg, 750 mg for patients weighing 60 to 100 kg, and 1000 mg for patients weighing greater than 100 kg. In Study SC-1, patients were randomized with stratification by body weight (100 kg) to receive ORENCIA 125 mg subcutaneous injections weekly, after a single intravenous loading dose of ORENCIA based on body weight or ORENCIA intravenously on Days 1, 15, 29, and every four weeks thereafter. Subjects continued taking their current dose of methotrexate from the day of randomization. - Clinical Response - The percent of ORENCIA-treated patients achieving ACR 20, 50, and 70 responses and major clinical response in Studies I, III, IV, and VI are shown in Table 4. ORENCIA-treated patients had higher ACR 20, 50, and 70 response rates at 6 months compared to placebo-treated patients. Month 6 ACR response rates in Study II for the 10 mg/kg group were similar to the ORENCIA group in Study III. - In Studies III and IV, improvement in the ACR 20 response rate versus placebo was observed within 15 days in some patients and within 29 days versus methotrexate in Study VI. In Studies II, III, and VI, ACR response rates were maintained to 12 months in ORENCIA-treated patients. ACR responses were maintained up to three years in the open-label extension of Study II. In Study III, ORENCIA-treated patients experienced greater improvement than placebo-treated patients in morning stiffness. - In Study VI, a greater proportion of patients treated with ORENCIA plus methotrexate achieved a low level of disease activity as measured by a DAS28-CRP less than 2.6 at 12 months compared to those treated with methotrexate plus placebo (Table 4). Of patients treated with ORENCIA plus methotrexate who achieved DAS28-CRP less than 2.6, 54% had no active joints, 17% had one active joint, 7% had two active joints, and 22% had three or more active joints, where an active joint was a joint that was rated as tender or swollen or both. - In Study SC-1, the main outcome measure was ACR 20 at 6 months. The pre-specified non-inferiority margin was a treatment difference of −7.5%. As shown in Table 4, the study demonstrated non-inferiority of ORENCIA administered subcutaneously to intravenous infusions of ORENCIA with respect to ACR 20 responses up to 6 months of treatment. ACR 50 and 70 responses are also shown in Table 4. No major differences in ACR responses were observed between intravenous and subcutaneous treatment groups in subgroups based on weight categories (less than 60 kg, 60 to 100 kg, and more than 100 kg; data not shown). - The results of the components of the ACR response criteria for Studies III, IV, and SC-1 are shown in Table 5 (results at Baseline and 6 months ). In ORENCIA-treated patients, greater improvement was seen in all ACR response criteria components through 6 and 12 months than in placebo-treated patients. - The percent of patients achieving the ACR 50 response for Study III by visit is shown in Figure 1. The time course for the ORENCIA group in Study VI was similar to that in Study III. - Figure 1: Percent of Patients Achieving ACR 50 Response by Visit- (Study III) - The percent of patients achieving the ACR 50 response for Study SC-1 in the ORENCIA subcutaneous (SC) and intravenous (IV) treatment arms at each treatment visit was as follows: Day 15—SC 3%, IV 5%; Day 29—SC 11%, IV 14%; Day 57—SC 24%, IV 30%; Day 85—SC 33%, IV 38%; Day 113—SC 39%, IV 41%; Day 141—SC 46%, IV 47%; Day 169—SC 51%, IV 50%. - Radiographic Response - In Study III and Study VI, structural joint damage was assessed radiographically and expressed as change from baseline in the Genant-modified Total Sharp Score (TSS) and its components, the Erosion Score (ES) and Joint Space Narrowing (JSN) score. ORENCIA/methotrexate slowed the progression of structural damage compared to placebo/methotrexate after 12 months of treatment as shown in Table 6. - In the open-label extension of Study III, 75% of patients initially randomized to ORENCIA/methotrexate and 65% of patients initially randomized to placebo/methotrexate were evaluated radiographically at Year 2. As shown in Table 6, progression of structural damage in ORENCIA/methotrexate-treated patients was further reduced in the second year of treatment. - Following 2 years of treatment with ORENCIA/methotrexate, 51% of patients had no progression of structural damage as defined by a change in the TSS of zero or less compared with baseline. Fifty-six percent (56%) of ORENCIA/methotrexate-treated patients had no progression during the first year compared to 45% of placebo/methotrexate-treated patients. In their second year of treatment with ORENCIA/methotrexate, more patients had no progression than in the first year (65% vs 56%). - Physical Function Response and Health-Related Outcomes - Improvement in physical function was measured by the Health Assessment Questionnaire Disability Index (HAQ-DI). In the HAQ-DI, ORENCIA demonstrated greater improvement from baseline versus placebo in Studies II-V and versus methotrexate in Study VI. In Study SC-1, improvement from baseline as measured by HAQ-DI at 6 months and over time was similar between subcutaneous and intravenous administration. The results from Studies II and III are shown in Table 7. Similar results were observed in Study V compared to placebo and in Study VI compared to methotrexate. During the open-label period of Study II, the improvement in physical function has been maintained for up to 3 years. - Health-related quality of life was assessed by the SF-36 questionnaire at 6 months in Studies II, III, and IV and at 12 months in Studies II and III. In these studies, improvement was observed in the ORENCIA group as compared with the placebo group in all 8 domains of the SF-36 as well as the Physical Component Summary (PCS) and the Mental Component Summary (MCS). - The safety and efficacy of ORENCIA were assessed in a three-part study including an open-label extension in children with polyarticular juvenile idiopathic arthritis (JIA). Patients 6 to 17 years of age (n=190) with moderately to severely active polyarticular JIA who had an inadequate response to one or more DMARDs, such as methotrexate or TNF antagonists, were treated. Patients had a disease duration of approximately 4 years with moderately to severely active disease at study entry, as determined by baseline counts of active joints (mean, 16) and joints with loss of motion (mean, 16); patients had elevated C-reactive protein (CRP) levels (mean, 3.2 mg/dL) and ESR (mean, 32 mm/h). The patients enrolled had subtypes of JIA that at disease onset included Oligoarticular (16%), Polyarticular (64%; 20% were rheumatoid factor positive), and Systemic (20%). At study entry, 74% of patients were receiving methotrexate (mean dose, 13.2 mg/m2 per week) and remained on a stable dose of methotrexate (those not receiving methotrexate did not initiate methotrexate treatment during the study). - In Period A (open-label, lead-in), patients received 10 mg/kg (maximum 1000 mg per dose) intravenously on days 1, 15, 29, and monthly thereafter. Response was assessed utilizing the ACR Pediatric 30 definition of improvement, defined as ≥30% improvement in at least 3 of the 6 JIA core set variables and ≥30% worsening in not more than 1 of the 6 JIA core set variables. Patients demonstrating an ACR Pedi 30 response at the end of Period A were randomized into the double-blind phase (Period B) and received either ORENCIA or placebo for 6 months or until disease flare. Disease flare was defined as a ≥30% worsening in at least 3 of the 6 JIA core set variables with ≥30% improvement in not more than 1 of the 6 JIA core set variables; ≥2 cm of worsening of the Physician or Parent Global Assessment was necessary if used as 1 of the 3 JIA core set variables used to define flare, and worsening in ≥2 joints was necessary if the number of active joints or joints with limitation of motion was used as 1 of the 3 JIA core set variables used to define flare. - At the conclusion of Period A, pediatric ACR 30/50/70 responses were 65%, 50%, and 28%, respectively. Pediatric ACR 30 responses were similar in all subtypes of JIA studied. - During the double-blind randomized withdrawal phase (Period B), ORENCIA-treated patients experienced significantly fewer disease flares compared to placebo-treated patients (20% vs 53%); 95% CI of the difference (15%, 52%). The risk of disease flare among patients continuing on ORENCIA was less than one-third than that for patients withdrawn from ORENCIA treatment (hazard ratio=0.31, 95% CI ). Among patients who received ORENCIA throughout the study (Period A, Period B, and the open-label extension Period C), the proportion of pediatric ACR 30/50/70 responders has remained consistent for 1 year. # How Supplied - For Intravenous Infusion - ORENCIA® (abatacept) lyophilized powder for intravenous infusion is supplied as an individually packaged, single-use vial with a silicone-free disposable syringe, providing 250 mg of abatacept in a 15-mL vial: NDC 0003-2187-10 - For Subcutaneous Injection - ORENCIA® (abatacept) injection solution for subcutaneous administration is supplied either as a single-dose disposable prefilled glass syringe with UltraSafe Passive® needle guard with flange extenders or as a single-dose disposable prefilled glass syringe with flange extender. The Type I glass syringe has a coated stopper and fixed stainless steel needle (5 bevel, 29-gauge thin wall, ½-inch needle) covered with a rigid needle shield. The prefilled syringe provides 125 mg of abatacept in 1 mL and is provided in the following packages: NDC 0003-2188-11: pack of 4 syringes with a passive needle safety guard NDC 0003-2188-31: pack of 4 syringes without a passive needle safety guard - NDC 0003-2188-11: pack of 4 syringes with a passive needle safety guard - NDC 0003-2188-31: pack of 4 syringes without a passive needle safety guard - Storage - ORENCIA lyophilized powder supplied in a vial should be refrigerated at 2°C to 8°C (36°F to 46°F). Do not use beyond the expiration date on the vial. Protect the vials from light by storing in the original package until time of use. - ORENCIA solution supplied in a prefilled syringe should be refrigerated at 2°C to 8°C (36°F to 46°F). Do not use beyond the expiration date on the prefilled syringe. Protect from light by storing in the original package until time of use. Do not allow the prefilled syringe to freeze. ## Storage There is limited information regarding Abatacept Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Concomitant Use With Biologic Medications for RA - Patients should be informed that they should not receive ORENCIA treatment concomitantly with a TNF antagonist, such as adalimumab, etanercept, and infliximab because such combination therapy may increase their risk for infections, and that they should not receive ORENCIA concomitantly with other biologic RA therapy, such as anakinra because there is not enough information to assess the safety and efficacy of such combination therapy. - Hypersensitivity - Patients should be instructed to immediately tell their healthcare professional if they experience symptoms of an allergic reaction during or for the first day after the administration of ORENCIA. - Infections - Patients should be asked if they have a history of recurrent infections, have underlying conditions which may predispose them to infections, or have chronic, latent, or localized infections. Patients should be asked if they have had tuberculosis (TB), a positive skin test for TB, or recently have been in close contact with someone who has had TB. Patients should be instructed that they may be tested for TB before they receive ORENCIA. Patients should be informed to tell their healthcare professional if they develop an infection during therapy with ORENCIA . - Immunizations - Patients should be informed that live vaccines should not be given concurrently with ORENCIA or within 3 months of its discontinuation. Caregivers of patients with juvenile idiopathic arthritis should be informed that the patient should be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating ORENCIA therapy and to discuss with their healthcare provider how best to handle future immunizations once ORENCIA therapy has been initiated. - Pregnancy and Nursing Mothers - Patients should be informed that ORENCIA has not been studied in pregnant women or nursing mothers so the effects of ORENCIA on pregnant women or nursing infants are not known. Patients should be instructed to tell their healthcare professional if they are pregnant, become pregnant, or are thinking about becoming pregnant. Patients should be instructed to tell their healthcare professional if they plan to breastfeed their infant. - Blood Glucose Testing - Intravenous Administration - Patients should be asked if they have diabetes. Maltose is contained in ORENCIA for intravenous administration and can give falsely elevated blood glucose readings with certain blood glucose monitors on the day of ORENCIA infusion. If a patient is using such a monitor, the patient should be advised to discuss with their healthcare professional methods that do not react with maltose. - Subcutaneous Administration - ORENCIA for subcutaneous administration does not contain maltose; therefore, patients do not need to alter their glucose monitoring. # Precautions with Alcohol - Alcohol-Abatacept interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Orencia® # Look-Alike Drug Names - Orencia® — Oracea® # Drug Shortage Status # Price	Abatacept 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 Abatacept is an immune modulator that is FDA approved for the {{{indicationType}}} of adult rheumatoid arthritis (RA), juvenile idiopathic arthritis. Common adverse reactions include headache, upper respiratory tract infection, nasopharyngitis, and nausea. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - ORENCIA® is indicated for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active rheumatoid arthritis. ORENCIA may be used as monotherapy or concomitantly with disease-modifying antirheumatic drugs (DMARDs) other than tumor necrosis factor (TNF) antagonists. - Intravenous Dosing Regimen - ORENCIA intravenous should be administered as a 30-minute intravenous infusion utilizing the weight range-based dosing specified in Table 1. Following the initial intravenous administration, an intravenous infusion should be given at 2 and 4 weeks after the first infusion and every 4 weeks thereafter. - Subcutaneous Dosing Regimen - ORENCIA 125 mg should be administered by subcutaneous injection once weekly and may be initiated with or without an intravenous loading dose. For patients initiating therapy with an intravenous loading dose, ORENCIA should be initiated with a single intravenous infusion (as per body weight categories listed in Table 1), followed by the first 125 mg subcutaneous injection administered within a day of the intravenous infusion. - Patients transitioning from ORENCIA intravenous therapy to subcutaneous administration should administer the first subcutaneous dose instead of the next scheduled intravenous dose. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Abatacept in adult patients. ### Non–Guideline-Supported Use - Dosing Information - Abatacept approximately 10 mg/kg as an IV infusion on days 1, 15, and 29, and every 4 weeks thereafter.[1] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Dosing Information - ORENCIA is indicated for reducing signs and symptoms in pediatric patients 6 years of age and older with moderately to severely active polyarticular juvenile idiopathic arthritis. ORENCIA may be used as monotherapy or concomitantly with methotrexate (MTX). - The recommended dose of ORENCIA for patients 6 to 17 years of age with juvenile idiopathic arthritis who weigh less than 75 kg is 10 mg/kg intravenously calculated based on the patient’s body weight at each administration. Pediatric patients weighing 75 kg or more should be administered ORENCIA following the adult intravenous dosing regimen, not to exceed a maximum dose of 1000 mg. ORENCIA should be administered as a 30-minute intravenous infusion. Following the initial administration, ORENCIA should be given at 2 and 4 weeks after the first infusion and every 4 weeks thereafter. Any unused portions in the vials must be immediately discarded. - The safety and efficacy of subcutaneous ORENCIA injection has not been studied in patients under 18 years of age. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Abatacept in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Abatacept in pediatric patients. # Contraindications None # Warnings ### Precautions - Concomitant Use with TNF Antagonists - In controlled clinical trials in patients with adult RA, patients receiving concomitant intravenous ORENCIA and TNF antagonist therapy experienced more infections (63%) and serious infections (4.4%) compared to patients treated with only TNF antagonists (43% and 0.8%, respectively). These trials failed to demonstrate an important enhancement of efficacy with concomitant administration of ORENCIA with TNF antagonist; therefore, concurrent therapy with ORENCIA and a TNF antagonist is not recommended. While transitioning from TNF antagonist therapy to ORENCIA therapy, patients should be monitored for signs of infection. - Hypersensitivity - In controlled, double-blind and open-label clinical trials, the occurrence of anaphylaxis and anaphylactoid reactions was rare (<0.1%) and was only observed in patients dosed with intravenous ORENCIA. Other reactions potentially associated with drug hypersensitivity, such as hypotension, urticaria, and dyspnea that occurred within 24 hours of ORENCIA infusion, were uncommon (<1%). Of the 190 patients with juvenile idiopathic arthritis treated with ORENCIA in clinical trials, there was one case of a hypersensitivity reaction (0.5%). Appropriate medical support measures for the treatment of hypersensitivity reactions should be available for immediate use in the event of a reaction. Anaphylaxis or anaphylactoid reactions can occur after the first infusion and can be life threatening. In postmarketing experience, a case of fatal anaphylaxis following the first infusion of ORENCIA has been reported. If an anaphylactic or other serious allergic reaction occurs, administration of ORENCIA should be stopped immediately with appropriate therapy instituted, and the use of ORENCIA should be permanently discontinued. - Infections - Serious infections, including sepsis and pneumonia, have been reported in patients receiving ORENCIA. Some of these infections have been fatal. Many of the serious infections have occurred in patients on concomitant immunosuppressive therapy which in addition to their underlying disease, could further predispose them to infection. Physicians should exercise caution when considering the use of ORENCIA in patients with a history of recurrent infections, underlying conditions which may predispose them to infections, or chronic, latent, or localized infections. Patients who develop a new infection while undergoing treatment with ORENCIA should be monitored closely. Administration of ORENCIA should be discontinued if a patient develops a serious infection. A higher rate of serious infections has been observed in adult RA patients treated with concurrent TNF antagonists and ORENCIA. - Prior to initiating immunomodulatory therapies, including ORENCIA, patients should be screened for latent tuberculosis infection with a tuberculin skin test. ORENCIA has not been studied in patients with a positive tuberculosis screen, and the safety of ORENCIA in individuals with latent tuberculosis infection is unknown. Patients testing positive in tuberculosis screening should be treated by standard medical practice prior to therapy with ORENCIA. - Antirheumatic therapies have been associated with hepatitis B reactivation. Therefore, screening for viral hepatitis should be performed in accordance with published guidelines before starting therapy with ORENCIA. In clinical studies with ORENCIA, patients who screened positive for hepatitis were excluded from study. - Immunizations - Live vaccines should not be given concurrently with ORENCIA or within 3 months of its discontinuation. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving ORENCIA. The efficacy of vaccination in patients receiving ORENCIA is not known. Based on its mechanism of action, ORENCIA may blunt the effectiveness of some immunizations. - It is recommended that patients with juvenile idiopathic arthritis be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating ORENCIA therapy. - Use in Patients with Chronic Obstructive Pulmonary Disease (COPD) - Adult COPD patients treated with ORENCIA developed adverse events more frequently than those treated with placebo, including COPD exacerbations, cough, rhonchi, and dyspnea. Use of ORENCIA in patients with RA and COPD should be undertaken with caution and such patients should be monitored for worsening of their respiratory status. - Immunosuppression - The possibility exists for drugs inhibiting T cell activation, including ORENCIA, to affect host defenses against infections and malignancies since T cells mediate cellular immune responses. The impact of treatment with ORENCIA on the development and course of malignancies is not fully understood. In clinical trials in patients with adult RA, a higher rate of infections was seen in ORENCIA-treated patients compared to placebo. # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not predict the rates observed in a broader patient population in clinical practice. - The data described herein reflect exposure to ORENCIA administered intravenously in patients with active RA in placebo-controlled studies (1955 patients with ORENCIA, 989 with placebo). The studies had either a double-blind, placebo-controlled period of 6 months (258 patients with ORENCIA, 133 with placebo) or 1 year (1697 patients with ORENCIA, 856 with placebo). A subset of these patients received concomitant biologic DMARD therapy, such as a TNF blocking agent (204 patients with ORENCIA, 134 with placebo). - The majority of patients in RA clinical studies received one or more of the following concomitant medications with ORENCIA: methotrexate, nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, TNF blocking agents, azathioprine, chloroquine, gold, hydroxychloroquine, leflunomide, sulfasalazine, and anakinra. - The most serious adverse reactions were serious infections and malignancies. - The most commonly reported adverse events (occurring in ≥10% of patients treated with ORENCIA) were headache, upper respiratory tract infection, nasopharyngitis, and nausea. - The adverse events most frequently resulting in clinical intervention (interruption or discontinuation of ORENCIA) were due to infection. The most frequently reported infections resulting in dose interruption were upper respiratory tract infection (1.0%), bronchitis (0.7%), and herpes zoster (0.7%). The most frequent infections resulting in discontinuation were pneumonia (0.2%), localized infection (0.2%), and bronchitis (0.1%). - Infections - In the placebo-controlled trials, infections were reported in 54% of ORENCIA-treated patients and 48% of placebo-treated patients. The most commonly reported infections (reported in 5%-13% of patients) were upper respiratory tract infection, nasopharyngitis, sinusitis, urinary tract infection, influenza, and bronchitis. Other infections reported in fewer than 5% of patients at a higher frequency (>0.5%) with ORENCIA compared to placebo, were rhinitis, herpes simplex, and pneumonia. - Serious infections were reported in 3.0% of patients treated with ORENCIA and 1.9% of patients treated with placebo. The most common (0.2%-0.5%) serious infections reported with ORENCIA were pneumonia, cellulitis, urinary tract infection, bronchitis, diverticulitis, and acute pyelonephritis. - Malignancies - In the placebo-controlled portions of the clinical trials (1955 patients treated with ORENCIA for a median of 12 months), the overall frequencies of malignancies were similar in the ORENCIA- and placebo-treated patients (1.3% and 1.1%, respectively). However, more cases of lung cancer were observed in ORENCIA-treated patients (4, 0.2%) than placebo-treated patients (0). In the cumulative ORENCIA clinical trials (placebo-controlled and uncontrolled, open-label) a total of 8 cases of lung cancer (0.21 cases per 100 patient-years) and 4 lymphomas (0.10 cases per 100 patient-years) were observed in 2688 patients (3827 patient-years). The rate observed for lymphoma is approximately 3.5-fold higher than expected in an age- and gender-matched general population based on the National Cancer Institute's Surveillance, Epidemiology, and End Results Database. Patients with RA, particularly those with highly active disease, are at a higher risk for the development of lymphoma. Other malignancies included skin, breast, bile duct, bladder, cervical, endometrial, lymphoma, melanoma, myelodysplastic syndrome, ovarian, prostate, renal, thyroid, and uterine cancers. The potential role of ORENCIA in the development of malignancies in humans is unknown. - Infusion-Related Reactions and Hypersensitivity Reactions - Acute infusion-related events (adverse reactions occurring within 1 hour of the start of the infusion) in Studies III, IV, and V were more common in the ORENCIA-treated patients than the placebo patients (9% for ORENCIA, 6% for placebo). The most frequently reported events (1%-2%) were dizziness, headache, and hypertension. - Acute infusion-related events that were reported in >0.1% and ≤1% of patients treated with ORENCIA included cardiopulmonary symptoms, such as hypotension, increased blood pressure, and dyspnea; other symptoms included nausea, flushing, urticaria, cough, hypersensitivity, pruritus, rash, and wheezing. Most of these reactions were mild (68%) to moderate (28%). Fewer than 1% of ORENCIA-treated patients discontinued due to an acute infusion-related event. In controlled trials, 6 ORENCIA-treated patients compared to 2 placebo-treated patients discontinued study treatment due to acute infusion-related events. - Anaphylaxis was observed in patients dosed with ORENCIA administered intravenously in controlled and open-label clinical trials, and the occurrence was rare (<0.1%). Other reactions potentially associated with drug hypersensitivity, such as hypotension, urticaria, and dyspnea that occurred within 24 hours of ORENCIA infusion, were uncommon (<1%). Appropriate medical support measures for the treatment of hypersensitivity reactions should be available for immediate use in the event of a reaction. - Adverse Reactions in Patients with COPD - In Study V, there were 37 patients with chronic obstructive pulmonary disease (COPD) who were treated with ORENCIA and 17 COPD patients who were treated with placebo. The COPD patients treated with ORENCIA developed adverse events more frequently than those treated with placebo (97% vs 88%, respectively). Respiratory disorders occurred more frequently in ORENCIA-treated patients compared to placebo-treated patients (43% vs 24%, respectively) including COPD exacerbation, cough, rhonchi, and dyspnea. A greater percentage of ORENCIA-treated patients developed a serious adverse event compared to placebo-treated patients (27% vs 6%), including COPD exacerbation (3 of 37 patients [8%]) and pneumonia (1 of 37 patients [3%]). - Other Adverse Reactions - Adverse events occurring in 3% or more of patients and at least 1% more frequently in ORENCIA-treated patients during placebo-controlled RA studies are summarized in Table 2. - Immunogenicity - Antibodies directed against the entire abatacept molecule or to the CTLA-4 portion of abatacept were assessed by ELISA assays in RA patients for up to 2 years following repeated treatment with ORENCIA. Thirty-four of 1993 (1.7%) patients developed binding antibodies to the entire abatacept molecule or to the CTLA-4 portion of abatacept. Because trough levels of abatacept can interfere with assay results, a subset analysis was performed. In this analysis it was observed that 9 of 154 (5.8%) patients that had discontinued treatment with ORENCIA for over 56 days developed antibodies. - Samples with confirmed binding activity to CTLA-4 were assessed for the presence of neutralizing antibodies in a cell-based luciferase reporter assay. Six of 9 (67%) evaluable patients were shown to possess neutralizing antibodies. However, the development of neutralizing antibodies may be underreported due to lack of assay sensitivity. - No correlation of antibody development to clinical response or adverse events was observed. - The data reflect the percentage of patients whose test results were positive for antibodies to abatacept in specific assays. The observed incidence of antibody (including neutralizing antibody) positivity in an assay is highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to abatacept with the incidence of antibodies to other products may be misleading. - Clinical Experience in Methotrexate-Naive Patients - Study VI was an active-controlled clinical trial in methotrexate-naive patients. The safety experience in these patients was consistent with Studies I-V. - Because clinical trials are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not predict the rates observed in a broader patient population in clinical practice. - Study SC-1 was a randomized, double-blind, double-dummy, non-inferiority study that compared the efficacy and safety of abatacept administered subcutaneously (SC) and intravenously (IV) in 1457 subjects with rheumatoid arthritis, receiving background methotrexate, and experiencing an inadequate response to methotrexate (MTX-IR). The safety experience and immunogenicity for ORENCIA administered subcutaneously was consistent with intravenous Studies I-VI. Due to the route of administration, injection site reactions and immunogenicity were evaluated in Study SC-1 and two other smaller studies discussed in the sections below. - Injection Site Reactions in Adult RA Patients Treated with Subcutaneous ORENCIA - Study SC-1 compared the safety of abatacept including injection site reactions following subcutaneous or intravenous administration. The overall frequency of injection site reactions was 2.6% (19/736) and 2.5% (18/721) for the subcutaneous abatacept group and the intravenous abatacept group (subcutaneous placebo), respectively. All these injection site reactions (including hematoma, pruritus, and erythema) were mild (83%) to moderate (17%) in severity, and none necessitated drug discontinuation. - Immunogenicity in Adult RA Patients Treated with Subcutaneous ORENCIA - Study SC-1 compared the immunogenicity to abatacept following subcutaneous or intravenous administration. The overall immunogenicity frequency to abatacept was 1.1% (8/725) and 2.3% (16/710) for the subcutaneous and intravenous groups, respectively. The rate is consistent with previous experience, and there was no correlation of immunogenicity with effects on pharmacokinetics, safety, or efficacy. - Immunogenicity and Safety of Subcutaneous ORENCIA Administration as Monotherapy without an Intravenous Loading Dose - Study SC-2 was conducted to determine the effect of monotherapy use of ORENCIA on immunogenicity following subcutaneous administration without an intravenous load in 100 RA patients, who had not previously received abatacept or other CTLA4Ig, who received either subcutaneous ORENCIA plus methotrexate (n=51) or subcutaneous ORENCIA monotherapy (n=49). No patients in either group developed anti-product antibodies after 4 months of treatment. The safety observed in this study was consistent with that observed in the other subcutaneous studies. - Immunogenicity and Safety of Subcutaneous ORENCIA upon Withdrawal (Three Months) and Restart of Treatment - Study SC-3 in the subcutaneous program was conducted to investigate the effect of withdrawal (three months) and restart of ORENCIA subcutaneous treatment on immunogenicity in RA patients treated concomitantly with methotrexate. One hundred sixty-seven patients were enrolled in the first 3-month treatment period and responders (n=120) were randomized to either subcutaneous ORENCIA or placebo for the second 3-month period (withdrawal period). Patients from this period then received open-label ORENCIA treatment in the final 3-month period of the study (period 3). At the end of the withdrawal period, 0/38 patients who continued to receive subcutaneous ORENCIA developed anti-product antibodies compared to 7/73 (9.6%) of patients who had subcutaneous ORENCIA withdrawn during this period. Half of the patients receiving subcutaneous placebo during the withdrawal period received a single intravenous infusion of ORENCIA at the start of period 3 and half received intravenous placebo. At the end of period 3, when all patients again received subcutaneous ORENCIA, the immunogenicity rates were 1/38 (2.6%) in the group receiving subcutaneous ORENCIA throughout, and 2/73 (2.7%) in the group that had received placebo during the withdrawal period. Upon reinitiating therapy, there were no injection reactions and no differences in response to therapy in patients who were withdrawn from subcutaneous therapy for up to 3 months relative to those who remained on subcutaneous therapy, whether therapy was reintroduced with or without an intravenous loading dose. The safety observed in this study was consistent with that observed in the other studies. - 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. - In general, the adverse events in pediatric patients were similar in frequency and type to those seen in adult patients. - ORENCIA has been studied in 190 pediatric patients, 6 to 17 years of age, with polyarticular juvenile idiopathic arthritis. Overall frequency of adverse events in the 4-month, lead-in, open-label period of the study was 70%; infections occurred at a frequency of 36%. The most common infections were upper respiratory tract infection and nasopharyngitis. The infections resolved without sequelae, and the types of infections were consistent with those commonly seen in outpatient pediatric populations. Other events that occurred at a prevalence of at least 5% were headache, nausea, diarrhea, cough, pyrexia, and abdominal pain. - A total of 6 serious adverse events (acute lymphocytic leukemia, ovarian cyst, varicella infection, disease flare [2], and joint wear) were reported during the initial 4 months of treatment with ORENCIA. - Of the 190 patients with juvenile idiopathic arthritis treated with ORENCIA in clinical trials, there was one case of a hypersensitivity reaction (0.5%). During Periods A, B, and C, acute infusion-related reactions occurred at a frequency of 4%, 2%, and 3%, respectively, and were consistent with the types of events reported in adults. - Upon continued treatment in the open-label extension period, the types of adverse events were similar in frequency and type to those seen in adult patients, except for a single patient diagnosed with multiple sclerosis while on open-label treatment. - Immunogenicity - Antibodies directed against the entire abatacept molecule or to the CTLA-4 portion of abatacept were assessed by ELISA assays in patients with juvenile idiopathic arthritis following repeated treatment with ORENCIA throughout the open-label period. For patients who were withdrawn from therapy for up to 6 months during the double-blind period, the rate of antibody formation to the CTLA-4 portion of the molecule was 41% (22/54), while for those who remained on therapy the rate was 13% (7/54). Twenty of these patients had samples that could be tested for antibodies with neutralizing activity; of these, 8 (40%) patients were shown to possess neutralizing antibodies. - The presence of antibodies was generally transient and titers were low. The presence of antibodies was not associated with adverse events, changes in efficacy, or an effect on serum concentrations of abatacept. For patients who were withdrawn from ORENCIA during the double-blind period for up to 6 months, no serious acute infusion-related events were observed upon re-initiation of ORENCIA therapy. ## Postmarketing Experience - Adverse reactions have been reported during the postapproval use of ORENCIA. 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 ORENCIA. Based on the postmarketing experience in adult RA patients, the following adverse reaction has been identified during postapproval use with ORENCIA. - Vasculitis (including cutaneous vasculitis and leukocytoclastic vasculitis) # Drug Interactions - TNF Antagonists - Concurrent administration of a TNF antagonist with ORENCIA has been associated with an increased risk of serious infections and no significant additional efficacy over use of the TNF antagonists alone. Concurrent therapy with ORENCIA and TNF antagonists is not recommended. - Other Biologic RA Therapy - There is insufficient experience to assess the safety and efficacy of ORENCIA administered concurrently with other biologic RA therapy, such as anakinra, and therefore such use is not recommended. - Blood Glucose Testing - Parenteral drug products containing maltose can interfere with the readings of blood glucose monitors that use test strips with glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ). The GDH-PQQ based glucose monitoring systems may react with the maltose present in ORENCIA for intravenous administration, resulting in falsely elevated blood glucose readings on the day of infusion. When receiving ORENCIA through intravenous administration, patients that require blood glucose monitoring should be advised to consider methods that do not react with maltose, such as those based on glucose dehydrogenase nicotine adenine dinucleotide (GDH-NAD), glucose oxidase, or glucose hexokinase test methods. - ORENCIA for subcutaneous administration does not contain maltose; therefore, patients do not need to alter their glucose monitoring. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - There are no adequate and well-controlled studies of ORENCIA use in pregnant women. Abatacept has been shown to cross the placenta in animals, and in animal reproduction studies alterations in immune function occurred. ORENCIA should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. - Abatacept was not teratogenic when administered to pregnant mice at doses up to 300 mg/kg and in pregnant rats and rabbits at doses up to 200 mg/kg daily representing approximately 29 times the exposure associated with the maximum recommended human dose (MRHD) of 10 mg/kg based on AUC (area under the time-concentration curve). - Abatacept administered to female rats every three days during early gestation and throughout the lactation period, produced no adverse effects in offspring at doses up to 45 mg/kg, representing 3 times the exposure associated with the MRHD of 10 mg/kg based on AUC. However, at 200 mg/kg, 11 times the MRHD exposure, alterations in immune function were observed consisting of a 9-fold increase in T-cell dependent antibody response in female pups and thyroid inflammation in one female pup. It is not known whether these findings indicate a risk for development of autoimmune diseases in humans exposed in utero to abatacept. However, exposure to abatacept in the juvenile rat, which may be more representative of the fetal immune system state in the human, resulted in immune system abnormalities including inflammation of the thyroid and pancreas. - Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to ORENCIA, a pregnancy registry has been established. Healthcare professionals are encouraged to register patients and pregnant women are encouraged to enroll themselves by calling 1-877-311-8972. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Abatacept in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Abatacept during labor and delivery. ### Nursing Mothers - It is not known whether ORENCIA is excreted into human milk or absorbed systemically after ingestion by a nursing infant. However, abatacept was excreted in rat milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ORENCIA, 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 - Intravenous ORENCIA is indicated for reducing signs and symptoms in pediatric patients with moderately to severely active polyarticular juvenile idiopathic arthritis ages 6 years and older. ORENCIA may be used as monotherapy or concomitantly with methotrexate. - Studies in juvenile rats exposed to ORENCIA prior to immune system maturity have shown immune system abnormalities including an increase in the incidence of infections leading to death as well as inflammation of the thyroid and pancreas. Studies in adult mice and monkeys have not demonstrated similar findings. As the immune system of the rat is undeveloped in the first few weeks after birth, the relevance of these results to humans greater than 6 years of age (where the immune system is largely developed) is unknown. - ORENCIA is not recommended for use in patients below the age of 6 years. - The safety and effectiveness of ORENCIA in pediatric patients below 6 years of age have not been established. The safety and efficacy of ORENCIA in pediatric patients for uses other than juvenile idiopathic arthritis have not been established. - The safety and efficacy of subcutaneous ORENCIA has not been studied in patients under 18 years of age. ### Geriatic Use - A total of 323 patients 65 years of age and older, including 53 patients 75 years and older, received ORENCIA in clinical studies. No overall differences in safety or effectiveness were observed between these patients and younger patients, but these numbers are too low to rule out differences. The frequency of serious infection and malignancy among ORENCIA-treated patients over age 65 was higher than for those under age 65. Because there is a higher incidence of infections and malignancies in the elderly population in general, caution should be used when treating the elderly. ### Gender There is no FDA guidance on the use of Abatacept with respect to specific gender populations. ### Race There is no FDA guidance on the use of Abatacept with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Abatacept in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Abatacept in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Abatacept in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Abatacept in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous - Subcutaneous ### Monitoring - While transitioning from TNF antagonist therapy to ORENCIA therapy, patients should be monitored for signs of infection. # IV Compatibility There is limited information regarding IV Compatibility of Abatacept in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - Doses up to 50 mg/kg have been administered intravenously without apparent toxic effect. ### Management - In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment instituted. ## Chronic Overdose There is limited information regarding Chronic Overdose of Abatacept in the drug label. # Pharmacology ## Mechanism of Action - Abatacept, a selective costimulation modulator, inhibits T cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. This interaction provides a costimulatory signal necessary for full activation of T lymphocytes. Activated T lymphocytes are implicated in the pathogenesis of RA and are found in the synovium of patients with RA. - In vitro, abatacept decreases T cell proliferation and inhibits the production of the cytokines TNF alpha (TNFα), interferon-γ, and interleukin-2. In a rat collagen-induced arthritis model, abatacept suppresses inflammation, decreases anti-collagen antibody production, and reduces antigen specific production of interferon-γ. The relationship of these biological response markers to the mechanisms by which ORENCIA exerts its effects in RA is unknown. ## Structure - ORENCIA® (abatacept) is a soluble fusion protein that consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to the modified Fc (hinge, CH2, and CH3 domains) portion of human immunoglobulin G1 (IgG1). Abatacept is produced by recombinant DNA technology in a mammalian cell expression system. The apparent molecular weight of abatacept is 92 kilodaltons. - ORENCIA lyophilized powder for intravenous infusion is supplied as a sterile, white, preservative-free, lyophilized powder for intravenous administration. Following reconstitution of the lyophilized powder with 10 mL of Sterile Water for Injection, USP, the solution of ORENCIA is clear, colorless to pale yellow, with a pH range of 7.2 to 7.8. Each single-use vial of ORENCIA provides 250 mg abatacept, maltose (500 mg), monobasic sodium phosphate (17.2 mg), and sodium chloride (14.6 mg) for administration. - ORENCIA solution for subcutaneous administration is supplied as a sterile, preservative-free, clear, colorless to pale-yellow solution with a pH of 6.8 to 7.4. Each single dose of subcutaneous injection provides 125 mg abatacept, dibasic sodium phosphate anhydrous (0.838 mg), monobasic sodium phosphate monohydrate (0.286 mg), poloxamer 188 (8 mg), sucrose (170 mg), and quantity sufficient to 1 mL with water for injection. Unlike the intravenous formulation, ORENCIA solution for subcutaneous administration contains no maltose. ## Pharmacodynamics - In clinical trials with ORENCIA at doses approximating 10 mg/kg, decreases were observed in serum levels of soluble interleukin-2 receptor (sIL-2R), interleukin-6 (IL-6), rheumatoid factor (RF), C-reactive protein (CRP), matrix metalloproteinase-3 (MMP3), and TNFα. The relationship of these biological response markers to the mechanisms by which ORENCIA exerts its effects in RA is unknown. ## Pharmacokinetics - Healthy Adults and Adult RA - Intravenous Administration - The pharmacokinetics of abatacept were studied in healthy adult subjects after a single 10 mg/kg intravenous infusion and in RA patients after multiple 10 mg/kg intravenous infusions (see Table 3). - The pharmacokinetics of abatacept in RA patients and healthy subjects appeared to be comparable. In RA patients, after multiple intravenous infusions, the pharmacokinetics of abatacept showed proportional increases of Cmax and AUC over the dose range of 2 mg/kg to 10 mg/kg. At 10 mg/kg, serum concentration appeared to reach a steady-state by day 60 with a mean (range) trough concentration of 24 mcg/mL (1 to 66 mcg/mL). No systemic accumulation of abatacept occurred upon continued repeated treatment with 10 mg/kg at monthly intervals in RA patients. - Population pharmacokinetic analyses in RA patients revealed that there was a trend toward higher clearance of abatacept with increasing body weight. Age and gender (when corrected for body weight) did not affect clearance. Concomitant methotrexate, NSAIDs, corticosteroids, and TNF blocking agents did not influence abatacept clearance. - No formal studies were conducted to examine the effects of either renal or hepatic impairment on the pharmacokinetics of abatacept. - Juvenile Idiopathic Arthritis - In patients 6 to 17 years of age, the mean (range) steady-state serum peak and trough concentrations of abatacept were 217 mcg/mL (57 to 700 mcg/mL) and 11.9 mcg/mL (0.15 to 44.6 mcg/mL). Population pharmacokinetic analyses of the serum concentration data showed that clearance of abatacept increased with baseline body weight. The estimated mean (range) clearance of abatacept in the juvenile idiopathic arthritis patients was 0.4 mL/h/kg (0.20 to 1.12 mL/h/kg). After accounting for the effect of body weight, the clearance of abatacept was not related to age and gender. Concomitant methotrexate, corticosteroids, and NSAIDs were also shown not to influence abatacept clearance. - Adult RA - Subcutaneous Administration - Abatacept exhibited linear pharmacokinetics following subcutaneous administration. The mean (range) for Cmin and Cmax at steady state observed after 85 days of treatment was 32.5 mcg/mL (6.6 to 113.8 mcg/mL) and 48.1 mcg/mL (9.8 to 132.4 mcg/mL), respectively. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. Mean estimates for systemic clearance (0.28 mL/h/kg), volume of distribution (0.11 L/kg), and terminal half-life (14.3 days) were comparable between subcutaneous and intravenous administration. - Study SC-2 was conducted to determine the effect of monotherapy use of ORENCIA on immunogenicity following subcutaneous administration without an intravenous load. When the intravenous loading dose was not administered, a mean trough concentration of 12.6 mcg/mL was achieved after 2 weeks of dosing. - Consistent with the intravenous data, population pharmacokinetic analyses for subcutaneous abatacept in RA patients revealed that there was a trend toward higher clearance of abatacept with increasing body weight. Age and gender (when corrected for body weight) did not affect apparent clearance. Concomitant medication, such as methotrexate, corticosteroids, and NSAIDs, did not influence abatacept apparent clearance. ## Nonclinical Toxicology - In a mouse carcinogenicity study, weekly subcutaneous injections of 20, 65, or 200 mg/kg of abatacept administered for up to 84 weeks in males and 88 weeks in females were associated with increases in the incidence of malignant lymphomas (all doses) and mammary gland tumors (intermediate- and high-dose in females). The mice from this study were infected with murine leukemia virus and mouse mammary tumor virus. These viruses are associated with an increased incidence of lymphomas and mammary gland tumors, respectively, in immunosuppressed mice. The doses used in these studies produced exposures 0.8, 2.0, and 3.0 times higher, respectively, than the exposure associated with the maximum recommended human dose (MRHD) of 10 mg/kg based on AUC (area under the time-concentration curve). The relevance of these findings to the clinical use of ORENCIA is unknown. - In a one-year toxicity study in cynomolgus monkeys, abatacept was administered intravenously once weekly at doses up to 50 mg/kg (producing 9 times the MRHD exposure based on AUC). Abatacept was not associated with any significant drug-related toxicity. Reversible pharmacological effects consisted of minimal transient decreases in serum IgG and minimal to severe lymphoid depletion of germinal centers in the spleen and/or lymph nodes. No evidence of lymphomas or preneoplastic morphologic changes was observed, despite the presence of a virus (lymphocryptovirus) known to cause these lesions in immunosuppressed monkeys within the time frame of this study. The relevance of these findings to the clinical use of ORENCIA is unknown. - No mutagenic potential of abatacept was observed in the in vitro bacterial reverse mutation (Ames) or Chinese hamster ovary/hypoxanthine guanine phosphoribosyl-transferase (CHO/HGPRT) forward point mutation assays with or without metabolic activation, and no chromosomal aberrations were observed in human lymphocytes treated with abatacept with or without metabolic activation. - Abatacept had no adverse effects on male or female fertility in rats at doses up to 200 mg/kg every three days (11 times the MRHD exposure based on AUC). - A juvenile animal study was conducted in rats dosed with abatacept from 4 to 94 days of age in which an increase in the incidence of infections leading to death occurred at all doses compared with controls. Altered T-cell subsets including increased T-helper cells and reduced T-regulatory cells were observed. In addition, inhibition of T-cell-dependent antibody responses (TDAR) was observed. Upon following these animals into adulthood, lymphocytic inflammation of the thyroid and pancreatic islets was observed. - In studies of adult mice and monkeys, inhibition of TDAR was apparent. However, infection and mortality, altered T-helper cells, and inflammation of thyroid and pancreas were not observed. # Clinical Studies - The efficacy and safety of ORENCIA for intravenous administration were assessed in six randomized, double-blind, controlled studies (five placebo-controlled and one active-controlled) in patients ≥18 years of age with active RA diagnosed according to American College of Rheumatology (ACR) criteria. Studies I, II, III, IV, and VI required patients to have at least 12 tender and 10 swollen joints at randomization. Study V did not require any specific number of tender or swollen joints. ORENCIA or placebo treatment was given intravenously at weeks 0, 2, and 4 and then every 4 weeks thereafter in intravenous Studies I, II, III, IV, and VI. The safety and efficacy of ORENCIA for subcutaneous administration were assessed in Study SC-1, which was a randomized, double-blind, double-dummy, non-inferiority study that compared abatacept administered subcutaneously and intravenously in 1457 subjects with rheumatoid arthritis (RA), receiving background methotrexate (MTX), and experiencing an inadequate response to methotrexate (MTX-IR). - Study I evaluated ORENCIA as monotherapy in 122 patients with active RA who had failed at least one non-biologic DMARD or etanercept. In Study II and Study III, the efficacy and safety of ORENCIA were assessed in patients with an inadequate response to methotrexate and who were continued on their stable dose of methotrexate. In Study IV, the efficacy and safety of ORENCIA were assessed in patients with an inadequate response to a TNF blocking agent, with the TNF blocking agent discontinued prior to randomization; other DMARDs were permitted. Study V primarily assessed safety in patients with active RA requiring additional intervention in spite of current therapy with DMARDs; all DMARDs used at enrollment were continued. Patients in Study V were not excluded for comorbid medical conditions. In Study VI, the efficacy and safety of ORENCIA were assessed in methotrexate-naive patients with RA of less than 2 years disease duration. In Study VI, patients previously naive to methotrexate were randomized to receive ORENCIA plus methotrexate or methotrexate plus placebo. In Study SC-1, the goal was to demonstrate the efficacy and safety of ORENCIA subcutaneous relative to ORENCIA intravenous administration in subjects with moderate to severely active RA and experiencing inadequate response to methotrexate, using a non-inferiority study design. - Study I patients were randomized to receive one of three doses of ORENCIA (0.5, 2, or 10 mg/kg) or placebo ending at week 8. Study II patients were randomized to receive ORENCIA 2 or 10 mg/kg or placebo for 12 months. Study III, IV, V, and VI patients were randomized to receive a dose of ORENCIA based on weight range or placebo for 12 months (Studies III, V, and VI) or 6 months (Study IV). The dose of ORENCIA was 500 mg for patients weighing less than 60 kg, 750 mg for patients weighing 60 to 100 kg, and 1000 mg for patients weighing greater than 100 kg. In Study SC-1, patients were randomized with stratification by body weight (<60 kg, 60 to 100 kg, >100 kg) to receive ORENCIA 125 mg subcutaneous injections weekly, after a single intravenous loading dose of ORENCIA based on body weight or ORENCIA intravenously on Days 1, 15, 29, and every four weeks thereafter. Subjects continued taking their current dose of methotrexate from the day of randomization. - Clinical Response - The percent of ORENCIA-treated patients achieving ACR 20, 50, and 70 responses and major clinical response in Studies I, III, IV, and VI are shown in Table 4. ORENCIA-treated patients had higher ACR 20, 50, and 70 response rates at 6 months compared to placebo-treated patients. Month 6 ACR response rates in Study II for the 10 mg/kg group were similar to the ORENCIA group in Study III. - In Studies III and IV, improvement in the ACR 20 response rate versus placebo was observed within 15 days in some patients and within 29 days versus methotrexate in Study VI. In Studies II, III, and VI, ACR response rates were maintained to 12 months in ORENCIA-treated patients. ACR responses were maintained up to three years in the open-label extension of Study II. In Study III, ORENCIA-treated patients experienced greater improvement than placebo-treated patients in morning stiffness. - In Study VI, a greater proportion of patients treated with ORENCIA plus methotrexate achieved a low level of disease activity as measured by a DAS28-CRP less than 2.6 at 12 months compared to those treated with methotrexate plus placebo (Table 4). Of patients treated with ORENCIA plus methotrexate who achieved DAS28-CRP less than 2.6, 54% had no active joints, 17% had one active joint, 7% had two active joints, and 22% had three or more active joints, where an active joint was a joint that was rated as tender or swollen or both. - In Study SC-1, the main outcome measure was ACR 20 at 6 months. The pre-specified non-inferiority margin was a treatment difference of −7.5%. As shown in Table 4, the study demonstrated non-inferiority of ORENCIA administered subcutaneously to intravenous infusions of ORENCIA with respect to ACR 20 responses up to 6 months of treatment. ACR 50 and 70 responses are also shown in Table 4. No major differences in ACR responses were observed between intravenous and subcutaneous treatment groups in subgroups based on weight categories (less than 60 kg, 60 to 100 kg, and more than 100 kg; data not shown). - The results of the components of the ACR response criteria for Studies III, IV, and SC-1 are shown in Table 5 (results at Baseline [BL] and 6 months [6 M]). In ORENCIA-treated patients, greater improvement was seen in all ACR response criteria components through 6 and 12 months than in placebo-treated patients. - The percent of patients achieving the ACR 50 response for Study III by visit is shown in Figure 1. The time course for the ORENCIA group in Study VI was similar to that in Study III. - Figure 1: Percent of Patients Achieving ACR 50 Response by Visit* (Study III) - The percent of patients achieving the ACR 50 response for Study SC-1 in the ORENCIA subcutaneous (SC) and intravenous (IV) treatment arms at each treatment visit was as follows: Day 15—SC 3%, IV 5%; Day 29—SC 11%, IV 14%; Day 57—SC 24%, IV 30%; Day 85—SC 33%, IV 38%; Day 113—SC 39%, IV 41%; Day 141—SC 46%, IV 47%; Day 169—SC 51%, IV 50%. - Radiographic Response - In Study III and Study VI, structural joint damage was assessed radiographically and expressed as change from baseline in the Genant-modified Total Sharp Score (TSS) and its components, the Erosion Score (ES) and Joint Space Narrowing (JSN) score. ORENCIA/methotrexate slowed the progression of structural damage compared to placebo/methotrexate after 12 months of treatment as shown in Table 6. - In the open-label extension of Study III, 75% of patients initially randomized to ORENCIA/methotrexate and 65% of patients initially randomized to placebo/methotrexate were evaluated radiographically at Year 2. As shown in Table 6, progression of structural damage in ORENCIA/methotrexate-treated patients was further reduced in the second year of treatment. - Following 2 years of treatment with ORENCIA/methotrexate, 51% of patients had no progression of structural damage as defined by a change in the TSS of zero or less compared with baseline. Fifty-six percent (56%) of ORENCIA/methotrexate-treated patients had no progression during the first year compared to 45% of placebo/methotrexate-treated patients. In their second year of treatment with ORENCIA/methotrexate, more patients had no progression than in the first year (65% vs 56%). - Physical Function Response and Health-Related Outcomes - Improvement in physical function was measured by the Health Assessment Questionnaire Disability Index (HAQ-DI). In the HAQ-DI, ORENCIA demonstrated greater improvement from baseline versus placebo in Studies II-V and versus methotrexate in Study VI. In Study SC-1, improvement from baseline as measured by HAQ-DI at 6 months and over time was similar between subcutaneous and intravenous administration. The results from Studies II and III are shown in Table 7. Similar results were observed in Study V compared to placebo and in Study VI compared to methotrexate. During the open-label period of Study II, the improvement in physical function has been maintained for up to 3 years. - Health-related quality of life was assessed by the SF-36 questionnaire at 6 months in Studies II, III, and IV and at 12 months in Studies II and III. In these studies, improvement was observed in the ORENCIA group as compared with the placebo group in all 8 domains of the SF-36 as well as the Physical Component Summary (PCS) and the Mental Component Summary (MCS). - The safety and efficacy of ORENCIA were assessed in a three-part study including an open-label extension in children with polyarticular juvenile idiopathic arthritis (JIA). Patients 6 to 17 years of age (n=190) with moderately to severely active polyarticular JIA who had an inadequate response to one or more DMARDs, such as methotrexate or TNF antagonists, were treated. Patients had a disease duration of approximately 4 years with moderately to severely active disease at study entry, as determined by baseline counts of active joints (mean, 16) and joints with loss of motion (mean, 16); patients had elevated C-reactive protein (CRP) levels (mean, 3.2 mg/dL) and ESR (mean, 32 mm/h). The patients enrolled had subtypes of JIA that at disease onset included Oligoarticular (16%), Polyarticular (64%; 20% were rheumatoid factor positive), and Systemic (20%). At study entry, 74% of patients were receiving methotrexate (mean dose, 13.2 mg/m2 per week) and remained on a stable dose of methotrexate (those not receiving methotrexate did not initiate methotrexate treatment during the study). - In Period A (open-label, lead-in), patients received 10 mg/kg (maximum 1000 mg per dose) intravenously on days 1, 15, 29, and monthly thereafter. Response was assessed utilizing the ACR Pediatric 30 definition of improvement, defined as ≥30% improvement in at least 3 of the 6 JIA core set variables and ≥30% worsening in not more than 1 of the 6 JIA core set variables. Patients demonstrating an ACR Pedi 30 response at the end of Period A were randomized into the double-blind phase (Period B) and received either ORENCIA or placebo for 6 months or until disease flare. Disease flare was defined as a ≥30% worsening in at least 3 of the 6 JIA core set variables with ≥30% improvement in not more than 1 of the 6 JIA core set variables; ≥2 cm of worsening of the Physician or Parent Global Assessment was necessary if used as 1 of the 3 JIA core set variables used to define flare, and worsening in ≥2 joints was necessary if the number of active joints or joints with limitation of motion was used as 1 of the 3 JIA core set variables used to define flare. - At the conclusion of Period A, pediatric ACR 30/50/70 responses were 65%, 50%, and 28%, respectively. Pediatric ACR 30 responses were similar in all subtypes of JIA studied. - During the double-blind randomized withdrawal phase (Period B), ORENCIA-treated patients experienced significantly fewer disease flares compared to placebo-treated patients (20% vs 53%); 95% CI of the difference (15%, 52%). The risk of disease flare among patients continuing on ORENCIA was less than one-third than that for patients withdrawn from ORENCIA treatment (hazard ratio=0.31, 95% CI [0.16, 0.59]). Among patients who received ORENCIA throughout the study (Period A, Period B, and the open-label extension Period C), the proportion of pediatric ACR 30/50/70 responders has remained consistent for 1 year. # How Supplied - For Intravenous Infusion - ORENCIA® (abatacept) lyophilized powder for intravenous infusion is supplied as an individually packaged, single-use vial with a silicone-free disposable syringe, providing 250 mg of abatacept in a 15-mL vial: NDC 0003-2187-10 - For Subcutaneous Injection - ORENCIA® (abatacept) injection solution for subcutaneous administration is supplied either as a single-dose disposable prefilled glass syringe with UltraSafe Passive® needle guard with flange extenders or as a single-dose disposable prefilled glass syringe with flange extender. The Type I glass syringe has a coated stopper and fixed stainless steel needle (5 bevel, 29-gauge thin wall, ½-inch needle) covered with a rigid needle shield. The prefilled syringe provides 125 mg of abatacept in 1 mL and is provided in the following packages: NDC 0003-2188-11: pack of 4 syringes with a passive needle safety guard NDC 0003-2188-31: pack of 4 syringes without a passive needle safety guard - NDC 0003-2188-11: pack of 4 syringes with a passive needle safety guard - NDC 0003-2188-31: pack of 4 syringes without a passive needle safety guard - Storage - ORENCIA lyophilized powder supplied in a vial should be refrigerated at 2°C to 8°C (36°F to 46°F). Do not use beyond the expiration date on the vial. Protect the vials from light by storing in the original package until time of use. - ORENCIA solution supplied in a prefilled syringe should be refrigerated at 2°C to 8°C (36°F to 46°F). Do not use beyond the expiration date on the prefilled syringe. Protect from light by storing in the original package until time of use. Do not allow the prefilled syringe to freeze. ## Storage There is limited information regarding Abatacept Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Concomitant Use With Biologic Medications for RA - Patients should be informed that they should not receive ORENCIA treatment concomitantly with a TNF antagonist, such as adalimumab, etanercept, and infliximab because such combination therapy may increase their risk for infections, and that they should not receive ORENCIA concomitantly with other biologic RA therapy, such as anakinra because there is not enough information to assess the safety and efficacy of such combination therapy. - Hypersensitivity - Patients should be instructed to immediately tell their healthcare professional if they experience symptoms of an allergic reaction during or for the first day after the administration of ORENCIA. - Infections - Patients should be asked if they have a history of recurrent infections, have underlying conditions which may predispose them to infections, or have chronic, latent, or localized infections. Patients should be asked if they have had tuberculosis (TB), a positive skin test for TB, or recently have been in close contact with someone who has had TB. Patients should be instructed that they may be tested for TB before they receive ORENCIA. Patients should be informed to tell their healthcare professional if they develop an infection during therapy with ORENCIA . - Immunizations - Patients should be informed that live vaccines should not be given concurrently with ORENCIA or within 3 months of its discontinuation. Caregivers of patients with juvenile idiopathic arthritis should be informed that the patient should be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating ORENCIA therapy and to discuss with their healthcare provider how best to handle future immunizations once ORENCIA therapy has been initiated. - Pregnancy and Nursing Mothers - Patients should be informed that ORENCIA has not been studied in pregnant women or nursing mothers so the effects of ORENCIA on pregnant women or nursing infants are not known. Patients should be instructed to tell their healthcare professional if they are pregnant, become pregnant, or are thinking about becoming pregnant. Patients should be instructed to tell their healthcare professional if they plan to breastfeed their infant. - Blood Glucose Testing - Intravenous Administration - Patients should be asked if they have diabetes. Maltose is contained in ORENCIA for intravenous administration and can give falsely elevated blood glucose readings with certain blood glucose monitors on the day of ORENCIA infusion. If a patient is using such a monitor, the patient should be advised to discuss with their healthcare professional methods that do not react with maltose. - Subcutaneous Administration - ORENCIA for subcutaneous administration does not contain maltose; therefore, patients do not need to alter their glucose monitoring. # Precautions with Alcohol - Alcohol-Abatacept interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Orencia®[2] # Look-Alike Drug Names - Orencia® — Oracea®[3] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Abatacept
670d6d9f6119e1a18b3160253cbb367d4bde7830	wikidoc	Urokinase	Urokinase Urokinase, also known as urokinase-type plasminogen activator (uPA), is a serine protease present in humans and other animals. The human urokinase protein was discovered, but not named, by McFarlane and Pilling in 1947. Urokinase was originally isolated from human urine, and it is also present in the blood and in the extracellular matrix of many tissues. The primary physiological substrate of this enzyme is plasminogen, which is an inactive form (zymogen) of the serine protease plasmin. Activation of plasmin triggers a proteolytic cascade that, depending on the physiological environment, participates in thrombolysis or extracellular matrix degradation. This cascade had been involved in vascular diseases and cancer progression. Urokinase is encoded in humans by the PLAU gene, which stands for "plasminogen activator, urokinase". The same symbol represents the gene in other animal species. # Function The PLAU gene encodes a serine protease (EC 3.4.21.73) involved in degradation of the extracellular matrix and possibly tumor cell migration and proliferation. A specific polymorphism in this gene may be associated with late-onset Alzheimer disease and also with decreased affinity for fibrin-binding. The protein encoded by this gene converts plasminogen to plasmin by specific cleavage of an Arg-Val bond in plasminogen. This gene's proprotein is cleaved at a Lys-Ile bond by plasmin to form a two-chain derivative in which a single disulfide bond connects the amino-terminal A-chain to the catalytically active, carboxy-terminal B-chain. This two-chain derivative is also called HMW-uPA (high molecular weight uPA). HMW-uPA can be further processed into LMW-uPA (low molecular weight uPA) by cleavage of chain A into a short chain A (A1) and an amino-terminal fragment. LMW-uPA is proteolytically active but does not bind to the uPA receptor. # Structure Urokinase is a 411-residue protein, consisting of three domains: the serine protease domain, the kringle domain, and the growth factor domain. Urokinase is synthesized as a zymogen form (prourokinase or single-chain urokinase), and is activated by proteolytic cleavage between Lys158 and Ile159. The two resulting chains are kept together by a disulfide bond. # Interaction partners The most important inhibitors of urokinase are the serpins plasminogen activator inhibitor-1 (PAI-1) and plasminogen activator inhibitor-2 (PAI-2), which inhibit the protease activity irreversibly. In the extracellular matrix, urokinase is tethered to the cell membrane by its interaction to the urokinase receptor. uPa also interacts with protein C inhibitor. # Urokinase and cancer Elevated expression levels of urokinase and several other components of the plasminogen activation system are found to be correlated with tumor malignancy. It is believed that the tissue degradation following plasminogen activation facilitates tissue invasion and, thus, contributes to metastasis. This makes urokinase an attractive drug target, and, so, inhibitors have been sought to be used as anticancer agents. However, incompatibilities between the human and murine systems hamper clinical evaluation of these agents. Through its interaction with the urokinase receptor, urokinase affects several other aspects of cancer biology such as cell adhesion, migration, and cellular mitotic pathways. As of December 7, 2012, Mesupron, a small molecule serine protease inhibitor developed by the WILEX pharmaceutical company, has completed phase II trials. Mesupron appears to be safe when combined with chemotherapeutic drug Capecitabine for the progression-free survival in human breast cancer. # Clinical applications Urokinase is effective for the restoration of flow to intravenous catheters blocked by clotted blood or fibrin (catheter clearance). Catheters are used extensively to administer treatments to patients for such purposes as dialysis, nutrition, antibiotic treatment and cancer treatment. Approximately 25% of catheters become blocked, meaning that affected patients cannot receive treatment until the catheter has been cleared or replaced. Urokinase is also used clinically as a thrombolytic agent in the treatment of severe or massive deep venous thrombosis, peripheral arterial occlusive disease, pulmonary embolism, acute myocardial infarction (AMI, heart attack), and occluded dialysis cannulas (catheter clearance). It is also administered intrapleurally to improve the drainage of complicated pleural effusions and empyemas. Urokinase is marketed as Kinlytic (formerly Abbokinase) and competes with recombinant tissue plasminogen activator (e.g., alteplase) as a thrombolytic drug. All plasminogen activators (urokinase, TPA) catalyze the production of plasmin, which in turn leads to the breakdown of the fibrin lattice structure in blood clots. While there are commonalities in the mode of action for urokinase and TPA, urokinase has some advantages for treatment of peripheral clots (Pulmonary Embolism, Deep Vein Thrombosis, Peripheral arterial occlusive disease). Unlike TPA, which is activated by binding to the fibrin within clots, urokinase is not sequestered by fibrin and therefore does not specifically attack hemostatic clots. This makes urokinase less likely to break down such hemostatic clots that are essential for ongoing blood vessel repair throughout the body. Dissolution of these “good” clots can lead to serious adverse events through hemorrhagic bleeding. Years of clinical study have confirmed the safety advantage of using urokinase. Consequently, urokinase has been preferentially used in deep venous thrombosis and peripheral arterial occlusive disease where it is administered directly to the site of the clot while TPA is preferred in AMI where peripheral bleeding is a secondary consideration.	Urokinase Urokinase, also known as urokinase-type plasminogen activator (uPA), is a serine protease present in humans and other animals. The human urokinase protein was discovered, but not named, by McFarlane and Pilling in 1947.[1] Urokinase was originally isolated from human urine, and it is also present in the blood and in the extracellular matrix of many tissues. The primary physiological substrate of this enzyme is plasminogen, which is an inactive form (zymogen) of the serine protease plasmin. Activation of plasmin triggers a proteolytic cascade that, depending on the physiological environment, participates in thrombolysis or extracellular matrix degradation. This cascade had been involved in vascular diseases and cancer progression.[2] Urokinase is encoded in humans by the PLAU gene, which stands for "plasminogen activator, urokinase".[3] The same symbol represents the gene in other animal species. # Function The PLAU gene encodes a serine protease (EC 3.4.21.73) involved in degradation of the extracellular matrix and possibly tumor cell migration and proliferation. A specific polymorphism in this gene may be associated with late-onset Alzheimer disease and also with decreased affinity for fibrin-binding. The protein encoded by this gene converts plasminogen to plasmin by specific cleavage of an Arg-Val bond in plasminogen. This gene's proprotein is cleaved at a Lys-Ile bond by plasmin to form a two-chain derivative in which a single disulfide bond connects the amino-terminal A-chain to the catalytically active, carboxy-terminal B-chain. This two-chain derivative is also called HMW-uPA (high molecular weight uPA). HMW-uPA can be further processed into LMW-uPA (low molecular weight uPA) by cleavage of chain A into a short chain A (A1) and an amino-terminal fragment. LMW-uPA is proteolytically active but does not bind to the uPA receptor.[4] # Structure Urokinase is a 411-residue protein, consisting of three domains: the serine protease domain, the kringle domain, and the growth factor domain. Urokinase is synthesized as a zymogen form (prourokinase or single-chain urokinase), and is activated by proteolytic cleavage between Lys158 and Ile159. The two resulting chains are kept together by a disulfide bond. # Interaction partners The most important inhibitors of urokinase are the serpins plasminogen activator inhibitor-1 (PAI-1) and plasminogen activator inhibitor-2 (PAI-2), which inhibit the protease activity irreversibly. In the extracellular matrix, urokinase is tethered to the cell membrane by its interaction to the urokinase receptor. uPa also interacts with protein C inhibitor.[5][6] # Urokinase and cancer Elevated expression levels of urokinase and several other components of the plasminogen activation system are found to be correlated with tumor malignancy. It is believed that the tissue degradation following plasminogen activation facilitates tissue invasion and, thus, contributes to metastasis. This makes urokinase an attractive drug target, and, so, inhibitors have been sought to be used as anticancer agents.[7][8] However, incompatibilities between the human and murine systems hamper clinical evaluation of these agents. Through its interaction with the urokinase receptor, urokinase affects several other aspects of cancer biology such as cell adhesion, migration, and cellular mitotic pathways. As of December 7, 2012, Mesupron, a small molecule serine protease inhibitor developed by the WILEX pharmaceutical company, has completed phase II trials.[9] Mesupron appears to be safe when combined with chemotherapeutic drug Capecitabine for the progression-free survival in human breast cancer.[10] # Clinical applications Urokinase is effective for the restoration of flow to intravenous catheters blocked by clotted blood or fibrin (catheter clearance). Catheters are used extensively to administer treatments to patients for such purposes as dialysis, nutrition, antibiotic treatment and cancer treatment. Approximately 25% of catheters become blocked, meaning that affected patients cannot receive treatment until the catheter has been cleared or replaced. Urokinase is also used clinically as a thrombolytic agent in the treatment of severe or massive deep venous thrombosis, peripheral arterial occlusive disease, pulmonary embolism, acute myocardial infarction (AMI, heart attack), and occluded dialysis cannulas (catheter clearance). It is also administered intrapleurally to improve the drainage of complicated pleural effusions and empyemas. Urokinase is marketed as Kinlytic (formerly Abbokinase) and competes with recombinant tissue plasminogen activator (e.g., alteplase) as a thrombolytic drug. All plasminogen activators (urokinase, TPA) catalyze the production of plasmin, which in turn leads to the breakdown of the fibrin lattice structure in blood clots. While there are commonalities in the mode of action for urokinase and TPA, urokinase has some advantages for treatment of peripheral clots (Pulmonary Embolism, Deep Vein Thrombosis, Peripheral arterial occlusive disease). Unlike TPA, which is activated by binding to the fibrin within clots, urokinase is not sequestered by fibrin and therefore does not specifically attack hemostatic clots. This makes urokinase less likely to break down such hemostatic clots that are essential for ongoing blood vessel repair throughout the body. Dissolution of these “good” clots can lead to serious adverse events through hemorrhagic bleeding. Years of clinical study have confirmed the safety advantage of using urokinase.[11] [12] Consequently, urokinase has been preferentially used in deep venous thrombosis and peripheral arterial occlusive disease where it is administered directly to the site of the clot while TPA is preferred in AMI where peripheral bleeding is a secondary consideration.	https://www.wikidoc.org/index.php/Abbokinase
952be3bc31a52e51cf8004235409f0d8799418c1	wikidoc	Terazosin	Terazosin # 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 Terazosin is a alpha-adrenergic blocker that is FDA approved for the {{{indicationType}}} of symptomatic benign prostatic hyperplasia (BPH) and hypertension. Common adverse reactions include orthostatic hypotension, palpitations, peripheral edema, nausea, asthenia, dizziness headache, somnolence and nasal congestion. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Initial dose : - 1 mg at bedtime is the starting dose for all patients (should not be exceeded as an initial dose). - Patients should be closely followed during initial administration in order to minimize the risk of severe hypotensive response. - Subsequent doses : - The initial dose should be increased in a stepwise fashion to 2 mg, 5 mg, or 10 mg once daily to achieve the desired improvement of symptoms and/or flow rates. - Doses of 10 mg once daily are generally required for the clinical response. - Treatment with 10 mg for a minimum of 4 to 6 weeks may be required to assess whether a beneficial response has been achieved. Some patients may not achieve a clinical response despite appropriate titration. :* :- Some patients responded at a 20 mg daily dose, however, there was an insufficient number of patients studied to draw definitive conclusions about this dose. - If terazosin administration is discontinued for several days or longer, therapy should be reinstituted using the initial dosing regimen. - Initial dose: - 1 mg at bedtime is the starting dose for all patients (this dose should not be exceeded). This initial dosing regimen should be strictly observed to minimize the potential for severe hypotensive effects. - Subsequent doses: - The dose may be slowly increased to achieve the desired blood pressure response. - The usual recommended dose range is 1 mg to 5 mg administered once a day. - Some patients may benefit from doses as high as 20 mg per day. - Doses over 20 mg do not appear to provide further blood pressure effect and doses over 40 mg have not been studied. - Blood pressure should be monitored at the end of the dosing interval to be sure control is maintained throughout the interval. - If response is substantially diminished at 24 hours an increased dose or use of a twice daily regimen can be considered. - If terazosin administration is discontinued for several days or longer, therapy should be reinstituted using the initial dosing regimen. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of terazosin in adult patients. ### Non–Guideline-Supported Use - Shows effect in patients with chronic prostatitis-chronic pelvic pain syndrome with no history of therapy with alpha-blockers. - Initial dosage: - 1 mg for 4 days - Following dosages: - 2 mg for 10 days, followed by 5 mg daily afterwards. - Terazosin has shown to be effective in reducing cholesterol and triglyceride levels in patients. However, there is conflicting data in these studies. - 2 - 10 mg/day, in one study. - 5, 10 or 20 mg/day, on a second study. - 10 mg/day - this study showed no effect of terazosin in lowering blodd lipids. - Terazosin has shown evidence, in one study, in the treatment of nocturia in male patients suffering from lower urinary tract symptoms. - Initial dosage: - 2 mg/day for 7 days - Following dosages: - 4 mg/day for the next 3 weeks - It has been proven to improve sperm count and, even though not proven by statistically, pregnancy rates may improve. - 2 mg/day - Terazosin appears to help prostate cancer patients with symptoms of radiation-induced urethritis. - 2 - 6 mg/day - Terazosin therapy appears to be effective in patients with spinal cord injury: - For management of autonomic dysreflexia. - For improvement of detrusor compliance, decreased bladder pressures and safe bladder volumes. - For reducing reducing obstruction of bladder outlet. - 10 mg/day - 5 mg/day # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-label Guideline-Supported Use of terazosin in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of terazosin in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non-Guideline-Supported Use of terazosin in pediatric patients. # Contraindications - Terazosin capsules are contraindicated in patients known to be hypersensitive to terazosin hydrochloride. # Warnings - Terazosin capsules, like other alpha-adrenergic blocking agents, can cause marked lowering of blood pressure, especially postural hypotension, and syncope in association with the first dose or first few days of therapy. A similar effect can be anticipated if therapy is interrupted for several days and then restarted. - Syncope has also been reported with other alpha-adrenergic blocking agents in association with rapid dosage increases or the introduction of another antihypertensive drug. - Syncope is believed to be due to an excessive postural hypotensive effect, although occasionally the syncopal episode has been preceded by a bout of severe supraventricular tachycardia with heart rates of 120 to 160 beats per minute. Additionally, the possibility of the contribution of hemodilution to the symptoms of postural hypotension should be considered. - To decrease the likelihood of syncope or excessive hypotension, treatment should: - Always be initiated with a 1 mg dose of terazosin capsules, given at bedtime. - The 2 mg, 5 mg and 10 mg capsules are not indicated as initial therapy. - Dosage should then be increased slowly, according to recommendations in the Dosage and Administration section and additional antihypertensive agents should be added with caution. - The patient should be cautioned to avoid situations, such as driving or hazardous tasks, where injury could result should syncope occur during initiation of therapy. In early investigational studies, where increasing single doses up to 7.5 mg were given at 3 day intervals, tolerance to the first dose phenomenon did not necessarily develop and the “first-dose” effect could be observed at all doses. Syncopal episodes occurred in 3 of the 14 subjects given terazosin at doses of 2.5, 5 and 7.5 mg, which are higher than the recommended initial dose; in addition, severe orthostatic hypotension (blood pressure falling to 50/0 mmHg) was seen in two others and dizziness, tachycardia, and lightheadedness occurred in most subjects. These adverse effects all occurred within 90 minutes of dosing. In three placebo-controlled BPH studies 1, 2, and 3, the incidence of postural hypotension in the terazosin treated patients was 5.1%, 5.2%, and 3.7% respectively. In multiple dose clinical trials involving nearly 2000 hypertensive patients treated with terazosin capsules, syncope was reported in about 1% of patients. Syncope was not necessarily associated only with the first dose. If syncope occurs, the patient should be placed in a recumbent position and treated supportively as necessary. There is evidence that the orthostatic effect of terazosin is greater, even in chronic use, shortly after dosing. The risk of the events is greatest during the initial seven days of treatment, but continues at all time intervals. - Rarely, terazosin and other α1-antagonists have been associated with priapism (painful penile erection, sustained for hours and unrelieved by sexual intercourse or masturbation). Two or three dozen cases have been reported. - Since this condition can lead to permanent impotence if not promptly treated, patients must be advised about the seriousness of the condition. # Adverse Reactions ## Clinical Trials Experience - The incidence of treatment-emergent adverse events has been ascertained clinical trials conducted worldwide. - All adverse events reported during these trials were recorded as adverse reactions. - The incidence rates presented below are based on combined data from six placebo-controlled trials involving once-a-day administration of terazosin at doses ranging from 1 to 20 mg. Table 1 summarizes those adverse events reported for patients in these trials when the incidence rate in the terazosin group was at least 1%, and was greater than that for the placebo group, or where the reaction is of clinical interest. Asthenia, postural hypotension, dizziness, somnolence, nasal congestion/rhinitis, and impotence were the only events that were significantly (p ≤ 0.05) more common in patients receiving terazosin than in patients receiving placebo. - The incidence of urinary tract infection was significantly lower in the patients receiving terazosin than in patients receiving placebo. An analysis of the incidence rate of hypotensive adverse events adjusted for the length of drug treatment has shown that the risk of the events is greatest during the initial seven days of treatment, but continues at all time intervals. - Additional adverse events have been reported, but these are, in general, not distinguishable from symptoms that might have occurred in the absence of exposure to terazosin. The safety profile of patients treated in the long-term open-label study was similar to that observed in the controlled studies. - The adverse events were usually transient and mild or moderate in intensity, but sometimes were serious enough to interrupt treatment. In the placebo-controlled clinical trials, the rates of premature termination due to adverse events were not statistically different between the placebo and terazosin groups. The adverse events that were bothersome, as judged by their being reported as reasons for discontinuation of therapy by at least 0.5% of the terazosin group and being reported more often than in the placebo group, are shown in Table 2. - The prevalence of adverse reactions has been ascertained from clinical trials conducted primarily in the United States. All adverse experiences (events) reported during these trials were recorded as adverse reactions. The prevalence rates presented below are based on combined data from fourteen placebo-controlled trials involving once-a-day administration of terazosin, as monotherapy or in combination with other antihypertensive agents, at doses ranging from 1 to 40 mg. Table 3 summarizes those adverse experiences reported for patients in these trials where the prevalence rate in the terazosin group was at least 5%, where the prevalence rate for the terazosin group was at least 2% and was greater than the prevalence rate for the placebo group, or where the reaction is of particular interest. - Asthenia, blurred vision, dizziness, nasal congestion, nausea, peripheral edema, palpitations and somnolence were the only symptoms that were significantly (p < 0.05) more common in patients receiving terazosin than in patients receiving placebo. - Similar adverse reaction rates were observed in placebo-controlled monotherapy trials. - Additional adverse reactions have been reported, but these are, in general, not distinguishable from symptoms that might have occurred in the absence of exposure to terazosin. The following additional adverse reactions were reported by at least 1% of 1987 patients who received terazosin in controlled or open, short- or long-term clinical trials or have been reported during marketing experience: - Anxiety - Insomnia - Arrhythmia - Vasodilation - Bronchitis - Cold symptoms - Epistaxis - Flu symptoms - Increased cough - Pharyngitis - Rhinitis - Constipation - Diarrhea - Dry mouth - Dyspepsia - Flatulence - Vomiting - Chest pain - Facial edema - Fever - Abdominal pain - Neck pain - Shoulder pain - Gout - Arthralgia - Arthritis - Joint disorder - Myalgia - Pruritus - Rash - Sweating - Abnormal vision - Conjunctivitis - Tinnitus. - Urinary frequency - Urinary incontinence primarily reported in postmenopausal women, urinary tract infection - The adverse reactions were usually mild or moderate in intensity but sometimes were serious enough to interrupt treatment. - The adverse reactions that were most bothersome, as judged by their being reported as reasons for discontinuation of therapy by at least 0.5% of the terazosin group and being reported more often than in the placebo group, are shown in Table 4. ## Postmarketing Experience - Post-marketing experience indicates that in rare instances patients may develop allergic reactions, including anaphylaxis, following administration of terazosin hydrochloride. - There have been reports of priapism and thrombocytopenia during post-marketing surveillance. - Atrial fibrillation has also been reported. - During cataract surgery, a variant of small pupil syndrome known as Intraoperative floppy iris syndrome (IFIS) has been reported in association with alpha-1 blocker therapy. # Drug Interactions - In controlled trials, terazosin have been added to diuretics, and several beta-adrenergic blockers; no unexpected interactions were observed. - Terazosin has also been used in patients on a variety of concomitant therapies; while these were not formal interaction studies, no interactions were observed. Terazosin has been used concomitantly in at least 50 patients on the following drugs or drug classes: - Analgesic/anti-inflammatory: - Acetaminophen - Aspirin - Codeine - Ibuprofen - Indomethacin - Antibiotics: - Erythromycin - Trimethoprim - Sulfamethoxazole - Anticholinergic/sympathomimetics - Phenylephrine hydrochloride - Phenylpropanolamine hydrochloride - Pseudoephedrine hydrochloride - Antigout - Allopurinol - Antihistamines - Chlorpheniramine - Cardiovascular agents: - Atenolol - Hydrochlorothiazide - Methyclothiazide - Propranolol - Corticosteroids - Gastrointestinal agents - Antacids - Hypoglycemics - Sedatives and tranquilizers - Diazepam - In a study (n=24) where terazosin and verapamil were administered concomitantly, terazosin’s mean AUC0-24 increased 11% after the first verapamil dose and after 3 weeks of verapamil treatment it increased by 24% with associated increases in Cmax (25%) and Cmin (32%) means. Terazosin mean Tmax decreased from 1.3 hours to 0.8 hours after 3 weeks of verapamil treatment. Statistically significant differences were not found in the verapamil level with and without terazosin. - In a study (n=6) where terazosin and captopril were administered concomitantly, plasma disposition of captopril was not influenced by concomitant administration of terazosin and terazosin maximum plasma concentrations increased linearly with dose at steady-state after administration of terazosin plus captopril. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Teratogenic Effects : - Terazosin capsules were not teratogenic in either rats or rabbits when administered at oral doses up to 280 and 60 times, respectively, the maximum recommended human dose. - Fetal resorptions occurred in rats dosed with 480 mg/kg/day, approximately 280 times the maximum recommended human dose. - Increased fetal resorptions, decreased fetal weight and an increased number of supernumerary ribs were observed in offspring of rabbits dosed with 60 times the maximum recommended human dose. - These findings (in both species) were most likely secondary to maternal toxicity. There are no adequate and well-controlled studies in pregnant women and the safety of terazosin in pregnancy has not been established. Terazosin capsules are not recommended during pregnancy unless the potential benefit justifies the potential risk to the mother and fetus. - Nonteratogenic Effects : - In a peri- and post-natal development study in rats, significantly more pups died in the group dosed with 120 mg/kg/day (> 75 times the maximum recommended human dose) than in the control group during the three-week postpartum period. Pregnancy Category (AUS): B2 - There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of terazosin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Terazosin during labor and delivery. ### Nursing Mothers - It is not known whether terazosin is excreted in breast milk. - Because many drugs are excreted in breast milk, caution should be exercised when terazosin capsules are administered to a nursing woman. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been determined. ### Geriatic Use There is no FDA guidance on the use of Terazosin in geriatric settings. ### Gender There is no FDA guidance on the use of Terazosin with respect to specific gender populations. ### Race There is no FDA guidance on the use of Terazosin with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Terazosin in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Terazosin in patients with hepatic impairment. ### Females of Reproductive Potential and Males - Terazosin was devoid of mutagenic potential when evaluated in vivo and in vitro (the Ames test, in vivo cytogenetics, the dominant lethal test in mice, in vivo Chinese hamster chromosome aberration test and V79 forward mutation assay). - Terazosin administered in the feed to rats at doses of 8, 40, and 250 mg/kg/day (70, 350, and 2100 mg/M2/day), for two years, was associated with a statistically significant increase in benign adrenal medullary tumors of male rats exposed to the 250 mg/kg dose. This dose is 175 times the maximum recommended human dose of 20 mg (12 mg/M2). Female rats were unaffected. - Terazosin was not oncogenic in mice when administered in feed for 2 years at a maximum tolerated dose of 32 mg/kg/day (110 mg/M2; 9 times the maximum recommended human dose). - The absence of mutagenicity in a battery of tests, of tumorigenicity of any cell type in the mouse carcinogenicity assay, of increased total tumor incidence in either species, and of proliferative adrenal lesions in female rats, suggests a male rat species-specific event. Numerous other diverse pharmaceutical and chemical compounds have also been associated with benign adrenal medullary tumors in male rats without supporting evidence for carcinogenicity in man. - The effect of terazosin on fertility was assessed in a standard fertility/reproductive performance study in which male and female rats were administered oral doses of 8, 30 and 120 mg/kg/day. Four of 20 male rats given 30 mg/kg (240 mg/M2; 20 times the maximum recommended human dose) and five of 19 male rats given 120 mg/kg (960 mg/M2; 80 times the maximum recommended human dose) failed to sire a litter. Testicular weights and morphology were unaffected by treatment. Vaginal smears at 30 and 120 mg/kg/day, however, appeared to contain less sperm than smears from control matings and good correlation was reported between sperm count and subsequent pregnancy. - Oral administration of terazosin for one or two years elicited a statistically significant increase in the incidence of testicular atrophy in rats exposed to 40 and 250 mg/kg/day (29 and 175 times the maximum recommended human dose), but not in rats exposed to 8 mg/kg/day (> 6 times the maximum recommended human dose). Testicular atrophy was also observed in dogs dosed with 300 mg/kg/day (> 500 times the maximum recommended human dose) for three months but not after one year when dosed with 20 mg/kg/day (38 times the maximum recommended human dose). This lesion has also been seen with Minipress®, another (marketed) selective-alpha-1 blocking agent. ### Immunocompromised Patients There is no FDA guidance one the use of Terazosin in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring - Terazosin capsules, like other alpha-adrenergic blocking agents, can cause marked lowering of blood pressure, especially postural hypotension, and syncope in association with the first dose or first few days of therapy. Blood pressure should be monitored, particularly when increasing the dosage of terazosin, in order to avoid syncope. - A patient taking terazosin should see an effect on his symptoms in 2 to 4 weeks. Therefore, continuous check-ups with the physician, to evaluate the progress regarding the BPH and monitor the blood pressure should be done, in addition to other regular check-ups. # IV Compatibility There is limited information regarding the compatibility of Terazosin and IV administrations. # Overdosage ## Acute Overdose - In case of overdosage of terazosin capsules leading to: - Hypotension ### Management - Support of the cardiovascular system is of first importance. - Restoration of blood pressure and normalization of heart rate may be accomplished by keeping the patient in the supine position. - If this measure is inadequate, shock should first be treated with volume expanders. - If necessary, vasopressors should then be used and renal function should be monitored and supported as needed. - Laboratory data indicate that terazosin is 90-94% protein bound; therefore, dialysis may not be of benefit. # Pharmacology ## Mechanism of Action - In animals, terazosin causes a decrease in blood pressure by decreasing total peripheral vascular resistance. The vasodilatory hypotensive action of terazosin appears to be produced mainly by blockade of alpha-1 adrenoceptors. ## Structure - Terazosin hydrochloride, an alpha-1-selective adrenoceptor blocking agent, is a quinazoline derivative represented by the following chemical name,molecular formula and structural formula: - (RS)-Piperazine, 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4--, monohydrochloride.C19H26ClN5O4 - Terazosin hydrochloride is a white, crystalline substance, freely soluble in water and isotonic saline and has molecular weight of 423.93. Each capsule, for oral administration, contains 1 mg, 2 mg, 5 mg or 10 mg of terazosin as terazosin hydrochlolde. In addition, each capsule contains the following inactive ingredients: - Colloidal silicon dioxide - Lactose monohydrate - Magnesium stearate - Pregelatinized starch. - The gelatin capsule contains: - Gelatin - Silicon dioxide - Sodium lauryl sulfate - Titanium dioxide. - The 1 mg shell also contains black iron oxide; the 2 mg capsule shell also contains D&C Yellow #10; the 5 mg capsule shell also contains D&C Yellow #10, FD&C Red #40 and D&C Red #28; the 10 mg capsule shell also contains FD&C Green #3 and D&C Yellow#10. ## Pharmacodynamics - The symptoms associated with BPH are related to bladder outlet obstruction, which is comprised of two underlying components: - A static component - A dynamic component. - The static component is a consequence of an increase in prostate size. Over time, the prostate will continue to enlarge. However, clinical studies have demonstrated that the size of the prostate does not correlate with the severity BPH symptoms or the degree of urinary obstruction. - The dynamic component is a function of an increase in smooth muscle tone in the prostate and bladder neck, leading to constriction of the bladder outlet. Smooth muscle tone is mediated by sympathetic nervous stimulation of alpha-1 adrenoceptors, which are abundant in the prostate, prostatic capsule and bladder neck. - The reduction in symptoms and improvement in urine flow rates following administration of terazosin is related to relaxation of smooth muscle produced by blockade of alpha-1 adrenoceptors in the bladder neck and prostate. Because there are relatively few alpha-1 adrenoceptors in the bladder body, terazosin is able to reduce the bladder outlet obstruction without affecting bladder contractility. - Terazosin has been studied in 1222 men with symptomatic BPH. In three placebo-controlled studies, symptom evaluation and uroflowmetric measurements were performed approximately 24 hours following dosing. Symptoms were quantified using the Boyarsky Index. The questionnaire evaluated both obstructive (hesitancy, intermittency, terminal dribbling, impairment of size and force of stream, sensation of incomplete bladder emptying) and irritative (nocturia, daytime frequency, urgency, dysuria) symptoms by rating each of the 9 symptoms from 0 to 3, for a total score of 27 points. Results from these studies indicated that terazosin statistically significantly improved symptoms and peak urine flow rates over placebo as follows: - In all three studies, both symptom scores and peak urine flow rates showed statistically significant improvement from baseline in patients treated with terazosin capsules from week 2 (or the first clinic visit) and throughout the study duration. - Analysis of the effect of terazosin capsules on individual urinary symptoms demonstrated that compared to placebo, terazosin significantly improved the symptoms of hesitancy, intermittency, impairment in size and force of urinary stream, sensation of incomplete emptying, terminal dribbling, daytime frequency and nocturia. - Global assessments of overall urinary function and symptoms were also performed by investigators who were blinded to patient treatment assignment. - In studies 1 and 3, patients treated with terazosin patients had a significantly (p ≤ 0.001) greater overall improvement compared to placebo treated patients. - In a short term study (Study 1), patients were randomized to either 2, 5 or 10 mg of terazosin or placebo. Patients randomized to the 10 mg group achieved a statistically significant response in both symptoms and peak flow rate compared to placebo (Figure 1). - In a long-term, open-label, non-placebo controlled clinical trial, 181 men were followed for 2 years and 58 of these men were followed for 30 months. The effect of terazosin on urinary symptom scores and peak flow rates was maintained throughout the study duration (Figures 2 and 3): - In this long-term trial, both symptom scores and peak urinary flow rates showed statistically significant improvement suggesting a relaxation of smooth muscle cells. Although blockade of alpha-1 adrenoceptors also lowers blood pressure in hypertensive patients with increased peripheral vascular resistance, terazosin treatment of normotensive men with BPH did not result in a clinically significant blood pressure lowering effect: - In animals, terazosin causes a decrease in blood pressure by decreasing total peripheral vascular resistance. The vasodilatory hypotensive action of terazosin appears to be produced mainly by blockade of alpha-1 adrenoceptors. - Terazosin decreases blood pressure gradually within 15 minutes following oral administration. - Patients in clinical trials of terazosin were administered once daily (the great majority) and twice daily regimens with total doses usually in the range of 5 to 20 mg/day, and had mild (about 77%, diastolic pressure 95 to 105 mmHg) or moderate (23%, diastolic pressure 105 to 115 mmHg) hypertension. Because terazosin, like all alpha antagonists, can cause unusually large falls in blood pressure after the first dose or first few doses, the initial dose was 1 mg in virtually all trials, with subsequent titration to a specified fixed dose or titration to some specified blood pressure end point (usually a supine diastolic pressure of 90 mmHg). - Blood pressure responses were measured at the end of the dosing interval (usually 24 hours) and effects were shown to persist throughout the interval, with the usual supine responses 5 to 10 mmHg systolic and 3.5 to 8 mmHg diastolic greater than placebo. The responses in the standing position tended to be somewhat larger, by 1 to 3 mmHg, although this was not true in all studies. The magnitude of the blood pressure responses was similar to prazosin and less than hydrochlorothiazide (in a single study of hypertensive patients). In measurements 24 hours after dosing, heart rate was unchanged. - Limited measurements of peak response (2 to 3 hours after dosing) during chronic terazosin administration indicate that it is greater than about twice the trough (24 hour) response, suggesting some attenuation of response at 24 hours, presumably due to a fall in blood terazosin concentrations at the end of the dose interval. This explanation is not established with certainty, however, and is not consistent with the similarity of blood pressure response to once daily and twice daily dosing and with the absence of an observed dose-response relationship over a range of 5 to 20 mg, i.e., if blood concentrations had fallen to the point of providing less than full effect at 24 hours, a shorter dosing interval or larger dose should have led to increased response. - Further dose response and dose duration studies are being carried out. Blood pressure should be measured at the end of the dose interval; if response is not satisfactory, patients may be tried on a larger dose or twice daily dosing regimen. The latter should also be considered if possibly blood pressure-related side effects, such as dizziness, palpitations, or orthostatic complaints, are seen within a few hours after dosing. - The greater blood pressure effect associated with peak plasma concentrations (first few hours after dosing) appears somewhat more position-dependent (greater in the erect position) than the effect of terazosin at 24 hours and in the erect position there is also a 6 to 10 beat per minute increase in heart rate in the first few hours after dosing. During the first 3 hours after dosing 12.5% of patients had a systolic pressure fall of 30 mmHg or more from supine to standing, or standing systolic pressure below 90 mmHg with a fall of at least 20 mmHg, compared to 4% of a placebo group. - There was a tendency for patients to gain weight during terazosin therapy. In placebo-controlled monotherapy trials, male and female patients receiving terazosin gained a mean of 1.7 and 2.2 pounds respectively, compared to losses of 0.2 and 1.2 pounds respectively in the placebo group. Both differences were statistically significant. During controlled clinical trials, patients receiving terazosin monotherapy had a small but statistically significant decrease (a 3% fall) compared to placebo in total cholesterol and the combined low-density and very-low-density lipoprotein fractions. No significant changes were observed in high-density lipoprotein fraction and triglycerides compared to placebo. - Analysis of clinical laboratory data following administration of terazosin suggested the possibility of hemodilution based on decreases in hematocrit, hemoglobin, white blood cells, total protein and albumin. Decreases in hematocrit and total protein have been observed with alpha-blockade and are attributed to hemodilution. ## Pharmacokinetics - Terazosin hydrochloride administered as capsules is essentially completely absorbed in man. - Administration of capsules immediately after meals had a minimal effect on the extent of absorption. The time to reach peak plasma concentration however, was delayed by about 40 minutes. - Terazosin has been shown to undergo minimal hepatic first-pass metabolism and nearly all of the circulating dose is in the form of parent drug. - The plasma levels peak about one hour after dosing, and then decline with a half-life of approximately 12 hours. - In a study that evaluated the effect of age on terazosin pharmacokinetics, the mean plasma half-lives were 14.0 and 11.4 hours for the age group ≥ 70 years and the age group of 20 to 39 years, respectively. After oral administration the plasma clearance was decreased by 31.7% in patients 70 years of age or older compared to that in patients 20 to 39 years of age. The drug is 90 to 94% bound to plasma proteins and binding is constant over the clinically observed concentration range. Approximately 10% of an orally administered dose is excreted as parent drug in the urine and approximately 20% is excreted in the feces. The remainder is eliminated as metabolites. Impaired renal function had no significant effect on the elimination of terazosin, and dosage adjustment of terazosin to compensate for the drug removal during hemodialysis (approximately 10%) does not appear to be necessary. Overall, approximately 40% of the administered dose is excreted in the urine and approximately 60% in the feces. The disposition of the compound in animals is qualitatively similar to that in man. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of terazosin in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of terazosin in the drug label. # How Supplied - Terazosin Capsules are available in four dosage strengths: - 1 mg Terazosin Capsules, USP are available as gray opaque cap/body printed “TL 383” in black ink. - Bottles of 90: NDC 59746-383-90 - Bottles of 100: NDC 59746-383-06 - Bottles of 500: NDC 59746-383-09 - Bottles of 1000: NDC 59746-383-10 - 2 mg Terazosin Capsules, USP are available as ivory opaque cap/body printed “TL 384” in black ink. - Bottles of 90: NDC 59746-384-90 - Bottles of 100: NDC 59746-384-06 - Bottles of 500: NDC 59746-384-09 - Bottles of 1000: NDC 59746-384-10 - 5 mg Terazosin Capsules, USP are available as bright orange opaque cap/body printed “TL 385” in black ink. - Bottles of 90: NDC 59746-385-90 - Bottles of 100: NDC 59746-385-06 - Bottles of 500: NDC 59746-385-09 - Bottles of 1000: NDC 59746-385-10 - 10 mg Terazosin Capsules, USP are available as light green opaque cap/body printed “TL 386” in black ink. - Bottles of 90: NDC 59746-386-90 - Bottles of 100: NDC 59746-386-06 - Bottles of 500: NDC 59746-386-09 - Bottles of 1000: NDC 59746-386-10 - Dispense in a tight, light-resistant container as defined in the USP. ## Storage - Recommended storage: - Store at 20° - 25°C (68° - 77°F) . - Protect from light and moisture. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information TERAZOSIN CAPSULES, USP - Generic Name: Terazosin (Ter-A-so-sin) - When used to treat hypertension or benign prostatic hyperplasia - Please read this leaflet before you start taking terazosin capsules. Also, read it each time you get a new prescription. This is a summary and should not take the place of a full discussion with your doctor who has additional information about Terazosin Capsules. You and your doctor should discuss Terazosin Capsules and your condition before you start taking it and at your regular checkups. - Terazosin Capsules are used to treat high blood pressure (hypertension). Terazosin Capsules are also used to treat benign prostatic hyperplasia (BPH) in men. This leaflet describes Terazosin Capsules as a treatment for hypertension or BPH. - What is hypertension (high blood pressure)? - Blood pressure is the tension of the blood within the blood vessels. If blood is pumped too forcefully, or if the blood vessels are too narrow, the pressure of the blood against the walls of the vessels rises. If high blood pressure is not treated, over time, the increased pressure can damage blood vessels or it can cause the heart to work too hard and may decrease the flow of blood to the heart, brain, and kidneys. As a result, these organs may become damaged and not function correctly. If high blood pressure is controlled, this damage is less likely to happen. - Treatment options for hypertension: - Non-drug treatments are sometimes effective in controlling mild hypertension. The most important lifestyle changes to lower blood pressure are to lose weight, reduce salt, fat, and alcohol in the diet, quit smoking, and exercise regularly. However, many hypertensive patients require one or more ongoing medications to control their blood pressure. There are different kinds of medications used to treat hypertension. Your doctor has prescribed Terazosin Capsules for you. - What Terazosin Capsules do to treat hypertension: - Terazosin capsules work by relaxing blood vessels so that blood passes through them more easily. This helps to lower blood pressure. - What is BPH? - The prostate is a gland located below the bladder of men. It surrounds the urethra (you-REETH-rah), which is a tube that drains urine from the bladder. BPH is an enlargement of the prostate gland. The symptoms of BPH, however, can be caused by an increase in the tightness of muscles in the prostate. If the muscles inside the prostate tighten, they can squeeze the urethra and slow the flow of urine. This can lead to symptoms such as: - A weak or interrupted stream when urinating - A feeling that you cannot empty your bladder completely - A feeling of delay when you start to urinate - A need to urinate often, especially at night, or - A feeling that you must urinate right away. - Treatment options for BPH. There are three main treatment options for BPH: - Program of monitoring or “Watchful Waiting” - Some men have an enlarged prostate gland, but no symptoms, or symptoms that are not bothersome. If this applies, you and your doctor may decide on a program of monitoring including regular checkups, instead of medication or surgery. - Medication - There are different kinds of medication used to treat BPH. Your doctor has prescribed Terazosin Capsules for you. See “What Terazosin Capsules do to treat BPH” below. - Surgery - Some patients may need surgery. Your doctor can describe several different surgical procedures to treat BPH. Which procedure is best depends on your symptoms and medical condition. - What Terazosin Capsules do to treat BPH - Terazosin Capsules relax the tightness of a certain type of muscle in the prostate and at the opening of the bladder. This may increase the rate of urine flow and/or decrease the symptoms you are having. - Terazosin Capsules help relieve the symptoms of BPH. It does NOT change the size of the prostate, which may continue to grow. However, a larger prostate does not necessarily cause more or worse symptoms. - If Terazosin Capsules are helping you, you should notice an effect on your particular symptoms in 2 to 4 weeks of starting to take the medication. - Even though you take Terazosin Capsules and they may help you, Terazosin Capsules may not prevent the need for surgery in the future. - Other important facts about Terazosin Capsules for BPH - You should see an effect on your symptoms in 2 to 4 weeks. So, you will need to continue seeing your doctor to check your progress regarding your BPH and to monitor your blood pressure in addition to your other regular checkups. - Your doctor has prescribed Terazosin Capsules for your BPH and not for prostate cancer. However, a man can have BPH and prostate cancer at the same time. Doctors usually recommend that men be checked for prostate cancer once a year when they turn 50 (or 40 if a family member has had prostate cancer). These checks should continue even if you are taking Terazosin Capsules. Terazosin Capsules are not a treatment for prostate cancer. - About Prostate Specific Antigen (PSA). Your doctor may have done a blood test called PSA. Your doctor is aware that Terazosin Capsules do not affect PSA levels. You may want to ask your doctor more about this if you have had a PSA test done. WARNINGS - Terazosin Capsules Can Cause a Sudden Drop in Blood Pressure After the very first dose. You may feel dizzy, faint, or “light-headed” particularly after you get up from bed or from a chair. This is more likely to occur after you’ve taken the first few doses, but can occur at any time while you are taking the drug. It can also occur if you stop taking the drug and then re-start treatment. - Because of this effect, your doctor may have told you to take Terazosin Capsules at bedtime. If you take Terazosin Capsules at bedtime but need to get up from bed to go to the bathroom, get up slowly and cautiously until you are sure how the medicine affects you. It is also important to get up slowly from a chair or bed at any time until you learn how you react to Terazosin Capsules. You should not drive or do any hazardous tasks until you are used to the effects of the medication. If you begin to feel dizzy, sit or lie down until you feel better. - You will start with a 1 mg dose of Terazosin Capsules. Then the dose will be increased as your body gets used to the effect of the medication. - Other side effects you could have while taking Terazosin Capsules include drowsiness, blurred or hazy vision, nausea, or “puffiness” of the feet or hands. Discuss any unexpected effects you notice with your doctor. - Extremely rarely, Terazosin Capsules and similar medications have caused painful erection of the penis, sustained for hours and unrelieved by sexual intercourse or masturbation. - This condition is serious, and if untreated it can be followed by permanent inability to have an erection. If you have a prolonged abnormal erection, call your doctor or go to an emergency room as soon as possible. - Follow your doctor’s instructions about how to take Terazosin Capsules. You must take it every day at the dose prescribed. Talk with your doctor if you don’t take it for a few days, you may have to restart it at a 1 mg dose and be cautious about possible dizziness. Do not share Terazosin Capsules with anyone else; it was prescribed only for you. - Keep Terazosin Capsules and all medicines out of the reach of children. # Precautions with Alcohol Alcohol-Terazosin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Hytrin # Look-Alike Drug Names N/A # Drug Shortage Status Drug Shortage # Price	Terazosin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, 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 Terazosin is a alpha-adrenergic blocker that is FDA approved for the {{{indicationType}}} of symptomatic benign prostatic hyperplasia (BPH) and hypertension. Common adverse reactions include orthostatic hypotension, palpitations, peripheral edema, nausea, asthenia, dizziness headache, somnolence and nasal congestion. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Initial dose : - 1 mg at bedtime is the starting dose for all patients (should not be exceeded as an initial dose). - Patients should be closely followed during initial administration in order to minimize the risk of severe hypotensive response. - Subsequent doses : - The initial dose should be increased in a stepwise fashion to 2 mg, 5 mg, or 10 mg once daily to achieve the desired improvement of symptoms and/or flow rates. - Doses of 10 mg once daily are generally required for the clinical response. - Treatment with 10 mg for a minimum of 4 to 6 weeks may be required to assess whether a beneficial response has been achieved. Some patients may not achieve a clinical response despite appropriate titration. :* :* Some patients responded at a 20 mg daily dose, however, there was an insufficient number of patients studied to draw definitive conclusions about this dose. - If terazosin administration is discontinued for several days or longer, therapy should be reinstituted using the initial dosing regimen. - Initial dose: - 1 mg at bedtime is the starting dose for all patients (this dose should not be exceeded). This initial dosing regimen should be strictly observed to minimize the potential for severe hypotensive effects. - Subsequent doses: - The dose may be slowly increased to achieve the desired blood pressure response. - The usual recommended dose range is 1 mg to 5 mg administered once a day. - Some patients may benefit from doses as high as 20 mg per day. - Doses over 20 mg do not appear to provide further blood pressure effect and doses over 40 mg have not been studied. - Blood pressure should be monitored at the end of the dosing interval to be sure control is maintained throughout the interval. - If response is substantially diminished at 24 hours an increased dose or use of a twice daily regimen can be considered. - If terazosin administration is discontinued for several days or longer, therapy should be reinstituted using the initial dosing regimen. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of terazosin in adult patients. ### Non–Guideline-Supported Use - Shows effect in patients with chronic prostatitis-chronic pelvic pain syndrome with no history of therapy with alpha-blockers. [1] - Initial dosage: - 1 mg for 4 days - Following dosages: - 2 mg for 10 days, followed by 5 mg daily afterwards. - Terazosin has shown to be effective in reducing cholesterol and triglyceride levels in patients. However, there is conflicting data in these studies. - 2 - 10 mg/day, in one study.[2] - 5, 10 or 20 mg/day, on a second study.[3] - 10 mg/day - this study showed no effect of terazosin in lowering blodd lipids.[4] - Terazosin has shown evidence, in one study, in the treatment of nocturia in male patients suffering from lower urinary tract symptoms.[5] - Initial dosage: - 2 mg/day for 7 days - Following dosages: - 4 mg/day for the next 3 weeks - It has been proven to improve sperm count and, even though not proven by statistically, pregnancy rates may improve.[6] - 2 mg/day - Terazosin appears to help prostate cancer patients with symptoms of radiation-induced urethritis. [7] - 2 - 6 mg/day - Terazosin therapy appears to be effective in patients with spinal cord injury: - For management of autonomic dysreflexia. - For improvement of detrusor compliance, decreased bladder pressures and safe bladder volumes. - For reducing reducing obstruction of bladder outlet. - 10 mg/day[8] - 5 mg/day[9][10] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-label Guideline-Supported Use of terazosin in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of terazosin in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non-Guideline-Supported Use of terazosin in pediatric patients. # Contraindications - Terazosin capsules are contraindicated in patients known to be hypersensitive to terazosin hydrochloride. # Warnings - Terazosin capsules, like other alpha-adrenergic blocking agents, can cause marked lowering of blood pressure, especially postural hypotension, and syncope in association with the first dose or first few days of therapy. A similar effect can be anticipated if therapy is interrupted for several days and then restarted. - Syncope has also been reported with other alpha-adrenergic blocking agents in association with rapid dosage increases or the introduction of another antihypertensive drug. - Syncope is believed to be due to an excessive postural hypotensive effect, although occasionally the syncopal episode has been preceded by a bout of severe supraventricular tachycardia with heart rates of 120 to 160 beats per minute. Additionally, the possibility of the contribution of hemodilution to the symptoms of postural hypotension should be considered. - To decrease the likelihood of syncope or excessive hypotension, treatment should: - Always be initiated with a 1 mg dose of terazosin capsules, given at bedtime. - The 2 mg, 5 mg and 10 mg capsules are not indicated as initial therapy. - Dosage should then be increased slowly, according to recommendations in the Dosage and Administration section and additional antihypertensive agents should be added with caution. - The patient should be cautioned to avoid situations, such as driving or hazardous tasks, where injury could result should syncope occur during initiation of therapy. In early investigational studies, where increasing single doses up to 7.5 mg were given at 3 day intervals, tolerance to the first dose phenomenon did not necessarily develop and the “first-dose” effect could be observed at all doses. Syncopal episodes occurred in 3 of the 14 subjects given terazosin at doses of 2.5, 5 and 7.5 mg, which are higher than the recommended initial dose; in addition, severe orthostatic hypotension (blood pressure falling to 50/0 mmHg) was seen in two others and dizziness, tachycardia, and lightheadedness occurred in most subjects. These adverse effects all occurred within 90 minutes of dosing. In three placebo-controlled BPH studies 1, 2, and 3, the incidence of postural hypotension in the terazosin treated patients was 5.1%, 5.2%, and 3.7% respectively. In multiple dose clinical trials involving nearly 2000 hypertensive patients treated with terazosin capsules, syncope was reported in about 1% of patients. Syncope was not necessarily associated only with the first dose. If syncope occurs, the patient should be placed in a recumbent position and treated supportively as necessary. There is evidence that the orthostatic effect of terazosin is greater, even in chronic use, shortly after dosing. The risk of the events is greatest during the initial seven days of treatment, but continues at all time intervals. - Rarely, terazosin and other α1-antagonists have been associated with priapism (painful penile erection, sustained for hours and unrelieved by sexual intercourse or masturbation). Two or three dozen cases have been reported. - Since this condition can lead to permanent impotence if not promptly treated, patients must be advised about the seriousness of the condition. # Adverse Reactions ## Clinical Trials Experience - The incidence of treatment-emergent adverse events has been ascertained clinical trials conducted worldwide. - All adverse events reported during these trials were recorded as adverse reactions. - The incidence rates presented below are based on combined data from six placebo-controlled trials involving once-a-day administration of terazosin at doses ranging from 1 to 20 mg. Table 1 summarizes those adverse events reported for patients in these trials when the incidence rate in the terazosin group was at least 1%, and was greater than that for the placebo group, or where the reaction is of clinical interest. Asthenia, postural hypotension, dizziness, somnolence, nasal congestion/rhinitis, and impotence were the only events that were significantly (p ≤ 0.05) more common in patients receiving terazosin than in patients receiving placebo. - The incidence of urinary tract infection was significantly lower in the patients receiving terazosin than in patients receiving placebo. An analysis of the incidence rate of hypotensive adverse events adjusted for the length of drug treatment has shown that the risk of the events is greatest during the initial seven days of treatment, but continues at all time intervals. - Additional adverse events have been reported, but these are, in general, not distinguishable from symptoms that might have occurred in the absence of exposure to terazosin. The safety profile of patients treated in the long-term open-label study was similar to that observed in the controlled studies. - The adverse events were usually transient and mild or moderate in intensity, but sometimes were serious enough to interrupt treatment. In the placebo-controlled clinical trials, the rates of premature termination due to adverse events were not statistically different between the placebo and terazosin groups. The adverse events that were bothersome, as judged by their being reported as reasons for discontinuation of therapy by at least 0.5% of the terazosin group and being reported more often than in the placebo group, are shown in Table 2. - The prevalence of adverse reactions has been ascertained from clinical trials conducted primarily in the United States. All adverse experiences (events) reported during these trials were recorded as adverse reactions. The prevalence rates presented below are based on combined data from fourteen placebo-controlled trials involving once-a-day administration of terazosin, as monotherapy or in combination with other antihypertensive agents, at doses ranging from 1 to 40 mg. Table 3 summarizes those adverse experiences reported for patients in these trials where the prevalence rate in the terazosin group was at least 5%, where the prevalence rate for the terazosin group was at least 2% and was greater than the prevalence rate for the placebo group, or where the reaction is of particular interest. - Asthenia, blurred vision, dizziness, nasal congestion, nausea, peripheral edema, palpitations and somnolence were the only symptoms that were significantly (p < 0.05) more common in patients receiving terazosin than in patients receiving placebo. - Similar adverse reaction rates were observed in placebo-controlled monotherapy trials. - Additional adverse reactions have been reported, but these are, in general, not distinguishable from symptoms that might have occurred in the absence of exposure to terazosin. The following additional adverse reactions were reported by at least 1% of 1987 patients who received terazosin in controlled or open, short- or long-term clinical trials or have been reported during marketing experience: - Anxiety - Insomnia - Arrhythmia - Vasodilation - Bronchitis - Cold symptoms - Epistaxis - Flu symptoms - Increased cough - Pharyngitis - Rhinitis - Constipation - Diarrhea - Dry mouth - Dyspepsia - Flatulence - Vomiting - Chest pain - Facial edema - Fever - Abdominal pain - Neck pain - Shoulder pain - Gout - Arthralgia - Arthritis - Joint disorder - Myalgia - Pruritus - Rash - Sweating - Abnormal vision - Conjunctivitis - Tinnitus. - Urinary frequency - Urinary incontinence primarily reported in postmenopausal women, urinary tract infection - The adverse reactions were usually mild or moderate in intensity but sometimes were serious enough to interrupt treatment. - The adverse reactions that were most bothersome, as judged by their being reported as reasons for discontinuation of therapy by at least 0.5% of the terazosin group and being reported more often than in the placebo group, are shown in Table 4. ## Postmarketing Experience - Post-marketing experience indicates that in rare instances patients may develop allergic reactions, including anaphylaxis, following administration of terazosin hydrochloride. - There have been reports of priapism and thrombocytopenia during post-marketing surveillance. - Atrial fibrillation has also been reported. - During cataract surgery, a variant of small pupil syndrome known as Intraoperative floppy iris syndrome (IFIS) has been reported in association with alpha-1 blocker therapy. # Drug Interactions - In controlled trials, terazosin have been added to diuretics, and several beta-adrenergic blockers; no unexpected interactions were observed. - Terazosin has also been used in patients on a variety of concomitant therapies; while these were not formal interaction studies, no interactions were observed. Terazosin has been used concomitantly in at least 50 patients on the following drugs or drug classes: - Analgesic/anti-inflammatory: - Acetaminophen - Aspirin - Codeine - Ibuprofen - Indomethacin - Antibiotics: - Erythromycin - Trimethoprim - Sulfamethoxazole - Anticholinergic/sympathomimetics - Phenylephrine hydrochloride - Phenylpropanolamine hydrochloride - Pseudoephedrine hydrochloride - Antigout - Allopurinol - Antihistamines - Chlorpheniramine - Cardiovascular agents: - Atenolol - Hydrochlorothiazide - Methyclothiazide - Propranolol - Corticosteroids - Gastrointestinal agents - Antacids - Hypoglycemics - Sedatives and tranquilizers - Diazepam - In a study (n=24) where terazosin and verapamil were administered concomitantly, terazosin’s mean AUC0-24 increased 11% after the first verapamil dose and after 3 weeks of verapamil treatment it increased by 24% with associated increases in Cmax (25%) and Cmin (32%) means. Terazosin mean Tmax decreased from 1.3 hours to 0.8 hours after 3 weeks of verapamil treatment. Statistically significant differences were not found in the verapamil level with and without terazosin. - In a study (n=6) where terazosin and captopril were administered concomitantly, plasma disposition of captopril was not influenced by concomitant administration of terazosin and terazosin maximum plasma concentrations increased linearly with dose at steady-state after administration of terazosin plus captopril. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Teratogenic Effects : - Terazosin capsules were not teratogenic in either rats or rabbits when administered at oral doses up to 280 and 60 times, respectively, the maximum recommended human dose. - Fetal resorptions occurred in rats dosed with 480 mg/kg/day, approximately 280 times the maximum recommended human dose. - Increased fetal resorptions, decreased fetal weight and an increased number of supernumerary ribs were observed in offspring of rabbits dosed with 60 times the maximum recommended human dose. - These findings (in both species) were most likely secondary to maternal toxicity. There are no adequate and well-controlled studies in pregnant women and the safety of terazosin in pregnancy has not been established. Terazosin capsules are not recommended during pregnancy unless the potential benefit justifies the potential risk to the mother and fetus. - Nonteratogenic Effects : - In a peri- and post-natal development study in rats, significantly more pups died in the group dosed with 120 mg/kg/day (> 75 times the maximum recommended human dose) than in the control group during the three-week postpartum period. Pregnancy Category (AUS): B2 - There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of terazosin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Terazosin during labor and delivery. ### Nursing Mothers - It is not known whether terazosin is excreted in breast milk. - Because many drugs are excreted in breast milk, caution should be exercised when terazosin capsules are administered to a nursing woman. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been determined. ### Geriatic Use There is no FDA guidance on the use of Terazosin in geriatric settings. ### Gender There is no FDA guidance on the use of Terazosin with respect to specific gender populations. ### Race There is no FDA guidance on the use of Terazosin with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Terazosin in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Terazosin in patients with hepatic impairment. ### Females of Reproductive Potential and Males - Terazosin was devoid of mutagenic potential when evaluated in vivo and in vitro (the Ames test, in vivo cytogenetics, the dominant lethal test in mice, in vivo Chinese hamster chromosome aberration test and V79 forward mutation assay). - Terazosin administered in the feed to rats at doses of 8, 40, and 250 mg/kg/day (70, 350, and 2100 mg/M2/day), for two years, was associated with a statistically significant increase in benign adrenal medullary tumors of male rats exposed to the 250 mg/kg dose. This dose is 175 times the maximum recommended human dose of 20 mg (12 mg/M2). Female rats were unaffected. - Terazosin was not oncogenic in mice when administered in feed for 2 years at a maximum tolerated dose of 32 mg/kg/day (110 mg/M2; 9 times the maximum recommended human dose). - The absence of mutagenicity in a battery of tests, of tumorigenicity of any cell type in the mouse carcinogenicity assay, of increased total tumor incidence in either species, and of proliferative adrenal lesions in female rats, suggests a male rat species-specific event. Numerous other diverse pharmaceutical and chemical compounds have also been associated with benign adrenal medullary tumors in male rats without supporting evidence for carcinogenicity in man. - The effect of terazosin on fertility was assessed in a standard fertility/reproductive performance study in which male and female rats were administered oral doses of 8, 30 and 120 mg/kg/day. Four of 20 male rats given 30 mg/kg (240 mg/M2; 20 times the maximum recommended human dose) and five of 19 male rats given 120 mg/kg (960 mg/M2; 80 times the maximum recommended human dose) failed to sire a litter. Testicular weights and morphology were unaffected by treatment. Vaginal smears at 30 and 120 mg/kg/day, however, appeared to contain less sperm than smears from control matings and good correlation was reported between sperm count and subsequent pregnancy. - Oral administration of terazosin for one or two years elicited a statistically significant increase in the incidence of testicular atrophy in rats exposed to 40 and 250 mg/kg/day (29 and 175 times the maximum recommended human dose), but not in rats exposed to 8 mg/kg/day (> 6 times the maximum recommended human dose). Testicular atrophy was also observed in dogs dosed with 300 mg/kg/day (> 500 times the maximum recommended human dose) for three months but not after one year when dosed with 20 mg/kg/day (38 times the maximum recommended human dose). This lesion has also been seen with Minipress®, another (marketed) selective-alpha-1 blocking agent. ### Immunocompromised Patients There is no FDA guidance one the use of Terazosin in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring - Terazosin capsules, like other alpha-adrenergic blocking agents, can cause marked lowering of blood pressure, especially postural hypotension, and syncope in association with the first dose or first few days of therapy. Blood pressure should be monitored, particularly when increasing the dosage of terazosin, in order to avoid syncope. - A patient taking terazosin should see an effect on his symptoms in 2 to 4 weeks. Therefore, continuous check-ups with the physician, to evaluate the progress regarding the BPH and monitor the blood pressure should be done, in addition to other regular check-ups. # IV Compatibility There is limited information regarding the compatibility of Terazosin and IV administrations. # Overdosage ## Acute Overdose - In case of overdosage of terazosin capsules leading to: - Hypotension ### Management - Support of the cardiovascular system is of first importance. - Restoration of blood pressure and normalization of heart rate may be accomplished by keeping the patient in the supine position. - If this measure is inadequate, shock should first be treated with volume expanders. - If necessary, vasopressors should then be used and renal function should be monitored and supported as needed. - Laboratory data indicate that terazosin is 90-94% protein bound; therefore, dialysis may not be of benefit. # Pharmacology ## Mechanism of Action - In animals, terazosin causes a decrease in blood pressure by decreasing total peripheral vascular resistance. The vasodilatory hypotensive action of terazosin appears to be produced mainly by blockade of alpha-1 adrenoceptors. ## Structure - Terazosin hydrochloride, an alpha-1-selective adrenoceptor blocking agent, is a quinazoline derivative represented by the following chemical name,molecular formula and structural formula: - (RS)-Piperazine, 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-[(tetrahydro-2-furanyl)carbonyl]-, monohydrochloride.C19H26ClN5O4 - Terazosin hydrochloride is a white, crystalline substance, freely soluble in water and isotonic saline and has molecular weight of 423.93. Each capsule, for oral administration, contains 1 mg, 2 mg, 5 mg or 10 mg of terazosin as terazosin hydrochlolde. In addition, each capsule contains the following inactive ingredients: - Colloidal silicon dioxide - Lactose monohydrate - Magnesium stearate - Pregelatinized starch. - The gelatin capsule contains: - Gelatin - Silicon dioxide - Sodium lauryl sulfate - Titanium dioxide. - The 1 mg shell also contains black iron oxide; the 2 mg capsule shell also contains D&C Yellow #10; the 5 mg capsule shell also contains D&C Yellow #10, FD&C Red #40 and D&C Red #28; the 10 mg capsule shell also contains FD&C Green #3 and D&C Yellow#10. ## Pharmacodynamics - The symptoms associated with BPH are related to bladder outlet obstruction, which is comprised of two underlying components: - A static component - A dynamic component. - The static component is a consequence of an increase in prostate size. Over time, the prostate will continue to enlarge. However, clinical studies have demonstrated that the size of the prostate does not correlate with the severity BPH symptoms or the degree of urinary obstruction. - The dynamic component is a function of an increase in smooth muscle tone in the prostate and bladder neck, leading to constriction of the bladder outlet. Smooth muscle tone is mediated by sympathetic nervous stimulation of alpha-1 adrenoceptors, which are abundant in the prostate, prostatic capsule and bladder neck. - The reduction in symptoms and improvement in urine flow rates following administration of terazosin is related to relaxation of smooth muscle produced by blockade of alpha-1 adrenoceptors in the bladder neck and prostate. Because there are relatively few alpha-1 adrenoceptors in the bladder body, terazosin is able to reduce the bladder outlet obstruction without affecting bladder contractility. - Terazosin has been studied in 1222 men with symptomatic BPH. In three placebo-controlled studies, symptom evaluation and uroflowmetric measurements were performed approximately 24 hours following dosing. Symptoms were quantified using the Boyarsky Index. The questionnaire evaluated both obstructive (hesitancy, intermittency, terminal dribbling, impairment of size and force of stream, sensation of incomplete bladder emptying) and irritative (nocturia, daytime frequency, urgency, dysuria) symptoms by rating each of the 9 symptoms from 0 to 3, for a total score of 27 points. Results from these studies indicated that terazosin statistically significantly improved symptoms and peak urine flow rates over placebo as follows: - In all three studies, both symptom scores and peak urine flow rates showed statistically significant improvement from baseline in patients treated with terazosin capsules from week 2 (or the first clinic visit) and throughout the study duration. - Analysis of the effect of terazosin capsules on individual urinary symptoms demonstrated that compared to placebo, terazosin significantly improved the symptoms of hesitancy, intermittency, impairment in size and force of urinary stream, sensation of incomplete emptying, terminal dribbling, daytime frequency and nocturia. - Global assessments of overall urinary function and symptoms were also performed by investigators who were blinded to patient treatment assignment. - In studies 1 and 3, patients treated with terazosin patients had a significantly (p ≤ 0.001) greater overall improvement compared to placebo treated patients. - In a short term study (Study 1), patients were randomized to either 2, 5 or 10 mg of terazosin or placebo. Patients randomized to the 10 mg group achieved a statistically significant response in both symptoms and peak flow rate compared to placebo (Figure 1). - In a long-term, open-label, non-placebo controlled clinical trial, 181 men were followed for 2 years and 58 of these men were followed for 30 months. The effect of terazosin on urinary symptom scores and peak flow rates was maintained throughout the study duration (Figures 2 and 3): - In this long-term trial, both symptom scores and peak urinary flow rates showed statistically significant improvement suggesting a relaxation of smooth muscle cells. Although blockade of alpha-1 adrenoceptors also lowers blood pressure in hypertensive patients with increased peripheral vascular resistance, terazosin treatment of normotensive men with BPH did not result in a clinically significant blood pressure lowering effect: - In animals, terazosin causes a decrease in blood pressure by decreasing total peripheral vascular resistance. The vasodilatory hypotensive action of terazosin appears to be produced mainly by blockade of alpha-1 adrenoceptors. - Terazosin decreases blood pressure gradually within 15 minutes following oral administration. - Patients in clinical trials of terazosin were administered once daily (the great majority) and twice daily regimens with total doses usually in the range of 5 to 20 mg/day, and had mild (about 77%, diastolic pressure 95 to 105 mmHg) or moderate (23%, diastolic pressure 105 to 115 mmHg) hypertension. Because terazosin, like all alpha antagonists, can cause unusually large falls in blood pressure after the first dose or first few doses, the initial dose was 1 mg in virtually all trials, with subsequent titration to a specified fixed dose or titration to some specified blood pressure end point (usually a supine diastolic pressure of 90 mmHg). - Blood pressure responses were measured at the end of the dosing interval (usually 24 hours) and effects were shown to persist throughout the interval, with the usual supine responses 5 to 10 mmHg systolic and 3.5 to 8 mmHg diastolic greater than placebo. The responses in the standing position tended to be somewhat larger, by 1 to 3 mmHg, although this was not true in all studies. The magnitude of the blood pressure responses was similar to prazosin and less than hydrochlorothiazide (in a single study of hypertensive patients). In measurements 24 hours after dosing, heart rate was unchanged. - Limited measurements of peak response (2 to 3 hours after dosing) during chronic terazosin administration indicate that it is greater than about twice the trough (24 hour) response, suggesting some attenuation of response at 24 hours, presumably due to a fall in blood terazosin concentrations at the end of the dose interval. This explanation is not established with certainty, however, and is not consistent with the similarity of blood pressure response to once daily and twice daily dosing and with the absence of an observed dose-response relationship over a range of 5 to 20 mg, i.e., if blood concentrations had fallen to the point of providing less than full effect at 24 hours, a shorter dosing interval or larger dose should have led to increased response. - Further dose response and dose duration studies are being carried out. Blood pressure should be measured at the end of the dose interval; if response is not satisfactory, patients may be tried on a larger dose or twice daily dosing regimen. The latter should also be considered if possibly blood pressure-related side effects, such as dizziness, palpitations, or orthostatic complaints, are seen within a few hours after dosing. - The greater blood pressure effect associated with peak plasma concentrations (first few hours after dosing) appears somewhat more position-dependent (greater in the erect position) than the effect of terazosin at 24 hours and in the erect position there is also a 6 to 10 beat per minute increase in heart rate in the first few hours after dosing. During the first 3 hours after dosing 12.5% of patients had a systolic pressure fall of 30 mmHg or more from supine to standing, or standing systolic pressure below 90 mmHg with a fall of at least 20 mmHg, compared to 4% of a placebo group. - There was a tendency for patients to gain weight during terazosin therapy. In placebo-controlled monotherapy trials, male and female patients receiving terazosin gained a mean of 1.7 and 2.2 pounds respectively, compared to losses of 0.2 and 1.2 pounds respectively in the placebo group. Both differences were statistically significant. During controlled clinical trials, patients receiving terazosin monotherapy had a small but statistically significant decrease (a 3% fall) compared to placebo in total cholesterol and the combined low-density and very-low-density lipoprotein fractions. No significant changes were observed in high-density lipoprotein fraction and triglycerides compared to placebo. - Analysis of clinical laboratory data following administration of terazosin suggested the possibility of hemodilution based on decreases in hematocrit, hemoglobin, white blood cells, total protein and albumin. Decreases in hematocrit and total protein have been observed with alpha-blockade and are attributed to hemodilution. ## Pharmacokinetics - Terazosin hydrochloride administered as capsules is essentially completely absorbed in man. - Administration of capsules immediately after meals had a minimal effect on the extent of absorption. The time to reach peak plasma concentration however, was delayed by about 40 minutes. - Terazosin has been shown to undergo minimal hepatic first-pass metabolism and nearly all of the circulating dose is in the form of parent drug. - The plasma levels peak about one hour after dosing, and then decline with a half-life of approximately 12 hours. - In a study that evaluated the effect of age on terazosin pharmacokinetics, the mean plasma half-lives were 14.0 and 11.4 hours for the age group ≥ 70 years and the age group of 20 to 39 years, respectively. After oral administration the plasma clearance was decreased by 31.7% in patients 70 years of age or older compared to that in patients 20 to 39 years of age. The drug is 90 to 94% bound to plasma proteins and binding is constant over the clinically observed concentration range. Approximately 10% of an orally administered dose is excreted as parent drug in the urine and approximately 20% is excreted in the feces. The remainder is eliminated as metabolites. Impaired renal function had no significant effect on the elimination of terazosin, and dosage adjustment of terazosin to compensate for the drug removal during hemodialysis (approximately 10%) does not appear to be necessary. Overall, approximately 40% of the administered dose is excreted in the urine and approximately 60% in the feces. The disposition of the compound in animals is qualitatively similar to that in man. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of terazosin in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of terazosin in the drug label. # How Supplied - Terazosin Capsules are available in four dosage strengths: - 1 mg Terazosin Capsules, USP are available as gray opaque cap/body printed “TL 383” in black ink. - Bottles of 90: NDC 59746-383-90 - Bottles of 100: NDC 59746-383-06 - Bottles of 500: NDC 59746-383-09 - Bottles of 1000: NDC 59746-383-10 - 2 mg Terazosin Capsules, USP are available as ivory opaque cap/body printed “TL 384” in black ink. - Bottles of 90: NDC 59746-384-90 - Bottles of 100: NDC 59746-384-06 - Bottles of 500: NDC 59746-384-09 - Bottles of 1000: NDC 59746-384-10 - 5 mg Terazosin Capsules, USP are available as bright orange opaque cap/body printed “TL 385” in black ink. - Bottles of 90: NDC 59746-385-90 - Bottles of 100: NDC 59746-385-06 - Bottles of 500: NDC 59746-385-09 - Bottles of 1000: NDC 59746-385-10 - 10 mg Terazosin Capsules, USP are available as light green opaque cap/body printed “TL 386” in black ink. - Bottles of 90: NDC 59746-386-90 - Bottles of 100: NDC 59746-386-06 - Bottles of 500: NDC 59746-386-09 - Bottles of 1000: NDC 59746-386-10 - Dispense in a tight, light-resistant container as defined in the USP. ## Storage - Recommended storage: - Store at 20° - 25°C (68° - 77°F) [see USP Controlled Room Temperature]. - Protect from light and moisture. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information TERAZOSIN CAPSULES, USP - Generic Name: Terazosin (Ter-A-so-sin) - When used to treat hypertension or benign prostatic hyperplasia - Please read this leaflet before you start taking terazosin capsules. Also, read it each time you get a new prescription. This is a summary and should not take the place of a full discussion with your doctor who has additional information about Terazosin Capsules. You and your doctor should discuss Terazosin Capsules and your condition before you start taking it and at your regular checkups. - Terazosin Capsules are used to treat high blood pressure (hypertension). Terazosin Capsules are also used to treat benign prostatic hyperplasia (BPH) in men. This leaflet describes Terazosin Capsules as a treatment for hypertension or BPH. - What is hypertension (high blood pressure)? - Blood pressure is the tension of the blood within the blood vessels. If blood is pumped too forcefully, or if the blood vessels are too narrow, the pressure of the blood against the walls of the vessels rises. If high blood pressure is not treated, over time, the increased pressure can damage blood vessels or it can cause the heart to work too hard and may decrease the flow of blood to the heart, brain, and kidneys. As a result, these organs may become damaged and not function correctly. If high blood pressure is controlled, this damage is less likely to happen. - Treatment options for hypertension: - Non-drug treatments are sometimes effective in controlling mild hypertension. The most important lifestyle changes to lower blood pressure are to lose weight, reduce salt, fat, and alcohol in the diet, quit smoking, and exercise regularly. However, many hypertensive patients require one or more ongoing medications to control their blood pressure. There are different kinds of medications used to treat hypertension. Your doctor has prescribed Terazosin Capsules for you. - What Terazosin Capsules do to treat hypertension: - Terazosin capsules work by relaxing blood vessels so that blood passes through them more easily. This helps to lower blood pressure. - What is BPH? - The prostate is a gland located below the bladder of men. It surrounds the urethra (you-REETH-rah), which is a tube that drains urine from the bladder. BPH is an enlargement of the prostate gland. The symptoms of BPH, however, can be caused by an increase in the tightness of muscles in the prostate. If the muscles inside the prostate tighten, they can squeeze the urethra and slow the flow of urine. This can lead to symptoms such as: - A weak or interrupted stream when urinating - A feeling that you cannot empty your bladder completely - A feeling of delay when you start to urinate - A need to urinate often, especially at night, or - A feeling that you must urinate right away. - Treatment options for BPH. There are three main treatment options for BPH: - Program of monitoring or “Watchful Waiting” - Some men have an enlarged prostate gland, but no symptoms, or symptoms that are not bothersome. If this applies, you and your doctor may decide on a program of monitoring including regular checkups, instead of medication or surgery. - Medication - There are different kinds of medication used to treat BPH. Your doctor has prescribed Terazosin Capsules for you. See “What Terazosin Capsules do to treat BPH” below. - Surgery - Some patients may need surgery. Your doctor can describe several different surgical procedures to treat BPH. Which procedure is best depends on your symptoms and medical condition. - What Terazosin Capsules do to treat BPH - Terazosin Capsules relax the tightness of a certain type of muscle in the prostate and at the opening of the bladder. This may increase the rate of urine flow and/or decrease the symptoms you are having. - Terazosin Capsules help relieve the symptoms of BPH. It does NOT change the size of the prostate, which may continue to grow. However, a larger prostate does not necessarily cause more or worse symptoms. - If Terazosin Capsules are helping you, you should notice an effect on your particular symptoms in 2 to 4 weeks of starting to take the medication. - Even though you take Terazosin Capsules and they may help you, Terazosin Capsules may not prevent the need for surgery in the future. - Other important facts about Terazosin Capsules for BPH - You should see an effect on your symptoms in 2 to 4 weeks. So, you will need to continue seeing your doctor to check your progress regarding your BPH and to monitor your blood pressure in addition to your other regular checkups. - Your doctor has prescribed Terazosin Capsules for your BPH and not for prostate cancer. However, a man can have BPH and prostate cancer at the same time. Doctors usually recommend that men be checked for prostate cancer once a year when they turn 50 (or 40 if a family member has had prostate cancer). These checks should continue even if you are taking Terazosin Capsules. Terazosin Capsules are not a treatment for prostate cancer. - About Prostate Specific Antigen (PSA). Your doctor may have done a blood test called PSA. Your doctor is aware that Terazosin Capsules do not affect PSA levels. You may want to ask your doctor more about this if you have had a PSA test done. WARNINGS - Terazosin Capsules Can Cause a Sudden Drop in Blood Pressure After the very first dose. You may feel dizzy, faint, or “light-headed” particularly after you get up from bed or from a chair. This is more likely to occur after you’ve taken the first few doses, but can occur at any time while you are taking the drug. It can also occur if you stop taking the drug and then re-start treatment. - Because of this effect, your doctor may have told you to take Terazosin Capsules at bedtime. If you take Terazosin Capsules at bedtime but need to get up from bed to go to the bathroom, get up slowly and cautiously until you are sure how the medicine affects you. It is also important to get up slowly from a chair or bed at any time until you learn how you react to Terazosin Capsules. You should not drive or do any hazardous tasks until you are used to the effects of the medication. If you begin to feel dizzy, sit or lie down until you feel better. - You will start with a 1 mg dose of Terazosin Capsules. Then the dose will be increased as your body gets used to the effect of the medication. - Other side effects you could have while taking Terazosin Capsules include drowsiness, blurred or hazy vision, nausea, or “puffiness” of the feet or hands. Discuss any unexpected effects you notice with your doctor. - Extremely rarely, Terazosin Capsules and similar medications have caused painful erection of the penis, sustained for hours and unrelieved by sexual intercourse or masturbation. - This condition is serious, and if untreated it can be followed by permanent inability to have an erection. If you have a prolonged abnormal erection, call your doctor or go to an emergency room as soon as possible. - Follow your doctor’s instructions about how to take Terazosin Capsules. You must take it every day at the dose prescribed. Talk with your doctor if you don’t take it for a few days, you may have to restart it at a 1 mg dose and be cautious about possible dizziness. Do not share Terazosin Capsules with anyone else; it was prescribed only for you. - Keep Terazosin Capsules and all medicines out of the reach of children. # Precautions with Alcohol Alcohol-Terazosin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Hytrin # Look-Alike Drug Names N/A # Drug Shortage Status Drug Shortage # Price	https://www.wikidoc.org/index.php/Abbott_45975
b53aac037c4948119374328e29f6d3970cb8b24e	wikidoc	Abciximab	Abciximab # 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 Abciximab is a Platelet aggregation inhibitor that is FDA approved for the prophylaxis of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Common adverse reactions include chest pain, hypotension, injection site pain, abdominal pain,nausea, vomiting, bleeding, backache. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - Initial dosage: 0.25 mg/kg IV bolus (10-60 minutes before the start of PCI) - Maitaining dosage: 0.125 mg/kg/min IV for 12 hours (max 10 ug/min) - Dosing Information - Initial dosage: 0.25 mg/kg IV bolus (10-60 minutes before the start of PCI) - Maitaining dosage: 10 ug/min IV for 18- 24h (concluding one hour after the PCI) - The safety and efficacy of Abciximab have only been investigated with concomitant administration of heparin and aspirin - In patients with failed PCIs, the continuous infusion of Abciximab should be stopped because there is no evidence for Abciximab efficacy in that setting. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - Developed by: American College of Cardiology Foundation (ACCF) and American Heart Association (AHA) - Class of Recommendation: Class IIa - Level of Evidence: Level A - Recommendation - initial dosage: 0.25 mg/kg IV bolus (over 5 minutes) - maitaing dosage: 10 ug/min IV (continued for 12 hours unless complications developed) ### Non–Guideline-Supported Use - Dosing information - initial dosage: 0.25 mg/kg IV bolus’‘’ - maitaing dosage: 10 ug/min IV for 12h - Dosing information - initial dosage: 0.25 mg/kg IV bolus - maitaing dosage: 10 ug/min IV for 12h - Dosing information - initial dosage: 0.25 mg/kg IV bolus - maitaing dosage: 10 ug/min IV for 12h - Dosing information - initial dosage: 0.25 mg/kg IV bolus - maitaing dosage: 10 ug/min IV for 12h # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) FDA Package Insert for Abciximab contains no information regarding Pediatric Indications and Dosage. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Abciximab in pediatric patients. ### Non–Guideline-Supported Use - Dosing information - loading dose: 0.25 mg/kg IV - follow-up: 0.125 mg/min IV for 12h # Contraindications Because Abciximab may increase the risk of bleeding, Abciximab is contraindicated in the following clinical situations: - Active internal bleeding - Recent (within six weeks) gastrointestinal (GI) or genitourinary (GU) bleeding of clinical significance. - History of cerebrovascular accident (CVA) within two years, or CVA with a significant residual neurological deficit - Bleeding diathesis - Administration of oral anticoagulants within seven days unless prothrombin time is <1.2 times control - Thrombocytopenia (<100,000 cells/mL) - Recent (within six weeks) major surgery or trauma - Intracranial neoplasm, arteriovenous malformation, or aneurysm - Severe uncontrolled hypertension - Presumed or documented history of vasculitis - Use of intravenous dextran before PCI, or intent to use it during an intervention Abciximab is also contraindicated in patients with known hypersensitivity to any component of this product or to murine proteins. # Warnings Abciximab has the potential to increase the risk of bleeding events, rarely including those with a fatal outcome, particularly in the presence of anticoagulation, e.g., from heparin, other anticoagulants, or thrombolytics The risk of major bleeds due to Abciximab therapy is increased in patients receiving thrombolytics and should be weighed against the anticipated benefits. Should serious bleeding occur that is not controllable with pressure, the infusion of Abciximab and any concomitant heparin should be stopped. Allergic reactions, some of which were anaphylaxis (sometimes fatal), have been reported rarely in patients treated with ReoPro. Patients with allergic reactions should receive appropriate treatment. Treatment of anaphylaxis should include immediate discontinuation of ReoPro administration and initiation of resuscitative measures. ## Precautions To minimize the risk of bleeding with Abciximab, it is important to use a low-dose, weight-adjusted heparin regimen, a weight-adjusted Abciximab bolus and infusion, strict anticoagulation guidelines, careful vascular access site management, discontinuation of heparin after the procedure and early femoral arterial sheath removal. Therapy with Abciximab requires careful attention to all potential bleeding sites including catheter insertion sites, arterial and venous puncture sites, cutdown sites, needle puncture sites, and gastrointestinal, genitourinary, pulmonary (alveolar), and retroperitoneal sites. Arterial and venous punctures, intramuscular injections, and use of urinary catheters, nasotracheal intubation, nasogastric tubes and automatic blood pressure cuffs should be minimized. When obtaining intravenous access, non-compressible sites (e.g., subclavian or jugular veins) should be avoided. Saline or heparin locks should be considered for blood drawing. Vascular puncture sites should be documented and monitored. Gentle care should be provided when removing dressings. Arterial access site care is important to prevent bleeding. Care should be taken when attempting vascular access that only the anterior wall of the femoral artery is punctured, avoiding a Seldinger (through and through) technique for obtaining sheath access. Femoral vein sheath placement should be avoided unless needed. While the vascular sheath is in place, patients should be maintained on complete bed rest with the head of the bed ≤ 30° and the affected limb restrained in a straight position. Patients may be medicated for back/groin pain as necessary. Discontinuation of heparin immediately upon completion of the procedure and removal of the arterial sheath within six hours is strongly recommended if APTT ≤ 50 sec or ACT≤ 175 sec . In all circumstances, heparin should be discontinued at least two hours prior to arterial sheath removal. Following sheath removal, pressure should be applied to the femoral artery for at least 30 minutes using either manual compression or a mechanical device for hemostasis. A pressure dressing should be applied following hemostasis. The patient should be maintained on bed rest for six to eight hours following sheath removal or discontinuation of Abciximab, or four hours following discontinuation of heparin, whichever is later. The pressure dressing should be removed prior to ambulation. The sheath insertion site and distal pulses of affected leg(s) should be frequently checked while the femoral artery sheath is in place and for six hours after femoral artery sheath removal. Any hematoma should be measured and monitored for enlargement. The following conditions have been associated with an increased risk of bleeding and may be additive with the effect of Abciximab in the angioplasty setting: PCI within 12 hours of the onset of symptoms for acute myocardial infarction, prolonged PCI (lasting more than 70 minutes) and failed PCI. In the EPIC, EPILOG, CAPTURE, and EPISTENT trials, Abciximab was used concomitantly with heparin and aspirin. For details of the anticoagulation algorithms used in these clinical trials,: Anticoagulation. Because Abciximab inhibits platelet aggregation, caution should be employed when it is used with other drugs that affect hemostasis, including thrombolytics, oral anticoagulants, non-steroidal anti-inflammatory drugs, dipyridamole, and ticlopidine. In the EPIC trial, there was limited experience with the administration of Abciximab with low molecular weight dextran. Low molecular weight dextran was usually given for the deployment of a coronary stent, for which oral anticoagulants were also given. In the 11 patients who received low molecular weight dextran with Abciximab, five had major bleeding events and four had minor bleeding events. None of the five placebo patients treated with low molecular weight dextran had a major or minor bleeding event . Because of observed synergistic effects on bleeding, Abciximab therapy should be used judiciously in patients who have received systemic thrombolytic therapy. The GUSTO V trial randomized patients with acute myocardial infarction to treatment with combined Abciximab and half-dose Reteplase, or full-dose Reteplase alone (15). In this trial, the incidence of moderate or severe nonintracranial bleeding was increased in those patients receiving Abciximab and half-dose Reteplase versus those receiving Reteplase alone (4.6% versus 2.3%, respectively). Thrombocytopenia, including severe thrombocytopenia, has been observed with Abciximab administration . Platelet counts should be monitored prior to, during, and after treatment with Abciximab. Acute decreases in platelet count should be differentiated between true thrombocytopenia and pseudothrombocytopenia . If true thrombocytopenia is verified, Abciximab should be immediately discontinued and the condition appropriately monitored and treated. In clinical trials, patients who developed thrombocytopenia were followed with daily platelet counts until their platelet count returned to normal. Heparin and aspirin were discontinued for platelet counts below 60,000 cells/μL and platelets were transfused for a platelet count below 50,000 cells/μL. Most cases of severe thrombocytopenia (< 50,000 cells/μL) occurred within the first 24 hours of Abciximab administration. In a registry study of Abciximab readministration, a history of thrombocytopenia associated with prior use of Abciximab was predictive of an increased risk of recurrent thrombocytopenia . Readministration within 30 days was associated with an increased incidence and severity of thrombocytopenia, as was a positive human anti-chimeric antibody (HACA) test at baseline, compared to the rates seen in studies with first administration. Restoration of Platelet Function- In the event of serious uncontrolled bleeding or the need for emergency surgery, Abciximab should be discontinued. If platelet function does not return to normal, it may be restored, at least in part, with platelet transfusions. Before infusion of Abciximab, prothrombin time, ACT, APTT, and platelet count should be measured to identify pre-existing hemostatic abnormalities. Based on an integrated analysis of data from all studies, the following guidelines may be utilized to minimize the risk for bleeding: - When Abciximab is initiated 18 to 24 hours before PCI, the APTT should be maintained between 60 and 85 seconds during the Abciximab and heparin infusion period. - During PCI the ACT should be maintained between 200 and 300 seconds. - If anticoagulation is continued in these patients following PCI, the APTT should be maintained between 55 and 75 seconds. - The APTT or ACT should be checked prior to arterial sheath removal. The sheath should not be removed unless APTT ≤ 50 seconds or ACT ≤ 175 seconds. - Platelet counts should be monitored prior to treatment, two to four hours following the bolus dose of Abciximab and at 24 hours or prior to discharge, whichever is first. If a patient experiences an acute platelet decrease (e.g., a platelet decrease to less than 100,000 cells/μL and a decrease of at least 25% from pre-treatment value), additional platelet counts should be determined. Platelet monitoring should continue until platelet counts return to normal. - To exclude pseudothrombocytopenia, a laboratory artifact due to in vitro anticoagulant interaction, blood samples should be drawn in three separate tubes containing ethylenediaminetetraacetic acid (EDTA), citrate and heparin, respectively. A low platelet count in EDTA but not in heparin and/or citrate is supportive of a diagnosis of pseudothrombocytopenia. Administration of Abciximab may result in the formation of HACA that could potentially cause allergic or hypersensitivity reactions (including anaphylaxis), thrombocytopenia or diminished benefit upon readministration of Abciximab . Readministration of Abciximab to patients undergoing PCI was assessed in a registry that included 1342 treatments in 1286 patients. Most patients were receiving their second Abciximab exposure; 15% were receiving the third or subsequent exposure. The overall rate of HACA positivity prior to the readministration was 6% and increased to 27% post-readministration. There were no reports of serious allergic reactions or anaphylaxis . Thrombocytopenia was observed at higher rates in the readministration study than in the phase 3 studies of first-time administration , suggesting that readministration may be associated with an increased incidence and severity of thrombocytopenia. # Adverse Reactions ## Clinical Trials Experience ### Bleeding Abciximab has the potential to increase the risk of bleeding, particularly in the presence of anticoagulation, e.g., from heparin, other anticoagulants or thrombolytics. Bleeding in the Phase 3 trials was classified as major, minor or insignificant by the criteria of the Thrombolysis in Myocardial Infarction study group (16). Major bleeding events were defined as either an intracranial hemorrhage or a decrease in hemoglobin greater than 5 g/dL. Minor bleeding events included spontaneous gross hematuria, spontaneous hematemesis, observed blood loss with a hemoglobin decrease of more than 3 g/dL, or a decrease in hemoglobin of at least 4 g/dL without an identified bleeding site. Insignificant bleeding events were defined as a decrease in hemoglobin of less than 3 g/dL or a decrease in hemoglobin between 3-4 g/dL without observed bleeding. In patients who received transfusions, the number of units of blood lost was estimated through an adaptation of the method of Landefeld, et al. (17). In the EPIC trial, in which a non-weight-adjusted, longer-duration heparin dose regimen was used, the most common complication during Abciximab therapy was bleeding during the first 36 hours. The incidences of major bleeding, minor bleeding and transfusion of blood products were significantly increased. Major bleeding occurred in 10.6% of patients in the Abciximab bolus plus infusion arm compared with 3.3% of patients in the placebo arm. Minor bleeding was seen in 16.8% of Abciximab bolus plus infusion patients and 9.2% of placebo patients (7). Approximately 70% of Abciximab-treated patients with major bleeding had bleeding at the arterial access site in the groin. Abciximab-treated patients also had a higher incidence of major bleeding events from gastrointestinal, genitourinary, retroperitoneal, and other sites. Bleeding rates were reduced in the CAPTURE trial, and further reduced in the EPILOG and EPISTENT trials by use of modified dosing regimens and specific patient management techniques. In EPILOG and EPISTENT, using the heparin and Abciximab dosing, sheath removal and arterial access site guidelines described under PRECAUTIONS, the incidence of major bleeding in patients treated with Abciximab and low-dose, weight-adjusted heparin was not significantly different from that in patients receiving placebo. Subgroup analyses in the EPIC and CAPTURE trials showed that non-CABG major bleeding was more common in Abciximab patients weighing ≤ 75 kg. In the EPILOG and EPISTENT trials, which used weight-adjusted heparin dosing, the non-CABG major bleeding rates for Abciximab-treated patients did not differ substantially by weight subgroup. Although data are limited, Abciximab treatment was not associated with excess major bleeding in patients who underwent CABG surgery. (The range among all treatment arms was 3-5% in EPIC, and 1-2% in the CAPTURE, EPILOG, and EPISTENT trials.) Some patients with prolonged bleeding times received platelet transfusions to correct the bleeding time prior to surgery. The rates of major bleeding, minor bleeding and bleeding events requiring transfusions in the CAPTURE, EPILOG, and EPISTENT trials are shown in Table 4. The rates of insignificant bleeding events are not included in Table 4. Cases of fatal bleeding have been reported rarely during post-marketing use of Abciximab Pulmonary alveolar hemorrhage has been rarely reported during use of Abciximab. This can present with any or all of the following in close association with ReoPro administration: hypoxemia, alveolar infiltrates on chest x-ray, hemoptysis, or an unexplained drop in hemoglobin. ### Intracranial Hemorrhage and Stroke The total incidence of intracranial hemorrhage and non-hemorrhagic stroke across all four trials was not significantly different, 9/3023 for placebo patients and 15/4680 for Abciximab-treated patients. The incidence of intracranial hemorrhage was 3/3023 for placebo patients and 7/4680 for Abciximab patients. ### Thrombocytopenia In the clinical trials, patients treated with Abciximab were more likely than patients treated with placebo to experience decreases in platelet counts. Among patients in the EPILOG and EPISTENT trials who were treated with Abciximab plus low-dose heparin, the proportion of patients with any thrombocytopenia (platelets less than 100,000 cells/μL) ranged from 2.5 to 3.0%. The incidence of severe thrombocytopenia (platelets less than 50,000 cells/μL) ranged from 0.4 to 1.0% and platelet transfusions were required in 0.9 to 1.1%, respectively. Modestly lower rates were observed among patients treated with placebo plus standard-dose heparin. Overall higher rates were observed among patients in the EPIC and CAPTURE trials treated with Abciximab plus longer duration heparin: 2.6 to 5.2% were found to have any thrombocytopenia, 0.9 to 1.7% had severe thrombocytopenia, and 2.1 to 5.5% required platelet transfusion, respectively. In a readministration registry study of patients receiving a second or subsequent exposure to Abciximab the incidence of any degree of thrombocytopenia was 5%, with an incidence of profound thrombocytopenia of 2% (<20,000 cell/μL). Factors associated with an increased risk of thrombocytopenia were a history of thrombocytopenia on previous Abciximab exposure, readministration within 30 days, and a positive HACA assay prior to the readministration. Among 14 patients who had thrombocytopenia associated with a prior exposure to Abciximab, 7 (50%) had recurrent thrombocytopenia. In 130 patients with a readministration interval of 30 days or less, 25 (19%) developed thrombocytopenia. Severe thrombocytopenia occurred in 19 of these patients. Among the 71 patients who had a positive HACA assay at baseline, 11 (15%) developed thrombocytopenia, 7 of which were severe. ### Allergic Reactions There have been rare reports of allergic reactions, some of which were anaphylaxis . ### Other Adverse Reactions Table 5 shows adverse events other than bleeding and thrombocytopenia from the combined EPIC, EPILOG and CAPTURE trials which occurred in patients in the bolus plus infusion arm at an incidence of more than 0.5% higher than in those treated with placebo. The following additional adverse events from the EPIC, EPILOG and CAPTURE trials were reported by investigators for patients treated with a bolus plus infusion of Abciximab at incidences which were less than 0.5% higher than for patients in the placebo arm. Cardiovascular System: ventricular tachycardia (1.4%), pseudoaneurysm (0.8%), palpitation (0.5%), arteriovenous fistula (0.4%), incomplete AV block (0.3%), nodal arrhythmia (0.2%), complete AV block (0.1%), embolism (limb)(0.1%); thrombophlebitis (0.1%); Gastrointestinal System: dyspepsia (2.1%), diarrhea (1.1%), ileus (0.1%), gastroesophogeal reflux (0.1%); Hemic and Lymphatic System: anemia (1.3%), leukocytosis (0.5%), petechiae (0.2%); Nervous System: dizziness (2.9%), anxiety (1.7%), abnormal thinking (1.3%), agitation (0.7%), hypesthesia (0.6%), confusion (0.5%) muscle contractions (0.4%), coma (0.2%), hypertonia (0.2%), diplopia (0.1%); Respiratory System: pneumonia (0.4%), rales (0.4%), pleural effusion (0.3%), bronchitis (0.3%) bronchospasm (0.3%), pleurisy (0.2%), pulmonary embolism (0.2%), rhonchi (0.1%); Musculoskeletal System: myalgia (0.2%); Urogenital System: urinary retention (0.7%), dysuria (0.4%), abnormal renal function (0.4%), frequent micturition (0.1%), cystalgia (0.1%), urinary incontinence (0.1%), prostatitis (0.1%); Miscellaneous: pain (5.4%), sweating increased (1.0%), asthenia (0.7%), incisional pain (0.6%), pruritus (0.5%), abnormal vision (0.3%), edema (0.3%), wound (0.2%), abscess (0.2%), cellulitis (0.2%), peripheral coldness (0.2%), injection site pain (0.1%), dry mouth (0.1%), pallor (0.1%), diabetes mellitus (0.1%), hyperkalemia (0.1%), enlarged abdomen (0.1%), bullous eruption (0.1%), inflammation (0.1%), drug toxicity (0.1%). ### Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. In the EPIC, EPILOG, and CAPTURE trials, positive HACA responses occurred in approximately 5.8% of these patients receiving a first exposure to Abciximab. No increase in hypersensitivity or allergic reactions was observed with Abciximab treatment . In a study of readministration of Abciximab to patients the overall rate of HACA positivity prior to the readministration was 6% and increased post-readministration to 27%. Among the 36 subjects receiving a fourth or greater Abciximab exposure, HACA positive assays were observed post-readministration in 16 subjects (44%). There were no reports of serious allergic reactions or anaphylaxis. HACA positive status was associated with an increased risk of thrombocytopenia . The data reflect the percentage of patients whose test results were considered positive for antibodies to Abciximab using an ELISA assay, and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Abciximab with the incidence of antibodies to other products may be misleading. ## Postmarketing Experience FDA Package Insert for Abcixmab contains no information regarding Adverse Reactions. # Drug Interactions Formal drug interaction studies with Abciximab have not been conducted. Abciximab has been administered to patients with ischemic heart disease treated concomitantly with a broad range of medications used in the treatment of angina, myocardial infarction and hypertension. These medications have included heparin, warfarin, beta-adrenergic receptor blockers, calcium channel antagonists, angiotensin converting enzyme inhibitors, intravenous and oral nitrates, ticlopidine, and aspirin. Heparin, other anticoagulants, thrombolytics, and antiplatelet agents are associated with an increase in bleeding. Patients with HACA titers may have allergic or hypersensitivity reactions when treated with other diagnostic or therapeutic monoclonal antibodies. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Animal reproduction studies have not been conducted with Abciximab. It is also not known whether Abciximab can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Abciximab should be given to a pregnant woman only if clearly needed. Pregnancy Category (AUS): C There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Abciximab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Abciximab during labor and delivery. ### Nursing Mothers It is not known whether this drug is excreted in human milk or absorbed systemically after ingestion. Because many drugs are excreted in human milk, caution should be exercised when Abciximab is administered to a nursing woman. ### Pediatric Use Safety and effectiveness in pediatric patients have not been studied. ### Geriatic Use Of the total number of 7860 patients in the four Phase 3 trials, 2933 (37%) were 65 and over, while 653 (8%) were 75 and over. No overall differences in safety or efficacy were observed between patients of age 65 to less than 75 as compared to younger patients. The clinical experience is not adequate to determine whether patients of age 75 or greater respond differently than younger patients. ### Gender There is no FDA guidance on the use of Abciximab with respect to specific gender populations. ### Race There is no FDA guidance on the use of Abciximab with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Abciximab in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Abciximab in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Abciximab in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Abciximab in patients who are immunocompromised. # Administration and Monitoring ### Administration The safety and efficacy of Abciximab have only been investigated with concomitant administration of heparin and aspirin as described in clinical studies. In patients with failed PCIs, the continuous infusion of Abciximab should be stopped because there is no evidence for Abciximab efficacy in that setting. In the event of serious bleeding that cannot be controlled by compression, Abciximab and heparin should be discontinued immediately. The recommended dosage of Abciximab in adults is a 0.25 mg/kg intravenous bolus administered 10-60 minutes before the start of PCI, followed by a continuous intravenous infusion of 0.125 μg/kg/min (to a maximum of 10 μg/min) for 12 hours. Patients with unstable angina not responding to conventional medical therapy and who are planned to undergo PCI within 24 hours may be treated with an Abciximab 0.25 mg/kg intravenous bolus followed by an 18- to 24-hour intravenous infusion of 10 μg/min, concluding one hour after the PCI. ### Instructions for Administration Parenteral drug products should be inspected visually for particulate matter prior to administration. Preparations of Abciximab containing visibly opaque particles should NOT be used. Hypersensitivity reactions should be anticipated whenever protein solutions such as Abciximab are administered. Epinephrine, dopamine, theophylline, antihistamines and corticosteroids should be available for immediate use. If symptoms of an allergic reaction or anaphylaxis appear, the infusion should be stopped and appropriate treatment given . As with all parenteral drug products, aseptic procedures should be used during the administration of Abciximab. Withdraw the necessary amount of Abciximab for bolus injection into a syringe. Filter the bolus injection using a sterile, non-pyrogenic, low protein-binding 0.2 or 5 μm syringe filter (Millipore SLGV025LS or SLSV025LS or equivalent). Withdraw the necessary amount of Abciximab for the continuous infusion into a syringe. Inject into an appropriate container of sterile 0.9% saline or 5% dextrose and infuse at the calculated rate via a continuous infusion pump. The continuous infusion should be filtered either upon admixture using a sterile, non-pyrogenic, low protein-binding 0.2 or 5 μm syringe filter (Millipore SLGV025LS or SLSV025LS or equivalent) or upon administration using an in-line, sterile, non-pyrogenic, low protein-binding 0.2 or 0.22 μm filter (Abbott #4524 or equivalent). Discard the unused portion at the end of the infusion. No incompatibilities have been shown with intravenous infusion fluids or commonly used cardiovascular drugs. Nevertheless, Abciximab should be administered in a separate intravenous line whenever possible and not mixed with other medications. No incompatibilities have been observed with glass bottles or polyvinyl chloride bags and administration sets. ### Monitoring - Vascular puncture sites should be documented and monitored. - Any hematoma should be measured and monitored for enlargement. - Platelet counts should be monitored prior to, during, two to four hours following the bolus dose of Abciximab and at 24 hours or prior to discharge, whichever is first. If a patient experiences an acute platelet decrease (e.g., a platelet decrease to less than 100,000 cells/μL and a decrease of at least 25% from pre-treatment value), additional platelet counts should be determined. Platelet monitoring should continue until platelet counts return to normal. - If true thrombocytopenia is verified, Abciximab should be immediately discontinued and the condition appropriately monitored and treated. # IV Compatibility - No incompatibilities have been shown with intravenous infusion fluids or commonly used cardiovascular drugs. Nevertheless, Abciximab should be administered in a separate intravenous line whenever possible and not mixed with other medications. - No incompatibilities have been observed with glass bottles or polyvinyl chloride bags and administration sets. # Overdosage There has been no experience of overdosage in human clinical trials # Pharmacology ## Mechanism of Action The mechanism of action is thought to involve steric hindrance and/or conformational effects to block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. ## Structure Abciximab, ReoPro®, is the Fab fragment of the chimeric human-murine monoclonal antibody 7E3. Abciximab binds to the glycoprotein (GP) IIb/IIIa receptor of human platelets and inhibits platelet aggregation. Abciximab also binds to the vitronectin (αvβ3) receptor found on platelets and vessel wall endothelial and smooth muscle cells. The chimeric 7E3 antibody is produced by continuous perfusion in mammalian cell culture. The 47,615 dalton Fab fragment is purified from cell culture supernatant by a series of steps involving specific viral inactivation and removal procedures, digestion with papain and column chromatography. ReoPro® is a clear, colorless, sterile, non-pyrogenic solution for intravenous (IV) use. Each single use vial contains 2 mg/mL of Abciximab in a buffered solution (pH 7.2) of 0.01 M sodium phosphate, 0.15 M sodium chloride and 0.001% polysorbate 80 in Water for Injection. No preservatives are added. ## Pharmacodynamics Intravenous administration in humans of single bolus doses of Abciximab from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function as measured by ex vivo platelet aggregation in response to adenosine diphosphate (ADP) or by prolongation of bleeding time. At the two highest doses (0.25 and 0.30 mg/kg) at two hours post injection (the first time point evaluated), over 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation in response to 20 μM ADP was almost abolished. The median bleeding time increased to over 30 minutes at both doses compared with a baseline value of approximately five minutes. Intravenous administration in humans of a single bolus dose of 0.25 mg/kg followed by a continuous infusion of 10 μg/min for periods of 12 to 96 hours produced sustained high-grade GPIIb/IIIa receptor blockade (≥ 80%) and inhibition of platelet function (ex vivo platelet aggregation in response to 5 μM or 20 μM ADP less than 20% of baseline and bleeding time greater than 30 minutes) for the duration of the infusion in most patients. Similar results were obtained when a weight-adjusted infusion dose (0.125 μg/kg/min to a maximum of 10 μg/min) was used in patients weighing up to 80 kg. Results in patients who received the 0.25 mg/kg bolus followed by a 5 μg/min infusion for 24 hours showed a similar initial receptor blockade and inhibition of platelet aggregation, but the response was not maintained throughout the infusion period. The onset of Abciximab-mediated platelet inhibition following a 0.25 mg/kg bolus and 0.125 μg/kg/min infusion was rapid and platelet aggregation was reduced to less than 20% of baseline in 8 of 10 patients at 10 minutes after treatment initiation. Low levels of GPIIb/IIIa receptor blockade are present for more than 10 days following cessation of the infusion. After discontinuation of Abciximab infusion, platelet function returns gradually to normal. Bleeding time returned to ≤ 12 minutes within 12 hours following the end of infusion in 15 of 20 patients (75%), and within 24 hours in 18 of 20 patients (90%). Ex vivo platelet aggregation in response to 5 μM ADP returned to ≥ 50% of baseline within 24 hours following the end of infusion in 11 of 32 patients (34%) and within 48 hours in 23 of 32 patients (72%). In response to 20 μM ADP, ex vivo platelet aggregation returned to ≥ 50% of baseline within 24 hours in 20 of 32 patients (62%) and within 48 hours in 28 of 32 patients (88%). ## Pharmacokinetics Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. Platelet function generally recovers over the course of 48 hours (5,6), although Abciximab remains in the circulation for 15 days or more in a platelet-bound state. Intravenous administration of a 0.25 mg/kg bolus dose of Abciximab followed by continuous infusion of 10 μg/min (or a weight-adjusted infusion of 0.125 μg/kg/min to a maximum of 10 μg/min) produces approximately constant free plasma concentrations throughout the infusion. At the termination of the infusion period, free plasma concentrations fall rapidly for approximately six hours then decline at a slower rate. ## Nonclinical Toxicology In vitro and in vivo mutagenicity studies have not demonstrated any mutagenic effect. Long-term studies in animals have not been performed to evaluate the carcinogenic potential or effects on fertility in male or female animals. # Clinical Studies Abciximab has been studied in four Phase 3 clinical trials, all of which evaluated the effect of Abciximab in patients undergoing percutaneous coronary intervention (PCI): in patients at high risk for abrupt closure of the treated coronary vessel (EPIC), in a broader group of patients (EPILOG), in unstable angina patients not responding to conventional medical therapy (CAPTURE), and in patients suitable for either conventional angioplasty/atherectomy or primary stent implantation (EPILOG Stent; EPISTENT). Percutaneous intervention included balloon angioplasty, atherectomy, or stent placement. All trials involved the use of various, concomitant heparin dose regimens and, unless contraindicated, aspirin (325 mg) was administered orally two hours prior to the planned procedure and then once daily. EPIC was a multicenter, double-blind, placebo-controlled trial of Abciximab in patients undergoing percutaneous transluminal coronary angioplasty or atherectomy (PTCA) who were at high risk for abrupt closure of the treated coronary vessel (7). Patients were allocated to treatment with: 1) Abciximab bolus plus infusion for 12 hours; 2) Abciximab bolus plus placebo infusion, or; 3) placebo bolus plus infusion. All patients received concomitant heparin (10,000 to 12,000 U bolus followed by an infusion for 12 hours). The primary endpoint was the composite of death, myocardial infarction (MI), or urgent intervention for recurrent ischemia within 30 days of randomization. The primary endpoint event rates in the Abciximab bolus plus infusion group were reduced mostly in the first 48 hours and this benefit was sustained through 30 days (7), 6 months (8), and three years (9). EPILOG was a randomized, double-blind, multicenter, placebo-controlled trial which evaluated Abciximab in a broad population of patients undergoing PCI (excluding patients with myocardial infarction and unstable angina meeting the EPIC high risk criteria) (10). Study procedures emphasized discontinuation of heparin after the procedure with early femoral arterial sheath removal and careful access site management . EPILOG was a three-arm trial comparing Abciximab plus standard-dose heparin, Abciximab plus low-dose heparin, and placebo plus standard-dose heparin. Abciximab and heparin infusions were weight-adjusted in all arms. The Abciximab bolus plus infusion regimen was: 0.25 mg/kg bolus followed by a 0.125 μg/kg/min infusion (to a maximum of 10 μg/min) for 12 hours. The heparin regimen was either a standard-dose regimen (initial 100 U/kg bolus, target ACT ≥ 300 seconds) or a low-dose regimen (initial 70 U/kg bolus, target ACT ≥ 200 seconds). The primary endpoint of the EPILOG trial was the composite of death or MI occurring within 30 days of PCI. The composite of death, MI, or urgent intervention was an important secondary endpoint. The endpoint events in the Abciximab treatment group were reduced mostly in the first 48 hours and this benefit was sustained through 30 days and six months (10) and one year (11). The (Kaplan-Meier) endpoint event rates at 30 days are shown in Table 1. At the six-month follow up visit, the event rate for death, MI, or repeat (urgent or non-urgent) intervention remained lower in the Abciximab treatment arms (22.3% and 22.8%, respectively, for the standard- and low-dose heparin arms) than in the placebo arm (25.8%) and the event rate for death, MI, or urgent intervention was substantially lower in the Abciximab treatment arms (8.3% and 8.4%, respectively, for the standard- and low-dose heparin arms) than in the placebo arm (14.7%). The treatment associated effects continued to persist at the one-year follow up visit. The proportionate reductions in endpoint event rates were similar irrespective of the type of coronary intervention used (balloon angioplasty, atherectomy, or stent placement). Risk assessment using the American College of Cardiology/American Heart Association clinical/morphological criteria had large inter-observer variability. Consequently, a low risk subgroup could not be reproducibly identified in which to evaluate efficacy. The EPISTENT trial was a randomized, multicenter trial evaluating three different treatment strategies in patients undergoing PCI: conventional PTCA with Abciximab plus low-dose heparin, primary intracoronary stent implantation with Abciximab plus low-dose heparin, and primary intracoronary stent implantation with placebo plus standard-dose heparin (12). The heparin dose was weight-adjusted in all arms. The JJIS Palmaz-Schatz stent was used in over 90% of the patients receiving stents. The two stent arms were blinded with respect to study agent (Abciximab or placebo) and heparin dose; the PCI arm with Abciximab was open-label. The Abciximab bolus plus infusion regimen was the same as that used in the EPILOG trial. The standard-dose and low-dose heparin regimens were the same as those used in the EPILOG trial. All patients were to receive aspirin; ticlopidine, if given, was to be started prior to study agent. Patient and access site management guidelines were the same as those for EPILOG, including a strong recommendation for early sheath removal. The results demonstrated benefit in both Abciximab arms (i.e., with and without stents) compared with stenting alone on the composite of death, MI, or urgent intervention (repeat PCI or CABG) within 30 days of PCI (12). The (Kaplan-Meier) endpoint event rates at 30 days are shown in Table 2. This benefit was maintained at 6 months: 12.1% of patients in the placebo/stent group experienced death, MI, or urgent revascularization compared with 6.4% of patients in the Abciximab/stent group (p<0.001 vs placebo/stent) and 9.2% in the Abciximab/PTCA group (p=0.051 vs placebo/stent). At 6 months, a reduction in the composite of death, MI, or all repeat (urgent or non-urgent) intervention was observed in the Abciximab/stent group compared with the placebo/stent group (15.4% vs 20.4%, p=0.006); the rate of this composite endpoint was similar in the Abciximab/PTCA and placebo/stent groups (22.4% vs 20.4%, p=0.467). (13) CAPTURE was a randomized, double-blind, multicenter, placebo-controlled trial of the use of Abciximab in unstable angina patients not responding to conventional medical therapy for whom PCI was planned, but not immediately performed (14). The CAPTURE trial involved the administration of placebo or Abciximab starting 18 to 24 hours prior to PCI and continuing until one hour after completion of the intervention. Patients were assessed as having unstable angina not responding to conventional medical therapy if they had at least one episode of myocardial ischemia despite bed rest and at least two hours of therapy with intravenous heparin and oral or intravenous nitrates. These patients were enrolled into the CAPTURE trial, if during a screening angiogram, they were determined to have a coronary lesion amenable to PCI. Patients received a bolus dose and intravenous infusion of placebo or Abciximab for 18 to 24 hours. At the end of the infusion period, the intervention was performed. The Abciximab or placebo infusion was discontinued one hour following the intervention. Patients were treated with intravenous heparin and oral or intravenous nitrates throughout the 18- to 24-hour Abciximab infusion period prior to the PCI. The Abciximab dose was a 0.25 mg/kg bolus followed by a continuous infusion at a rate of 10 μg/min. The CAPTURE trial incorporated weight adjustment of the standard heparin dose only during the performance of the intervention, but did not investigate the effect of a lower heparin dose, and arterial sheaths were left in place for approximately 40 hours. The primary endpoint of the CAPTURE trial was the occurrence of any of the following events within 30 days of PCI: death, MI, or urgent intervention. The 30-day (Kaplan-Meier) primary endpoint event rates are shown in Table 3. The 30-day results are consistent with the results of the other three trials, with the greatest effects on the myocardial infarction and urgent intervention components of the composite endpoint. As secondary endpoints, the components of the composite endpoint were analyzed separately for the period prior to the PCI and the period from the beginning of the intervention through Day 30. The greatest difference in MI occurred in the post-intervention period: the rates of MI were lower in the Abciximab group compared with placebo (Abciximab 3.6%, placebo 6.1%). There was also a reduction in MI occurring prior to the PCI (Abciximab 0.6%, placebo 2.0%). An Abciximab-associated reduction in the incidence of urgent intervention occurred in the post-intervention period. No effect on mortality was observed in either period. At six months of follow up, the composite endpoint of death, MI, or all repeat intervention (urgent or non-urgent) was not different between the Abciximab and placebo groups (Abciximab 31.0%, placebo 30.8%, p=0.77). Mortality was uncommon in all four trials. Similar mortality rates were observed in all arms within each trial. Patient follow-up through one year of the EPISTENT trial suggested decreased mortality among patients treated with Abciximab and stent placement compared to patients treated with stent alone (8/794 vs. 19/809, p=0.037). Data from earlier studies with balloon angioplasty were not suggestive of the same benefit. In all four trials, the rates of acute MI were significantly lower in the groups treated with Abciximab. Most of the Abciximab treatment effect was seen in reduction in the rate of acute non-Q-wave MI. Urgent intervention rates were also lower in Abciximab-treated groups in these trials. ### Anticoagulation Weight-adjusted low dose heparin, weight-adjusted Abciximab, careful vascular access site management and discontinuation of heparin after the procedure with early femoral arterial sheath removal were used. The initial heparin bolus was based upon the results of the baseline ACT, according to the following regimen: ACT < 150 seconds: administer 70 U/kg heparin ACT 150 - 199 seconds: administer 50 U/kg heparin ACT ≥ 200 seconds: administer no heparin Additional 20 U/kg heparin boluses were given to achieve and maintain an ACT of ≥ 200 seconds during the procedure. Discontinuation of heparin immediately after the procedure and removal of the arterial sheath within six hours were strongly recommended in the trials. If prolonged heparin therapy or delayed sheath removal was clinically indicated, heparin was adjusted to keep the APTT at a target of 60 to 85 seconds (EPILOG) or 55 to 75 seconds (EPISTENT). Anticoagulation was initiated prior to the administration of Abciximab. Anticoagulation was initiated with an intravenous heparin infusion to achieve a target APTT of 60 to 85 seconds. The heparin infusion was not uniformly weight adjusted in this trial. The heparin infusion was maintained during the Abciximab infusion and was adjusted to achieve an ACT of 300 seconds or an APTT of 70 seconds during the PCI. Following the intervention, heparin management was as outlined above for the EPILOG trial. # How Supplied Abciximab (ReoPro®) 2 mg/mL is supplied in 5 mL vials containing 10 mg (NDC 0002-7140-01). ## Storage Vials should be stored at 2 to 8 °C (36 to 46 °F). Do not freeze. Do not shake. Do not use beyond the expiration date. Discard any unused portion left in the vial # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information FDA Package Insert for Abciximab contains no information regarding Patient Information. # Precautions with Alcohol Alcohol-Abciximab 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 Abciximab Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Abciximab Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Abciximab Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]; Aparna Vuppala, M.B.B.S. [3] # 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 Abciximab is a Platelet aggregation inhibitor that is FDA approved for the prophylaxis of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Common adverse reactions include chest pain, hypotension, injection site pain, abdominal pain,nausea, vomiting, bleeding, backache. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - Initial dosage: 0.25 mg/kg IV bolus (10-60 minutes before the start of PCI) - Maitaining dosage: 0.125 mg/kg/min IV for 12 hours (max 10 ug/min) - Dosing Information - Initial dosage: 0.25 mg/kg IV bolus (10-60 minutes before the start of PCI) - Maitaining dosage: 10 ug/min IV for 18- 24h (concluding one hour after the PCI) - The safety and efficacy of Abciximab have only been investigated with concomitant administration of heparin and aspirin - In patients with failed PCIs, the continuous infusion of Abciximab should be stopped because there is no evidence for Abciximab efficacy in that setting. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - Developed by: American College of Cardiology Foundation (ACCF) and American Heart Association (AHA) - Class of Recommendation: Class IIa - Level of Evidence: Level A - Recommendation - initial dosage: 0.25 mg/kg IV bolus (over 5 minutes) - maitaing dosage: 10 ug/min IV (continued for 12 hours unless complications developed) ### Non–Guideline-Supported Use - Dosing information - initial dosage: 0.25 mg/kg IV bolus’‘’ - maitaing dosage: 10 ug/min IV for 12h [1] - Dosing information - initial dosage: 0.25 mg/kg IV bolus - maitaing dosage: 10 ug/min IV for 12h [2] - Dosing information - initial dosage: 0.25 mg/kg IV bolus - maitaing dosage: 10 ug/min IV for 12h [3] - Dosing information - initial dosage: 0.25 mg/kg IV bolus - maitaing dosage: 10 ug/min IV for 12h [4] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) FDA Package Insert for Abciximab contains no information regarding Pediatric Indications and Dosage. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Abciximab in pediatric patients. ### Non–Guideline-Supported Use - Dosing information - loading dose: 0.25 mg/kg IV - follow-up: 0.125 mg/min IV for 12h [5] # Contraindications Because Abciximab may increase the risk of bleeding, Abciximab is contraindicated in the following clinical situations: - Active internal bleeding - Recent (within six weeks) gastrointestinal (GI) or genitourinary (GU) bleeding of clinical significance. - History of cerebrovascular accident (CVA) within two years, or CVA with a significant residual neurological deficit - Bleeding diathesis - Administration of oral anticoagulants within seven days unless prothrombin time is <1.2 times control - Thrombocytopenia (<100,000 cells/mL) - Recent (within six weeks) major surgery or trauma - Intracranial neoplasm, arteriovenous malformation, or aneurysm - Severe uncontrolled hypertension - Presumed or documented history of vasculitis - Use of intravenous dextran before PCI, or intent to use it during an intervention Abciximab is also contraindicated in patients with known hypersensitivity to any component of this product or to murine proteins. # Warnings Abciximab has the potential to increase the risk of bleeding events, rarely including those with a fatal outcome, particularly in the presence of anticoagulation, e.g., from heparin, other anticoagulants, or thrombolytics The risk of major bleeds due to Abciximab therapy is increased in patients receiving thrombolytics and should be weighed against the anticipated benefits. Should serious bleeding occur that is not controllable with pressure, the infusion of Abciximab and any concomitant heparin should be stopped. Allergic reactions, some of which were anaphylaxis (sometimes fatal), have been reported rarely in patients treated with ReoPro. Patients with allergic reactions should receive appropriate treatment. Treatment of anaphylaxis should include immediate discontinuation of ReoPro administration and initiation of resuscitative measures. ## Precautions To minimize the risk of bleeding with Abciximab, it is important to use a low-dose, weight-adjusted heparin regimen, a weight-adjusted Abciximab bolus and infusion, strict anticoagulation guidelines, careful vascular access site management, discontinuation of heparin after the procedure and early femoral arterial sheath removal. Therapy with Abciximab requires careful attention to all potential bleeding sites including catheter insertion sites, arterial and venous puncture sites, cutdown sites, needle puncture sites, and gastrointestinal, genitourinary, pulmonary (alveolar), and retroperitoneal sites. Arterial and venous punctures, intramuscular injections, and use of urinary catheters, nasotracheal intubation, nasogastric tubes and automatic blood pressure cuffs should be minimized. When obtaining intravenous access, non-compressible sites (e.g., subclavian or jugular veins) should be avoided. Saline or heparin locks should be considered for blood drawing. Vascular puncture sites should be documented and monitored. Gentle care should be provided when removing dressings. Arterial access site care is important to prevent bleeding. Care should be taken when attempting vascular access that only the anterior wall of the femoral artery is punctured, avoiding a Seldinger (through and through) technique for obtaining sheath access. Femoral vein sheath placement should be avoided unless needed. While the vascular sheath is in place, patients should be maintained on complete bed rest with the head of the bed ≤ 30° and the affected limb restrained in a straight position. Patients may be medicated for back/groin pain as necessary. Discontinuation of heparin immediately upon completion of the procedure and removal of the arterial sheath within six hours is strongly recommended if APTT ≤ 50 sec or ACT≤ 175 sec . In all circumstances, heparin should be discontinued at least two hours prior to arterial sheath removal. Following sheath removal, pressure should be applied to the femoral artery for at least 30 minutes using either manual compression or a mechanical device for hemostasis. A pressure dressing should be applied following hemostasis. The patient should be maintained on bed rest for six to eight hours following sheath removal or discontinuation of Abciximab, or four hours following discontinuation of heparin, whichever is later. The pressure dressing should be removed prior to ambulation. The sheath insertion site and distal pulses of affected leg(s) should be frequently checked while the femoral artery sheath is in place and for six hours after femoral artery sheath removal. Any hematoma should be measured and monitored for enlargement. The following conditions have been associated with an increased risk of bleeding and may be additive with the effect of Abciximab in the angioplasty setting: PCI within 12 hours of the onset of symptoms for acute myocardial infarction, prolonged PCI (lasting more than 70 minutes) and failed PCI. In the EPIC, EPILOG, CAPTURE, and EPISTENT trials, Abciximab was used concomitantly with heparin and aspirin. For details of the anticoagulation algorithms used in these clinical trials,: Anticoagulation. Because Abciximab inhibits platelet aggregation, caution should be employed when it is used with other drugs that affect hemostasis, including thrombolytics, oral anticoagulants, non-steroidal anti-inflammatory drugs, dipyridamole, and ticlopidine. In the EPIC trial, there was limited experience with the administration of Abciximab with low molecular weight dextran. Low molecular weight dextran was usually given for the deployment of a coronary stent, for which oral anticoagulants were also given. In the 11 patients who received low molecular weight dextran with Abciximab, five had major bleeding events and four had minor bleeding events. None of the five placebo patients treated with low molecular weight dextran had a major or minor bleeding event . Because of observed synergistic effects on bleeding, Abciximab therapy should be used judiciously in patients who have received systemic thrombolytic therapy. The GUSTO V trial randomized patients with acute myocardial infarction to treatment with combined Abciximab and half-dose Reteplase, or full-dose Reteplase alone (15). In this trial, the incidence of moderate or severe nonintracranial bleeding was increased in those patients receiving Abciximab and half-dose Reteplase versus those receiving Reteplase alone (4.6% versus 2.3%, respectively). Thrombocytopenia, including severe thrombocytopenia, has been observed with Abciximab administration . Platelet counts should be monitored prior to, during, and after treatment with Abciximab. Acute decreases in platelet count should be differentiated between true thrombocytopenia and pseudothrombocytopenia . If true thrombocytopenia is verified, Abciximab should be immediately discontinued and the condition appropriately monitored and treated. In clinical trials, patients who developed thrombocytopenia were followed with daily platelet counts until their platelet count returned to normal. Heparin and aspirin were discontinued for platelet counts below 60,000 cells/μL and platelets were transfused for a platelet count below 50,000 cells/μL. Most cases of severe thrombocytopenia (< 50,000 cells/μL) occurred within the first 24 hours of Abciximab administration. In a registry study of Abciximab readministration, a history of thrombocytopenia associated with prior use of Abciximab was predictive of an increased risk of recurrent thrombocytopenia . Readministration within 30 days was associated with an increased incidence and severity of thrombocytopenia, as was a positive human anti-chimeric antibody (HACA) test at baseline, compared to the rates seen in studies with first administration. Restoration of Platelet Function- In the event of serious uncontrolled bleeding or the need for emergency surgery, Abciximab should be discontinued. If platelet function does not return to normal, it may be restored, at least in part, with platelet transfusions. Before infusion of Abciximab, prothrombin time, ACT, APTT, and platelet count should be measured to identify pre-existing hemostatic abnormalities. Based on an integrated analysis of data from all studies, the following guidelines may be utilized to minimize the risk for bleeding: - When Abciximab is initiated 18 to 24 hours before PCI, the APTT should be maintained between 60 and 85 seconds during the Abciximab and heparin infusion period. - During PCI the ACT should be maintained between 200 and 300 seconds. - If anticoagulation is continued in these patients following PCI, the APTT should be maintained between 55 and 75 seconds. - The APTT or ACT should be checked prior to arterial sheath removal. The sheath should not be removed unless APTT ≤ 50 seconds or ACT ≤ 175 seconds. - Platelet counts should be monitored prior to treatment, two to four hours following the bolus dose of Abciximab and at 24 hours or prior to discharge, whichever is first. If a patient experiences an acute platelet decrease (e.g., a platelet decrease to less than 100,000 cells/μL and a decrease of at least 25% from pre-treatment value), additional platelet counts should be determined. Platelet monitoring should continue until platelet counts return to normal. - To exclude pseudothrombocytopenia, a laboratory artifact due to in vitro anticoagulant interaction, blood samples should be drawn in three separate tubes containing ethylenediaminetetraacetic acid (EDTA), citrate and heparin, respectively. A low platelet count in EDTA but not in heparin and/or citrate is supportive of a diagnosis of pseudothrombocytopenia. Administration of Abciximab may result in the formation of HACA that could potentially cause allergic or hypersensitivity reactions (including anaphylaxis), thrombocytopenia or diminished benefit upon readministration of Abciximab . Readministration of Abciximab to patients undergoing PCI was assessed in a registry that included 1342 treatments in 1286 patients. Most patients were receiving their second Abciximab exposure; 15% were receiving the third or subsequent exposure. The overall rate of HACA positivity prior to the readministration was 6% and increased to 27% post-readministration. There were no reports of serious allergic reactions or anaphylaxis . Thrombocytopenia was observed at higher rates in the readministration study than in the phase 3 studies of first-time administration , suggesting that readministration may be associated with an increased incidence and severity of thrombocytopenia. # Adverse Reactions ## Clinical Trials Experience ### Bleeding Abciximab has the potential to increase the risk of bleeding, particularly in the presence of anticoagulation, e.g., from heparin, other anticoagulants or thrombolytics. Bleeding in the Phase 3 trials was classified as major, minor or insignificant by the criteria of the Thrombolysis in Myocardial Infarction study group (16). Major bleeding events were defined as either an intracranial hemorrhage or a decrease in hemoglobin greater than 5 g/dL. Minor bleeding events included spontaneous gross hematuria, spontaneous hematemesis, observed blood loss with a hemoglobin decrease of more than 3 g/dL, or a decrease in hemoglobin of at least 4 g/dL without an identified bleeding site. Insignificant bleeding events were defined as a decrease in hemoglobin of less than 3 g/dL or a decrease in hemoglobin between 3-4 g/dL without observed bleeding. In patients who received transfusions, the number of units of blood lost was estimated through an adaptation of the method of Landefeld, et al. (17). In the EPIC trial, in which a non-weight-adjusted, longer-duration heparin dose regimen was used, the most common complication during Abciximab therapy was bleeding during the first 36 hours. The incidences of major bleeding, minor bleeding and transfusion of blood products were significantly increased. Major bleeding occurred in 10.6% of patients in the Abciximab bolus plus infusion arm compared with 3.3% of patients in the placebo arm. Minor bleeding was seen in 16.8% of Abciximab bolus plus infusion patients and 9.2% of placebo patients (7). Approximately 70% of Abciximab-treated patients with major bleeding had bleeding at the arterial access site in the groin. Abciximab-treated patients also had a higher incidence of major bleeding events from gastrointestinal, genitourinary, retroperitoneal, and other sites. Bleeding rates were reduced in the CAPTURE trial, and further reduced in the EPILOG and EPISTENT trials by use of modified dosing regimens and specific patient management techniques. In EPILOG and EPISTENT, using the heparin and Abciximab dosing, sheath removal and arterial access site guidelines described under PRECAUTIONS, the incidence of major bleeding in patients treated with Abciximab and low-dose, weight-adjusted heparin was not significantly different from that in patients receiving placebo. Subgroup analyses in the EPIC and CAPTURE trials showed that non-CABG major bleeding was more common in Abciximab patients weighing ≤ 75 kg. In the EPILOG and EPISTENT trials, which used weight-adjusted heparin dosing, the non-CABG major bleeding rates for Abciximab-treated patients did not differ substantially by weight subgroup. Although data are limited, Abciximab treatment was not associated with excess major bleeding in patients who underwent CABG surgery. (The range among all treatment arms was 3-5% in EPIC, and 1-2% in the CAPTURE, EPILOG, and EPISTENT trials.) Some patients with prolonged bleeding times received platelet transfusions to correct the bleeding time prior to surgery. The rates of major bleeding, minor bleeding and bleeding events requiring transfusions in the CAPTURE, EPILOG, and EPISTENT trials are shown in Table 4. The rates of insignificant bleeding events are not included in Table 4. Cases of fatal bleeding have been reported rarely during post-marketing use of Abciximab Pulmonary alveolar hemorrhage has been rarely reported during use of Abciximab. This can present with any or all of the following in close association with ReoPro administration: hypoxemia, alveolar infiltrates on chest x-ray, hemoptysis, or an unexplained drop in hemoglobin. ### Intracranial Hemorrhage and Stroke The total incidence of intracranial hemorrhage and non-hemorrhagic stroke across all four trials was not significantly different, 9/3023 for placebo patients and 15/4680 for Abciximab-treated patients. The incidence of intracranial hemorrhage was 3/3023 for placebo patients and 7/4680 for Abciximab patients. ### Thrombocytopenia In the clinical trials, patients treated with Abciximab were more likely than patients treated with placebo to experience decreases in platelet counts. Among patients in the EPILOG and EPISTENT trials who were treated with Abciximab plus low-dose heparin, the proportion of patients with any thrombocytopenia (platelets less than 100,000 cells/μL) ranged from 2.5 to 3.0%. The incidence of severe thrombocytopenia (platelets less than 50,000 cells/μL) ranged from 0.4 to 1.0% and platelet transfusions were required in 0.9 to 1.1%, respectively. Modestly lower rates were observed among patients treated with placebo plus standard-dose heparin. Overall higher rates were observed among patients in the EPIC and CAPTURE trials treated with Abciximab plus longer duration heparin: 2.6 to 5.2% were found to have any thrombocytopenia, 0.9 to 1.7% had severe thrombocytopenia, and 2.1 to 5.5% required platelet transfusion, respectively. In a readministration registry study of patients receiving a second or subsequent exposure to Abciximab the incidence of any degree of thrombocytopenia was 5%, with an incidence of profound thrombocytopenia of 2% (<20,000 cell/μL). Factors associated with an increased risk of thrombocytopenia were a history of thrombocytopenia on previous Abciximab exposure, readministration within 30 days, and a positive HACA assay prior to the readministration. Among 14 patients who had thrombocytopenia associated with a prior exposure to Abciximab, 7 (50%) had recurrent thrombocytopenia. In 130 patients with a readministration interval of 30 days or less, 25 (19%) developed thrombocytopenia. Severe thrombocytopenia occurred in 19 of these patients. Among the 71 patients who had a positive HACA assay at baseline, 11 (15%) developed thrombocytopenia, 7 of which were severe. ### Allergic Reactions There have been rare reports of allergic reactions, some of which were anaphylaxis . ### Other Adverse Reactions Table 5 shows adverse events other than bleeding and thrombocytopenia from the combined EPIC, EPILOG and CAPTURE trials which occurred in patients in the bolus plus infusion arm at an incidence of more than 0.5% higher than in those treated with placebo. The following additional adverse events from the EPIC, EPILOG and CAPTURE trials were reported by investigators for patients treated with a bolus plus infusion of Abciximab at incidences which were less than 0.5% higher than for patients in the placebo arm. Cardiovascular System: ventricular tachycardia (1.4%), pseudoaneurysm (0.8%), palpitation (0.5%), arteriovenous fistula (0.4%), incomplete AV block (0.3%), nodal arrhythmia (0.2%), complete AV block (0.1%), embolism (limb)(0.1%); thrombophlebitis (0.1%); Gastrointestinal System: dyspepsia (2.1%), diarrhea (1.1%), ileus (0.1%), gastroesophogeal reflux (0.1%); Hemic and Lymphatic System: anemia (1.3%), leukocytosis (0.5%), petechiae (0.2%); Nervous System: dizziness (2.9%), anxiety (1.7%), abnormal thinking (1.3%), agitation (0.7%), hypesthesia (0.6%), confusion (0.5%) muscle contractions (0.4%), coma (0.2%), hypertonia (0.2%), diplopia (0.1%); Respiratory System: pneumonia (0.4%), rales (0.4%), pleural effusion (0.3%), bronchitis (0.3%) bronchospasm (0.3%), pleurisy (0.2%), pulmonary embolism (0.2%), rhonchi (0.1%); Musculoskeletal System: myalgia (0.2%); Urogenital System: urinary retention (0.7%), dysuria (0.4%), abnormal renal function (0.4%), frequent micturition (0.1%), cystalgia (0.1%), urinary incontinence (0.1%), prostatitis (0.1%); Miscellaneous: pain (5.4%), sweating increased (1.0%), asthenia (0.7%), incisional pain (0.6%), pruritus (0.5%), abnormal vision (0.3%), edema (0.3%), wound (0.2%), abscess (0.2%), cellulitis (0.2%), peripheral coldness (0.2%), injection site pain (0.1%), dry mouth (0.1%), pallor (0.1%), diabetes mellitus (0.1%), hyperkalemia (0.1%), enlarged abdomen (0.1%), bullous eruption (0.1%), inflammation (0.1%), drug toxicity (0.1%). ### Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. In the EPIC, EPILOG, and CAPTURE trials, positive HACA responses occurred in approximately 5.8% of these patients receiving a first exposure to Abciximab. No increase in hypersensitivity or allergic reactions was observed with Abciximab treatment . In a study of readministration of Abciximab to patients the overall rate of HACA positivity prior to the readministration was 6% and increased post-readministration to 27%. Among the 36 subjects receiving a fourth or greater Abciximab exposure, HACA positive assays were observed post-readministration in 16 subjects (44%). There were no reports of serious allergic reactions or anaphylaxis. HACA positive status was associated with an increased risk of thrombocytopenia . The data reflect the percentage of patients whose test results were considered positive for antibodies to Abciximab using an ELISA assay, and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Abciximab with the incidence of antibodies to other products may be misleading. ## Postmarketing Experience FDA Package Insert for Abcixmab contains no information regarding Adverse Reactions. # Drug Interactions Formal drug interaction studies with Abciximab have not been conducted. Abciximab has been administered to patients with ischemic heart disease treated concomitantly with a broad range of medications used in the treatment of angina, myocardial infarction and hypertension. These medications have included heparin, warfarin, beta-adrenergic receptor blockers, calcium channel antagonists, angiotensin converting enzyme inhibitors, intravenous and oral nitrates, ticlopidine, and aspirin. Heparin, other anticoagulants, thrombolytics, and antiplatelet agents are associated with an increase in bleeding. Patients with HACA titers may have allergic or hypersensitivity reactions when treated with other diagnostic or therapeutic monoclonal antibodies. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Animal reproduction studies have not been conducted with Abciximab. It is also not known whether Abciximab can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Abciximab should be given to a pregnant woman only if clearly needed. Pregnancy Category (AUS): C There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Abciximab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Abciximab during labor and delivery. ### Nursing Mothers It is not known whether this drug is excreted in human milk or absorbed systemically after ingestion. Because many drugs are excreted in human milk, caution should be exercised when Abciximab is administered to a nursing woman. ### Pediatric Use Safety and effectiveness in pediatric patients have not been studied. ### Geriatic Use Of the total number of 7860 patients in the four Phase 3 trials, 2933 (37%) were 65 and over, while 653 (8%) were 75 and over. No overall differences in safety or efficacy were observed between patients of age 65 to less than 75 as compared to younger patients. The clinical experience is not adequate to determine whether patients of age 75 or greater respond differently than younger patients. ### Gender There is no FDA guidance on the use of Abciximab with respect to specific gender populations. ### Race There is no FDA guidance on the use of Abciximab with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Abciximab in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Abciximab in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Abciximab in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Abciximab in patients who are immunocompromised. # Administration and Monitoring ### Administration The safety and efficacy of Abciximab have only been investigated with concomitant administration of heparin and aspirin as described in clinical studies. In patients with failed PCIs, the continuous infusion of Abciximab should be stopped because there is no evidence for Abciximab efficacy in that setting. In the event of serious bleeding that cannot be controlled by compression, Abciximab and heparin should be discontinued immediately. The recommended dosage of Abciximab in adults is a 0.25 mg/kg intravenous bolus administered 10-60 minutes before the start of PCI, followed by a continuous intravenous infusion of 0.125 μg/kg/min (to a maximum of 10 μg/min) for 12 hours. Patients with unstable angina not responding to conventional medical therapy and who are planned to undergo PCI within 24 hours may be treated with an Abciximab 0.25 mg/kg intravenous bolus followed by an 18- to 24-hour intravenous infusion of 10 μg/min, concluding one hour after the PCI. ### Instructions for Administration Parenteral drug products should be inspected visually for particulate matter prior to administration. Preparations of Abciximab containing visibly opaque particles should NOT be used. Hypersensitivity reactions should be anticipated whenever protein solutions such as Abciximab are administered. Epinephrine, dopamine, theophylline, antihistamines and corticosteroids should be available for immediate use. If symptoms of an allergic reaction or anaphylaxis appear, the infusion should be stopped and appropriate treatment given . As with all parenteral drug products, aseptic procedures should be used during the administration of Abciximab. Withdraw the necessary amount of Abciximab for bolus injection into a syringe. Filter the bolus injection using a sterile, non-pyrogenic, low protein-binding 0.2 or 5 μm syringe filter (Millipore SLGV025LS or SLSV025LS or equivalent). Withdraw the necessary amount of Abciximab for the continuous infusion into a syringe. Inject into an appropriate container of sterile 0.9% saline or 5% dextrose and infuse at the calculated rate via a continuous infusion pump. The continuous infusion should be filtered either upon admixture using a sterile, non-pyrogenic, low protein-binding 0.2 or 5 μm syringe filter (Millipore SLGV025LS or SLSV025LS or equivalent) or upon administration using an in-line, sterile, non-pyrogenic, low protein-binding 0.2 or 0.22 μm filter (Abbott #4524 or equivalent). Discard the unused portion at the end of the infusion. No incompatibilities have been shown with intravenous infusion fluids or commonly used cardiovascular drugs. Nevertheless, Abciximab should be administered in a separate intravenous line whenever possible and not mixed with other medications. No incompatibilities have been observed with glass bottles or polyvinyl chloride bags and administration sets. ### Monitoring - Vascular puncture sites should be documented and monitored. - Any hematoma should be measured and monitored for enlargement. - Platelet counts should be monitored prior to, during, two to four hours following the bolus dose of Abciximab and at 24 hours or prior to discharge, whichever is first. If a patient experiences an acute platelet decrease (e.g., a platelet decrease to less than 100,000 cells/μL and a decrease of at least 25% from pre-treatment value), additional platelet counts should be determined. Platelet monitoring should continue until platelet counts return to normal. - If true thrombocytopenia is verified, Abciximab should be immediately discontinued and the condition appropriately monitored and treated. # IV Compatibility - No incompatibilities have been shown with intravenous infusion fluids or commonly used cardiovascular drugs. Nevertheless, Abciximab should be administered in a separate intravenous line whenever possible and not mixed with other medications. - No incompatibilities have been observed with glass bottles or polyvinyl chloride bags and administration sets. # Overdosage There has been no experience of overdosage in human clinical trials # Pharmacology ## Mechanism of Action The mechanism of action is thought to involve steric hindrance and/or conformational effects to block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. ## Structure Abciximab, ReoPro®, is the Fab fragment of the chimeric human-murine monoclonal antibody 7E3. Abciximab binds to the glycoprotein (GP) IIb/IIIa receptor of human platelets and inhibits platelet aggregation. Abciximab also binds to the vitronectin (αvβ3) receptor found on platelets and vessel wall endothelial and smooth muscle cells. The chimeric 7E3 antibody is produced by continuous perfusion in mammalian cell culture. The 47,615 dalton Fab fragment is purified from cell culture supernatant by a series of steps involving specific viral inactivation and removal procedures, digestion with papain and column chromatography. ReoPro® is a clear, colorless, sterile, non-pyrogenic solution for intravenous (IV) use. Each single use vial contains 2 mg/mL of Abciximab in a buffered solution (pH 7.2) of 0.01 M sodium phosphate, 0.15 M sodium chloride and 0.001% polysorbate 80 in Water for Injection. No preservatives are added. ## Pharmacodynamics Intravenous administration in humans of single bolus doses of Abciximab from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function as measured by ex vivo platelet aggregation in response to adenosine diphosphate (ADP) or by prolongation of bleeding time. At the two highest doses (0.25 and 0.30 mg/kg) at two hours post injection (the first time point evaluated), over 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation in response to 20 μM ADP was almost abolished. The median bleeding time increased to over 30 minutes at both doses compared with a baseline value of approximately five minutes. Intravenous administration in humans of a single bolus dose of 0.25 mg/kg followed by a continuous infusion of 10 μg/min for periods of 12 to 96 hours produced sustained high-grade GPIIb/IIIa receptor blockade (≥ 80%) and inhibition of platelet function (ex vivo platelet aggregation in response to 5 μM or 20 μM ADP less than 20% of baseline and bleeding time greater than 30 minutes) for the duration of the infusion in most patients. Similar results were obtained when a weight-adjusted infusion dose (0.125 μg/kg/min to a maximum of 10 μg/min) was used in patients weighing up to 80 kg. Results in patients who received the 0.25 mg/kg bolus followed by a 5 μg/min infusion for 24 hours showed a similar initial receptor blockade and inhibition of platelet aggregation, but the response was not maintained throughout the infusion period. The onset of Abciximab-mediated platelet inhibition following a 0.25 mg/kg bolus and 0.125 μg/kg/min infusion was rapid and platelet aggregation was reduced to less than 20% of baseline in 8 of 10 patients at 10 minutes after treatment initiation. Low levels of GPIIb/IIIa receptor blockade are present for more than 10 days following cessation of the infusion. After discontinuation of Abciximab infusion, platelet function returns gradually to normal. Bleeding time returned to ≤ 12 minutes within 12 hours following the end of infusion in 15 of 20 patients (75%), and within 24 hours in 18 of 20 patients (90%). Ex vivo platelet aggregation in response to 5 μM ADP returned to ≥ 50% of baseline within 24 hours following the end of infusion in 11 of 32 patients (34%) and within 48 hours in 23 of 32 patients (72%). In response to 20 μM ADP, ex vivo platelet aggregation returned to ≥ 50% of baseline within 24 hours in 20 of 32 patients (62%) and within 48 hours in 28 of 32 patients (88%). ## Pharmacokinetics Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. Platelet function generally recovers over the course of 48 hours (5,6), although Abciximab remains in the circulation for 15 days or more in a platelet-bound state. Intravenous administration of a 0.25 mg/kg bolus dose of Abciximab followed by continuous infusion of 10 μg/min (or a weight-adjusted infusion of 0.125 μg/kg/min to a maximum of 10 μg/min) produces approximately constant free plasma concentrations throughout the infusion. At the termination of the infusion period, free plasma concentrations fall rapidly for approximately six hours then decline at a slower rate. ## Nonclinical Toxicology In vitro and in vivo mutagenicity studies have not demonstrated any mutagenic effect. Long-term studies in animals have not been performed to evaluate the carcinogenic potential or effects on fertility in male or female animals. # Clinical Studies Abciximab has been studied in four Phase 3 clinical trials, all of which evaluated the effect of Abciximab in patients undergoing percutaneous coronary intervention (PCI): in patients at high risk for abrupt closure of the treated coronary vessel (EPIC), in a broader group of patients (EPILOG), in unstable angina patients not responding to conventional medical therapy (CAPTURE), and in patients suitable for either conventional angioplasty/atherectomy or primary stent implantation (EPILOG Stent; EPISTENT). Percutaneous intervention included balloon angioplasty, atherectomy, or stent placement. All trials involved the use of various, concomitant heparin dose regimens and, unless contraindicated, aspirin (325 mg) was administered orally two hours prior to the planned procedure and then once daily. EPIC was a multicenter, double-blind, placebo-controlled trial of Abciximab in patients undergoing percutaneous transluminal coronary angioplasty or atherectomy (PTCA) who were at high risk for abrupt closure of the treated coronary vessel (7). Patients were allocated to treatment with: 1) Abciximab bolus plus infusion for 12 hours; 2) Abciximab bolus plus placebo infusion, or; 3) placebo bolus plus infusion. All patients received concomitant heparin (10,000 to 12,000 U bolus followed by an infusion for 12 hours). The primary endpoint was the composite of death, myocardial infarction (MI), or urgent intervention for recurrent ischemia within 30 days of randomization. The primary endpoint event rates in the Abciximab bolus plus infusion group were reduced mostly in the first 48 hours and this benefit was sustained through 30 days (7), 6 months (8), and three years (9). EPILOG was a randomized, double-blind, multicenter, placebo-controlled trial which evaluated Abciximab in a broad population of patients undergoing PCI (excluding patients with myocardial infarction and unstable angina meeting the EPIC high risk criteria) (10). Study procedures emphasized discontinuation of heparin after the procedure with early femoral arterial sheath removal and careful access site management . EPILOG was a three-arm trial comparing Abciximab plus standard-dose heparin, Abciximab plus low-dose heparin, and placebo plus standard-dose heparin. Abciximab and heparin infusions were weight-adjusted in all arms. The Abciximab bolus plus infusion regimen was: 0.25 mg/kg bolus followed by a 0.125 μg/kg/min infusion (to a maximum of 10 μg/min) for 12 hours. The heparin regimen was either a standard-dose regimen (initial 100 U/kg bolus, target ACT ≥ 300 seconds) or a low-dose regimen (initial 70 U/kg bolus, target ACT ≥ 200 seconds). The primary endpoint of the EPILOG trial was the composite of death or MI occurring within 30 days of PCI. The composite of death, MI, or urgent intervention was an important secondary endpoint. The endpoint events in the Abciximab treatment group were reduced mostly in the first 48 hours and this benefit was sustained through 30 days and six months (10) and one year (11). The (Kaplan-Meier) endpoint event rates at 30 days are shown in Table 1. At the six-month follow up visit, the event rate for death, MI, or repeat (urgent or non-urgent) intervention remained lower in the Abciximab treatment arms (22.3% and 22.8%, respectively, for the standard- and low-dose heparin arms) than in the placebo arm (25.8%) and the event rate for death, MI, or urgent intervention was substantially lower in the Abciximab treatment arms (8.3% and 8.4%, respectively, for the standard- and low-dose heparin arms) than in the placebo arm (14.7%). The treatment associated effects continued to persist at the one-year follow up visit. The proportionate reductions in endpoint event rates were similar irrespective of the type of coronary intervention used (balloon angioplasty, atherectomy, or stent placement). Risk assessment using the American College of Cardiology/American Heart Association clinical/morphological criteria had large inter-observer variability. Consequently, a low risk subgroup could not be reproducibly identified in which to evaluate efficacy. The EPISTENT trial was a randomized, multicenter trial evaluating three different treatment strategies in patients undergoing PCI: conventional PTCA with Abciximab plus low-dose heparin, primary intracoronary stent implantation with Abciximab plus low-dose heparin, and primary intracoronary stent implantation with placebo plus standard-dose heparin (12). The heparin dose was weight-adjusted in all arms. The JJIS Palmaz-Schatz stent was used in over 90% of the patients receiving stents. The two stent arms were blinded with respect to study agent (Abciximab or placebo) and heparin dose; the PCI arm with Abciximab was open-label. The Abciximab bolus plus infusion regimen was the same as that used in the EPILOG trial. The standard-dose and low-dose heparin regimens were the same as those used in the EPILOG trial. All patients were to receive aspirin; ticlopidine, if given, was to be started prior to study agent. Patient and access site management guidelines were the same as those for EPILOG, including a strong recommendation for early sheath removal. The results demonstrated benefit in both Abciximab arms (i.e., with and without stents) compared with stenting alone on the composite of death, MI, or urgent intervention (repeat PCI or CABG) within 30 days of PCI (12). The (Kaplan-Meier) endpoint event rates at 30 days are shown in Table 2. This benefit was maintained at 6 months: 12.1% of patients in the placebo/stent group experienced death, MI, or urgent revascularization compared with 6.4% of patients in the Abciximab/stent group (p<0.001 vs placebo/stent) and 9.2% in the Abciximab/PTCA group (p=0.051 vs placebo/stent). At 6 months, a reduction in the composite of death, MI, or all repeat (urgent or non-urgent) intervention was observed in the Abciximab/stent group compared with the placebo/stent group (15.4% vs 20.4%, p=0.006); the rate of this composite endpoint was similar in the Abciximab/PTCA and placebo/stent groups (22.4% vs 20.4%, p=0.467). (13) CAPTURE was a randomized, double-blind, multicenter, placebo-controlled trial of the use of Abciximab in unstable angina patients not responding to conventional medical therapy for whom PCI was planned, but not immediately performed (14). The CAPTURE trial involved the administration of placebo or Abciximab starting 18 to 24 hours prior to PCI and continuing until one hour after completion of the intervention. Patients were assessed as having unstable angina not responding to conventional medical therapy if they had at least one episode of myocardial ischemia despite bed rest and at least two hours of therapy with intravenous heparin and oral or intravenous nitrates. These patients were enrolled into the CAPTURE trial, if during a screening angiogram, they were determined to have a coronary lesion amenable to PCI. Patients received a bolus dose and intravenous infusion of placebo or Abciximab for 18 to 24 hours. At the end of the infusion period, the intervention was performed. The Abciximab or placebo infusion was discontinued one hour following the intervention. Patients were treated with intravenous heparin and oral or intravenous nitrates throughout the 18- to 24-hour Abciximab infusion period prior to the PCI. The Abciximab dose was a 0.25 mg/kg bolus followed by a continuous infusion at a rate of 10 μg/min. The CAPTURE trial incorporated weight adjustment of the standard heparin dose only during the performance of the intervention, but did not investigate the effect of a lower heparin dose, and arterial sheaths were left in place for approximately 40 hours. The primary endpoint of the CAPTURE trial was the occurrence of any of the following events within 30 days of PCI: death, MI, or urgent intervention. The 30-day (Kaplan-Meier) primary endpoint event rates are shown in Table 3. The 30-day results are consistent with the results of the other three trials, with the greatest effects on the myocardial infarction and urgent intervention components of the composite endpoint. As secondary endpoints, the components of the composite endpoint were analyzed separately for the period prior to the PCI and the period from the beginning of the intervention through Day 30. The greatest difference in MI occurred in the post-intervention period: the rates of MI were lower in the Abciximab group compared with placebo (Abciximab 3.6%, placebo 6.1%). There was also a reduction in MI occurring prior to the PCI (Abciximab 0.6%, placebo 2.0%). An Abciximab-associated reduction in the incidence of urgent intervention occurred in the post-intervention period. No effect on mortality was observed in either period. At six months of follow up, the composite endpoint of death, MI, or all repeat intervention (urgent or non-urgent) was not different between the Abciximab and placebo groups (Abciximab 31.0%, placebo 30.8%, p=0.77). Mortality was uncommon in all four trials. Similar mortality rates were observed in all arms within each trial. Patient follow-up through one year of the EPISTENT trial suggested decreased mortality among patients treated with Abciximab and stent placement compared to patients treated with stent alone (8/794 vs. 19/809, p=0.037). Data from earlier studies with balloon angioplasty were not suggestive of the same benefit. In all four trials, the rates of acute MI were significantly lower in the groups treated with Abciximab. Most of the Abciximab treatment effect was seen in reduction in the rate of acute non-Q-wave MI. Urgent intervention rates were also lower in Abciximab-treated groups in these trials. ### Anticoagulation Weight-adjusted low dose heparin, weight-adjusted Abciximab, careful vascular access site management and discontinuation of heparin after the procedure with early femoral arterial sheath removal were used. The initial heparin bolus was based upon the results of the baseline ACT, according to the following regimen: ACT < 150 seconds: administer 70 U/kg heparin ACT 150 - 199 seconds: administer 50 U/kg heparin ACT ≥ 200 seconds: administer no heparin Additional 20 U/kg heparin boluses were given to achieve and maintain an ACT of ≥ 200 seconds during the procedure. Discontinuation of heparin immediately after the procedure and removal of the arterial sheath within six hours were strongly recommended in the trials. If prolonged heparin therapy or delayed sheath removal was clinically indicated, heparin was adjusted to keep the APTT at a target of 60 to 85 seconds (EPILOG) or 55 to 75 seconds (EPISTENT). Anticoagulation was initiated prior to the administration of Abciximab. Anticoagulation was initiated with an intravenous heparin infusion to achieve a target APTT of 60 to 85 seconds. The heparin infusion was not uniformly weight adjusted in this trial. The heparin infusion was maintained during the Abciximab infusion and was adjusted to achieve an ACT of 300 seconds or an APTT of 70 seconds during the PCI. Following the intervention, heparin management was as outlined above for the EPILOG trial. # How Supplied Abciximab (ReoPro®) 2 mg/mL is supplied in 5 mL vials containing 10 mg (NDC 0002-7140-01). ## Storage Vials should be stored at 2 to 8 °C (36 to 46 °F). Do not freeze. Do not shake. Do not use beyond the expiration date. Discard any unused portion left in the vial # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information FDA Package Insert for Abciximab contains no information regarding Patient Information. # Precautions with Alcohol Alcohol-Abciximab 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 Abciximab Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Abciximab Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Abciximab
c23a4545e705c82e37ce39cbaadd3db27a15257d	wikidoc	Pap smear	Pap smear Synonyms and keywords: Papanikolaou test; papanicolaou test; pap test; cervical smear; smear test # Overview In gynecology, Pap smear is a medical screening method, invented by Georgios Papanikolaou, primarily designed to detect premalignant and malignant processes in the ectocervix. It may also detect infections and abnormalities in the endocervix and endometrium. # Procedure The endocervix may be partially sampled with the device used to obtain the ectocervical sample, but due to the anatomy of this area, consistent and reliable sampling cannot be guaranteed. As abnormal endocervical cells may be sampled, those examining them are taught to recognize them. The endometrium is not directly sampled with the device used to sample the ectocervix. Cells may exfoliate onto the cervix and be collected from there, so as with endocervical cells, abnormal cells can be recognised if present but the Pap Test should not be used as a screening tool for endometrial malignancy. The pre-cancerous changes (called dysplasias or cervical or endocervical intraepithelial neoplasia) are usually caused by sexually transmitted human papillomaviruses (HPVs). The test aims to detect and prevent the progression of HPV-induced cervical cancer and other abnormalities in the female genital tract by sampling cells from the outer opening of the cervix (Latin for "neck") of the uterus and the endocervix. The sampling technique changed very little since its invention by Georgios Papanikolaou (1883–1962) to detect cyclic hormonal changes in vaginal cells in the early 20th century until the development of liquid based cell thinlayer technology. The test remains an effective, widely used method for early detection of cervical cancer and pre-cancer. The UK's call and recall system is among the best; estimates of its effectiveness vary widely but it may prevent about 700 deaths per year in the UK. It is not a perfect test. "A nurse performing 200 tests each year would prevent a death once in 38 years. During this time she or he would care for over 152 women with abnormal results, over 79 women would be referred for investigation, over 53 would have abnormal biopsy results, and over 17 would have persisting abnormalities for more than two years. At least one woman during the 38 years would die from cervical cancer despite being screened." HPV vaccine may offer better prospects in the long term. It is generally recommended that sexually active females seek Pap smear testing annually, although guidelines may vary from country to country. If results are abnormal, and depending on the nature of the abnormality, the test may need to be repeated in three to twelve months. If the abnormality requires closer scrutiny, the patient may be referred for detailed inspection of the cervix by colposcopy. The patient may also be referred for HPV DNA testing, which can serve as an adjunct (or even as an alternative) to Pap testing. About 5% to 7% of pap smears produce abnormal results, such as dysplasia, possibly indicating a pre-cancerous condition. Although many low grade cervical dysplasias spontaneously regress without ever leading to cervical cancer, dysplasia can serve as an indication that increased vigilance is needed. Endocervical and endometrial abnormalities can also be detected, as can a number of infectious processes, including yeast and Trichomonas vaginalis. A small proportion of abnormalities are reported as of "uncertain significance". # Technical Aspects Samples are collected from the outer opening or os of the cervix using an Aylesbury spatula or (more frequently with the advent of liquid-based cytology) a plastic-fronded broom. The cells are placed on a glass slide and checked for abnormalities in the laboratory. The sample is stained using the Papanicolaou technique, in which tinctorial dyes and acids are selectively retained by cells. Unstained cells can not be visualized with light microscopy. The stains chosen by Papanicolau were selected to highlight cytoplasmic keratinization, which actually has almost nothing to do with the nuclear features used to make diagnoses now. The sample is then screened by a specially trained and qualified cytotechnologist using a light microscope. The terminology for who screens the sample varies according the country; in the UK, the personnel are known as Cytoscreeners, Biomedical scientists (BMS), Advanced Practitioners and Pathologists. The latter two take responsibility for reporting the abnormal sample which may require further investigation. Studies of the accuracy of conventional cytology report: - Sensitivity 72% - Specificity 94% In the United States, physicians who fail to diagnose cervical cancer from a pap smear have been convicted of negligent homicide. In 1988 and 1989, Karen Smith had received pap smears which were argued to have "unequivocally" shown that she had cancer; yet the lab had not made the diagnosis. She died on March 8 1995. Later, a physician and a laboratory technician were convicted of negligent homicide. These events have led to even more rigorous quality assurance programs, and to emphasizing that this is a screening, not a diagnostic, test, associated with a small irreducible error rate. # Liquid Based Monolayer Cytology Since the mid-1990s, techniques based around placing the sample into a vial containing a liquid medium which preserves the cells have been increasingly used. The media are primarily ethanol based. Two of the types are Sure-Path (TriPath Imaging) and Thin-Prep (Cytyc Corp). Once placed into the vial, the sample is processed at the laboratory into a cell thin-layer, stained, and examined by light microscopy. The liquid sample has the advantage of being suitable for low and high risk HPV testing and reduced unsatisfactory specimens from 4.1% to 2.6%. Proper sample acquisition is crucial to the accuracy of the test; clearly, a cell that is not in the sample cannot be evaluated. Studies of the accuracy of liquid based monolayer cytology report: - Sensitivity 61% to 66% - Specificity 82% to 91% Some, but not all studies, report increased sensitivity from the liquid based smears. # Results In screening a general or low-risk population, most Pap results are normal. In the United States, about 2–3 million abnormal Pap smear results are found each year. Most abnormal results are mildly abnormal (ASC-US (typically 2–5% of Pap results) or low-grade squamous intraepithelial lesion (LSIL) (about 2% of results)), indicating HPV infection. Although most low-grade cervical dysplasias spontaneously regress without ever leading to cervical cancer, dysplasia can serve as an indication that increased vigilance is needed. In a typical scenario, about 0.5% of Pap results are high-grade SIL (HSIL), and less than 0.5% of results indicate cancer; 0.2 to 0.8% of results indicate Atypical Glandular Cells of Undetermined Significance (AGC-NOS). As liquid based preparations (LBPs) become a common medium for testing, atypical result rates have increased. The median rate for all preparations with low-grade squamous intraepithelial lesions using LBPs was 2.9% compared with a 2003 median rate of 2.1%. Rates for high-grade squamous intraepithelial lesions (median, 0.5%) and atypical squamous cells have changed little. Abnormal results are reported according to the Bethesda system. They include: - Squamous cell abnormalities (SIL) Atypical squamous cells of undetermined significance (ASC-US) Atypical squamous cells – cannot exclude HSIL (ASC-H) Low-grade squamous intraepithelial lesion (LGSIL or LSIL) High-grade squamous intraepithelial lesion (HGSIL or HSIL) Squamous cell carcinoma - Atypical squamous cells of undetermined significance (ASC-US) - Atypical squamous cells – cannot exclude HSIL (ASC-H) - Low-grade squamous intraepithelial lesion (LGSIL or LSIL) - High-grade squamous intraepithelial lesion (HGSIL or HSIL) - Squamous cell carcinoma - Glandular epithelial cell abnormalities Atypical Glandular Cells not otherwise specified (AGC or AGC-NOS) - Atypical Glandular Cells not otherwise specified (AGC or AGC-NOS) Endocervical and endometrial abnormalities can also be detected, as can a number of infectious processes, including yeast, herpes simplex virus and trichomoniasis. However it is not very sensitive at detecting these infections, so absence of detection on a Pap does not mean absence of the infection. # Effectiveness The Pap test, when combined with a regular program of screening and appropriate follow-up, can reduce cervical cancer deaths by up to 80%. Failure of prevention of cancer by the Pap test can occur for many reasons, including not getting regular screening, lack of appropriate follow up of abnormal results, and sampling and interpretation errors. In the US, over half of all invasive cancers occur in women that have never had a Pap smear; an additional 10 to 20% of cancers occur in women that have not had a Pap smear in the preceding five years. About one-quarter of US cervical cancers were in women that had an abnormal Pap smear, but did not get appropriate follow-up (woman did not return for care, or clinician did not perform recommended tests or treatment). Adenocarcinoma of the cervix has not been shown to be prevented by Pap tests. In the UK, which has a Pap smear screening program, Adenocarcinoma accounts for about 15% of all cervical cancers Estimates of the effectiveness of the United Kingdom's call and recall system vary widely, but it may prevent about 700 deaths per year in the UK. A medical practitioner performing 200 tests each year would prevent a death once in 38 years, while seeing 152 women with abnormal results, referring 79 for investigation, obtaining 53 abnormal biopsy results, and seeing 17 persisting abnormalities lasting longer than two years. At least one woman during the 38 years would die from cervical cancer despite being screened. Since the population of the UK is about 61 million, the maximum number of women who could be receiving Pap smears in the UK is around 15 million to 20 million (eliminating the percentage of the population under 20 and over 65). This would indicate that the use of Pap smear screening in the UK saves the life of 1 person for every approximately 20,000 people tested (assuming 15,000,000 are being tested yearly). If only 10,000,000 are actually tested each year, then it would save the life of 1 person for every approximately 15,000 people tested. # Human Papillomavirus Testing The presence of HPV indicates that the person has been infected, the majority of women who get infected will successfully clear the infection within 18 months. It is those who have an infection of prolonged duration with high risk types (e.g. types 16,18,31,45) that are more likely to develop Cervical Intraepithelial Neoplasia due to the effects that HPV has on DNA. Studies of the accuracy of HPV testing report: - Sensitivity 88% to 91% (for detecting CIN 3 or higher) to 97% (for detecting CIN2+) - Specificity 73% to 79% (for detecting CIN 3 or higher) to 93% (for detecting CIN 3 or higher) By adding the more sensitive HPV Test, the specificity may decline. However, the drop in specificity is not definite. If the specificity does decline, this results in increased numbers of false positive tests and many women who did not have disease having colposcopy and treatment. A worthwhile screening test requires a balance between the sensitivity and specificity to ensure that those having a disease are correctly identified as having it and equally importantly those not identifying those without the disease as having it. Due to the liquid based pap smears having a false negative rate of 15-35%, the American College of Obstetricians and Gynecologists and American Society for Colposcopy and Cervical Pathology have recommended the use of HPV testing in addition to the pap smear in all women over the age of 30. Regarding the role of HPV testing, randomized controlled trials have compared HPV to colposcopy. HPV testing appears as sensitive as immediate colposcopy while reducing the number of colposcopies needed. Randomized controlled trial have suggested that HPV testing could follow abnormal cytology or could precede cervical cytology examination. A study published in April 2007 suggested the act of performing a Pap smear produces an inflammatory cytokine response, which may initiate immunologic clearance of HPV, therefore reducing the risk of cervical cancer. Women who had even a single Pap smear in their history had a lower incidence of cancer. "A statistically significant decline in the HPV positivity rate correlated with the lifetime number of Pap smears received." # Automated Analysis In the last decade there have been successful attempts to develop automated, computer image analysis systems for screening. Automation may improve sensitivity and reduce unsatisfactory specimens. One of these has been FDA approved and functions in high volume reference laboratories, with human oversight. # Practical Aspects The physician or operator collecting a sample for the test inserts a speculum into the patient's vagina, to obtain a cell sample from the cervix. A pap smear appointment is normally not scheduled during menstruation. The procedure is usually just slightly painful, because of the neuroanatomy of the cervix. However, this can depend on the patient's anatomy, the skill of the practitioner, psychological factors, and other conditions. Results usually take about 3 weeks. Slight bleeding, cramps, and other discomfort can occur afterwards. Other tests, including the TruTest, an endometrial biopsy used for early detection of uterine cancer, can be performed during the same visit. # 2012 ACS, ASCCP and ASCP Release New Screening Guidelines for Cervical Cancer (DO NOT EDIT) # 2012 U.S. Preventive Services Task Force Recommendation Statement for Screening for Cervical Cancer (DO NOT EDIT)	Pap smear For patient information, click here Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] Synonyms and keywords: Papanikolaou test; papanicolaou test; pap test; cervical smear; smear test # Overview In gynecology, Pap smear is a medical screening method, invented by Georgios Papanikolaou, primarily designed to detect premalignant and malignant processes in the ectocervix. It may also detect infections and abnormalities in the endocervix and endometrium. # Procedure The endocervix may be partially sampled with the device used to obtain the ectocervical sample, but due to the anatomy of this area, consistent and reliable sampling cannot be guaranteed. As abnormal endocervical cells may be sampled, those examining them are taught to recognize them. The endometrium is not directly sampled with the device used to sample the ectocervix. Cells may exfoliate onto the cervix and be collected from there, so as with endocervical cells, abnormal cells can be recognised if present but the Pap Test should not be used as a screening tool for endometrial malignancy. The pre-cancerous changes (called dysplasias or cervical or endocervical intraepithelial neoplasia) are usually caused by sexually transmitted human papillomaviruses (HPVs). The test aims to detect and prevent the progression of HPV-induced cervical cancer and other abnormalities in the female genital tract by sampling cells from the outer opening of the cervix (Latin for "neck") of the uterus and the endocervix. The sampling technique changed very little since its invention by Georgios Papanikolaou (1883–1962) to detect cyclic hormonal changes in vaginal cells in the early 20th century until the development of liquid based cell thinlayer technology. The test remains an effective, widely used method for early detection of cervical cancer and pre-cancer. The UK's call and recall system is among the best; estimates of its effectiveness vary widely but it may prevent about 700 deaths per year in the UK. It is not a perfect test. "A nurse performing 200 tests each year would prevent a death once in 38 years. During this time she or he would care for over 152 women with abnormal results, over 79 women would be referred for investigation, over 53 would have abnormal biopsy results, and over 17 would have persisting abnormalities for more than two years. At least one woman during the 38 years would die from cervical cancer despite being screened."[1] HPV vaccine may offer better prospects in the long term. It is generally recommended that sexually active females seek Pap smear testing annually, although guidelines may vary from country to country. If results are abnormal, and depending on the nature of the abnormality, the test may need to be repeated in three to twelve months. If the abnormality requires closer scrutiny, the patient may be referred for detailed inspection of the cervix by colposcopy. The patient may also be referred for HPV DNA testing, which can serve as an adjunct (or even as an alternative) to Pap testing. About 5% to 7% of pap smears produce abnormal results, such as dysplasia, possibly indicating a pre-cancerous condition. Although many low grade cervical dysplasias spontaneously regress without ever leading to cervical cancer, dysplasia can serve as an indication that increased vigilance is needed. Endocervical and endometrial abnormalities can also be detected, as can a number of infectious processes, including yeast and Trichomonas vaginalis. A small proportion of abnormalities are reported as of "uncertain significance". # Technical Aspects Samples are collected from the outer opening or os of the cervix using an Aylesbury spatula or (more frequently with the advent of liquid-based cytology) a plastic-fronded broom. The cells are placed on a glass slide and checked for abnormalities in the laboratory. The sample is stained using the Papanicolaou technique, in which tinctorial dyes and acids are selectively retained by cells. Unstained cells can not be visualized with light microscopy. The stains chosen by Papanicolau were selected to highlight cytoplasmic keratinization, which actually has almost nothing to do with the nuclear features used to make diagnoses now. The sample is then screened by a specially trained and qualified cytotechnologist using a light microscope. The terminology for who screens the sample varies according the country; in the UK, the personnel are known as Cytoscreeners, Biomedical scientists (BMS), Advanced Practitioners and Pathologists. The latter two take responsibility for reporting the abnormal sample which may require further investigation. Studies of the accuracy of conventional cytology report: - Sensitivity 72%[2] - Specificity 94%[2] In the United States, physicians who fail to diagnose cervical cancer from a pap smear have been convicted of negligent homicide. In 1988 and 1989, Karen Smith had received pap smears which were argued to have "unequivocally" shown that she had cancer; yet the lab had not made the diagnosis. She died on March 8 1995. Later, a physician and a laboratory technician were convicted of negligent homicide. These events have led to even more rigorous quality assurance programs, and to emphasizing that this is a screening, not a diagnostic, test, associated with a small irreducible error rate. # Liquid Based Monolayer Cytology Since the mid-1990s, techniques based around placing the sample into a vial containing a liquid medium which preserves the cells have been increasingly used. The media are primarily ethanol based. Two of the types are Sure-Path (TriPath Imaging) and Thin-Prep (Cytyc Corp). Once placed into the vial, the sample is processed at the laboratory into a cell thin-layer, stained, and examined by light microscopy. The liquid sample has the advantage of being suitable for low and high risk HPV testing and reduced unsatisfactory specimens from 4.1% to 2.6%.[3] Proper sample acquisition is crucial to the accuracy of the test; clearly, a cell that is not in the sample cannot be evaluated. Studies of the accuracy of liquid based monolayer cytology report: - Sensitivity 61%[4] to 66%[2] - Specificity 82%[4] to 91%[2] Some[3], but not all studies[2][4], report increased sensitivity from the liquid based smears. # Results In screening a general or low-risk population, most Pap results are normal. In the United States, about 2–3 million abnormal Pap smear results are found each year.[5] Most abnormal results are mildly abnormal (ASC-US (typically 2–5% of Pap results) or low-grade squamous intraepithelial lesion (LSIL) (about 2% of results)), indicating HPV infection.[citation needed] Although most low-grade cervical dysplasias spontaneously regress without ever leading to cervical cancer, dysplasia can serve as an indication that increased vigilance is needed. In a typical scenario, about 0.5% of Pap results are high-grade SIL (HSIL), and less than 0.5% of results indicate cancer; 0.2 to 0.8% of results indicate Atypical Glandular Cells of Undetermined Significance (AGC-NOS).[citation needed] As liquid based preparations (LBPs) become a common medium for testing, atypical result rates have increased. The median rate for all preparations with low-grade squamous intraepithelial lesions using LBPs was 2.9% compared with a 2003 median rate of 2.1%. Rates for high-grade squamous intraepithelial lesions (median, 0.5%) and atypical squamous cells have changed little.[6] Abnormal results are reported according to the Bethesda system.[7] They include: - Squamous cell abnormalities (SIL) Atypical squamous cells of undetermined significance (ASC-US) Atypical squamous cells – cannot exclude HSIL (ASC-H) Low-grade squamous intraepithelial lesion (LGSIL or LSIL) High-grade squamous intraepithelial lesion (HGSIL or HSIL) Squamous cell carcinoma - Atypical squamous cells of undetermined significance (ASC-US) - Atypical squamous cells – cannot exclude HSIL (ASC-H) - Low-grade squamous intraepithelial lesion (LGSIL or LSIL) - High-grade squamous intraepithelial lesion (HGSIL or HSIL) - Squamous cell carcinoma - Glandular epithelial cell abnormalities Atypical Glandular Cells not otherwise specified (AGC or AGC-NOS) - Atypical Glandular Cells not otherwise specified (AGC or AGC-NOS) Endocervical and endometrial abnormalities can also be detected, as can a number of infectious processes, including yeast, herpes simplex virus and trichomoniasis. However it is not very sensitive at detecting these infections, so absence of detection on a Pap does not mean absence of the infection. # Effectiveness The Pap test, when combined with a regular program of screening and appropriate follow-up, can reduce cervical cancer deaths by up to 80%.[8] Failure of prevention of cancer by the Pap test can occur for many reasons, including not getting regular screening, lack of appropriate follow up of abnormal results, and sampling and interpretation errors.[9] In the US, over half of all invasive cancers occur in women that have never had a Pap smear; an additional 10 to 20% of cancers occur in women that have not had a Pap smear in the preceding five years. About one-quarter of US cervical cancers were in women that had an abnormal Pap smear, but did not get appropriate follow-up (woman did not return for care, or clinician did not perform recommended tests or treatment). Adenocarcinoma of the cervix has not been shown to be prevented by Pap tests.[9] In the UK, which has a Pap smear screening program, Adenocarcinoma accounts for about 15% of all cervical cancers[10] Estimates of the effectiveness of the United Kingdom's call and recall system vary widely, but it may prevent about 700 deaths per year in the UK. A medical practitioner performing 200 tests each year would prevent a death once in 38 years, while seeing 152 women with abnormal results, referring 79 for investigation, obtaining 53 abnormal biopsy results, and seeing 17 persisting abnormalities lasting longer than two years. At least one woman during the 38 years would die from cervical cancer despite being screened.[1] Since the population of the UK is about 61 million, the maximum number of women who could be receiving Pap smears in the UK is around 15 million to 20 million (eliminating the percentage of the population under 20 and over 65). This would indicate that the use of Pap smear screening in the UK saves the life of 1 person for every approximately 20,000 people tested (assuming 15,000,000 are being tested yearly). If only 10,000,000 are actually tested each year, then it would save the life of 1 person for every approximately 15,000 people tested. # Human Papillomavirus Testing The presence of HPV indicates that the person has been infected, the majority of women who get infected will successfully clear the infection within 18 months. It is those who have an infection of prolonged duration with high risk types[11] (e.g. types 16,18,31,45) that are more likely to develop Cervical Intraepithelial Neoplasia due to the effects that HPV has on DNA. Studies of the accuracy of HPV testing report: - Sensitivity 88% to 91% (for detecting CIN 3 or higher)[4] to 97% (for detecting CIN2+)[12] - Specificity 73% to 79% (for detecting CIN 3 or higher)[4] to 93% (for detecting CIN 3 or higher)[12] By adding the more sensitive HPV Test, the specificity may decline. However, the drop in specificity is not definite. [13] If the specificity does decline, this results in increased numbers of false positive tests and many women who did not have disease having colposcopy[14] and treatment. A worthwhile screening test requires a balance between the sensitivity and specificity to ensure that those having a disease are correctly identified as having it and equally importantly those not identifying those without the disease as having it. Due to the liquid based pap smears having a false negative rate of 15-35%, the American College of Obstetricians and Gynecologists and American Society for Colposcopy and Cervical Pathology[15] have recommended the use of HPV testing in addition to the pap smear in all women over the age of 30. Regarding the role of HPV testing, randomized controlled trials have compared HPV to colposcopy. HPV testing appears as sensitive as immediate colposcopy while reducing the number of colposcopies needed.[16] Randomized controlled trial have suggested that HPV testing could follow abnormal cytology[4] or could precede cervical cytology examination.[12] A study published in April 2007 suggested the act of performing a Pap smear produces an inflammatory cytokine response, which may initiate immunologic clearance of HPV, therefore reducing the risk of cervical cancer. Women who had even a single Pap smear in their history had a lower incidence of cancer. "A statistically significant decline in the HPV positivity rate correlated with the lifetime number of Pap smears received."[17] # Automated Analysis In the last decade there have been successful attempts to develop automated, computer image analysis systems for screening.[18] Automation may improve sensitivity and reduce unsatisfactory specimens.[19] One of these has been FDA approved and functions in high volume reference laboratories, with human oversight. # Practical Aspects The physician or operator collecting a sample for the test inserts a speculum into the patient's vagina, to obtain a cell sample from the cervix. A pap smear appointment is normally not scheduled during menstruation. The procedure is usually just slightly painful, because of the neuroanatomy of the cervix. However, this can depend on the patient's anatomy, the skill of the practitioner, psychological factors, and other conditions. Results usually take about 3 weeks. Slight bleeding, cramps, and other discomfort can occur afterwards. Other tests, including the TruTest, an endometrial biopsy used for early detection of uterine cancer, can be performed during the same visit. # 2012 ACS, ASCCP and ASCP Release New Screening Guidelines for Cervical Cancer (DO NOT EDIT)[20] # 2012 U.S. Preventive Services Task Force Recommendation Statement for Screening for Cervical Cancer (DO NOT EDIT)[21]	https://www.wikidoc.org/index.php/Abnormal_pap_smear
f2845ad54b0ccda570c9cf7915699fbb8e043751	wikidoc	Digestion	Digestion # Overview Digestion is the process of metabolism where by a biological entity processes a substance in order to chemically and mechanically convert the substance for the body to use. In mammals, preparation for digestion begins with the cephalic phase in which saliva is produced in the mouth and digestive enzymes are produced in the stomach. Mechanical and chemical digestion begin in the mouth where food is chewed, and mixed with saliva to break down starches. The stomach continues to break food down mechanically and chemically through the churning of the stomach and mixing with enzymes. Absorption occurs in the stomach and gastrointestinal tract, and the process finishes with excretion. Digestion occurs at the multicellular, cellular, and sub-cellular levels in animals and some plants. This process takes place in the digestive system, gastrointestinal tract, or alimentary canal. The digestive system as a whole is a one-way tube with accessory organs like the liver, gallbladder, and pancreas that assist in the chemical processes involved in digestion. Digestion is usually divided into mechanical processing to reduce the size of food particles and chemical action to further reduce the size of particles and prepare them for absorption. In most vertebrates, digestion is a multi-stage process in the digestive system, following ingestion of the raw materials, most often other organisms. The process of ingestion usually involves some type of mechanical and chemical processing. Digestion is separated into four separate processes: - Ingestion: placing food into the mouth - Mechanical digestion & chemical digestion: mastication to tear and crush food, and churning of the stomach. Addition of chemicals (acid, bile, enzymes, and water) to break down complex molecules into simple structures - Absorption: movement of nutrients from the digestive system to the circulatory and lymphatic capillaries through osmosis, active transport, and diffusion - Egestion: Removal of undigested materials from the digestive tract through defecation Underlying the process is muscle movement throughout the system, swallowing and peristalsis. # Human digestion process ## Phases of human digestion - Cephalic phase - This phase occurs before food enters the stomach and involves preparation of the body for eating and digestion. Sight and thought stimulate the cerebral cortex. Taste and smell stimulus is sent to the hypothalamus and medulla oblongata. After this it is routed through the vagus nerve. - Gastric phase - This phase takes 3 to 4 hours. It is stimulated by distention of the stomach and alkaline pH. Distention activates long and myentric reflexes. This activates the release of acetylcholine which stimulates the release of more gastric juices. As protein enters the stomach, it binds to hydrogen ions, which raises the pH of the stomach to an alkalinelevel. This triggers G cells to release gastrin, which in turn stimulates parietal cells to secrete HCl. HCl release is also triggered by acetylcholine and histamine. - Intestinal phase - This phase has 2 parts, the excitatory and the inhibitory. Partially-digested food fills the duodenum. This triggers intestinal gastrin to be released. Enterogastric reflex inhibits vagal nuclei, activating sympathetic fibers causing the pyloric sphincter to tighten to prevent more food from entering, and inhibits local reflexes. ## Oral cavity In humans, digestion begins in the oral cavity where food is chewed. Saliva is secreted in large amounts (1-1.5 litre/day) by three pairs of exocrine salivary glands (parotid, submandibular, and sublingual) in the oral cavity, and is mixed with the chewed food by the tongue. There are two types of saliva. One is a thin, watery secretion, and its purpose is to wet the food. The other is a thick, mucous secretion, and it acts as a lubricant and causes food particles to stick together and form a bolus. The saliva serves to clean the oral cavity and moisten the food, and contains digestive enzymes such as salivary amylase, which aids in the chemical breakdown of polysaccharides such as starch into disaccharides such as maltose. It also contains mucin, a glycoprotein which helps soften the food into a bolus. Swallowing transports the chewed food into the esophagus, passing through the oropharynx and hypopharynx. The mechanism for swallowing is coordinated by the swallowing center in the medulla oblongata and pons. The reflex is initiated by touch receptors in the pharynx as the bolus of food is pushed to the back of the mouth. ## Esophagus The esophagus, a narrow, muscular tube about 20 centimeters (8 inches) long, starts at the pharynx, passes through the thorax and diaphragm, and ends at the cardiac orifice of the stomach. The wall of the esophagus is made up of two layers of smooth muscles, which form a continuous layer from the esophagus to the rectum and contract slowly, over long periods of time. The inner layer of muscles is arranged circularly in a series of descending rings, while the outer layer is arranged longitudinally. At the top of the esophagus, is a flap of tissue called the epiglottis that closes during swallowing to prevent food from entering the trachea (windpipe). The chewed food is pushed down the esophagus to the stomach through peristaltic contraction of these muscles. It takes only seconds for food to pass through the esophagus, and little digestion actually takes place. ## Stomach The food enters the stomach after passing through the cardiac orifice. In the stomach, food is further broken apart, and thoroughly mixed with a gastric acid and digestive enzymes that break down proteins. The acid itself does not break down food molecules, rather, the acid provides an optimum pH for the reaction of the enzyme pepsin. The parietal cells of the stomach also secrete a glycoprotein called intrinsic factor which enables the absorption of vitamin B-12. Other small molecules such as alcohol are absorbed in the stomach as well by passing through the membrane of the stomach and entering the circulatory system directly. The transverse section of ailimentary canal reveals four distinct and well developed layers called serosa, muscular coat, submucosa and mucosa. Serosa: It is the outermost thin layer of single cells called mesothelial cells. Muscular coat: It is very well developed for churning of food. It has outer longitudinal, middle smooth and inner oblique muscles. Submucosa: It has connective tissue containing lymph vessels, blood vessels and nerves. Mucosa: It contains large folds filled with connective tissue. The gastric glands have a packing of lamina propria. Gastric glands may be simple or branched tubular secreting mucus, hydrochloric acid, pepsinogen and renin. ## Small intestine After being processed in the stomach, food is passed to the small intestine via the pyloric sphincter. The majority of digestion and absorption occur here as chyme enters the duodenum. Here it is further mixed with three different liquids: - bile, which emulsifies fats to allow absorption, neutralizes the chyme, and is used to excrete waste products such as bilin and bile acids (which has other uses as well). It is not an enzyme, however. - pancreatic juice made by the pancreas - intestinal enzymes of the alkaline mucosal membranes. The enzymes include: maltase, lactase and sucrase, to process sugars; trypsin and chymotrypsin are also added in the small intestine Most nutrient absorption takes place in the small intestine. As the acid level changes in the small intestines, more enzymes are activated to split apart the molecular structure of the various nutrients so they may be absorbed into the circulatory or lymphatic systems. Nutrients pass through the small intestine's wall, which contains small, finger-like structures called villi, each of which is covered with even smaller hair-like structures called microvilli. The blood, which has absorbed nutrients, is carried away from the small intestine via the hepatic portal vein and goes to the liver for filtering, removal of toxins, and nutrient processing. The small intestine and remainder of the digestive tract undergoes peristalsis to transport food from the stomach to the rectum and allow food to be mixed with the digestive juices and absorbed. The circular muscles and longitudinal muscles are antagonistic muscles, with one contracting as the other relaxes. When the circular muscles contract, the lumen becomes narrower and longer and the food is squeezed and pushed forward. When the longitudinal muscles contract, the circular muscles relax and the gut dilates to become wider and shorter to allow food to enter. In the stomach there is another phase that is called Mucus. ## Large intestine After the food has been passed through the small intestine, the food enters the large intestine. The large intestine is roughly 1.5 meters long, with three parts: the cecum at the junction with the small intestine, the colon, and the rectum. The colon itself has four parts: the ascending colon, the transverse colon, the descending colon, and the sigmoid colon. The large intestine absorbs water from the bolus and stores feces until it can be egested. Food products that cannot go through the villi, such as cellulose (dietary fiber), are mixed with other waste products from the body and become feces. ## Carbohydrate digestion Carbohydrates are formed in growing plants and are found in grains, leafy vegetables, and other edible plant foods. The molecular structure of these plants is complex, or a polysaccharide; poly is a prefix meaning many. Plants form carbohydrate chains during growth by trapping carbon from the atmosphere, initially carbon dioxide (CO2). Carbon is stored within the plant along with water (H2O) to form a complex starch containing a combination of carbon-hydrogen-oxygen in a fixed ratio of 1:2:1 respectively. Plants with a high sugar content and table sugar represent a less complex structure and are called disaccharides, or two sugar molecules bonded. Once digestion of either of these forms of carbohydrates are complete, the result is a single sugar structure, a monosaccharide. These monosaccharides can be absorbed into the blood and used by individual cells to produce the energy compound adenosine triphosphate (ATP). The digestive system starts the process of breaking down polysaccharides in the mouth through the introduction of amylase, a digestive enzyme in saliva. The high acid content of the stomach inhibits the enzyme activity, so carbohydrate digestion is suspended in the stomach. Upon emptying into the small intestines, potential hydrogen (pH) changes dramatically from a strong acid to an alkaline content. The pancreas secretes bicarbonate to neutralize the acid from the stomach, and the mucus secreted in the tissue lining the intestines is alkaline which promotes digestive enzyme activity. Amylase is present in the small intestines and works with other enzymes to complete the breakdown of carbohydrate into a monosaccharide which is absorbed into the surrounding capillaries of the villi. Nutrients in the blood are transported to the liver via the hepatic portal circuit, or loop, where final carbohydrate digestion is accomplished in the liver. The liver accomplishes carbohydrate digestion in response to the hormones insulin and glucagon. As blood glucose levels increase following digestion of a meal, the pancreas secretes insulin causing the liver to transform glucose to glycogen, which is stored in the liver, adipose tissue, and in muscle cells, preventing hyperglycemia. A few hours following a meal, blood glucose will drop due to muscle activity, and the pancreas will now secrete glucagon which causes glycogen to be converted into glucose to prevent hypoglycemia. Note: In the discussion of digestion of carbohydrates; nouns ending in the suffix -ose usually indicate a sugar, such as lactose. Nouns ending in the suffix -ase indicates the enzyme that will break down the sugar, such as lactase. Enzymes usually begin with the substrate (substance) they are breaking down. For example: maltose, a disaccharide, is broken down by the enzyme maltase (by the process of hydrolysis), resulting in a two glucose molecules, a monosaccharide. ## Fat digestion The presence of fat in the small intestine produces hormones which stimulate the release of lipase from the pancreas and bile from the gallbladder. The lipase (activated by acid) breaks down the fat into monoglycerides and fatty acids. The bile emulsifies the fatty acids so they may be easily absorbed. Short- and medium chain fatty acids are absorbed directly into the blood via intestine capillaries and travel through the portal vein just as other absorbed nutrients do. However, long chain fatty acids are too large to be directly released into the tiny intestinal capillaries. Instead they are absorbed into the fatty walls of the intestine villi and reassembled again into triglycerides. The triglycerides are coated with cholesterol and protein (protein coat) into a compound called a chylomicron. Within the villi, the chylomicron enters a lymphatic capillary called a lacteal, which merges into larger lymphatic vessels. It is transported via the lymphatic system and the thoracic duct up to a location near the heart (where the arteries and veins are larger). The thoracic duct empties the chylomicrons into the bloodstream via the left subclavian vein. At this point the chylomicrons can transport the triglycerides to where they are needed. ## Digestive hormones There are at least four hormones that aid and regulate the digestive system: - Gastrin - is in the stomach and stimulates the gastric glands to secrete pepsinogen(an inactive form of the enzyme pepsin) and hydrochloric acid. Secretion of gastrin is stimulated by food arriving in stomach. The secretion is inhibited by low pH . - Secretin - is in the duodenum and signals the secretion of sodium bicarbonate in the pancreas and it stimulates the bile secretion in the liver. This hormone responds to the acidity of the chyme. - Cholecystokinin (CCK) - is in the duodenum and stimulates the release of digestive enzymes in the pancreas and stimulates the emptying of bile in the gall bladder. This hormone is secreted in response to fat in chyme. - Gastric inhibitory peptide (GIP) - is in the duodenum and decreases the stomach churning in turn slowing the emptying in the stomach. Another function is to induce insulin secretion. ## Significance of pH in digestion Digestion is a complex process which is controlled by several factors. pH plays a crucial role in a normally functioning digestive tract. In the mouth, pharynx, and esophagus, pH is typically about 6.8, very weakly acidic. Saliva controls pH in this region of the digestive tract. Salivary amylase is contained in saliva and starts the breakdown of carbohydrates into monosaccharides. Most digestive enzymes are sensitive to pH and will not function in a low-pH environment like the stomach. Low pH (below 5) indicates a strong acid, while a high pH (above 8) indicates a strong base; the concentration of the acid or base, however, does also play a role. pH in the stomach is very acidic and inhibits the breakdown of carbohydrates while there. The strong acid content of the stomach provides two benefits, both serving to denature proteins for further digestion in the small intestines, as well as providing non-specific immunity, retarding or eliminating various pathogens. In the small intestines, the duodenum provides critical pH balancing to activate digestive enzymes. The liver secretes bile into the duodenum to neutralise the acidic conditions from the stomach. Also the pancreatic duct empties into the duodenum, adding bicarbonate to neutralize the acidic chyme, thus creating a neutral environment. The mucosal tissue of the small intestines is alkaline, creating a pH of about 8.5, thus enabling absorption in a mild alkaline in the environment. # Specialized organs in non-human animals Organisms have evolved specialized organs to aid in the digestion of their food, modifying tongues, teeth, and other organs to assist in digestion. Certain insects may have a crop or enlarged esophagus, while birds and cockroaches have developed gizzards to assist in the digestion of tough materials. Herbivores have evolved cecums (or an abomasum in the case of ruminants) to break down cellulose in plants.	Digestion Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Digestion is the process of metabolism where by a biological entity processes a substance in order to chemically and mechanically convert the substance for the body to use. In mammals, preparation for digestion begins with the cephalic phase in which saliva is produced in the mouth and digestive enzymes are produced in the stomach. Mechanical and chemical digestion begin in the mouth where food is chewed, and mixed with saliva to break down starches. The stomach continues to break food down mechanically and chemically through the churning of the stomach and mixing with enzymes. Absorption occurs in the stomach and gastrointestinal tract, and the process finishes with excretion. Digestion occurs at the multicellular, cellular, and sub-cellular levels in animals and some plants. This process takes place in the digestive system, gastrointestinal tract, or alimentary canal. The digestive system as a whole is a one-way tube with accessory organs like the liver, gallbladder, and pancreas that assist in the chemical processes involved in digestion. Digestion is usually divided into mechanical processing to reduce the size of food particles and chemical action to further reduce the size of particles and prepare them for absorption. In most vertebrates, digestion is a multi-stage process in the digestive system, following ingestion of the raw materials, most often other organisms. The process of ingestion usually involves some type of mechanical and chemical processing. Digestion is separated into four separate processes: - Ingestion: placing food into the mouth - Mechanical digestion & chemical digestion: mastication to tear and crush food, and churning of the stomach. Addition of chemicals (acid, bile, enzymes, and water) to break down complex molecules into simple structures - Absorption: movement of nutrients from the digestive system to the circulatory and lymphatic capillaries through osmosis, active transport, and diffusion - Egestion: Removal of undigested materials from the digestive tract through defecation Underlying the process is muscle movement throughout the system, swallowing and peristalsis. # Human digestion process ## Phases of human digestion - Cephalic phase - This phase occurs before food enters the stomach and involves preparation of the body for eating and digestion. Sight and thought stimulate the cerebral cortex. Taste and smell stimulus is sent to the hypothalamus and medulla oblongata. After this it is routed through the vagus nerve. - Gastric phase - This phase takes 3 to 4 hours. It is stimulated by distention of the stomach and alkaline pH. Distention activates long and myentric reflexes. This activates the release of acetylcholine which stimulates the release of more gastric juices. As protein enters the stomach, it binds to hydrogen ions, which raises the pH of the stomach to an alkalinelevel. This triggers G cells to release gastrin, which in turn stimulates parietal cells to secrete HCl. HCl release is also triggered by acetylcholine and histamine. - Intestinal phase - This phase has 2 parts, the excitatory and the inhibitory. Partially-digested food fills the duodenum. This triggers intestinal gastrin to be released. Enterogastric reflex inhibits vagal nuclei, activating sympathetic fibers causing the pyloric sphincter to tighten to prevent more food from entering, and inhibits local reflexes. ## Oral cavity In humans, digestion begins in the oral cavity where food is chewed. Saliva is secreted in large amounts (1-1.5 litre/day) by three pairs of exocrine salivary glands (parotid, submandibular, and sublingual) in the oral cavity, and is mixed with the chewed food by the tongue. There are two types of saliva. One is a thin, watery secretion, and its purpose is to wet the food. The other is a thick, mucous secretion, and it acts as a lubricant and causes food particles to stick together and form a bolus. The saliva serves to clean the oral cavity and moisten the food, and contains digestive enzymes such as salivary amylase, which aids in the chemical breakdown of polysaccharides such as starch into disaccharides such as maltose. It also contains mucin, a glycoprotein which helps soften the food into a bolus. Swallowing transports the chewed food into the esophagus, passing through the oropharynx and hypopharynx. The mechanism for swallowing is coordinated by the swallowing center in the medulla oblongata and pons. The reflex is initiated by touch receptors in the pharynx as the bolus of food is pushed to the back of the mouth. ## Esophagus The esophagus, a narrow, muscular tube about 20 centimeters (8 inches) long, starts at the pharynx, passes through the thorax and diaphragm, and ends at the cardiac orifice of the stomach. The wall of the esophagus is made up of two layers of smooth muscles, which form a continuous layer from the esophagus to the rectum and contract slowly, over long periods of time. The inner layer of muscles is arranged circularly in a series of descending rings, while the outer layer is arranged longitudinally. At the top of the esophagus, is a flap of tissue called the epiglottis that closes during swallowing to prevent food from entering the trachea (windpipe). The chewed food is pushed down the esophagus to the stomach through peristaltic contraction of these muscles. It takes only seconds for food to pass through the esophagus, and little digestion actually takes place. ## Stomach The food enters the stomach after passing through the cardiac orifice. In the stomach, food is further broken apart, and thoroughly mixed with a gastric acid and digestive enzymes that break down proteins. The acid itself does not break down food molecules, rather, the acid provides an optimum pH for the reaction of the enzyme pepsin. The parietal cells of the stomach also secrete a glycoprotein called intrinsic factor which enables the absorption of vitamin B-12. Other small molecules such as alcohol are absorbed in the stomach as well by passing through the membrane of the stomach and entering the circulatory system directly. The transverse section of ailimentary canal reveals four distinct and well developed layers called serosa, muscular coat, submucosa and mucosa. Serosa: It is the outermost thin layer of single cells called mesothelial cells. Muscular coat: It is very well developed for churning of food. It has outer longitudinal, middle smooth and inner oblique muscles. Submucosa: It has connective tissue containing lymph vessels, blood vessels and nerves. Mucosa: It contains large folds filled with connective tissue. The gastric glands have a packing of lamina propria. Gastric glands may be simple or branched tubular secreting mucus, hydrochloric acid, pepsinogen and renin. ## Small intestine After being processed in the stomach, food is passed to the small intestine via the pyloric sphincter. The majority of digestion and absorption occur here as chyme enters the duodenum. Here it is further mixed with three different liquids: - bile, which emulsifies fats to allow absorption, neutralizes the chyme, and is used to excrete waste products such as bilin and bile acids (which has other uses as well). It is not an enzyme, however. - pancreatic juice made by the pancreas - intestinal enzymes of the alkaline mucosal membranes. The enzymes include: maltase, lactase and sucrase, to process sugars; trypsin and chymotrypsin are also added in the small intestine Most nutrient absorption takes place in the small intestine. As the acid level changes in the small intestines, more enzymes are activated to split apart the molecular structure of the various nutrients so they may be absorbed into the circulatory or lymphatic systems. Nutrients pass through the small intestine's wall, which contains small, finger-like structures called villi, each of which is covered with even smaller hair-like structures called microvilli. The blood, which has absorbed nutrients, is carried away from the small intestine via the hepatic portal vein and goes to the liver for filtering, removal of toxins, and nutrient processing. The small intestine and remainder of the digestive tract undergoes peristalsis to transport food from the stomach to the rectum and allow food to be mixed with the digestive juices and absorbed. The circular muscles and longitudinal muscles are antagonistic muscles, with one contracting as the other relaxes. When the circular muscles contract, the lumen becomes narrower and longer and the food is squeezed and pushed forward. When the longitudinal muscles contract, the circular muscles relax and the gut dilates to become wider and shorter to allow food to enter. In the stomach there is another phase that is called Mucus. ## Large intestine After the food has been passed through the small intestine, the food enters the large intestine. The large intestine is roughly 1.5 meters long, with three parts: the cecum at the junction with the small intestine, the colon, and the rectum. The colon itself has four parts: the ascending colon, the transverse colon, the descending colon, and the sigmoid colon. The large intestine absorbs water from the bolus and stores feces until it can be egested. Food products that cannot go through the villi, such as cellulose (dietary fiber), are mixed with other waste products from the body and become feces. ## Carbohydrate digestion Carbohydrates are formed in growing plants and are found in grains, leafy vegetables, and other edible plant foods. The molecular structure of these plants is complex, or a polysaccharide; poly is a prefix meaning many. Plants form carbohydrate chains during growth by trapping carbon from the atmosphere, initially carbon dioxide (CO2). Carbon is stored within the plant along with water (H2O) to form a complex starch containing a combination of carbon-hydrogen-oxygen in a fixed ratio of 1:2:1 respectively. Plants with a high sugar content and table sugar represent a less complex structure and are called disaccharides, or two sugar molecules bonded. Once digestion of either of these forms of carbohydrates are complete, the result is a single sugar structure, a monosaccharide. These monosaccharides can be absorbed into the blood and used by individual cells to produce the energy compound adenosine triphosphate (ATP). The digestive system starts the process of breaking down polysaccharides in the mouth through the introduction of amylase, a digestive enzyme in saliva. The high acid content of the stomach inhibits the enzyme activity, so carbohydrate digestion is suspended in the stomach. Upon emptying into the small intestines, potential hydrogen (pH) changes dramatically from a strong acid to an alkaline content. The pancreas secretes bicarbonate to neutralize the acid from the stomach, and the mucus secreted in the tissue lining the intestines is alkaline which promotes digestive enzyme activity. Amylase is present in the small intestines and works with other enzymes to complete the breakdown of carbohydrate into a monosaccharide which is absorbed into the surrounding capillaries of the villi. Nutrients in the blood are transported to the liver via the hepatic portal circuit, or loop, where final carbohydrate digestion is accomplished in the liver. The liver accomplishes carbohydrate digestion in response to the hormones insulin and glucagon. As blood glucose levels increase following digestion of a meal, the pancreas secretes insulin causing the liver to transform glucose to glycogen, which is stored in the liver, adipose tissue, and in muscle cells, preventing hyperglycemia. A few hours following a meal, blood glucose will drop due to muscle activity, and the pancreas will now secrete glucagon which causes glycogen to be converted into glucose to prevent hypoglycemia. Note: In the discussion of digestion of carbohydrates; nouns ending in the suffix -ose usually indicate a sugar, such as lactose. Nouns ending in the suffix -ase indicates the enzyme that will break down the sugar, such as lactase. Enzymes usually begin with the substrate (substance) they are breaking down. For example: maltose, a disaccharide, is broken down by the enzyme maltase (by the process of hydrolysis), resulting in a two glucose molecules, a monosaccharide. ## Fat digestion The presence of fat in the small intestine produces hormones which stimulate the release of lipase from the pancreas and bile from the gallbladder. The lipase (activated by acid) breaks down the fat into monoglycerides and fatty acids. The bile emulsifies the fatty acids so they may be easily absorbed. Short- and medium chain fatty acids are absorbed directly into the blood via intestine capillaries and travel through the portal vein just as other absorbed nutrients do. However, long chain fatty acids are too large to be directly released into the tiny intestinal capillaries. Instead they are absorbed into the fatty walls of the intestine villi and reassembled again into triglycerides. The triglycerides are coated with cholesterol and protein (protein coat) into a compound called a chylomicron. Within the villi, the chylomicron enters a lymphatic capillary called a lacteal, which merges into larger lymphatic vessels. It is transported via the lymphatic system and the thoracic duct up to a location near the heart (where the arteries and veins are larger). The thoracic duct empties the chylomicrons into the bloodstream via the left subclavian vein. At this point the chylomicrons can transport the triglycerides to where they are needed. ## Digestive hormones There are at least four hormones that aid and regulate the digestive system: - Gastrin - is in the stomach and stimulates the gastric glands to secrete pepsinogen(an inactive form of the enzyme pepsin) and hydrochloric acid. Secretion of gastrin is stimulated by food arriving in stomach. The secretion is inhibited by low pH . - Secretin - is in the duodenum and signals the secretion of sodium bicarbonate in the pancreas and it stimulates the bile secretion in the liver. This hormone responds to the acidity of the chyme. - Cholecystokinin (CCK) - is in the duodenum and stimulates the release of digestive enzymes in the pancreas and stimulates the emptying of bile in the gall bladder. This hormone is secreted in response to fat in chyme. - Gastric inhibitory peptide (GIP) - is in the duodenum and decreases the stomach churning in turn slowing the emptying in the stomach. Another function is to induce insulin secretion. ## Significance of pH in digestion Digestion is a complex process which is controlled by several factors. pH plays a crucial role in a normally functioning digestive tract. In the mouth, pharynx, and esophagus, pH is typically about 6.8, very weakly acidic. Saliva controls pH in this region of the digestive tract. Salivary amylase is contained in saliva and starts the breakdown of carbohydrates into monosaccharides. Most digestive enzymes are sensitive to pH and will not function in a low-pH environment like the stomach. Low pH (below 5) indicates a strong acid, while a high pH (above 8) indicates a strong base; the concentration of the acid or base, however, does also play a role. pH in the stomach is very acidic and inhibits the breakdown of carbohydrates while there. The strong acid content of the stomach provides two benefits, both serving to denature proteins for further digestion in the small intestines, as well as providing non-specific immunity, retarding or eliminating various pathogens. In the small intestines, the duodenum provides critical pH balancing to activate digestive enzymes. The liver secretes bile into the duodenum to neutralise the acidic conditions from the stomach. Also the pancreatic duct empties into the duodenum, adding bicarbonate to neutralize the acidic chyme, thus creating a neutral environment. The mucosal tissue of the small intestines is alkaline, creating a pH of about 8.5, thus enabling absorption in a mild alkaline in the environment. # Specialized organs in non-human animals Organisms have evolved specialized organs to aid in the digestion of their food, modifying tongues, teeth, and other organs to assist in digestion. Certain insects may have a crop or enlarged esophagus, while birds and cockroaches have developed gizzards to assist in the digestion of tough materials. Herbivores have evolved cecums (or an abomasum in the case of ruminants) to break down cellulose in plants.	https://www.wikidoc.org/index.php/Absorption_(digestive)
a0e9b8c11244e90a36ab3bec0030fcefa0f16c2c	wikidoc	Acadesine	Acadesine # Overview Acadesine (INN), also known as 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside, AICA-riboside, and AICAR, is an AMP-activated protein kinase activator which is used for the treatment of acute lymphoblastic leukemia and may have applications in treating other disorders such as diabetes. Acadesine is an adenosine regulating agent developed by PeriCor Therapeutics and licensed to Schering-Plough in 2007 for phase III studies. The drug is a potential first-in-class agent for prevention of reperfusion injury in CABG surgery. Schering began patient enrollment in phase III studies in May, 2009. The trial was terminated in late 2010 based on an interim futility analysis. # Chemistry Reaction of 2-bromo tribenzoyl ribose with 1,2-diaminomaleionitrile results in the displacement of the anomeric halogen by one of the amino groups and the formation of the aminosugar largely as the β-anomer. Treatment of this product with methyl orthoformate in the presence of a base leads to the replacement of the alkoxy groups in orthoformate by the adjacent amines, resulting in the formation of the imidazole ring. Reaction with alkoxide then interestingly converts the nitrile nearest the sugar to an iminoester; the benzoyl groups are cleaved in the process. Hofmann rearrangement in the presence of a bromine and a base converts the iminoester to the corresponding primary amine. Basic hydrolysis then converts the remaining nitrile to an amide, affording acadesine. # Pharmacology and use in doping Acadesine acts as an AMP-activated protein kinase agonist. It stimulates glucose uptake and increases the activity of p38 mitogen-activated protein kinases α and β in skeletal muscle tissue, as well as suppressing apoptosis by reducing production of reactive oxygen compounds inside the cell. In 2008, researchers at the Salk Institute discovered that acadesine injected in mice significantly improved their performance in endurance-type exercise, apparently by converting fast-twitch muscle fibers to the more energy-efficient, fat-burning, slow-twitch type. They also looked at the administration of GW 501516 (also called GW1516) in combination with acadesine. Given to mice that did not exercise, this combination activated 40% of the genes that were turned on when mice were given GW1516 and made to exercise. This result drew attention to the compound as a possible athletic endurance aid. One of the lead researchers from this study has developed a urine test to detect it and has made the test available to the International Olympic Committee, and the World Anti-Doping Agency (WADA) has added acadesine to the prohibited list from 2009 onwards. The British Medical Journal reported in 2009 that WADA had found evidence that acadesine was used by cyclists in the 2009 Tour de France.	Acadesine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Acadesine (INN), also known as 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside, AICA-riboside, and AICAR, is an AMP-activated protein kinase activator[1] which is used for the treatment of acute lymphoblastic leukemia[2] and may have applications in treating other disorders such as diabetes.[3] Acadesine is an adenosine regulating agent developed by PeriCor Therapeutics and licensed to Schering-Plough in 2007 for phase III studies. The drug is a potential first-in-class agent for prevention of reperfusion injury in CABG surgery. Schering began patient enrollment in phase III studies in May, 2009. The trial was terminated in late 2010 based on an interim futility analysis.[4][5] # Chemistry Reaction of 2-bromo tribenzoyl ribose with 1,2-diaminomaleionitrile results in the displacement of the anomeric halogen by one of the amino groups and the formation of the aminosugar largely as the β-anomer. Treatment of this product with methyl orthoformate in the presence of a base leads to the replacement of the alkoxy groups in orthoformate by the adjacent amines, resulting in the formation of the imidazole ring. Reaction with alkoxide then interestingly converts the nitrile nearest the sugar to an iminoester; the benzoyl groups are cleaved in the process. Hofmann rearrangement in the presence of a bromine and a base converts the iminoester to the corresponding primary amine. Basic hydrolysis then converts the remaining nitrile to an amide, affording acadesine.[6] # Pharmacology and use in doping Acadesine acts as an AMP-activated protein kinase agonist.[7] It stimulates glucose uptake and increases the activity of p38 mitogen-activated protein kinases α and β in skeletal muscle tissue,[8] as well as suppressing apoptosis by reducing production of reactive oxygen compounds inside the cell.[9] In 2008, researchers at the Salk Institute discovered that acadesine injected in mice significantly improved their performance in endurance-type exercise, apparently by converting fast-twitch muscle fibers to the more energy-efficient, fat-burning, slow-twitch type. They also looked at the administration of GW 501516 (also called GW1516) in combination with acadesine. Given to mice that did not exercise, this combination activated 40% of the genes that were turned on when mice were given GW1516 and made to exercise. This result drew attention to the compound as a possible athletic endurance aid.[10] One of the lead researchers from this study has developed a urine test to detect it and has made the test available to the International Olympic Committee, and the World Anti-Doping Agency (WADA) has added acadesine to the prohibited list from 2009 onwards.[11] The British Medical Journal reported in 2009 that WADA had found evidence that acadesine was used by cyclists in the 2009 Tour de France.[12]	https://www.wikidoc.org/index.php/Acadesine
2a4d7168d33ea24c6e67589770712c736197dd38	wikidoc	Acalculia	Acalculia # Overview Acalculia (not to be confused with dyscalculia), from the Greek "a" meaning "not" and Latin "calculare", which means "to count", is an acquired impairment in which patients have difficulty performing simple mathematical tasks, such as adding, subtracting, multiplying and even simply stating which of two numbers is larger. Acalculia is distinguished from dyscalculia in that acalculia is acquired late in life due to neurological injury such as stroke, while dyscalculia is a specific developmental disorder first observed during the acquisition of mathematical knowledge. # Variations Acalculia is associated with lesions of the parietal lobe (especially the angular gyrus) and the frontal lobe and can be an early sign of dementia. Acalculia is sometimes observed as a "pure" deficit, but is commonly observed as one of a constellation of symptoms, including agraphia, finger agnosia and left-right confusion, after damage to the left angular gyrus, known as Gerstmann's syndrome (Gerstmann, 1940; Mayer et al., 1999). Studies of patients with lesions to the parietal lobe have demonstrated that lesions to the angular gyrus tend to lead to greater impairments in memorized mathematical facts, such as multiplication tables, with relatively unimpaired subtraction abilities. Conversely, patients with lesions in the region of the intraparietal sulcus tend to have greater deficits in subtraction, with preserved mulitiplication abilities (Dehaene and Cohen, 1997). These double dissociations lend support to the idea that different regions of the parietal cortex are involved in different aspects of numerical processing. # Related Chapters - Gerstmann's syndrome - Numerical cognition	Acalculia For patient information click here Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Acalculia (not to be confused with dyscalculia), from the Greek "a" meaning "not" and Latin "calculare", which means "to count", is an acquired impairment in which patients have difficulty performing simple mathematical tasks, such as adding, subtracting, multiplying and even simply stating which of two numbers is larger. Acalculia is distinguished from dyscalculia in that acalculia is acquired late in life due to neurological injury such as stroke, while dyscalculia is a specific developmental disorder first observed during the acquisition of mathematical knowledge. # Variations Acalculia is associated with lesions of the parietal lobe (especially the angular gyrus) and the frontal lobe and can be an early sign of dementia. Acalculia is sometimes observed as a "pure" deficit, but is commonly observed as one of a constellation of symptoms, including agraphia, finger agnosia and left-right confusion, after damage to the left angular gyrus, known as Gerstmann's syndrome (Gerstmann, 1940; Mayer et al., 1999). Studies of patients with lesions to the parietal lobe have demonstrated that lesions to the angular gyrus tend to lead to greater impairments in memorized mathematical facts, such as multiplication tables, with relatively unimpaired subtraction abilities. Conversely, patients with lesions in the region of the intraparietal sulcus tend to have greater deficits in subtraction, with preserved mulitiplication abilities (Dehaene and Cohen, 1997). These double dissociations lend support to the idea that different regions of the parietal cortex are involved in different aspects of numerical processing. # Related Chapters - Gerstmann's syndrome - Numerical cognition	https://www.wikidoc.org/index.php/Acalculia
60c6ec1e40c9a5e6fe392b04a54ab418ae385aad	wikidoc	Accessory	Accessory Accessory may refer to: - Accessory (legal term), a person who assists a criminal but is not present at the crime - Accessory (band), with members Dirk Steyer and Ivo Lottig - Fashion accessory, i.e. an item used to complement a fashion or style - Video game accessory, a piece of hardware used for playing video games - Accessory nucleus, in anatomy, a cranial nerve nucleus - Accessory nerve - Accessory suite, a secondary dwelling on a parcel of land.	Accessory Accessory may refer to: - Accessory (legal term), a person who assists a criminal but is not present at the crime - Accessory (band), with members Dirk Steyer and Ivo Lottig - Fashion accessory, i.e. an item used to complement a fashion or style - Video game accessory, a piece of hardware used for playing video games - Accessory nucleus, in anatomy, a cranial nerve nucleus - Accessory nerve - Accessory suite, a secondary dwelling on a parcel of land. Template:Disambig Template:WH Template:WS	https://www.wikidoc.org/index.php/Accessory
80be2654ea76b62fc8332a14b0c6f90b68bc9415	wikidoc	Albuterol	Albuterol # 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 Albuterol is a beta-2 adrenergic agonist that is FDA approved for the prophylaxis of exercise-induced bronchospasm and bronchospasm in patients with reversible obstructive airway disease. There is a Black Box Warning for this drug as shown here. Common adverse reactions include tachyarrhythmia, hypokalemia, nausea, pharyngitis, throat irritation, feeling nervous, headache, tremor, cough, rhinitis, upper respiratory infection, and viral lower respiratory infection. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Acute Episodes of Bronchospasm - Dosing information (Aerosol,Inhalant) - Usual dosage: two inhalations repeated every four to six hours - In some patients, one inhalation every four hours may be sufficient. More frequent administration or a larger number of inhalations are not recommended. - It is recommended to "test spray" Albuterol Inhalation Aerosol into the air before using for the first time and in cases where the aerosol has not been used for a prolonged period of time. - The use of Albuterol Inhalation Aerosol can be continued as medically indicated to control recurring bouts of bronchospasm. During this time most patients gain optimal benefit from regular use of the inhaler. Safe usage for periods extending over several years has been documented. - If a previously effective dosage regimen fails to provide the usual response, this may be a marker of destabilization of asthma and requires reevaluation of the patient and the treatment regimen, giving special consideration to the possible need for anti-inflammatory treatment, e.g., corticosteroids. - Exercise-Induced Bronchospasm Prevention - Usual dosage for adults and pediatric patients 4 years and older is two inhalations 15 minutes before exercise. For treatment, see above. - Dosing information (Tablet) - Usual starting dosage: 2 or 4 mg PO tid or aid - Dosage Adjustment - A dosage above 4 mg four times a day should be used only when the patient fails to respond. If a favorable response does not occur with the 4 mg initial dosage, it should be cautiously increased stepwise up to a maximum of 8 mg four times a day as tolerated. - Elderly Patients and Those Sensitive to Beta-adrenergic Stimulators - An initial dosage: 2 mg PO tid or qid. If adequate bronchodilation is not obtained, dosage may be increased gradually to as much as 8 mg three or four times a day. - The total daily dose should not exceed 32 mg in adults. - Dosing information (Syrup) - Usual starting dosage: 2 mg (1 teaspoonful) or 4 mg (2 teaspoonfuls) three or four times a day. - Dosage Adjustment - A dosage above 4 mg four times a day should be used only when the patient fails to respond. If a favorable response does not occur with the 4-mg initial dosage, it should be cautiously increased stepwise up to a maximum of 8 mg four times a day as tolerated. - Dosing information (Solution) - Usual dosage for adults: 2.5 mg three to four times daily by nebulization. More frequent administration or higher doses are not recommended. To administer 2.5 mg of albuterol, dilute 0.5 mL of the 0.5% inhalation solution with 2.5 mL of sterile normal saline solution. The flow rate is regulated to suit the particular nebulizer so that albuterol sulfate inhalation solution will be delivered over approximately 5 to 15 minutes. - The use of albuterol sulfate inhalation solution can be continued as medically indicated to control recurring bouts of bronchospasm. During this time most patients gain optimal benefit from regular use of the inhalation solution. - If a previously effective dosage regimen fails to provide the usual relief, medical advice should be sought immediately as this is often a sign of seriously worsening asthma that would require reassessment of therapy. - Drug compatibility (physical and chemical), efficacy, and safety of albuterol sulfate inhalation solution when mixed with other drugs in a nebulizer have not been established. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Albuterol in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Albuterol in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ### Bronchospasm - Dosing information (Tablet) - Usual starting dosage: 2 or 4 mg PO tid or aid - Dosage Adjustment - Children Over 12 Years of Age - For adults and children 12 years and older, a dosage above 4 mg four times a day should be used only when the patient fails to respond. If a favorable response does not occur with the 4 mg initial dosage, it should be cautiously increased stepwise up to a maximum of 8 mg four times a day as tolerated. - Children 6 to 12 Years of Age Who Fail to Respond to the Initial Starting Dosage of 2 mg Four Times a Day - For children from 6 to 12 years of age who fail to respond to the initial starting dosage of 2 mg four times a day, the dosage may be cautiously increased stepwise, but not to exceed 24 mg/day (given in divided doses). - Dosing information (Syrup) - The usual starting dosage for adults and children over 14 years of age is 2 mg (1 teaspoonful) or 4 mg (2 teaspoonfuls) three or four times a day. - The usual starting dosage for children over 6 years to 14 years of age is 2 mg (1 teaspoonful) three or four times a day. - Dosing in children 2 to 5 years of age should be initiated at 0.1 mg/kg of body weight three times a day. This starting dosage should not exceed 2 mg (1 teaspoonful) three times a day. - Dosage Adjustment - For adults and children over 14 years of age, a dosage above 4 mg four times a day should be used only when the patient fails to respond. If a favorable response does not occur with the 4-mg initial dosage, it should be cautiously increased stepwise up to a maximum of 8 mg four times a day as tolerated. - For children over 6 years to 14 years of age who fail to respond to the initial starting dosage of 2 mg four times a day, the dosage may be cautiously increased stepwise, but not to exceed 24 mg/day (given in divided doses). - For children from 2 to 5 years of age who do not respond satisfactorily to the initial starting dosage, the dosage may be increased stepwise to 0.2 mg/kg of body weight three times a day, but not to exceed a maximum of 4 mg (2 teaspoonfuls) given three times a day. - Dosing information (Solution) - The usual dosage for children 12 years of age and older : 2.5 mg three to four times daily by nebulization. More frequent administration or higher doses are not recommended. To administer 2.5 mg of albuterol, dilute 0.5 mL of the 0.5% inhalation solution with 2.5 mL of sterile normal saline solution. The flow rate is regulated to suit the particular nebulizer so that albuterol sulfate inhalation solution will be delivered over approximately 5 to 15 minutes. - The use of albuterol sulfate inhalation solution can be continued as medically indicated to control recurring bouts of bronchospasm. During this time most patients gain optimal benefit from regular use of the inhalation solution. - If a previously effective dosage regimen fails to provide the usual relief, medical advice should be sought immediately as this is often a sign of seriously worsening asthma that would require reassessment of therapy. - Drug compatibility (physical and chemical), efficacy, and safety of albuterol sulfate inhalation solution when mixed with other drugs in a nebulizer have not been established. - For children 2 to 12 years of age, initial dosing should be based upon body weight (0.1 to 0.15 mg/kg per dose), with subsequent dosing titrated to achieve the desired clinical response. Dosing should not exceed 2.5 mg three to four times daily by nebulization. The following table outlines approximate dosing according to body weight. The appropriate volume of the 0.5% inhalation solution should be diluted in sterile normal saline solution to a total volume of 3 mL prior to administration via nebulization. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Albuterol in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Albuterol in pediatric patients. # Contraindications Albuterol is contraindicated in patients with a history of hypersensitivity to albuterol or any of its components. # Warnings ### Paradoxical bronchospasm Albuterol can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs, Albuterol Inhalation Aerosol should be discontinued immediately and alternative therapy instituted. It should be recognized that paradoxical bronchospasm, when associated with inhaled formulations, frequently occurs with the first use of a new canister or vial. ### Cardiovascular Effects Albuterol, like all other beta-adrenergic agonists, can produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of Albuterol Inhalation Aerosol at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiogram (ECG) changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Therefore, albuterol, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. ### Deterioration of Asthma Asthma may deteriorate acutely over a period of hours or chronically over several days or longer. If the patient needs more doses of Albuterol Inhalation Aerosol than usual, this may be a marker of destabilization of asthma and requires reevaluation of the patient and treatment regimen, giving special consideration to the possible need for anti-inflammatory treatment, e.g., corticosteroids. ### Use of Anti-Inflammatory Agents The use of beta-adrenergic agonist bronchodilators alone may not be adequate to control asthma in many patients. Early consideration should be given to adding anti-inflammatory agents, e.g., corticosteroids. ### Immediate Hypersensitivity Reactions Immediate hypersensitivity reactions may occur after administration of Albuterol Inhalation Aerosol, as demonstrated by rare cases of urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema. The contents of Albuterol Inhalation Aerosol are under pressure. Do not puncture. Do not use or store near heat or open flame. Exposure to temperatures above 120°F may cause bursting. Never throw container into fire or incinerator. Avoid spraying in eyes. Keep out of reach of children. Microbial Contamination (only in solution): To avoid microbial contamination, proper aseptic technique should be used each time the bottle is opened. Precautions should be taken to prevent contact of the dropper tip of the bottle with any surface, including the nebulizer reservoir and associated ventilatory equipment. In addition, if the solution changes color or becomes cloudy, it should not be used. ## PRECAUTIONS ### General Albuterol, as with all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension; in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus; and in patients who are unusually responsive to sympathomimetic amines. Clinically significant changes in systolic and diastolic blood pressure have been seen in individual patients and could be expected to occur in some patients after use of any beta-adrenergic bronchodilator. Large doses of intravenous albuterol have been reported to aggravate preexisting diabetes mellitus and ketoacidosis. As with other beta-agonists, albuterol may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease is usually transient, not requiring supplementation. Although there have been no reports concerning the use of Albuterol Inhalation Aerosol during labor and delivery, it has been reported that high doses of albuterol administered intravenously inhibit uterine contractions. Although this effect is extremely unlikely as a consequence of aerosol use, it should be kept in mind. # Adverse Reactions ## Clinical Trials Experience The adverse reactions to albuterol are similar in nature to reactions to other sympathomimetic agents, although the incidence of certain cardiovascular effects is lower with albuterol. Cases of urticaria, angioedema, rash, bronchospasm, hoarseness, oropharyngeal edema, and arrhythmias (including atrial fibrillation, supraventricular tachycardia, extrasystoles) have been reported after the use of albuterol inhalation aerosol. In addition, albuterol, like other sympathomimetic agents, can cause adverse reactions such as hypertension, angina, vertigo, central nervous system stimulation, sleeplessness, and unusual taste. ## Postmarketing Experience There is limited information regarding Albuterol Postmarketing Experience in the drug label. # Drug Interactions Other short-acting sympathomimetic aerosol bronchodilators should not be used concomitantly with albuterol. If additional adrenergic drugs are to be administered by any route, they should be used with caution to avoid deleterious cardiovascular effects. ### Monoamine Oxidase Inhibitors or Tricyclic Antidepressants Albuterol should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within two weeks of discontinuation of such agents, because the action of albuterol on the vascular system may be potentiated. ### Beta-Blockers Beta-adrenergic receptor blocking agents not only block the pulmonary effect of beta-agonists, such as albuterol, but may produce severe bronchospasm in asthmatic patients. Therefore, patients with asthma should not normally be treated with beta-blockers. However, under certain circumstances, e.g., as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents in patients with asthma. In this setting, cardioselective beta-blockers should be considered, although they should be administered with caution. ### Diuretics The ECG changes and/or hypokalemia that may result from the administration of nonpotassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of beta-agonists with nonpotassium-sparing diuretics. ### Digoxin Mean decreases of 16% to 22% in serum digoxin levels were demonstrated after single-dose intravenous and oral administration of albuterol, respectively, to normal volunteers who had received digoxin for 10 days. The clinical significance of these findings for patients with obstructive airway disease who are receiving albuterol and digoxin on a chronic basis is unclear. Nevertheless, it would be prudent to carefully evaluate the serum digoxin levels in patients who are currently receiving digoxin and albuterol. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C Albuterol sulfate has been shown to be teratogenic in mice. A study in CD-1 mice at subcutaneous (sc) doses of 0.025, 0.25, and 2.5 mg/kg (approximately 2/25, 1.0, and 8.0 times, respectively, the maximum recommended daily inhalation dose for adults on a mg/m2 basis), showed cleft palate formation in 5 of 111 (4.5%) fetuses at 0.25 mg/kg and in 10 of 108 (9.3%) fetuses at 2.5 mg/kg. The drug did not induce cleft palate formation at the lowest dose, 0.025 mg/kg. Cleft palate also occurred in 22 of 72 (30.5%) fetuses from females treated with 2.5 mg/kg of isoproterenol (positive control) sc (approximately 8 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis). A reproduction study in Stride Dutch rabbits revealed cranioschisis in 7 of 19 (37%) fetuses when albuterol sulfate was administered orally at a 50 mg/kg dose (approximately 680 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis). There are no adequate and well-controlled studies in pregnant women. Albuterol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. During worldwide marketing experience, various congenital anomalies, including cleft palate and limb defects, have been rarely reported in the offspring of patients being treated with albuterol. Some of the mothers were taking multiple medications during their pregnancies. No consistent pattern of defects can be discerned, and a relationship between albuterol use and congenital anomalies has not been established. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Albuterol in women who are pregnant. ### Labor and Delivery Because of the potential for beta-agonist interference with uterine contractility, use of albuterol for relief of bronchospasm during labor should be restricted to those patients in whom the benefits clearly outweigh the risk. ### Nursing Mothers It is not known whether this drug is excreted in human milk. Because of the potential for tumorigenicity shown for albuterol in some animal studies, 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 Safety and effectiveness in pediatric patients below 4 years of age have not been established. ### Geriatic Use There is no FDA guidance on the use of Albuterol in geriatric settings. ### Gender There is no FDA guidance on the use of Albuterol with respect to specific gender populations. ### Race There is no FDA guidance on the use of Albuterol with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Albuterol in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Albuterol in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Albuterol in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Albuterol in patients who are immunocompromised. ### Tocolysis Albuterol has not been approved for the management of preterm labor. The benefit:risk ratio when albuterol is administered for tocolysis has not been established. Serious adverse reactions, including maternal pulmonary edema, have been reported during or following treatment of premature labor with beta2-agonists, including albuterol. # Administration and Monitoring ### Administration Inhale and oral ### Monitoring FDA Package Insert for Albuterol contains no information regarding Drug Monitoring. # IV Compatibility There is limited information about the IV Compatibility. # Overdosage The expected symptoms with overdosage are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the symptoms listed under ADVERSE REACTIONS, e.g., seizures, angina, hypertension, hypotension, tachycardia with rates up to 200 beats/minute, arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, and sleeplessness. hypokalemia may also occur. As with all sympathomimetic aerosol medications, cardiac arrest and even death may be associated with abuse of Albuterol Inhalation Aerosol. Treatment consists of discontinuation of Albuterol Inhalation Aerosol together with appropriate symptomatic therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of Albuterol Inhalation Aerosol. The oral median lethal dose of albuterol sulfate in mice is greater than 2000 mg/kg (approximately 6800 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis, or, approximately 3200 times the maximum recommended daily inhalation dose for children on a mg/m2 basis). In mature rats, the sc median lethal dose of albuterol sulfate is approximately 450 mg/kg (approximately 3000 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis, or, approximately 1400 times the maximum recommended daily inhalation dose for children on a mg/m2 basis). In small young rats, the sc median lethal dose of albuterol sulfate is approximately 2000 mg/kg (approximately 14,000 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis, or, approximately 6400 times the maximum recommended daily inhalation dose for children on a mg/m2 basis). The inhalation median lethal dose has not been determined in animals. # Pharmacology ## Mechanism of Action Albuterol is typically used to treat bronchospasm (due to any cause, allergen asthma or exercise-induced), as well as chronic obstructive pulmonary disease. Emergency medical practice commonly treats people presenting with asthma who report taking their Albuterol inhaler as prescribed with Albuterol. In general, people tolerate large doses well. Other uses include in cystic fibrosis, along with ipratropium bromide, acetylcysteine, and pulmozyme and subtypes of congenital myasthenic syndromes associated to mutations in Dok-7. As a β2-agonist, Albuterol also finds use in obstetrics. Intravenous Albuterol can be used as a tocolytic to relax the uterine smooth muscle to delay premature labor. While preferred over agents such as atosiban and ritodrine, its role has largely been replaced by the calcium-channel blocker nifedipine, which is more effective, better tolerated and orally administered. Albuterol is used to treat acute hyperkalemia as it stimulates potassium to flow in cells thus lowering the level in the blood. Albuterol has also been trialled in spinal muscular atrophy where it appears to show modest benefits. The drug is speculated to modulate the alternative splicing of the SMN2 gene, increasing the amount of the SMN protein whose deficiency is regarded as the root cause of the disease. ## Structure The active component of Albuterol Inhalation Aerosol is albuterol (α1-(tert-butylamino)methyl-4-hydroxy-m-xylene-α,α'-diol), a relatively selective beta2-adrenergic bronchodilator, having the following structural formula: Albuterol is the official generic name in the United States. The World Health Organization recommended name for the drug is salbutamol. The molecular weight of albuterol is 239.2, and the molecular formula is C13H21NO3. Albuterol is a white to off-white crystalline solid. It is soluble in ethanol, sparingly soluble in water, and very soluble in chloroform. Albuterol Inhalation Aerosol is a pressurized metered-dose aerosol unit for oral inhalation. It contains a microcrystalline (95% ≤ 10 µm) suspension of albuterol in propellants (trichloromonofluoromethane and dichlorodifluoromethane) with oleic acid. Each actuation delivers 100 mcg of albuterol from the valve and 90 mcg of albuterol from the mouthpiece. Each canister provides 200 inhalations. ## Pharmacodynamics In vitro studies and in vivo pharmacologic studies have demonstrated that albuterol has a preferential effect on beta2-adrenergic receptors compared with isoproterenol. While it is recognized that beta2-adrenergic receptors are the predominant receptors in bronchial smooth muscle, data indicate that there is a population of beta2-receptors in the human heart existing in a concentration between 10% and 50%. The precise function of these receptors has not been established. The pharmacologic effects of beta-adrenergic agonist drugs, including albuterol, are at least in part attributable to stimulation through beta-adrenergic receptors of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3', 5'- adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels are associated with relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells. Albuterol has been shown in most controlled clinical trials to have more effect on the respiratory tract, in the form of bronchial smooth muscle relaxation, than isoproterenol at comparable doses while producing fewer cardiovascular effects. Controlled clinical studies and other clinical experience have shown that inhaled albuterol, like other beta-adrenergic agonist drugs, can produce a significant cardiovascular effect in some patients, as measured by pulse rate, blood pressure, symptoms, and/or electrocardiographic changes. Albuterol is longer acting than isoproterenol in most patients by any route of administration because it is not a substrate for the cellular uptake processes for catecholamines nor for catechol-O-methyl transferase. The effects of rising doses of albuterol and isoproterenol aerosols were studied in volunteers and asthmatic patients. Results in normal volunteers indicated that albuterol is one half to one quarter as active as isoproterenol in producing increases in heart rate. In asthmatic patients similar cardiovascular differentiation between the two drugs was also seen. ### Preclinical Intravenous studies in rats with albuterol sulfate have demonstrated that albuterol crosses the blood brain barrier and reaches brain concentrations amounting to approximately 5.0% of the plasma concentrations. In structures outside the brain barrier (pineal and pituitary glands), albuterol concentrations were found to be 100 times those in the whole brain. Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of cardiac arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when beta-agonists and methylxanthines are administered concurrently. The clinical significance of these findings is unknown. ## Pharmacokinetics Because of its gradual absorption from the bronchi, systemic levels of albuterol are low after inhalation of recommended doses. Studies undertaken with four subjects administered tritiated albuterol resulted in maximum plasma concentrations occurring within two to four hours. Due to the sensitivity of the assay method, the metabolic rate and half-life of elimination of albuterol in plasma could not be determined. However, urinary excretion provided data indicating that albuterol has an elimination half-life of 3.8 hours. Approximately 72% of the inhaled dose is excreted within 24 hours in the urine, and consists of 28% as unchanged drug and 44% as metabolite. ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, Impairment of Fertility In a two-year study in Sprague-Dawley rats, albuterol sulfate caused a significant dose-related increase in the incidence of benign leiomyomas of the mesovarium at dietary doses of 2.0, 10, and 50 mg/kg (approximately 15, 70, and 340 times, respectively, the maximum recommended daily inhalation dose for adults on a mg/m2 basis, or, approximately 6, 30, and 160 times, respectively, the maximum recommended daily inhalation dose in children on a mg/m2 basis). In another study this effect was blocked by the coadministration of propranolol, a non-selective beta-adrenergic antagonist. In an 18-month study in CD-1 mice, albuterol sulfate showed no evidence of tumorigenicity at dietary doses of up to 500 mg/kg (approximately 1700 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis, or, approximately 800 times the maximum recommended daily inhalation dose for children on a mg/m2 basis). In a 22-month study in the Golden hamster, albuterol sulfate showed no evidence of tumorigenicity at dietary doses of up to 50 mg/kg (approximately 225 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis, or, approximately 110 times the maximum recommended daily inhalation dose for children on a mg/m2 basis). Albuterol sulfate was not mutagenic in the Ames test with or without metabolic activation using tester strains S. typhimurium TA1537, TA1538, and TA98 or E. Coli WP2, WP2uvrA, and WP67. No forward mutation was seen in yeast strain S. cerevisiae S9 nor any mitotic gene conversion in yeast strain S. cerevisiae JD1 with or without metabolic activation. Fluctuation assays in S. typhimurium TA98 and E.Coli WP2, both with metabolic activation, were negative. Albuterol sulfate was not clastogenic in a human peripheral lymphocyte assay or in an AH1 strain mouse micronucleus assay at intraperitoneal doses of up to 200 mg/kg. Reproduction studies in rats demonstrated no evidence of impaired fertility at oral doses of up to 50 mg/kg (approximately 340 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis). # Clinical Studies In controlled clinical trials involving adults with asthma, the onset of improvement in pulmonary function was within 15 minutes, as determined by both MMEF (maximum midexpiratory flow rate) and FEV1 (forced expiratory volume in one second). MMEF measurements also showed that near maximum improvement in pulmonary function generally occurs within 60 to 90 minutes following two inhalations of albuterol and that clinically significant improvement generally continues for three to four hours in most patients. Some patients showed a therapeutic response (defined by maintaining FEV1 values 15% or more above baseline) that was still apparent at 6 hours. Continued effectiveness of albuterol was demonstrated over a 13-week period in these same trials. In controlled clinical trials involving children 4 to 12 years of age, FEV1 measurements showed that maximum improvement in pulmonary function occurs within 30 to 60 minutes. The onset of clinically significant (≥15%) improvement in FEV1 was observed as soon as five minutes following 180 mcg of albuterol in 18 of 30 (60%) children in a controlled dose-ranging study. Clinically significant improvement in FEV1 continued in the majority of patients for two hours and in 33% to 47% for four hours among 56 patients receiving inhalation aerosol in one pediatric study. In a second study among 48 patients receiving inhalation aerosol, clinically significant improvement continued in the majority for up to one hour and in 23% to 40% for four hours. In addition, at least 50% of the patients in both studies achieved an improvement in FEF25%–75% (forced expiratory flow rate between 25% and 75% of the forced vital capacity) of at least 20% for 2 to 5 hours. Continued effectiveness of albuterol was demonstrated over the 12-week study period. In other clinical studies in adults and children, two inhalations of albuterol aerosol taken approximately 15 minutes before exercise prevented exercise-induced bronchospasm, as demonstrated by the maintenance of FEV1 within 80% of baseline values in the majority of patients. One study in adults also evaluated the duration of the prophylactic effect to repeated exercise challenges, which was evident at 4 hours in a majority of the patients and at 6 hours in approximately one third of the patients. # How Supplied ### Albuterol Inhalation Aerosol Albuterol Inhalation Aerosol is supplied in 17 g canisters containing 200 metered inhalations (NDC 17270-721-01) in boxes of one. Each actuation delivers 100 mcg of albuterol from the valve and 90 mcg of albuterol from the mouthpiece. Each canister is supplied with a blue oral adapter and patient's instructions. Also available, Albuterol Inhalation Aerosol Refill with patient's instructions (NDC 17270-721-02). The blue adapter supplied with Albuterol Inhalation Aerosol should not be used with any other product canisters, and the adapters from other products should not be used with an Albuterol Inhalation Aerosol canister. The correct amount of medication in each canister cannot be assured after 200 actuations, even though the canister is not completely empty. The canister should be discarded when the labeled number of actuations have been used. ### Albuterol Tablet Albuterol tablets, USP; 2 mg of albuterol as the sulfate, are white, round, scored, debossed MP 47 Albuterol tablets, USP; 4 mg of albuterol as the sulfate, are white, round, scored, debossed MP 88 ### ALBUTEROL SULFATE syrup Albuterol Sulfate Syrup, a clear, yellow liquid with a strawberry flavor, contains 2 mg of albuterol (present as the sulfate) per 5 mL in bottles of 16 fluid ounces (one pint). ### ALBUTEROL SULFATE inhalation solution Albuterol sulfate inhalation solution, 0.5% is supplied in amber glass bottles, with a calibrated dropper and with patient instructions in the following size: 20 mL bottles - NDC 24208-347-20 ## Storage ### Albuterol Inhalation Aerosol Store between 15°–30°C (59°–86°F). As with most inhaled medications in aerosol canisters, the therapeutic effect of this medication may decrease when the canister is cold; for best results, the canister should be at room temperature before use. ### Albuterol Tablet Store at 20° to 25°C (68° to 77°F). DISPENSE IN TIGHT, LIGHT-RESISTANT CONTAINER. ### ALBUTEROL SULFATE syrup Store at 20° to 25°C (68° to 77°F). ### ALBUTEROL SULFATE inhalation solution Storage: Store between 2°-25°C (36°-77°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information The action of Albuterol Inhalation Aerosol may last up to six hours or longer. Albuterol Inhalation Aerosol should not be used more frequently than recommended. Do not increase the dose or frequency of Albuterol Inhalation Aerosol without consulting your physician. If you find that treatment with Albuterol Inhalation Aerosol becomes less effective for symptomatic relief, your symptoms become worse, and/or you need to use the product more frequently than usual, you should seek medical attention immediately. While you are using Albuterol Inhalation Aerosol, other inhaled drugs and asthma medications should be taken only as directed by your physician. Common adverse effects include palpitations, chest pain, rapid heart rate, and tremor or nervousness. If you are pregnant or nursing, contact your physician about use of Albuterol Inhalation Aerosol. Effective and safe use of Albuterol Inhalation Aerosol includes an understanding of the way that it should be administered. In general, the technique for administering Albuterol Inhalation Aerosol to children is similar to that for adults, since children's smaller ventilatory exchange capacity automatically provides proportionally smaller aerosol intake. Children should use Albuterol Inhalation Aerosol under adult supervision, as instructed by the patient's physician. # Precautions with Alcohol Alcohol-Albuterol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Accuneb - Proventil - Proventil HFA - Proventil Repetabs - Ventolin - Ventolin HFA - VoSpire ER - ProAir HFA # Look-Alike Drug Names There is limited information about the look-alike drug names. # Drug Shortage Status # Price	Albuterol Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, 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. # Black Box Warning # Overview Albuterol is a beta-2 adrenergic agonist that is FDA approved for the prophylaxis of exercise-induced bronchospasm and bronchospasm in patients with reversible obstructive airway disease. There is a Black Box Warning for this drug as shown here. Common adverse reactions include tachyarrhythmia, hypokalemia, nausea, pharyngitis, throat irritation, feeling nervous, headache, tremor, cough, rhinitis, upper respiratory infection, and viral lower respiratory infection. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Acute Episodes of Bronchospasm - Dosing information (Aerosol,Inhalant) - Usual dosage: two inhalations repeated every four to six hours - In some patients, one inhalation every four hours may be sufficient. More frequent administration or a larger number of inhalations are not recommended. - It is recommended to "test spray" Albuterol Inhalation Aerosol into the air before using for the first time and in cases where the aerosol has not been used for a prolonged period of time. - The use of Albuterol Inhalation Aerosol can be continued as medically indicated to control recurring bouts of bronchospasm. During this time most patients gain optimal benefit from regular use of the inhaler. Safe usage for periods extending over several years has been documented. - If a previously effective dosage regimen fails to provide the usual response, this may be a marker of destabilization of asthma and requires reevaluation of the patient and the treatment regimen, giving special consideration to the possible need for anti-inflammatory treatment, e.g., corticosteroids. - Exercise-Induced Bronchospasm Prevention - Usual dosage for adults and pediatric patients 4 years and older is two inhalations 15 minutes before exercise. For treatment, see above. - Dosing information (Tablet) - Usual starting dosage: 2 or 4 mg PO tid or aid - Dosage Adjustment - A dosage above 4 mg four times a day should be used only when the patient fails to respond. If a favorable response does not occur with the 4 mg initial dosage, it should be cautiously increased stepwise up to a maximum of 8 mg four times a day as tolerated. - Elderly Patients and Those Sensitive to Beta-adrenergic Stimulators - An initial dosage: 2 mg PO tid or qid. If adequate bronchodilation is not obtained, dosage may be increased gradually to as much as 8 mg three or four times a day. - The total daily dose should not exceed 32 mg in adults. - Dosing information (Syrup) - Usual starting dosage: 2 mg (1 teaspoonful) or 4 mg (2 teaspoonfuls) three or four times a day. - Dosage Adjustment - A dosage above 4 mg four times a day should be used only when the patient fails to respond. If a favorable response does not occur with the 4-mg initial dosage, it should be cautiously increased stepwise up to a maximum of 8 mg four times a day as tolerated. - Dosing information (Solution) - Usual dosage for adults: 2.5 mg three to four times daily by nebulization. More frequent administration or higher doses are not recommended. To administer 2.5 mg of albuterol, dilute 0.5 mL of the 0.5% inhalation solution with 2.5 mL of sterile normal saline solution. The flow rate is regulated to suit the particular nebulizer so that albuterol sulfate inhalation solution will be delivered over approximately 5 to 15 minutes. - The use of albuterol sulfate inhalation solution can be continued as medically indicated to control recurring bouts of bronchospasm. During this time most patients gain optimal benefit from regular use of the inhalation solution. - If a previously effective dosage regimen fails to provide the usual relief, medical advice should be sought immediately as this is often a sign of seriously worsening asthma that would require reassessment of therapy. - Drug compatibility (physical and chemical), efficacy, and safety of albuterol sulfate inhalation solution when mixed with other drugs in a nebulizer have not been established. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Albuterol in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Albuterol in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ### Bronchospasm - Dosing information (Tablet) - Usual starting dosage: 2 or 4 mg PO tid or aid - Dosage Adjustment - Children Over 12 Years of Age - For adults and children 12 years and older, a dosage above 4 mg four times a day should be used only when the patient fails to respond. If a favorable response does not occur with the 4 mg initial dosage, it should be cautiously increased stepwise up to a maximum of 8 mg four times a day as tolerated. - Children 6 to 12 Years of Age Who Fail to Respond to the Initial Starting Dosage of 2 mg Four Times a Day - For children from 6 to 12 years of age who fail to respond to the initial starting dosage of 2 mg four times a day, the dosage may be cautiously increased stepwise, but not to exceed 24 mg/day (given in divided doses). - Dosing information (Syrup) - The usual starting dosage for adults and children over 14 years of age is 2 mg (1 teaspoonful) or 4 mg (2 teaspoonfuls) three or four times a day. - The usual starting dosage for children over 6 years to 14 years of age is 2 mg (1 teaspoonful) three or four times a day. - Dosing in children 2 to 5 years of age should be initiated at 0.1 mg/kg of body weight three times a day. This starting dosage should not exceed 2 mg (1 teaspoonful) three times a day. - Dosage Adjustment - For adults and children over 14 years of age, a dosage above 4 mg four times a day should be used only when the patient fails to respond. If a favorable response does not occur with the 4-mg initial dosage, it should be cautiously increased stepwise up to a maximum of 8 mg four times a day as tolerated. - For children over 6 years to 14 years of age who fail to respond to the initial starting dosage of 2 mg four times a day, the dosage may be cautiously increased stepwise, but not to exceed 24 mg/day (given in divided doses). - For children from 2 to 5 years of age who do not respond satisfactorily to the initial starting dosage, the dosage may be increased stepwise to 0.2 mg/kg of body weight three times a day, but not to exceed a maximum of 4 mg (2 teaspoonfuls) given three times a day. - Dosing information (Solution) - The usual dosage for children 12 years of age and older : 2.5 mg three to four times daily by nebulization. More frequent administration or higher doses are not recommended. To administer 2.5 mg of albuterol, dilute 0.5 mL of the 0.5% inhalation solution with 2.5 mL of sterile normal saline solution. The flow rate is regulated to suit the particular nebulizer so that albuterol sulfate inhalation solution will be delivered over approximately 5 to 15 minutes. - The use of albuterol sulfate inhalation solution can be continued as medically indicated to control recurring bouts of bronchospasm. During this time most patients gain optimal benefit from regular use of the inhalation solution. - If a previously effective dosage regimen fails to provide the usual relief, medical advice should be sought immediately as this is often a sign of seriously worsening asthma that would require reassessment of therapy. - Drug compatibility (physical and chemical), efficacy, and safety of albuterol sulfate inhalation solution when mixed with other drugs in a nebulizer have not been established. - For children 2 to 12 years of age, initial dosing should be based upon body weight (0.1 to 0.15 mg/kg per dose), with subsequent dosing titrated to achieve the desired clinical response. Dosing should not exceed 2.5 mg three to four times daily by nebulization. The following table outlines approximate dosing according to body weight. The appropriate volume of the 0.5% inhalation solution should be diluted in sterile normal saline solution to a total volume of 3 mL prior to administration via nebulization. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Albuterol in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Albuterol in pediatric patients. # Contraindications Albuterol is contraindicated in patients with a history of hypersensitivity to albuterol or any of its components. # Warnings ### Paradoxical bronchospasm Albuterol can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs, Albuterol Inhalation Aerosol should be discontinued immediately and alternative therapy instituted. It should be recognized that paradoxical bronchospasm, when associated with inhaled formulations, frequently occurs with the first use of a new canister or vial. ### Cardiovascular Effects Albuterol, like all other beta-adrenergic agonists, can produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of Albuterol Inhalation Aerosol at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiogram (ECG) changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Therefore, albuterol, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. ### Deterioration of Asthma Asthma may deteriorate acutely over a period of hours or chronically over several days or longer. If the patient needs more doses of Albuterol Inhalation Aerosol than usual, this may be a marker of destabilization of asthma and requires reevaluation of the patient and treatment regimen, giving special consideration to the possible need for anti-inflammatory treatment, e.g., corticosteroids. ### Use of Anti-Inflammatory Agents The use of beta-adrenergic agonist bronchodilators alone may not be adequate to control asthma in many patients. Early consideration should be given to adding anti-inflammatory agents, e.g., corticosteroids. ### Immediate Hypersensitivity Reactions Immediate hypersensitivity reactions may occur after administration of Albuterol Inhalation Aerosol, as demonstrated by rare cases of urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema. The contents of Albuterol Inhalation Aerosol are under pressure. Do not puncture. Do not use or store near heat or open flame. Exposure to temperatures above 120°F may cause bursting. Never throw container into fire or incinerator. Avoid spraying in eyes. Keep out of reach of children. Microbial Contamination (only in solution): To avoid microbial contamination, proper aseptic technique should be used each time the bottle is opened. Precautions should be taken to prevent contact of the dropper tip of the bottle with any surface, including the nebulizer reservoir and associated ventilatory equipment. In addition, if the solution changes color or becomes cloudy, it should not be used. ## PRECAUTIONS ### General Albuterol, as with all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension; in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus; and in patients who are unusually responsive to sympathomimetic amines. Clinically significant changes in systolic and diastolic blood pressure have been seen in individual patients and could be expected to occur in some patients after use of any beta-adrenergic bronchodilator. Large doses of intravenous albuterol have been reported to aggravate preexisting diabetes mellitus and ketoacidosis. As with other beta-agonists, albuterol may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease is usually transient, not requiring supplementation. Although there have been no reports concerning the use of Albuterol Inhalation Aerosol during labor and delivery, it has been reported that high doses of albuterol administered intravenously inhibit uterine contractions. Although this effect is extremely unlikely as a consequence of aerosol use, it should be kept in mind. # Adverse Reactions ## Clinical Trials Experience The adverse reactions to albuterol are similar in nature to reactions to other sympathomimetic agents, although the incidence of certain cardiovascular effects is lower with albuterol. Cases of urticaria, angioedema, rash, bronchospasm, hoarseness, oropharyngeal edema, and arrhythmias (including atrial fibrillation, supraventricular tachycardia, extrasystoles) have been reported after the use of albuterol inhalation aerosol. In addition, albuterol, like other sympathomimetic agents, can cause adverse reactions such as hypertension, angina, vertigo, central nervous system stimulation, sleeplessness, and unusual taste. ## Postmarketing Experience There is limited information regarding Albuterol Postmarketing Experience in the drug label. # Drug Interactions Other short-acting sympathomimetic aerosol bronchodilators should not be used concomitantly with albuterol. If additional adrenergic drugs are to be administered by any route, they should be used with caution to avoid deleterious cardiovascular effects. ### Monoamine Oxidase Inhibitors or Tricyclic Antidepressants Albuterol should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within two weeks of discontinuation of such agents, because the action of albuterol on the vascular system may be potentiated. ### Beta-Blockers Beta-adrenergic receptor blocking agents not only block the pulmonary effect of beta-agonists, such as albuterol, but may produce severe bronchospasm in asthmatic patients. Therefore, patients with asthma should not normally be treated with beta-blockers. However, under certain circumstances, e.g., as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents in patients with asthma. In this setting, cardioselective beta-blockers should be considered, although they should be administered with caution. ### Diuretics The ECG changes and/or hypokalemia that may result from the administration of nonpotassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of beta-agonists with nonpotassium-sparing diuretics. ### Digoxin Mean decreases of 16% to 22% in serum digoxin levels were demonstrated after single-dose intravenous and oral administration of albuterol, respectively, to normal volunteers who had received digoxin for 10 days. The clinical significance of these findings for patients with obstructive airway disease who are receiving albuterol and digoxin on a chronic basis is unclear. Nevertheless, it would be prudent to carefully evaluate the serum digoxin levels in patients who are currently receiving digoxin and albuterol. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C Albuterol sulfate has been shown to be teratogenic in mice. A study in CD-1 mice at subcutaneous (sc) doses of 0.025, 0.25, and 2.5 mg/kg (approximately 2/25, 1.0, and 8.0 times, respectively, the maximum recommended daily inhalation dose for adults on a mg/m2 basis), showed cleft palate formation in 5 of 111 (4.5%) fetuses at 0.25 mg/kg and in 10 of 108 (9.3%) fetuses at 2.5 mg/kg. The drug did not induce cleft palate formation at the lowest dose, 0.025 mg/kg. Cleft palate also occurred in 22 of 72 (30.5%) fetuses from females treated with 2.5 mg/kg of isoproterenol (positive control) sc (approximately 8 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis). A reproduction study in Stride Dutch rabbits revealed cranioschisis in 7 of 19 (37%) fetuses when albuterol sulfate was administered orally at a 50 mg/kg dose (approximately 680 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis). There are no adequate and well-controlled studies in pregnant women. Albuterol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. During worldwide marketing experience, various congenital anomalies, including cleft palate and limb defects, have been rarely reported in the offspring of patients being treated with albuterol. Some of the mothers were taking multiple medications during their pregnancies. No consistent pattern of defects can be discerned, and a relationship between albuterol use and congenital anomalies has not been established. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Albuterol in women who are pregnant. ### Labor and Delivery Because of the potential for beta-agonist interference with uterine contractility, use of albuterol for relief of bronchospasm during labor should be restricted to those patients in whom the benefits clearly outweigh the risk. ### Nursing Mothers It is not known whether this drug is excreted in human milk. Because of the potential for tumorigenicity shown for albuterol in some animal studies, 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 Safety and effectiveness in pediatric patients below 4 years of age have not been established. ### Geriatic Use There is no FDA guidance on the use of Albuterol in geriatric settings. ### Gender There is no FDA guidance on the use of Albuterol with respect to specific gender populations. ### Race There is no FDA guidance on the use of Albuterol with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Albuterol in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Albuterol in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Albuterol in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Albuterol in patients who are immunocompromised. ### Tocolysis Albuterol has not been approved for the management of preterm labor. The benefit:risk ratio when albuterol is administered for tocolysis has not been established. Serious adverse reactions, including maternal pulmonary edema, have been reported during or following treatment of premature labor with beta2-agonists, including albuterol. # Administration and Monitoring ### Administration Inhale and oral ### Monitoring FDA Package Insert for Albuterol contains no information regarding Drug Monitoring. # IV Compatibility There is limited information about the IV Compatibility. # Overdosage The expected symptoms with overdosage are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the symptoms listed under ADVERSE REACTIONS, e.g., seizures, angina, hypertension, hypotension, tachycardia with rates up to 200 beats/minute, arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, and sleeplessness. hypokalemia may also occur. As with all sympathomimetic aerosol medications, cardiac arrest and even death may be associated with abuse of Albuterol Inhalation Aerosol. Treatment consists of discontinuation of Albuterol Inhalation Aerosol together with appropriate symptomatic therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of Albuterol Inhalation Aerosol. The oral median lethal dose of albuterol sulfate in mice is greater than 2000 mg/kg (approximately 6800 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis, or, approximately 3200 times the maximum recommended daily inhalation dose for children on a mg/m2 basis). In mature rats, the sc median lethal dose of albuterol sulfate is approximately 450 mg/kg (approximately 3000 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis, or, approximately 1400 times the maximum recommended daily inhalation dose for children on a mg/m2 basis). In small young rats, the sc median lethal dose of albuterol sulfate is approximately 2000 mg/kg (approximately 14,000 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis, or, approximately 6400 times the maximum recommended daily inhalation dose for children on a mg/m2 basis). The inhalation median lethal dose has not been determined in animals. # Pharmacology ## Mechanism of Action Albuterol is typically used to treat bronchospasm (due to any cause, allergen asthma or exercise-induced), as well as chronic obstructive pulmonary disease. Emergency medical practice commonly treats people presenting with asthma who report taking their Albuterol inhaler as prescribed with Albuterol. In general, people tolerate large doses well. Other uses include in cystic fibrosis, along with ipratropium bromide, acetylcysteine, and pulmozyme and subtypes of congenital myasthenic syndromes associated to mutations in Dok-7. As a β2-agonist, Albuterol also finds use in obstetrics. Intravenous Albuterol can be used as a tocolytic to relax the uterine smooth muscle to delay premature labor. While preferred over agents such as atosiban and ritodrine, its role has largely been replaced by the calcium-channel blocker nifedipine, which is more effective, better tolerated and orally administered.[1] Albuterol is used to treat acute hyperkalemia as it stimulates potassium to flow in cells thus lowering the level in the blood. Albuterol has also been trialled in spinal muscular atrophy where it appears to show modest benefits. The drug is speculated to modulate the alternative splicing of the SMN2 gene, increasing the amount of the SMN protein whose deficiency is regarded as the root cause of the disease. ## Structure The active component of Albuterol Inhalation Aerosol is albuterol (α1-(tert-butylamino)methyl-4-hydroxy-m-xylene-α,α'-diol), a relatively selective beta2-adrenergic bronchodilator, having the following structural formula: Albuterol is the official generic name in the United States. The World Health Organization recommended name for the drug is salbutamol. The molecular weight of albuterol is 239.2, and the molecular formula is C13H21NO3. Albuterol is a white to off-white crystalline solid. It is soluble in ethanol, sparingly soluble in water, and very soluble in chloroform. Albuterol Inhalation Aerosol is a pressurized metered-dose aerosol unit for oral inhalation. It contains a microcrystalline (95% ≤ 10 µm) suspension of albuterol in propellants (trichloromonofluoromethane and dichlorodifluoromethane) with oleic acid. Each actuation delivers 100 mcg of albuterol from the valve and 90 mcg of albuterol from the mouthpiece. Each canister provides 200 inhalations. ## Pharmacodynamics In vitro studies and in vivo pharmacologic studies have demonstrated that albuterol has a preferential effect on beta2-adrenergic receptors compared with isoproterenol. While it is recognized that beta2-adrenergic receptors are the predominant receptors in bronchial smooth muscle, data indicate that there is a population of beta2-receptors in the human heart existing in a concentration between 10% and 50%. The precise function of these receptors has not been established. The pharmacologic effects of beta-adrenergic agonist drugs, including albuterol, are at least in part attributable to stimulation through beta-adrenergic receptors of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3', 5'- adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels are associated with relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells. Albuterol has been shown in most controlled clinical trials to have more effect on the respiratory tract, in the form of bronchial smooth muscle relaxation, than isoproterenol at comparable doses while producing fewer cardiovascular effects. Controlled clinical studies and other clinical experience have shown that inhaled albuterol, like other beta-adrenergic agonist drugs, can produce a significant cardiovascular effect in some patients, as measured by pulse rate, blood pressure, symptoms, and/or electrocardiographic changes. Albuterol is longer acting than isoproterenol in most patients by any route of administration because it is not a substrate for the cellular uptake processes for catecholamines nor for catechol-O-methyl transferase. The effects of rising doses of albuterol and isoproterenol aerosols were studied in volunteers and asthmatic patients. Results in normal volunteers indicated that albuterol is one half to one quarter as active as isoproterenol in producing increases in heart rate. In asthmatic patients similar cardiovascular differentiation between the two drugs was also seen. ### Preclinical Intravenous studies in rats with albuterol sulfate have demonstrated that albuterol crosses the blood brain barrier and reaches brain concentrations amounting to approximately 5.0% of the plasma concentrations. In structures outside the brain barrier (pineal and pituitary glands), albuterol concentrations were found to be 100 times those in the whole brain. Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of cardiac arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when beta-agonists and methylxanthines are administered concurrently. The clinical significance of these findings is unknown. ## Pharmacokinetics Because of its gradual absorption from the bronchi, systemic levels of albuterol are low after inhalation of recommended doses. Studies undertaken with four subjects administered tritiated albuterol resulted in maximum plasma concentrations occurring within two to four hours. Due to the sensitivity of the assay method, the metabolic rate and half-life of elimination of albuterol in plasma could not be determined. However, urinary excretion provided data indicating that albuterol has an elimination half-life of 3.8 hours. Approximately 72% of the inhaled dose is excreted within 24 hours in the urine, and consists of 28% as unchanged drug and 44% as metabolite. ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, Impairment of Fertility In a two-year study in Sprague-Dawley rats, albuterol sulfate caused a significant dose-related increase in the incidence of benign leiomyomas of the mesovarium at dietary doses of 2.0, 10, and 50 mg/kg (approximately 15, 70, and 340 times, respectively, the maximum recommended daily inhalation dose for adults on a mg/m2 basis, or, approximately 6, 30, and 160 times, respectively, the maximum recommended daily inhalation dose in children on a mg/m2 basis). In another study this effect was blocked by the coadministration of propranolol, a non-selective beta-adrenergic antagonist. In an 18-month study in CD-1 mice, albuterol sulfate showed no evidence of tumorigenicity at dietary doses of up to 500 mg/kg (approximately 1700 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis, or, approximately 800 times the maximum recommended daily inhalation dose for children on a mg/m2 basis). In a 22-month study in the Golden hamster, albuterol sulfate showed no evidence of tumorigenicity at dietary doses of up to 50 mg/kg (approximately 225 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis, or, approximately 110 times the maximum recommended daily inhalation dose for children on a mg/m2 basis). Albuterol sulfate was not mutagenic in the Ames test with or without metabolic activation using tester strains S. typhimurium TA1537, TA1538, and TA98 or E. Coli WP2, WP2uvrA, and WP67. No forward mutation was seen in yeast strain S. cerevisiae S9 nor any mitotic gene conversion in yeast strain S. cerevisiae JD1 with or without metabolic activation. Fluctuation assays in S. typhimurium TA98 and E.Coli WP2, both with metabolic activation, were negative. Albuterol sulfate was not clastogenic in a human peripheral lymphocyte assay or in an AH1 strain mouse micronucleus assay at intraperitoneal doses of up to 200 mg/kg. Reproduction studies in rats demonstrated no evidence of impaired fertility at oral doses of up to 50 mg/kg (approximately 340 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis). # Clinical Studies In controlled clinical trials involving adults with asthma, the onset of improvement in pulmonary function was within 15 minutes, as determined by both MMEF (maximum midexpiratory flow rate) and FEV1 (forced expiratory volume in one second). MMEF measurements also showed that near maximum improvement in pulmonary function generally occurs within 60 to 90 minutes following two inhalations of albuterol and that clinically significant improvement generally continues for three to four hours in most patients. Some patients showed a therapeutic response (defined by maintaining FEV1 values 15% or more above baseline) that was still apparent at 6 hours. Continued effectiveness of albuterol was demonstrated over a 13-week period in these same trials. In controlled clinical trials involving children 4 to 12 years of age, FEV1 measurements showed that maximum improvement in pulmonary function occurs within 30 to 60 minutes. The onset of clinically significant (≥15%) improvement in FEV1 was observed as soon as five minutes following 180 mcg of albuterol in 18 of 30 (60%) children in a controlled dose-ranging study. Clinically significant improvement in FEV1 continued in the majority of patients for two hours and in 33% to 47% for four hours among 56 patients receiving inhalation aerosol in one pediatric study. In a second study among 48 patients receiving inhalation aerosol, clinically significant improvement continued in the majority for up to one hour and in 23% to 40% for four hours. In addition, at least 50% of the patients in both studies achieved an improvement in FEF25%–75% (forced expiratory flow rate between 25% and 75% of the forced vital capacity) of at least 20% for 2 to 5 hours. Continued effectiveness of albuterol was demonstrated over the 12-week study period. In other clinical studies in adults and children, two inhalations of albuterol aerosol taken approximately 15 minutes before exercise prevented exercise-induced bronchospasm, as demonstrated by the maintenance of FEV1 within 80% of baseline values in the majority of patients. One study in adults also evaluated the duration of the prophylactic effect to repeated exercise challenges, which was evident at 4 hours in a majority of the patients and at 6 hours in approximately one third of the patients. # How Supplied ### Albuterol Inhalation Aerosol Albuterol Inhalation Aerosol is supplied in 17 g canisters containing 200 metered inhalations (NDC 17270-721-01) in boxes of one. Each actuation delivers 100 mcg of albuterol from the valve and 90 mcg of albuterol from the mouthpiece. Each canister is supplied with a blue oral adapter and patient's instructions. Also available, Albuterol Inhalation Aerosol Refill with patient's instructions (NDC 17270-721-02). The blue adapter supplied with Albuterol Inhalation Aerosol should not be used with any other product canisters, and the adapters from other products should not be used with an Albuterol Inhalation Aerosol canister. The correct amount of medication in each canister cannot be assured after 200 actuations, even though the canister is not completely empty. The canister should be discarded when the labeled number of actuations have been used. ### Albuterol Tablet Albuterol tablets, USP; 2 mg of albuterol as the sulfate, are white, round, scored, debossed MP 47 Albuterol tablets, USP; 4 mg of albuterol as the sulfate, are white, round, scored, debossed MP 88 ### ALBUTEROL SULFATE syrup Albuterol Sulfate Syrup, a clear, yellow liquid with a strawberry flavor, contains 2 mg of albuterol (present as the sulfate) per 5 mL in bottles of 16 fluid ounces (one pint). ### ALBUTEROL SULFATE inhalation solution Albuterol sulfate inhalation solution, 0.5% is supplied in amber glass bottles, with a calibrated dropper and with patient instructions in the following size: 20 mL bottles - NDC 24208-347-20 ## Storage ### Albuterol Inhalation Aerosol Store between 15°–30°C (59°–86°F). As with most inhaled medications in aerosol canisters, the therapeutic effect of this medication may decrease when the canister is cold; for best results, the canister should be at room temperature before use. ### Albuterol Tablet Store at 20° to 25°C (68° to 77°F). DISPENSE IN TIGHT, LIGHT-RESISTANT CONTAINER. ### ALBUTEROL SULFATE syrup Store at 20° to 25°C (68° to 77°F). ### ALBUTEROL SULFATE inhalation solution Storage: Store between 2°-25°C (36°-77°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information The action of Albuterol Inhalation Aerosol may last up to six hours or longer. Albuterol Inhalation Aerosol should not be used more frequently than recommended. Do not increase the dose or frequency of Albuterol Inhalation Aerosol without consulting your physician. If you find that treatment with Albuterol Inhalation Aerosol becomes less effective for symptomatic relief, your symptoms become worse, and/or you need to use the product more frequently than usual, you should seek medical attention immediately. While you are using Albuterol Inhalation Aerosol, other inhaled drugs and asthma medications should be taken only as directed by your physician. Common adverse effects include palpitations, chest pain, rapid heart rate, and tremor or nervousness. If you are pregnant or nursing, contact your physician about use of Albuterol Inhalation Aerosol. Effective and safe use of Albuterol Inhalation Aerosol includes an understanding of the way that it should be administered. In general, the technique for administering Albuterol Inhalation Aerosol to children is similar to that for adults, since children's smaller ventilatory exchange capacity automatically provides proportionally smaller aerosol intake. Children should use Albuterol Inhalation Aerosol under adult supervision, as instructed by the patient's physician. # Precautions with Alcohol Alcohol-Albuterol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Accuneb - Proventil - Proventil HFA - Proventil Repetabs - Ventolin - Ventolin HFA - VoSpire ER - ProAir HFA # Look-Alike Drug Names There is limited information about the look-alike drug names. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Accuneb
dd3e0b382ed8dfd298d37cf8fecd9d0ca2fbb2d3	wikidoc	Quinapril	Quinapril For information about Quinapril hydrochlorothiazide ‎, click here. - Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus - Monotherapy Dosing Information - Initial dosage: Quinapril 10 - 20 mg PO qd .Dosage should be adjusted according to blood pressure response measured at peak (2–6 hours after dosing) and trough (predosing). Generally, dosage adjustments should be made at intervals of at least 2 weeks. - Maintenance dose: Quinapril 20 - 80 mg PO qd on two divided doses, adjust dose based on response (MAX 80 mg/day) In some patients treated once daily, the antihypertensive effect may diminish toward the end of the dosing interval. In such patients an increase in dosage or twice daily administration may be warranted. In general, doses of 40–80 mg and divided doses give a somewhat greater effect at the end of the dosing interval. - Concomitant diuretic dosing information - If blood pressure is not adequately controlled with Accupril monotherapy, a diuretic may be added. In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally can occur following the initial dose of Accupril. To reduce the likelihood of hypotension, the diuretic should, if possible, be discontinued 2 to 3 days prior to beginning therapy with Accupril (see WARNINGS). Then, if blood pressure is not controlled with Accupril alone, diuretic therapy should be resumed. - Initial dosage: 5 mg used with careful medical supervision for several hours and until blood pressure has stabilized. - The dosage should subsequently be titrated (as described above) to the optimal response (see Warnings and Precautions, and Drug Interactions). - Renal Impairment - Kinetic data indicate that the apparent elimination half-life of quinaprilat increases as creatinine clearance decreases. Recommended starting doses, based on clinical and pharmacokinetic data from patients with renal impairment, are as follows: - Patients should subsequently have their dosage titrated (as described above) to the optimal response. - Dosing information of use in elderly (≥65 years) - Recommended initial dosage:10 mg PO qd followed by titration (as described above) to the optimal response. - Dosing Information: Adjunct - Initial dose : 5 mg PO bid - Maintenance dose: 20-40 mg PO bid - Following the initial dose of ACCUPRIL, the patient should be observed under medical supervision for at least two hours for the presence of hypotension or orthostatis and, if present, until blood pressure stabilizes. The appearance of hypotension, orthostatis, or azotemia early in dose titration should not preclude further careful dose titration. Consideration should be given to reducing the dose of concomitant diuretics. ## Dose ajustments in patient with heart failure and renal impairment or hyponatremia - Pharmacokinetic data indicate that quinapril elimination is dependent on level of renal function. In patients with heart failure and renal impairment, the recommended initial dose of accupril is 5 mg in patients with a creatinine clearance above 30 mL/min and 2.5 mg in patients with a creatinine clearance of 10 to 30 mL/min. There is insufficient data for dosage recommendation in patients with a creatinine clearance less than 10 mL/min (see Dosage and Administration, Heart Failure, Warnings and Precautions, Drug Interactions). - If the initial dose is well tolerated, accupril may be administered the following day as a twice daily regimen. In the absence of excessive hypotension or significant deterioration of renal function, the dose may be increased at weekly intervals based on clinical and hemodynamic response. - Dosing information - 10-40 mg PO qd - Dosing information - 0.02 or 0.04 mg/kg - Dosing information - 10-20 mg - Dosing Information - Initial dose : Quinapril 5 - 10 mg PO qd should be used. - Maintenance dose: Quinapril titrate till (MAX 80 mg/day) - Do not co-administer aliskiren with accupril in patients with diabetes. - Presumably because angiotensin-converting inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including accupril) may be subject to a variety of adverse reactions, some of them serious. - Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with ACE inhibitors and has been seen in 0.1% of patients receiving accupril. - In two similarly sized U.S. postmarketing trials that, combined, enrolled over 3,000 black patients and over 19,000 non-blacks, angioedema was reported in 0.30% and 0.55% of blacks (in study 1 and 2 respectively) and 0.39% and 0.17% of non-blacks. - Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, treatment with accupril should be discontinued immediately, the patient treated in accordance with accepted medical care, and carefully observed until the swelling disappears. In instances where swelling is confined to the face and lips, the condition generally resolves without treatment; antihistamines may be useful in relieving symptoms. Where there is involvement of the tongue, glottis, or larynx likely to cause airway obstruction, emergency therapy including, but not limited to, subcutaneous epinephrine solution 1:1000 (0.3 to 0.5 mL) should be promptly administered. - Patients taking concomitant mTOR inhibitor (e.g. temsirolimus) therapy may be at increased risk for 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. - Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor. - Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge. - 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. - 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. - Excessive hypotension is rare in patients with uncomplicated hypertension treated with accupril alone. Patients with heart failure given accupril commonly have some reduction in blood pressure, but discontinuation of therapy because of continuing symptomatic hypotension usually is not necessary when dosing instructions are followed. Caution should be observed when initiating therapy in patients with heart failure. In controlled studies, syncope was observed in 0.4% of patients (N=3203); this incidence was similar to that observed for captopril (1%) and enalapril (0.8%). - Patients at risk of excessive hypotension, sometimes associated with oliguria and/or progressive azotemia, and rarely with acute renal failure and/or death, include patients with the following conditions or characteristics: heart failure, hyponatremia, high dose diuretic therapy, recent intensive diuresis or increase in diuretic dose, renal dialysis, or severe volume and/or salt depletion of any etiology. It may be advisable to eliminate the diuretic (except in patients with heart failure), reduce the diuretic dose or cautiously increase salt intake (except in patients with heart failure) before initiating therapy with accupril in patients at risk for excessive hypotension who are able to tolerate such adjustments. - In patients at risk of excessive hypotension, therapy with accupril should be started under close medical supervision. Such patients should be followed closely for the first two weeks of treatment and whenever the dose of accupril and/or diuretic is increased. Similar considerations may apply to patients with ischemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in a myocardial infarction or a cerebrovascular accident. - If excessive hypotension occurs, the patient should be placed in the supine position and, if necessary, receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further doses of accupril, which usually can be given without difficulty once the blood pressure has stabilized. If symptomatic hypotension develops, a dose reduction or discontinuation of accupril or concomitant diuretic may be necessary. - Another ACE inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression rarely in patients with uncomplicated hypertension, but more frequently in patients with renal impairment, especially if they also have a collagen vascular disease, such as systemic lupus erythematosus or scleroderma. Agranulocytosis did occur during accupril treatment in one patient with a history of neutropenia during previous captopril therapy. Available data from clinical trials of Accupril are insufficient to show that, in patients without prior reactions to other ACE inhibitors, Accupril does not cause agranulocytosis at similar rates. As with other ACE inhibitors, periodic monitoring of white blood cell counts in patients with collagen vascular disease and/or renal disease should be considered. - 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 Accupril 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 Accupril, unless it is considered life-saving 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 Accupril for hypotension, oliguria, and hyperkalemia. - No teratogenic effects of Accupril were seen in studies of pregnant rats and rabbits. On a mg/kg basis, the doses used were up to 180 times (in rats) and one time (in rabbits) the maximum recommended human dose. # Precautions - As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors, including Accupril, may be associated with oliguria and/or progressive azotemia and rarely acute renal failure and/or death. - In clinical studies in hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine have been observed in some patients following ACE inhibitor therapy. These increases were almost always reversible upon discontinuation of the ACE inhibitor and/or diuretic therapy. In such patients, renal function should be monitored during the first few weeks of therapy. - Some patients with hypertension or heart failure with no apparent preexisting renal vascular disease have developed increases in blood urea and serum creatinine, usually minor and transient, especially when Accupril has been given concomitantly with a diuretic. This is more likely to occur in patients with preexisting renal impairment. Dosage reduction and/or discontinuation of any diuretic and/or Accupril may be required. - Evaluation of patients with hypertension or heart failure should always include assessment of renal function. - In clinical trials, hyperkalemia (serum potassium ≥5.8 mmol/L) occurred in approximately 2% of patients receiving Accupril. In most cases, elevated serum potassium levels were isolated values which resolved despite continued therapy. Less than 0.1% of patients discontinued therapy due to hyperkalemia. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes, which should be used cautiously, if at all, with Accupril. - Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent non-productive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough. - In patients undergoing major surgery or during anesthesia with agents that produce hypotension, Accupril will block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion. - Accupril has been evaluated for safety in 4960 subjects and patients. Of these, 3203 patients, including 655 elderly patients, participated in controlled clinical trials. Accupril has been evaluated for long-term safety in over 1400 patients treated for 1 year or more. - Adverse experiences were usually mild and transient. - In placebo-controlled trials, discontinuation of therapy because of adverse events was required in 4.7% of patients with hypertension. - Adverse experiences probably or possibly related to therapy or of unknown relationship to therapy occurring in 1% or more of the 1563 patients in placebo-controlled hypertension trials who were treated with Accupril are shown below: - Accupril has been evaluated for safety in 1222 Accupril treated patients. Of these, 632 patients participated in controlled clinical trials. In placebo-controlled trials, discontinuation of therapy because of adverse events was required in 6.8% of patients with congestive heart failure. - Adverse experiences probably or possibly related or of unknown relationship to therapy occurring in 1% or more of the 585 patients in placebo-controlled congestive heart failure trials who were treated with Accupril are shown below: - Clinical adverse experiences probably, possibly, or definitely related, or of uncertain relationship to therapy occurring in 0.5% to 1.0% (except as noted) of the patients with CHF or hypertension treated with Accupril (with or without concomitant diuretic) in controlled or uncontrolled trials (N=4847) and less frequent, clinically significant events seen in clinical trials or post-marketing experience (the rarer events are in italics) include (listed by body system): - back pain, malaise, viral infections, anaphylactoid reaction. - palpitation, vasodilation, tachycardia, heart failure, hyperkalemia, myocardial infarction, cerebrovascular accident, hypertensive crisis, angina pectoris, orthostatic hypotension, cardiac rhythm disturbances, cardiogenic shock - hemolytic anemia - Flatulence, dry mouth or throat, constipation, gastrointestinal hemorrhage, pancreatitis, abnormal liver function tests, dyspepsia - Somnolence, vertigo, syncope, nervousness, depression, insomnia, paresthesia - Alopecia, increased sweating, pemphigus, pruritus, exfoliative dermatitis, photosensitivity reaction, dermatopolymyositis - urinary tract infection, impotence, acute renal failure, worsening renal failure - Eosinophilic pneumonitis - Amblyopia, edema, arthralgia, pharyngitis, agranulocytosis, hepatitis, thrombocytopenia - Angioedema has been reported in patients receiving Accupril (0.1%). Angioedema associated with laryngeal edema may be fatal. If angioedema of the face, extremities, lips, tongue, glottis, and/or larynx occurs, treatment with Accupril should be discontinued and appropriate therapy instituted immediately. - Increases (>1.25 times the upper limit of normal) in serum creatinine and blood urea nitrogen were observed in 2% and 2%, respectively, of all patients treated with Accupril alone. Increases are more likely to occur in patients receiving concomitant diuretic therapy than in those on Accupril alone. These increases often remit on continued therapy. In controlled studies of heart failure, increases in blood urea nitrogen and serum creatinine were observed in 11% and 8%, respectively, of patients treated with Accupril; most often these patients were receiving diuretics with or without digitalis. - As with other ACE inhibitors, patients on diuretics, especially those on recently instituted diuretic therapy, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with Accupril. The possibility of hypotensive effects with Accupril may be minimized by either discontinuing the diuretic or cautiously increasing salt intake prior to initiation of treatment with Accupril. If it is not possible to discontinue the diuretic, the starting dose of quinapril should be reduced. ## Agents increasing serum potassium - Quinapril can attenuate potassium loss caused by thiazide diuretics and increase serum potassium when used alone. If concomitant therapy of Accupril with potassium-sparing diuretics (eg, spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes is indicated, they should be used with caution along with appropriate monitoring of serum potassium. ## Tetracycline and other drugs that interact with magnesium - Simultaneous administration of tetracycline with Accupril reduced the absorption of tetracycline by approximately 28% to 37%, possibly due to the high magnesium content in Accupril tablets. This interaction should be considered if coprescribing Accupril and tetracycline or other drugs that interact with magnesium. ## Lithium - Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, it may increase the risk of lithium toxicity. ## 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. ## 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, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including quinapril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving quinapril and NSAID therapy. - The antihypertensive effect of ACE inhibitors, including quinapril may be attenuated by NSAIDs. ## Agents that inhibit mTOR - Patients taking concomitant mTOR inhibitor (e.g. temsirolimus) therapy may be at increased risk for angioedema. ## Other agents - Drug interaction studies of Accupril with other agents showed: - Multiple dose therapy with propranolol or cimetidine has no effect on the pharmacokinetics of single doses of Accupril. The anticoagulant effect of a single dose of warfarin (measured by prothrombin time) was not significantly changed by quinapril coadministration twice-daily. Accupril treatment did not affect the pharmacokinetics of digoxin. - No pharmacokinetic interaction was observed when single doses of Accupril and hydrochlorothiazide were administered concomitantly. Co-administration of multiple 10 mg doses of atorvastatin with 80 mg of Accupril resulted in no significant change in the steady-state pharmacokinetic parameters of atorvastatin. ## 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 Accupril and other agents that affect the RAS. - Do not co-administer aliskiren with Accupril in patients with diabetes. Avoid concomitant use of aliskiren with Accupril in patients with renal impairment (GFR <60 mL/min/1.73 m2). ## Carcinogenesis, Mutagenesis, Impairment of Fertility - Quinapril hydrochloride was not carcinogenic in mice or rats when given in doses up to 75 or 100 mg/kg/day (50 to 60 times the maximum human daily dose, respectively, on an mg/kg basis and 3.8 to 10 times the maximum human daily dose when based on an mg/m2 basis) for 104 weeks. Female rats given the highest dose level had an increased incidence of mesenteric lymph node hemangiomas and skin/subcutaneous lipomas. Neither quinapril nor quinaprilat were mutagenic in the Ames bacterial assay with or without metabolic activation. Quinapril was also negative in the following genetic toxicology studies: in vitro mammalian cell point mutation, sister chromatid exchange in cultured mammalian cells, micronucleus test with mice, in vitro chromosome aberration with V79 cultured lung cells, and in an in vivo cytogenetic study with rat bone marrow. There were no adverse effects on fertility or reproduction in rats at doses up to 100 mg/kg/day (60 and 10 times the maximum daily human dose when based on mg/kg and mg/m2, respectively). - 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 Accupril, unless it is considered life-saving 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 Accupril for hypotension, oliguria, and hyperkalemia. - No teratogenic effects of Accupril were seen in studies of pregnant rats and rabbits. On a mg/kg basis, the doses used were up to 180 times (in rats) and one time (in rabbits) the maximum recommended human dose. - 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. Removal of Accupril, which crosses the placenta, from the neonatal circulation is not significantly accelerated by these means. - The safety and effectiveness of Accupril in pediatric patients have not been established. - This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. 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. - Elderly patients exhibited increased area under the plasma concentration time curve and peak levels for quinaprilat compared to values observed in younger patients; this appeared to relate to decreased renal function rather than to age itself. ## Monotherapy The recommended initial dosage of accupril in patients not on diuretics is 10 or 20 mg once daily. Dosage should be adjusted according to blood pressure response measured at peak (2–6 hours after dosing) and trough (predosing). Generally, dosage adjustments should be made at intervals of at least 2 weeks. Most patients have required dosages of 20, 40, or 80 mg/day, given as a single dose or in two equally divided doses. In some patients treated once daily, the antihypertensive effect may diminish toward the end of the dosing interval. In such patients an increase in dosage or twice daily administration may be warranted. In general, doses of 40–80 mg and divided doses give a somewhat greater effect at the end of the dosing interval. ## Concomitant Diuretics If blood pressure is not adequately controlled with accupril monotherapy, a diuretic may be added. In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally can occur following the initial dose of accupril. To reduce the likelihood of hypotension, the diuretic should, if possible, be discontinued 2 to 3 days prior to beginning therapy with accupril. Then, if blood pressure is not controlled with accupril alone, diuretic therapy should be resumed. If the diuretic cannot be discontinued, an initial dose of 5 mg accupril should be used with careful medical supervision for several hours and until blood pressure has stabilized. The dosage should subsequently be titrated (as described above) to the optimal response. ## Renal Impairment Kinetic data indicate that the apparent elimination half-life of quinaprilat increases as creatinine clearance decreases. Recommended starting doses, based on clinical and pharmacokinetic data from patients with renal impairment, are as follows: Patients should subsequently have their dosage titrated (as described above) to the optimal response. ## Elderly (≥65 years) The recommended initial dosage of Accupril in elderly patients is 10 mg given once daily followed by titration (as described above) to the optimal response. # Heart Failure Accupril is indicated as adjunctive therapy when added to conventional therapy including diuretics and/or digitalis. The recommended starting dose is 5 mg twice daily. This dose may improve symptoms of heart failure, but increases in exercise duration have generally required higher doses. Therefore, if the initial dosage of accupril is well tolerated, patients should then be titrated at weekly intervals until an effective dose, usually 20 to 40 mg daily given in two equally divided doses, is reached or undesirable hypotension, orthostatis, or azotemia prohibit reaching this dose. Following the initial dose of accupril, the patient should be observed under medical supervision for at least two hours for the presence of hypotension or orthostatis and, if present, until blood pressure stabilizes. The appearance of hypotension, orthostatis, or azotemia early in dose titration should not preclude further careful dose titration. Consideration should be given to reducing the dose of concomitant diuretics. ## Dose Adjustments in Patients with Heart Failure and Renal Impairment or Hyponatremia Pharmacokinetic data indicate that quinapril elimination is dependent on level of renal function. In patients with heart failure and renal impairment, the recommended initial dose of Accupril is 5 mg in patients with a creatinine clearance above 30 mL/min and 2.5 mg in patients with a creatinine clearance of 10 to 30 mL/min. There is insufficient data for dosage recommendation in patients with a creatinine clearance less than 10 mL/min. If the initial dose is well tolerated, accupril may be administered the following day as a twice daily regimen. In the absence of excessive hypotension or significant deterioration of renal function, the dose may be increased at weekly intervals based on clinical and hemodynamic response. - As with other ACE inhibitors, periodic monitoring of white blood cell counts in patients with collagen vascular disease and/or renal disease should be considered. - As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors, including ACCUPRIL, may be associated with oliguria and/or progressive azotemia and rarely acute renal failure and/or death. In clinical studies in hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine have been observed in some patients following ACE inhibitor therapy. These increases were almost always reversible upon discontinuation of the ACE inhibitor and/or diuretic therapy. In such patients, renal function should be monitored during the first few weeks of therapy. - Quinapril can attenuate potassium loss caused by thiazide diuretics and increase serum potassium when used alone. If concomitant therapy of ACCUPRIL with potassium-sparing diuretics (eg, spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes is indicated, they should be used with caution along with appropriate monitoring of serum potassium. - Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, it may increase the risk of lithium toxicity. - In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including quinapril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving quinapril and NSAID therapy. The antihypertensive effect of ACE inhibitors, including quinapril may be attenuated by NSAIDs. - 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 ACCUPRIL and other agents that affect the RAS. Do not co-administer aliskiren with ACCUPRIL in patients with diabetes. Avoid concomitant use of aliskiren with ACCUPRIL in patients with renal impairment (GFR <60 mL/min/1.73 m2). - Clinical studies of Accupril 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. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. 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. Elderly patients exhibited increased area under the plasma concentration time curve and peak levels for quinaprilat compared to values observed in younger patients; this appeared to relate to decreased renal function rather than to age itself. No specific information is available on the treatment of overdosage with quinapril. The most likely clinical manifestation would be symptoms attributable to severe hypotension. Laboratory determinations of serum levels of quinapril and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of quinapril overdose. No data are available to suggest physiological maneuvers (eg, maneuvers to change pH of the urine) that might accelerate elimination of quinapril and its metabolites. Hemodialysis and peritoneal dialysis have little effect on the elimination of quinapril and quinaprilat. Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of quinapril overdose, but angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of quinapril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat quinapril overdose by infusion of normal saline solution. - While the principal mechanism of antihypertensive effect is thought to be through the renin-angiotensin-aldosterone system, quinapril exerts antihypertensive actions even in patients with low renin hypertension. Accupril was an effective antihypertensive in all races studied, although it was somewhat less effective in blacks (usually a predominantly low renin group) than in nonblacks. ACE is identical to kininase II, an enzyme that degrades bradykinin, a potent peptide vasodilator; whether increased levels of bradykinin play a role in the therapeutic effect of quinapril remains to be elucidated. Quinapril hydrochloride is chemically described as , 3R*] ]-2-amino]-1-oxopropyl]-1,2,3,4-tetrahydro-3- isoquinolinecarboxylic acid, monohydrochloride. Its empirical formula is C25H30N2O5 HCl and its structural formula is: Quinapril hydrochloride is a white to off-white amorphous powder that is freely soluble in aqueous solvents. Quinapril tablets USP contain 5 mg, 10 mg, 20 mg, or 40 mg of quinapril for oral administration. Each film-coated tablet also contains crospovidone, iron oxide yellow, lecithin, magnesium carbonate, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol, povidone, talc, titanium dioxide and xanthan gum. - In patients with renal insufficiency, the elimination half-life of quinaprilat increases as creatinine clearance decreases. There is a linear correlation between plasma quinaprilat clearance and creatinine clearance. In patients with end-stage renal disease, chronic hemodialysis or continuous ambulatory peritoneal dialysis has little effect on the elimination of quinapril and quinaprilat. Elimination of quinaprilat may be reduced in elderly patients (≥65 years) and in those with heart failure; this reduction is attributable to decrease in renal function. Quinaprilat concentrations are reduced in patients with alcoholic cirrhosis due to impaired deesterification of quinapril. Studies in rats indicate that quinapril and its metabolites do not cross the blood-brain barrier. - Quinapril hydrochloride was not carcinogenic in mice or rats when given in doses up to 75 or 100 mg/kg/day (50 to 60 times the maximum human daily dose, respectively, on an mg/kg basis and 3.8 to 10 times the maximum human daily dose when based on an mg/m2 basis) for 104 weeks. Female rats given the highest dose level had an increased incidence of mesenteric lymph node hemangiomas and skin/subcutaneous lipomas. Neither quinapril nor quinaprilat were mutagenic in the Ames bacterial assay with or without metabolic activation. Quinapril was also negative in the following genetic toxicology studies: in vitro mammalian cell point mutation, sister chromatid exchange in cultured mammalian cells, micronucleus test with mice, in vitro chromosome aberration with V79 cultured lung cells, and in an in vivo cytogenetic study with rat bone marrow. There were no adverse effects on fertility or reproduction in rats at doses up to 100 mg/kg/day (60 and 10 times the maximum daily human dose when based on mg/kg and mg/m2, respectively). - Administration of 10 to 80 mg of Accupril to patients with mild to severe hypertension results in a reduction of sitting and standing blood pressure to about the same extent with minimal effect on heart rate. Symptomatic postural hypotension is infrequent although it can occur in patients who are salt-and,or volume-depleted. Antihypertensive activity commences within 1 hour with peak effects usually achieved by 2 to 4 hours after dosing. During chronic therapy, most of the blood pressure lowering effect of a given dose is obtained in 1–2 weeks. In multiple-dose studies, 10–80 mg per day in single or divided doses lowered systolic and diastolic blood pressure throughout the dosing interval, with a trough effect of about 5–11,3–7 mm Hg. The trough effect represents about 50% of the peak effect. While the dose-response relationship is relatively flat, doses of 40–80 mg were somewhat more effective at trough than 10–20 mg, and twice daily dosing tended to give a somewhat lower trough blood pressure than once daily dosing with the same total dose. The antihypertensive effect of Accupril continues during long-term therapy, with no evidence of loss of effectiveness. - Hemodynamic assessments in patients with hypertension indicate that blood pressure reduction produced by quinapril is accompanied by a reduction in total peripheral resistance and renal vascular resistance with little or no change in heart rate, cardiac index, renal blood flow, glomerular filtration rate, or filtration fraction. - Use of Accupril with a thiazide diuretic gives a blood-pressure lowering effect greater than that seen with either agent alone. - In patients with hypertension, Accupril 10–40 mg was similar in effectiveness to captopril, enalapril, propranolol, and thiazide diuretics. - Therapeutic effects appear to be the same for elderly (≥65 years of age) and younger adult patients given the same daily dosages, with no increase in adverse events in elderly patients. ## Heart Failure - In a placebo-controlled trial involving patients with congestive heart failure treated with digitalis and diuretics, parenteral quinaprilat, the active metabolite of quinapril, reduced pulmonary capillary wedge pressure and systemic vascular resistance and increased cardiac output,index. Similar favorable hemodynamic effects were seen with oral quinapril in baseline-controlled trials, and such effects appeared to be maintained during chronic oral quinapril therapy. Quinapril reduced renal hepatic vascular resistance and increased renal and hepatic blood flow with glomerular filtration rate remaining unchanged. - A significant dose response relationship for improvement in maximal exercise tolerance has been observed with Accupril therapy. Beneficial effects on the severity of heart failure as measured by New York Heart Association (NYHA) classification and Quality of Life and on symptoms of dyspnea, fatigue, and edema were evident after 6 months in a double-blind, placebo-controlled study. Favorable effects were maintained for up to two years of open label therapy. The effects of quinapril on long-term mortality in heart failure have not been evaluated. 5-mg tablets brown, film-coated, elliptical scored tablets, coded "PD 527" on one side and "5" on the other. NDC 0071-0527-23 bottles of 90 tablets NDC 0071-0527-40 10 × 10 unit dose blisters 10-mg tablets brown, film-coated, triangular tablets, coded "PD 530" on one side and "10" on the other. NDC 0071-0530-23 bottles of 90 tablets NDC 0071-0530-40 10 × 10 unit dose blisters 20-mg tablets brown, film-coated, round tablets, coded "PD 532" on one side and "20" on the other. NDC 0071-0532-23 bottles of 90 tablets NDC 0071-0532-40 10 × 10 unit dose blisters 40-mg tablets brown, film-coated, elliptical tablets, coded "PD 535" on one side and "40" on the other. NDC 0071-0535-23 bottles of 90 tablets Dispense in well-closed containers as defined in the USP. Protect from light. - Female patients of childbearing age should be told about the consequences of exposure to ACCUPRIL 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. - Angioedema - Angioedema, including laryngeal edema can occur with treatment with ACE inhibitors, especially following the first dose. Patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema (swelling of face, extremities, eyes, lips, tongue, difficulty in swallowing or breathing) and to stop taking the drug until they have consulted with their physician (see Warnings). - Symptomatic hypotension - Patients should be cautioned that lightheadedness can occur, especially during the first few days of ACCUPRIL therapy, and that it should be reported to a physician. If actual syncope occurs, patients should be told to not take the drug until they have consulted with their physician (see Warnings)). - All patients should be cautioned that inadequate fluid intake or excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure because of reduction in fluid volume, with the same consequences of lightheadedness and possible syncope. - Patients planning to undergo any surgery and/or anesthesia should be told to inform their physician that they are taking an ACE inhibitor. - Hyperkalemia - Patients should be told not to use potassium supplements or salt substitutes containing potassium without consulting their physician (see Warnings)). - Neutropenia - Patients should be told to report promptly any indication of infection (eg, sore throat, fever) which could be a sign of neutropenia. NOTE: As with many other drugs, certain advice to patients being treated with ACCUPRIL is warranted. This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects. - ↑ Dominguez LJ, Barbagallo M, Kattah W, Garcia D, Sowers JR (1995) Quinapril reduces microalbuminuria in essential hypertensive and in diabetic hypertensive subjects. Am J Hypertens 8 (8):808-14. DOI:10.1016/0895-7061(95)00143-D PMID: 7576397 - ↑ Müller M, Schindler E, Kwapisz M, Klemm S, Akintürk H, Heidt M et al. (2000) Effect of intraoperative angiotensin-converting enzyme inhibition by quinaprilat on hypertension after coronary artery surgery. Br J Anaesth 84 (3):396-8. PMID: 10793603 - ↑ Schön HR, Schömig A (1995) Dtsch Med Wochenschr 120 (13):429-35. DOI:10.1055/s-2008-1055363 PMID: 7712932 - ↑ "". 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}	Quinapril For information about Quinapril hydrochlorothiazide ‎, click here. - Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus - Monotherapy Dosing Information - Initial dosage: Quinapril 10 - 20 mg PO qd .Dosage should be adjusted according to blood pressure response measured at peak (2–6 hours after dosing) and trough (predosing). Generally, dosage adjustments should be made at intervals of at least 2 weeks. - Maintenance dose: Quinapril 20 - 80 mg PO qd on two divided doses, adjust dose based on response (MAX 80 mg/day) In some patients treated once daily, the antihypertensive effect may diminish toward the end of the dosing interval. In such patients an increase in dosage or twice daily administration may be warranted. In general, doses of 40–80 mg and divided doses give a somewhat greater effect at the end of the dosing interval. - Concomitant diuretic dosing information - If blood pressure is not adequately controlled with Accupril monotherapy, a diuretic may be added. In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally can occur following the initial dose of Accupril. To reduce the likelihood of hypotension, the diuretic should, if possible, be discontinued 2 to 3 days prior to beginning therapy with Accupril (see WARNINGS). Then, if blood pressure is not controlled with Accupril alone, diuretic therapy should be resumed. - Initial dosage: 5 mg used with careful medical supervision for several hours and until blood pressure has stabilized. - The dosage should subsequently be titrated (as described above) to the optimal response (see Warnings and Precautions, and Drug Interactions). - Renal Impairment - Kinetic data indicate that the apparent elimination half-life of quinaprilat increases as creatinine clearance decreases. Recommended starting doses, based on clinical and pharmacokinetic data from patients with renal impairment, are as follows: - Patients should subsequently have their dosage titrated (as described above) to the optimal response. - Dosing information of use in elderly (≥65 years) - Recommended initial dosage:10 mg PO qd followed by titration (as described above) to the optimal response. - Dosing Information: Adjunct - Initial dose : 5 mg PO bid - Maintenance dose: 20-40 mg PO bid - Following the initial dose of ACCUPRIL, the patient should be observed under medical supervision for at least two hours for the presence of hypotension or orthostatis and, if present, until blood pressure stabilizes. The appearance of hypotension, orthostatis, or azotemia early in dose titration should not preclude further careful dose titration. Consideration should be given to reducing the dose of concomitant diuretics. ### Dose ajustments in patient with heart failure and renal impairment or hyponatremia - Pharmacokinetic data indicate that quinapril elimination is dependent on level of renal function. In patients with heart failure and renal impairment, the recommended initial dose of accupril is 5 mg in patients with a creatinine clearance above 30 mL/min and 2.5 mg in patients with a creatinine clearance of 10 to 30 mL/min. There is insufficient data for dosage recommendation in patients with a creatinine clearance less than 10 mL/min (see Dosage and Administration, Heart Failure, Warnings and Precautions, Drug Interactions). - If the initial dose is well tolerated, accupril may be administered the following day as a twice daily regimen. In the absence of excessive hypotension or significant deterioration of renal function, the dose may be increased at weekly intervals based on clinical and hemodynamic response. - Dosing information - 10-40 mg PO qd [1] - Dosing information - 0.02 or 0.04 mg/kg [2] - Dosing information - 10-20 mg[3] - Dosing Information - Initial dose : Quinapril 5 - 10 mg PO qd should be used. - Maintenance dose: Quinapril titrate till (MAX 80 mg/day) - Do not co-administer aliskiren with accupril in patients with diabetes. - Presumably because angiotensin-converting inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including accupril) may be subject to a variety of adverse reactions, some of them serious. - Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with ACE inhibitors and has been seen in 0.1% of patients receiving accupril. - In two similarly sized U.S. postmarketing trials that, combined, enrolled over 3,000 black patients and over 19,000 non-blacks, angioedema was reported in 0.30% and 0.55% of blacks (in study 1 and 2 respectively) and 0.39% and 0.17% of non-blacks. - Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, treatment with accupril should be discontinued immediately, the patient treated in accordance with accepted medical care, and carefully observed until the swelling disappears. In instances where swelling is confined to the face and lips, the condition generally resolves without treatment; antihistamines may be useful in relieving symptoms. Where there is involvement of the tongue, glottis, or larynx likely to cause airway obstruction, emergency therapy including, but not limited to, subcutaneous epinephrine solution 1:1000 (0.3 to 0.5 mL) should be promptly administered. - Patients taking concomitant mTOR inhibitor (e.g. temsirolimus) therapy may be at increased risk for 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. - Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor. - Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge. - 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. - 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. - Excessive hypotension is rare in patients with uncomplicated hypertension treated with accupril alone. Patients with heart failure given accupril commonly have some reduction in blood pressure, but discontinuation of therapy because of continuing symptomatic hypotension usually is not necessary when dosing instructions are followed. Caution should be observed when initiating therapy in patients with heart failure. In controlled studies, syncope was observed in 0.4% of patients (N=3203); this incidence was similar to that observed for captopril (1%) and enalapril (0.8%). - Patients at risk of excessive hypotension, sometimes associated with oliguria and/or progressive azotemia, and rarely with acute renal failure and/or death, include patients with the following conditions or characteristics: heart failure, hyponatremia, high dose diuretic therapy, recent intensive diuresis or increase in diuretic dose, renal dialysis, or severe volume and/or salt depletion of any etiology. It may be advisable to eliminate the diuretic (except in patients with heart failure), reduce the diuretic dose or cautiously increase salt intake (except in patients with heart failure) before initiating therapy with accupril in patients at risk for excessive hypotension who are able to tolerate such adjustments. - In patients at risk of excessive hypotension, therapy with accupril should be started under close medical supervision. Such patients should be followed closely for the first two weeks of treatment and whenever the dose of accupril and/or diuretic is increased. Similar considerations may apply to patients with ischemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in a myocardial infarction or a cerebrovascular accident. - If excessive hypotension occurs, the patient should be placed in the supine position and, if necessary, receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further doses of accupril, which usually can be given without difficulty once the blood pressure has stabilized. If symptomatic hypotension develops, a dose reduction or discontinuation of accupril or concomitant diuretic may be necessary. - Another ACE inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression rarely in patients with uncomplicated hypertension, but more frequently in patients with renal impairment, especially if they also have a collagen vascular disease, such as systemic lupus erythematosus or scleroderma. Agranulocytosis did occur during accupril treatment in one patient with a history of neutropenia during previous captopril therapy. Available data from clinical trials of Accupril are insufficient to show that, in patients without prior reactions to other ACE inhibitors, Accupril does not cause agranulocytosis at similar rates. As with other ACE inhibitors, periodic monitoring of white blood cell counts in patients with collagen vascular disease and/or renal disease should be considered. - 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 Accupril 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 Accupril, unless it is considered life-saving 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 Accupril for hypotension, oliguria, and hyperkalemia. - No teratogenic effects of Accupril were seen in studies of pregnant rats and rabbits. On a mg/kg basis, the doses used were up to 180 times (in rats) and one time (in rabbits) the maximum recommended human dose. ## Precautions - As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors, including Accupril, may be associated with oliguria and/or progressive azotemia and rarely acute renal failure and/or death. - In clinical studies in hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine have been observed in some patients following ACE inhibitor therapy. These increases were almost always reversible upon discontinuation of the ACE inhibitor and/or diuretic therapy. In such patients, renal function should be monitored during the first few weeks of therapy. - Some patients with hypertension or heart failure with no apparent preexisting renal vascular disease have developed increases in blood urea and serum creatinine, usually minor and transient, especially when Accupril has been given concomitantly with a diuretic. This is more likely to occur in patients with preexisting renal impairment. Dosage reduction and/or discontinuation of any diuretic and/or Accupril may be required. - Evaluation of patients with hypertension or heart failure should always include assessment of renal function. - In clinical trials, hyperkalemia (serum potassium ≥5.8 mmol/L) occurred in approximately 2% of patients receiving Accupril. In most cases, elevated serum potassium levels were isolated values which resolved despite continued therapy. Less than 0.1% of patients discontinued therapy due to hyperkalemia. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes, which should be used cautiously, if at all, with Accupril. - Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent non-productive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough. - In patients undergoing major surgery or during anesthesia with agents that produce hypotension, Accupril will block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion. - Accupril has been evaluated for safety in 4960 subjects and patients. Of these, 3203 patients, including 655 elderly patients, participated in controlled clinical trials. Accupril has been evaluated for long-term safety in over 1400 patients treated for 1 year or more. - Adverse experiences were usually mild and transient. - In placebo-controlled trials, discontinuation of therapy because of adverse events was required in 4.7% of patients with hypertension. - Adverse experiences probably or possibly related to therapy or of unknown relationship to therapy occurring in 1% or more of the 1563 patients in placebo-controlled hypertension trials who were treated with Accupril are shown below: - Accupril has been evaluated for safety in 1222 Accupril treated patients. Of these, 632 patients participated in controlled clinical trials. In placebo-controlled trials, discontinuation of therapy because of adverse events was required in 6.8% of patients with congestive heart failure. - Adverse experiences probably or possibly related or of unknown relationship to therapy occurring in 1% or more of the 585 patients in placebo-controlled congestive heart failure trials who were treated with Accupril are shown below: - Clinical adverse experiences probably, possibly, or definitely related, or of uncertain relationship to therapy occurring in 0.5% to 1.0% (except as noted) of the patients with CHF or hypertension treated with Accupril (with or without concomitant diuretic) in controlled or uncontrolled trials (N=4847) and less frequent, clinically significant events seen in clinical trials or post-marketing experience (the rarer events are in italics) include (listed by body system): - back pain, malaise, viral infections, anaphylactoid reaction. - palpitation, vasodilation, tachycardia, heart failure, hyperkalemia, myocardial infarction, cerebrovascular accident, hypertensive crisis, angina pectoris, orthostatic hypotension, cardiac rhythm disturbances, cardiogenic shock - hemolytic anemia - Flatulence, dry mouth or throat, constipation, gastrointestinal hemorrhage, pancreatitis, abnormal liver function tests, dyspepsia - Somnolence, vertigo, syncope, nervousness, depression, insomnia, paresthesia - Alopecia, increased sweating, pemphigus, pruritus, exfoliative dermatitis, photosensitivity reaction, dermatopolymyositis - urinary tract infection, impotence, acute renal failure, worsening renal failure - Eosinophilic pneumonitis - Amblyopia, edema, arthralgia, pharyngitis, agranulocytosis, hepatitis, thrombocytopenia - Angioedema has been reported in patients receiving Accupril (0.1%). Angioedema associated with laryngeal edema may be fatal. If angioedema of the face, extremities, lips, tongue, glottis, and/or larynx occurs, treatment with Accupril should be discontinued and appropriate therapy instituted immediately. - Increases (>1.25 times the upper limit of normal) in serum creatinine and blood urea nitrogen were observed in 2% and 2%, respectively, of all patients treated with Accupril alone. Increases are more likely to occur in patients receiving concomitant diuretic therapy than in those on Accupril alone. These increases often remit on continued therapy. In controlled studies of heart failure, increases in blood urea nitrogen and serum creatinine were observed in 11% and 8%, respectively, of patients treated with Accupril; most often these patients were receiving diuretics with or without digitalis. - As with other ACE inhibitors, patients on diuretics, especially those on recently instituted diuretic therapy, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with Accupril. The possibility of hypotensive effects with Accupril may be minimized by either discontinuing the diuretic or cautiously increasing salt intake prior to initiation of treatment with Accupril. If it is not possible to discontinue the diuretic, the starting dose of quinapril should be reduced. ### Agents increasing serum potassium - Quinapril can attenuate potassium loss caused by thiazide diuretics and increase serum potassium when used alone. If concomitant therapy of Accupril with potassium-sparing diuretics (eg, spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes is indicated, they should be used with caution along with appropriate monitoring of serum potassium. ### Tetracycline and other drugs that interact with magnesium - Simultaneous administration of tetracycline with Accupril reduced the absorption of tetracycline by approximately 28% to 37%, possibly due to the high magnesium content in Accupril tablets. This interaction should be considered if coprescribing Accupril and tetracycline or other drugs that interact with magnesium. ### Lithium - Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, it may increase the risk of lithium toxicity. ### 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. ### 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, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including quinapril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving quinapril and NSAID therapy. - The antihypertensive effect of ACE inhibitors, including quinapril may be attenuated by NSAIDs. ### Agents that inhibit mTOR - Patients taking concomitant mTOR inhibitor (e.g. temsirolimus) therapy may be at increased risk for angioedema. ### Other agents - Drug interaction studies of Accupril with other agents showed: - Multiple dose therapy with propranolol or cimetidine has no effect on the pharmacokinetics of single doses of Accupril. The anticoagulant effect of a single dose of warfarin (measured by prothrombin time) was not significantly changed by quinapril coadministration twice-daily. Accupril treatment did not affect the pharmacokinetics of digoxin. - No pharmacokinetic interaction was observed when single doses of Accupril and hydrochlorothiazide were administered concomitantly. Co-administration of multiple 10 mg doses of atorvastatin with 80 mg of Accupril resulted in no significant change in the steady-state pharmacokinetic parameters of atorvastatin. ### 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 Accupril and other agents that affect the RAS. - Do not co-administer aliskiren with Accupril in patients with diabetes. Avoid concomitant use of aliskiren with Accupril in patients with renal impairment (GFR <60 mL/min/1.73 m2). ### Carcinogenesis, Mutagenesis, Impairment of Fertility - Quinapril hydrochloride was not carcinogenic in mice or rats when given in doses up to 75 or 100 mg/kg/day (50 to 60 times the maximum human daily dose, respectively, on an mg/kg basis and 3.8 to 10 times the maximum human daily dose when based on an mg/m2 basis) for 104 weeks. Female rats given the highest dose level had an increased incidence of mesenteric lymph node hemangiomas and skin/subcutaneous lipomas. Neither quinapril nor quinaprilat were mutagenic in the Ames bacterial assay with or without metabolic activation. Quinapril was also negative in the following genetic toxicology studies: in vitro mammalian cell point mutation, sister chromatid exchange in cultured mammalian cells, micronucleus test with mice, in vitro chromosome aberration with V79 cultured lung cells, and in an in vivo cytogenetic study with rat bone marrow. There were no adverse effects on fertility or reproduction in rats at doses up to 100 mg/kg/day (60 and 10 times the maximum daily human dose when based on mg/kg and mg/m2, respectively). - 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 Accupril, unless it is considered life-saving 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 Accupril for hypotension, oliguria, and hyperkalemia. - No teratogenic effects of Accupril were seen in studies of pregnant rats and rabbits. On a mg/kg basis, the doses used were up to 180 times (in rats) and one time (in rabbits) the maximum recommended human dose. - 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. Removal of Accupril, which crosses the placenta, from the neonatal circulation is not significantly accelerated by these means. - The safety and effectiveness of Accupril in pediatric patients have not been established. - This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. 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. - Elderly patients exhibited increased area under the plasma concentration time curve and peak levels for quinaprilat compared to values observed in younger patients; this appeared to relate to decreased renal function rather than to age itself. ### Monotherapy The recommended initial dosage of accupril in patients not on diuretics is 10 or 20 mg once daily. Dosage should be adjusted according to blood pressure response measured at peak (2–6 hours after dosing) and trough (predosing). Generally, dosage adjustments should be made at intervals of at least 2 weeks. Most patients have required dosages of 20, 40, or 80 mg/day, given as a single dose or in two equally divided doses. In some patients treated once daily, the antihypertensive effect may diminish toward the end of the dosing interval. In such patients an increase in dosage or twice daily administration may be warranted. In general, doses of 40–80 mg and divided doses give a somewhat greater effect at the end of the dosing interval. ### Concomitant Diuretics If blood pressure is not adequately controlled with accupril monotherapy, a diuretic may be added. In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally can occur following the initial dose of accupril. To reduce the likelihood of hypotension, the diuretic should, if possible, be discontinued 2 to 3 days prior to beginning therapy with accupril. Then, if blood pressure is not controlled with accupril alone, diuretic therapy should be resumed. If the diuretic cannot be discontinued, an initial dose of 5 mg accupril should be used with careful medical supervision for several hours and until blood pressure has stabilized. The dosage should subsequently be titrated (as described above) to the optimal response. ### Renal Impairment Kinetic data indicate that the apparent elimination half-life of quinaprilat increases as creatinine clearance decreases. Recommended starting doses, based on clinical and pharmacokinetic data from patients with renal impairment, are as follows: Patients should subsequently have their dosage titrated (as described above) to the optimal response. ### Elderly (≥65 years) The recommended initial dosage of Accupril in elderly patients is 10 mg given once daily followed by titration (as described above) to the optimal response. ## Heart Failure Accupril is indicated as adjunctive therapy when added to conventional therapy including diuretics and/or digitalis. The recommended starting dose is 5 mg twice daily. This dose may improve symptoms of heart failure, but increases in exercise duration have generally required higher doses. Therefore, if the initial dosage of accupril is well tolerated, patients should then be titrated at weekly intervals until an effective dose, usually 20 to 40 mg daily given in two equally divided doses, is reached or undesirable hypotension, orthostatis, or azotemia prohibit reaching this dose. Following the initial dose of accupril, the patient should be observed under medical supervision for at least two hours for the presence of hypotension or orthostatis and, if present, until blood pressure stabilizes. The appearance of hypotension, orthostatis, or azotemia early in dose titration should not preclude further careful dose titration. Consideration should be given to reducing the dose of concomitant diuretics. ### Dose Adjustments in Patients with Heart Failure and Renal Impairment or Hyponatremia Pharmacokinetic data indicate that quinapril elimination is dependent on level of renal function. In patients with heart failure and renal impairment, the recommended initial dose of Accupril is 5 mg in patients with a creatinine clearance above 30 mL/min and 2.5 mg in patients with a creatinine clearance of 10 to 30 mL/min. There is insufficient data for dosage recommendation in patients with a creatinine clearance less than 10 mL/min. If the initial dose is well tolerated, accupril may be administered the following day as a twice daily regimen. In the absence of excessive hypotension or significant deterioration of renal function, the dose may be increased at weekly intervals based on clinical and hemodynamic response. - As with other ACE inhibitors, periodic monitoring of white blood cell counts in patients with collagen vascular disease and/or renal disease should be considered. - As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors, including ACCUPRIL, may be associated with oliguria and/or progressive azotemia and rarely acute renal failure and/or death. In clinical studies in hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine have been observed in some patients following ACE inhibitor therapy. These increases were almost always reversible upon discontinuation of the ACE inhibitor and/or diuretic therapy. In such patients, renal function should be monitored during the first few weeks of therapy. - Quinapril can attenuate potassium loss caused by thiazide diuretics and increase serum potassium when used alone. If concomitant therapy of ACCUPRIL with potassium-sparing diuretics (eg, spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes is indicated, they should be used with caution along with appropriate monitoring of serum potassium. - Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, it may increase the risk of lithium toxicity. - In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including quinapril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving quinapril and NSAID therapy. The antihypertensive effect of ACE inhibitors, including quinapril may be attenuated by NSAIDs. - 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 ACCUPRIL and other agents that affect the RAS. Do not co-administer aliskiren with ACCUPRIL in patients with diabetes. Avoid concomitant use of aliskiren with ACCUPRIL in patients with renal impairment (GFR <60 mL/min/1.73 m2). - Clinical studies of Accupril 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. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. 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. Elderly patients exhibited increased area under the plasma concentration time curve and peak levels for quinaprilat compared to values observed in younger patients; this appeared to relate to decreased renal function rather than to age itself. No specific information is available on the treatment of overdosage with quinapril. The most likely clinical manifestation would be symptoms attributable to severe hypotension. Laboratory determinations of serum levels of quinapril and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of quinapril overdose. No data are available to suggest physiological maneuvers (eg, maneuvers to change pH of the urine) that might accelerate elimination of quinapril and its metabolites. Hemodialysis and peritoneal dialysis have little effect on the elimination of quinapril and quinaprilat. Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of quinapril overdose, but angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of quinapril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat quinapril overdose by infusion of normal saline solution. - While the principal mechanism of antihypertensive effect is thought to be through the renin-angiotensin-aldosterone system, quinapril exerts antihypertensive actions even in patients with low renin hypertension. Accupril was an effective antihypertensive in all races studied, although it was somewhat less effective in blacks (usually a predominantly low renin group) than in nonblacks. ACE is identical to kininase II, an enzyme that degrades bradykinin, a potent peptide vasodilator; whether increased levels of bradykinin play a role in the therapeutic effect of quinapril remains to be elucidated. Quinapril hydrochloride is chemically described as [3S-[2[R(R)], 3R*] ]-2-[2-[ [1- (ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-3- isoquinolinecarboxylic acid, monohydrochloride. Its empirical formula is C25H30N2O5 •HCl and its structural formula is: Quinapril hydrochloride is a white to off-white amorphous powder that is freely soluble in aqueous solvents. Quinapril tablets USP contain 5 mg, 10 mg, 20 mg, or 40 mg of quinapril for oral administration. Each film-coated tablet also contains crospovidone, iron oxide yellow, lecithin, magnesium carbonate, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol, povidone, talc, titanium dioxide and xanthan gum. - In patients with renal insufficiency, the elimination half-life of quinaprilat increases as creatinine clearance decreases. There is a linear correlation between plasma quinaprilat clearance and creatinine clearance. In patients with end-stage renal disease, chronic hemodialysis or continuous ambulatory peritoneal dialysis has little effect on the elimination of quinapril and quinaprilat. Elimination of quinaprilat may be reduced in elderly patients (≥65 years) and in those with heart failure; this reduction is attributable to decrease in renal function. Quinaprilat concentrations are reduced in patients with alcoholic cirrhosis due to impaired deesterification of quinapril. Studies in rats indicate that quinapril and its metabolites do not cross the blood-brain barrier. - Quinapril hydrochloride was not carcinogenic in mice or rats when given in doses up to 75 or 100 mg/kg/day (50 to 60 times the maximum human daily dose, respectively, on an mg/kg basis and 3.8 to 10 times the maximum human daily dose when based on an mg/m2 basis) for 104 weeks. Female rats given the highest dose level had an increased incidence of mesenteric lymph node hemangiomas and skin/subcutaneous lipomas. Neither quinapril nor quinaprilat were mutagenic in the Ames bacterial assay with or without metabolic activation. Quinapril was also negative in the following genetic toxicology studies: in vitro mammalian cell point mutation, sister chromatid exchange in cultured mammalian cells, micronucleus test with mice, in vitro chromosome aberration with V79 cultured lung cells, and in an in vivo cytogenetic study with rat bone marrow. There were no adverse effects on fertility or reproduction in rats at doses up to 100 mg/kg/day (60 and 10 times the maximum daily human dose when based on mg/kg and mg/m2, respectively). - Administration of 10 to 80 mg of Accupril to patients with mild to severe hypertension results in a reduction of sitting and standing blood pressure to about the same extent with minimal effect on heart rate. Symptomatic postural hypotension is infrequent although it can occur in patients who are salt-and,or volume-depleted. Antihypertensive activity commences within 1 hour with peak effects usually achieved by 2 to 4 hours after dosing. During chronic therapy, most of the blood pressure lowering effect of a given dose is obtained in 1–2 weeks. In multiple-dose studies, 10–80 mg per day in single or divided doses lowered systolic and diastolic blood pressure throughout the dosing interval, with a trough effect of about 5–11,3–7 mm Hg. The trough effect represents about 50% of the peak effect. While the dose-response relationship is relatively flat, doses of 40–80 mg were somewhat more effective at trough than 10–20 mg, and twice daily dosing tended to give a somewhat lower trough blood pressure than once daily dosing with the same total dose. The antihypertensive effect of Accupril continues during long-term therapy, with no evidence of loss of effectiveness. - Hemodynamic assessments in patients with hypertension indicate that blood pressure reduction produced by quinapril is accompanied by a reduction in total peripheral resistance and renal vascular resistance with little or no change in heart rate, cardiac index, renal blood flow, glomerular filtration rate, or filtration fraction. - Use of Accupril with a thiazide diuretic gives a blood-pressure lowering effect greater than that seen with either agent alone. - In patients with hypertension, Accupril 10–40 mg was similar in effectiveness to captopril, enalapril, propranolol, and thiazide diuretics. - Therapeutic effects appear to be the same for elderly (≥65 years of age) and younger adult patients given the same daily dosages, with no increase in adverse events in elderly patients. ### Heart Failure - In a placebo-controlled trial involving patients with congestive heart failure treated with digitalis and diuretics, parenteral quinaprilat, the active metabolite of quinapril, reduced pulmonary capillary wedge pressure and systemic vascular resistance and increased cardiac output,index. Similar favorable hemodynamic effects were seen with oral quinapril in baseline-controlled trials, and such effects appeared to be maintained during chronic oral quinapril therapy. Quinapril reduced renal hepatic vascular resistance and increased renal and hepatic blood flow with glomerular filtration rate remaining unchanged. - A significant dose response relationship for improvement in maximal exercise tolerance has been observed with Accupril therapy. Beneficial effects on the severity of heart failure as measured by New York Heart Association (NYHA) classification and Quality of Life and on symptoms of dyspnea, fatigue, and edema were evident after 6 months in a double-blind, placebo-controlled study. Favorable effects were maintained for up to two years of open label therapy. The effects of quinapril on long-term mortality in heart failure have not been evaluated. 5-mg tablets brown, film-coated, elliptical scored tablets, coded "PD 527" on one side and "5" on the other. NDC 0071-0527-23 bottles of 90 tablets NDC 0071-0527-40 10 × 10 unit dose blisters 10-mg tablets brown, film-coated, triangular tablets, coded "PD 530" on one side and "10" on the other. NDC 0071-0530-23 bottles of 90 tablets NDC 0071-0530-40 10 × 10 unit dose blisters 20-mg tablets brown, film-coated, round tablets, coded "PD 532" on one side and "20" on the other. NDC 0071-0532-23 bottles of 90 tablets NDC 0071-0532-40 10 × 10 unit dose blisters 40-mg tablets brown, film-coated, elliptical tablets, coded "PD 535" on one side and "40" on the other. NDC 0071-0535-23 bottles of 90 tablets Dispense in well-closed containers as defined in the USP. Protect from light. - Female patients of childbearing age should be told about the consequences of exposure to ACCUPRIL 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. - Angioedema - Angioedema, including laryngeal edema can occur with treatment with ACE inhibitors, especially following the first dose. Patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema (swelling of face, extremities, eyes, lips, tongue, difficulty in swallowing or breathing) and to stop taking the drug until they have consulted with their physician (see Warnings). - Symptomatic hypotension - Patients should be cautioned that lightheadedness can occur, especially during the first few days of ACCUPRIL therapy, and that it should be reported to a physician. If actual syncope occurs, patients should be told to not take the drug until they have consulted with their physician (see Warnings)). - All patients should be cautioned that inadequate fluid intake or excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure because of reduction in fluid volume, with the same consequences of lightheadedness and possible syncope. - Patients planning to undergo any surgery and/or anesthesia should be told to inform their physician that they are taking an ACE inhibitor. - Hyperkalemia - Patients should be told not to use potassium supplements or salt substitutes containing potassium without consulting their physician (see Warnings)). - Neutropenia - Patients should be told to report promptly any indication of infection (eg, sore throat, fever) which could be a sign of neutropenia. NOTE: As with many other drugs, certain advice to patients being treated with ACCUPRIL is warranted. This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects. - ↑ Dominguez LJ, Barbagallo M, Kattah W, Garcia D, Sowers JR (1995) Quinapril reduces microalbuminuria in essential hypertensive and in diabetic hypertensive subjects. Am J Hypertens 8 (8):808-14. DOI:10.1016/0895-7061(95)00143-D PMID: 7576397 - ↑ Müller M, Schindler E, Kwapisz M, Klemm S, Akintürk H, Heidt M et al. (2000) Effect of intraoperative angiotensin-converting enzyme inhibition by quinaprilat on hypertension after coronary artery surgery. Br J Anaesth 84 (3):396-8. PMID: 10793603 - ↑ Schön HR, Schömig A (1995) [Long-term treatment with quinapril in chronic aortic and mitral insufficiency.] Dtsch Med Wochenschr 120 (13):429-35. DOI:10.1055/s-2008-1055363 PMID: 7712932 - ↑ "https://www.ismp.org". 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("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/Accuprin
51bddd4422786319c3af576e60c698b1950f669e	wikidoc	Acetamide	Acetamide # Overview Acetamide (or acetic acid amide or ethanamide), CH3CONH2, the amide of acetic acid, is a white crystalline solid in pure form. It is produced by dehydrating ammonium acetate. It is used as a plasticizer and in the synthesis of many other organic compounds. Acetamide is not extremely combustible, but releases irritating fumes when ignited. It is toxic by inhalation (of dust), ingestion, skin and eye contact. Skin or eye contact may cause redness and pain. The derivative N,N-dimethylacetamide (DMA), which has two methyl groups replacing the amine protons, is used as a solvent. N-methylacetamide is often used as the simplest model in studies of the peptide bond. Recent work on the Robert C. Byrd Green Bank Telescope has resulted in the discovery of several organic (carbon-based) compounds near the center of the Milky Way galaxy. Acetamide has been detected. This is particularly important as acetamide has an amide bond, similar to the essential bond between amino acids in proteins. This supports the theory that organic molecules that can lead to life (as we know it on Earth) can form in space. # Cancer link Acetamide has been found to cause cancer in laboratory animals. It is classified in Group 2B "possible human carcinogen" by the IARC.	Acetamide Template:Chembox new # Overview Acetamide (or acetic acid amide or ethanamide), CH3CONH2, the amide of acetic acid, is a white crystalline solid in pure form. It is produced by dehydrating ammonium acetate. It is used as a plasticizer and in the synthesis of many other organic compounds. Acetamide is not extremely combustible, but releases irritating fumes when ignited. It is toxic by inhalation (of dust), ingestion, skin and eye contact. Skin or eye contact may cause redness and pain. The derivative N,N-dimethylacetamide (DMA), which has two methyl groups replacing the amine protons, is used as a solvent. N-methylacetamide is often used as the simplest model in studies of the peptide bond. Recent work on the Robert C. Byrd Green Bank Telescope has resulted in the discovery of several organic (carbon-based) compounds near the center of the Milky Way galaxy. Acetamide has been detected. This is particularly important as acetamide has an amide bond, similar to the essential bond between amino acids in proteins. This supports the theory that organic molecules that can lead to life (as we know it on Earth) can form in space. # Cancer link Acetamide has been found to cause cancer in laboratory animals. It is classified in Group 2B "possible human carcinogen" by the IARC.	https://www.wikidoc.org/index.php/Acetamide
0d964c5ca80fe94e7b0723b47082cae480799be5	wikidoc	Ketonuria	Ketonuria # Overview To view a comprehensive algorithm of common findings of urine composition and urine output, click here Ketonuria is a medical condition in which ketone bodies are present in the urine. It is seen in conditions wherein the body produces excess ketones as an alternative source of energy. It is seen during starvation or more commonly in type I diabetes mellitus. Production of ketone bodies is a normal response to a shortage of glucose, meant to provide an alternate source of fuel from fatty acids. After 24 hrs fasting, ketone body levels increase in blood (called ketonemia or ketosis but all of it used up by the muscles no ketone bodies are left to be excreted in urine. # Pathophysiology Ketones are metabolic end products of fatty acid metabolism. In healthy individuals, ketones are formed in the liver and are completely metabolized so that only negligible amounts appear in the urine. However, when carbohydrates are unavailable or unable to be used as an energy source, fat becomes the predominant body fuel instead of carbohydrates and excessive amounts of ketones are formed as a metabolic byproduct. A finding of ketones in the urine indicates that the body is using fat as the major source of energy. Ketone bodies that appear in the urine when fats are burned for energy are acetoacetate and beta-hydroxybutyric acid. The gas acetone is also produced, but is exhaled. Normally, the urine should not contain enough ketones to give a positive reading. As with tests for glucose, acetone can be tested by a dipstick or by a tablet. The results are reported as small, moderate, or large amounts of acetone. A small amount of acetone is a value under 20mg/dl; a moderate amount is a value of 30-40mg/dl, and a finding of 80mg/dl or greater is reported as a large amount. # Screening Screening for ketonuria is done frequently for acutely ill patients, presurgical patients, and pregnant women. Any diabetic patient who has elevated levels of blood and urine glucose should be tested for urinary ketones. In addition, when diabetic treatment is being switched from insulin to oral hypoglycemic agents, the patient's urine should be monitored for ketonuria. The development of ketonuria within 24 hours after insulin withdrawal usually indicates a poor response to the oral hypoglycemic agents. Diabetic patients who use oral hypoglycemic agents should have their urine tested regularly for glucose and ketones because oral hypoglycemic agents, unlike insulin, do not control diabetes when an acute infection or other illness develops. In conditions associated with acidosis, urinary ketones are tested to assess the severity of acidosis and to monitor treatment response. Urine ketones appear before there is any significant increase in blood ketones; therefore, urine ketone measurement is especially helpful in emergency situations. During pregnancy, early detection of ketonuria is essential because ketoacidosis is a factor associated with intrauterine death. # Causes of ketosis and ketonuria - Metabolic abnormalities such as diabetes, renal glycosuria, or glycogen storage disease - Dietary conditions such as starvation, fasting, high protein, or low carbohydrate diets, prolonged vomiting, and anorexia - Conditions in which metabolism is increased, such as hyperthyroidism, fever, pregnancy or lactation In nondiabetic persons, ketonuria may occur during acute illness or severe stress. Approximately 15% of hospitalized patients may have ketonuria, even though they do not have diabetes. In a diabetic patient, ketone bodies in the urine suggest that the patient is not adequately controlled and that adjustments of medication, diet, or both should be made promptly. In the nondiabetic patient, ketonuria reflects a reduced carbohydrate metabolism and excessive fat metabolism. # Test equipment Ketostix is Bayer's brand name for test strips to measure the level of ketones in the urine. Other brands of ketone test strips are Uriscan and Atkins.	Ketonuria # Overview Template:SignSymptom infobox To view a comprehensive algorithm of common findings of urine composition and urine output, click here Ketonuria is a medical condition in which ketone bodies are present in the urine. It is seen in conditions wherein the body produces excess ketones as an alternative source of energy. It is seen during starvation or more commonly in type I diabetes mellitus. Production of ketone bodies is a normal response to a shortage of glucose, meant to provide an alternate source of fuel from fatty acids. After 24 hrs fasting, ketone body levels increase in blood (called ketonemia or ketosis but all of it used up by the muscles no ketone bodies are left to be excreted in urine. # Pathophysiology Ketones are metabolic end products of fatty acid metabolism. In healthy individuals, ketones are formed in the liver and are completely metabolized so that only negligible amounts appear in the urine. However, when carbohydrates are unavailable or unable to be used as an energy source, fat becomes the predominant body fuel instead of carbohydrates and excessive amounts of ketones are formed as a metabolic byproduct. A finding of ketones in the urine indicates that the body is using fat as the major source of energy. Ketone bodies that appear in the urine when fats are burned for energy are acetoacetate and beta-hydroxybutyric acid. The gas acetone is also produced, but is exhaled. Normally, the urine should not contain enough ketones to give a positive reading. As with tests for glucose, acetone can be tested by a dipstick or by a tablet. The results are reported as small, moderate, or large amounts of acetone. A small amount of acetone is a value under 20mg/dl; a moderate amount is a value of 30-40mg/dl, and a finding of 80mg/dl or greater is reported as a large amount. # Screening Screening for ketonuria is done frequently for acutely ill patients, presurgical patients, and pregnant women. Any diabetic patient who has elevated levels of blood and urine glucose should be tested for urinary ketones. In addition, when diabetic treatment is being switched from insulin to oral hypoglycemic agents, the patient's urine should be monitored for ketonuria. The development of ketonuria within 24 hours after insulin withdrawal usually indicates a poor response to the oral hypoglycemic agents. Diabetic patients who use oral hypoglycemic agents should have their urine tested regularly for glucose and ketones because oral hypoglycemic agents, unlike insulin, do not control diabetes when an acute infection or other illness develops. In conditions associated with acidosis, urinary ketones are tested to assess the severity of acidosis and to monitor treatment response. Urine ketones appear before there is any significant increase in blood ketones; therefore, urine ketone measurement is especially helpful in emergency situations. During pregnancy, early detection of ketonuria is essential because ketoacidosis is a factor associated with intrauterine death. # Causes of ketosis and ketonuria - Metabolic abnormalities such as diabetes, renal glycosuria, or glycogen storage disease - Dietary conditions such as starvation, fasting, high protein, or low carbohydrate diets, prolonged vomiting, and anorexia - Conditions in which metabolism is increased, such as hyperthyroidism, fever, pregnancy or lactation In nondiabetic persons, ketonuria may occur during acute illness or severe stress. Approximately 15% of hospitalized patients may have ketonuria, even though they do not have diabetes. In a diabetic patient, ketone bodies in the urine suggest that the patient is not adequately controlled and that adjustments of medication, diet, or both should be made promptly. In the nondiabetic patient, ketonuria reflects a reduced carbohydrate metabolism and excessive fat metabolism. # Test equipment Ketostix is Bayer's brand name for test strips to measure the level of ketones in the urine. Other brands of ketone test strips are Uriscan and Atkins. # External links - http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=cm.chapter.4143 Template:Abnormal clinical and laboratory findings de:Ketonurie et:Ketonuuria Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Acetonuria

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